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Clinical Trial Results:
A Phase Ib/II, Open-Label Study Evaluating the Safety and Pharmacokinetics of GDC-0199 (ABT-199) in Combination With Rituximab (R) or Obinutuzumab (G) Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) in Patients With B-Cell Non-Hodgkin’s Lymphoma (NHL) and Diffuse Large B-cell Lymphoma (DLBCL)

Summary
EudraCT number	2013-003749-40
Trial protocol	FR NL HU CZ ES AT
Global end of trial date	28 Jun 2019

Results information
Results version number	v3(current)
This version publication date	17 Jun 2020
First version publication date	12 Jul 2018
Other versions	v1 , v2
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

GO27878

ISRCTN number

US NCT number

NCT02055820

WHO universal trial number (UTN)

Sponsor organisation name

Hoffmann-La Roche

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Scientific contact

Medical Communications, Hoffmann-La Roche, +41 616878333, global.trial_information@roche.com

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

28 Jun 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

28 Jun 2019

Was the trial ended prematurely?

Main objective of the trial

This is a multicenter, open-label, dose-finding study of venetoclax administered orally in combination with rituximab (R) or obinutuzumab (G) and standard doses of cyclophosphamide, doxorubicin, vincristine and oral prednisone (CHOP) in participants with Non-Hodgkin's Lymphoma (NHL). The study consisted of 2 stages: a dose-finding Phase Ib stage and a Phase II expansion stage. In the Phase I portion of the study, participants were randomized to one of 2 treatment arms venetoclax in combination with R-CHOP (Arm A) and venetoclax in combination with G-CHOP (Arm B) and explored the doses of venetoclax in combination with R-CHOP and G-CHOP. For the Phase II portion of the study, the venetoclax dose for venetoclax + R-CHOP was on a non-continuous dosing schedule as determined by the Phase Ib portion of the study based on safety and tolerability observed in participants treated in the dose escalation portion of the study.

Protection of trial subjects

All study subjects were required to read and sign an Informed Consent Form

Background therapy

Evidence for comparator

On 17 July 2016, Roche/Genentech as the sponsor of Study BO21005 (Goya study), a Phase III study that evaluated G CHOP versus R-CHOP in 1L DLBCL, informed through a press release that the primary endpoint of investigator-assessed PFS was not met. Given these results, Arm B (venetoclax + G-CHOP) was not expanded in Phase II in participants who are first-line with DLBCL

Actual start date of recruitment

17 Nov 2013

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Safety

Long term follow-up duration

2 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 18

Country: Number of subjects enrolled

Austria: 11

Country: Number of subjects enrolled

Canada: 19

Country: Number of subjects enrolled

Czech Republic: 25

Country: Number of subjects enrolled

Spain: 11

Country: Number of subjects enrolled

France: 63

Country: Number of subjects enrolled

Hungary: 12

Country: Number of subjects enrolled

Italy: 20

Country: Number of subjects enrolled

Netherlands: 8

Country: Number of subjects enrolled

United States: 77

Worldwide total number of subjects

264

EEA total number of subjects

150

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

137

From 65 to 84 years

126

85 years and over

Subject disposition

Top of page

Recruitment details

At start the trial had a randomised-controlled component, until July 2016 once the arm B (Gazyva) got closed following the publication of results of another trial. Since July 2016, the trial was single-arm, not randomised anymore, and kept including patients in only 1 arm (Arm A, rituximab).

Screening details

Phase I: Patients must have histologically confirmed B‑cell NHL (never received R‑CHOP treatment), except MCL or SLL. Any relapsed/refractory patients should have received only a single previous treatment regimen Phase II: Patients must have previously untreated CD20‑positive DLBCL and IPI score must be 2-5.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Venetoclax 200 mg +R-CHOP

Arm description

Phase I: Subjects received 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle consisted of 21 days. Subjects who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

Arm type

Experimental

Investigational medicinal product name

Venetoclax

Investigational medicinal product code

Other name

GDC-0199

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Venetoclax 200 milligram (mg) tablets will be administered orally once daily (QD) on Days 4−10 of Cycle 1 and Days 1−10 of Cycles 2−8 during Phase I.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 750 milligrams per square meter (mg/m^2) administered intravenously (IV) on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Doxorubicin 50 mg/m^2 administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Vincristine 1.4 mg/m^2 (maximum 2 mg) administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Prednisone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone 100 mg per day orally on Days 1-5 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Rituximab 375 mg/m^2 dose administered IV on Day 1 of every 21-day cycle up to Cycle 8.

Venetoclax 400 mg +R-CHOP

Arm description

Arm type

Experimental

Investigational medicinal product name

Venetoclax

Investigational medicinal product code

Other name

GDC-0199

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Venetoclax 400 milligrams (mg) tablets will be administered orally once daily (QD) on Days 4−10 of Cycle 1 and Days 1−10 of Cycles 2−8 during Phase I.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 750 milligrams per square meter (mg/m^2) administered intravenously (IV) on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Doxorubicin 50 mg/m^2 administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Vincristine 1.4 mg/m^2 (maximum 2 mg) administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Prednisone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone 100 mg per day orally on Days 1-5 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Rituximab 375 mg/m^2 dose administered IV on Day 1 of every 21-day cycle up to Cycle 8.

Venetoclax 600 mg +R-CHOP

Arm description

Arm type

Experimental

Investigational medicinal product name

Venetoclax

Investigational medicinal product code

Other name

GDC-0199

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Venetoclax 600 milligrams (mg) tablets will be administered orally once daily (QD) on Days 4−10 of Cycle 1 and Days 1−10 of Cycles 2−8 during Phase I.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 750 milligrams per square meter (mg/m^2) administered intravenously (IV) on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion, Solution for infusion

Routes of administration

Intravenous use, Intravenous use

Dosage and administration details

Rituximab 375 mg/m^2 dose administered IV on Day 1 of every 21-day cycle up to Cycle 8.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Doxorubicin 50 mg/m^2 administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Vincristine 1.4 mg/m^2 (maximum 2 mg) administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Prednisone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone 100 mg per day orally on Days 1-5 of each 21-day cycle up to Cycle 6.

Venetoclax 800 mg +R-CHOP

Arm description

Arm type

Experimental

Investigational medicinal product name

Venetoclax

Investigational medicinal product code

Other name

GDC-0199

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Venetoclax 800 milligrams (mg) tablets will be administered orally once daily (QD) on Days 4−10 of Cycle 1 and Days 1−10 of Cycles 2−8 during Phase I and II.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 750 milligrams per square meter (mg/m^2) administered intravenously (IV) on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Doxorubicin 50 mg/m^2 administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Rituximab 375 mg/m^2 dose administered IV on Day 1 of every 21-day cycle up to Cycle 8.

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Vincristine 1.4 mg/m^2 (maximum 2 mg) administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Prednisone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone 100 mg per day orally on Days 1-5 of each 21-day cycle up to Cycle 6.

Venetoclax 800 mg +R-CHOP Phase II

Arm description

Phase II: Subjects received 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle consisted of 21 days. Subjects who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

Arm type

Experimental

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Rituximab 375 mg/m^2 dose administered IV on Day 1 of every 21-day cycle up to Cycle 8.

Investigational medicinal product name

Venetoclax

Investigational medicinal product code

Other name

GDC-0199

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Venetoclax 800 milligrams (mg) tablets will be administered orally once daily (QD) on Days 4−10 of Cycle 1 and Days 1−10 of Cycles 2−8 during Phase II.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 750 milligrams per square meter (mg/m^2) administered intravenously (IV) on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Doxorubicin 50 mg/m^2 administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Vincristine 1.4 mg/m^2 (maximum 2 mg) administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Prednisone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone 100 mg per day orally on Days 1-5 of each 21-day cycle up to Cycle 6.

Venetoclax 200 mg +G-CHOP

Arm description

Phase I: Subjects received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. Subjects who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

Arm type

Experimental

Investigational medicinal product name

Obinutuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Obinutuzumab administered by IV infusion as an absolute dose of 1000 mg on Days 1, 8, 15 of Cycle 1 and Day 1 of Cycles 2-8 (cycle length = 21 days).

Investigational medicinal product name

Venetoclax

Investigational medicinal product code

Other name

GDC-0199

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Venetoclax 200 milligrams (mg) tablets will be administered orally once daily (QD) on Days 4−10 of Cycle 1 and Days 1−10 of Cycles 2−8 during Phase I.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 750 milligrams per square meter (mg/m^2) administered intravenously (IV) on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Doxorubicin 50 mg/m^2 administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Vincristine 1.4 mg/m^2 (maximum 2 mg) administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Prednisone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone 100 mg per day orally on Days 1-5 of each 21-day cycle up to Cycle 6.

Venetoclax 400 mg +G-CHOP

Arm description

Arm type

Experimental

Investigational medicinal product name

Obinutuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Obinutuzumab administered by IV infusion as an absolute dose of 1000 mg on Days 1, 8, 15 of Cycle 1 and Day 1 of Cycles 2-8 (cycle length = 21 days).

Investigational medicinal product name

Venetoclax

Investigational medicinal product code

Other name

GDC-0199

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Venetoclax 400 milligrams (mg) tablets will be administered orally once daily (QD) on Days 4−10 of Cycle 1 and Days 1−10 of Cycles 2−8 during Phase I.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 750 milligrams per square meter (mg/m^2) administered intravenously (IV) on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Doxorubicin 50 mg/m^2 administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Vincristine 1.4 mg/m^2 (maximum 2 mg) administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Prednisone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone 100 mg per day orally on Days 1-5 of each 21-day cycle up to Cycle 6.

Venetoclax 600 mg +G-CHOP

Arm description

Arm type

Experimental

Investigational medicinal product name

Venetoclax

Investigational medicinal product code

Other name

GDC-0199

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Venetoclax 600 milligrams (mg) tablets will be administered orally once daily (QD) on Days 4−10 of Cycle 1 and Days 1−10 of Cycles 2−8 during Phase I.

Investigational medicinal product name

Obinutuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Obinutuzumab administered by IV infusion as an absolute dose of 1000 mg on Days 1, 8, 15 of Cycle 1 and Day 1 of Cycles 2-8 (cycle length = 21 days).

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 750 milligrams per square meter (mg/m^2) administered intravenously (IV) on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Doxorubicin 50 mg/m^2 administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Vincristine 1.4 mg/m^2 (maximum 2 mg) administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Prednisone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone 100 mg per day orally on Days 1-5 of each 21-day cycle up to Cycle 6.

Venetoclax 800 mg +G-CHOP A

Arm description

Phase I: Subjects received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. In this arm venetoclax was administered as follows: Cycle 1 Days 4-10; Cycles 2-8 Days 1-10, Subjects who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

Arm type

Experimental

Investigational medicinal product name

Obinutuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Obinutuzumab administered by IV infusion as an absolute dose of 1000 mg on Days 1, 8, 15 of Cycle 1 and Day 1 of Cycles 2-8 (cycle length = 21 days).

Investigational medicinal product name

Venetoclax

Investigational medicinal product code

Other name

GDC-0199

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Venetoclax 800 milligrams (mg) tablets will be administered orally once daily (QD) on Days 4−10 of Cycle 1 and Days 1−10 of Cycles 2−8 during Phase I.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 750 milligrams per square meter (mg/m^2) administered intravenously (IV) on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Doxorubicin 50 mg/m^2 administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Vincristine 1.4 mg/m^2 (maximum 2 mg) administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Venetoclax 800 mg +G-CHOP B

Arm description

Phase I: Subjects received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. In this arm venetoclax was administered as follows: Cycle 1 Days 4-8; Cycles 2-8 Days 1-5. Subjects who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

Arm type

Experimental

Investigational medicinal product name

Obinutuzumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Obinutuzumab administered by IV infusion as an absolute dose of 1000 mg on Days 1, 8, 15 of Cycle 1 and Day 1 of Cycles 2-8 (cycle length = 21 days).

Investigational medicinal product name

Venetoclax

Investigational medicinal product code

Other name

GDC-0199

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Venetoclax 800 milligrams (mg) tablets will be administered orally once daily (QD) on Days 4−8 of Cycle 1 and Days 1−5 of Cycles 2−8 during Phase I.

Investigational medicinal product name

Cyclophosphamide

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cyclophosphamide 750 milligrams per square meter (mg/m^2) administered intravenously (IV) on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Doxorubicin 50 mg/m^2 administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Vincristine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Vincristine 1.4 mg/m^2 (maximum 2 mg) administered IV on Day 1 of each 21-day cycle up to Cycle 6.

Investigational medicinal product name

Prednisone

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Prednisone 100 mg per day orally on Days 1-5 of each 21-day cycle up to Cycle 6.

Number of subjects in period 1	Venetoclax 200 mg +R-CHOP	Venetoclax 400 mg +R-CHOP	Venetoclax 600 mg +R-CHOP	Venetoclax 800 mg +R-CHOP	Venetoclax 800 mg +R-CHOP Phase II	Venetoclax 200 mg +G-CHOP	Venetoclax 400 mg +G-CHOP	Venetoclax 600 mg +G-CHOP	Venetoclax 800 mg +G-CHOP A	Venetoclax 800 mg +G-CHOP B
Started	7	3	8	6	208	7	7	6	6	6
Completed	6	3	7	3	159	5	5	6	6	6
Not completed	1	0	1	3	49	2	2	0	0	0
Consent withdrawn by subject	-	-	-	-	12	1	-	-	-	-
Death	1	-	1	2	33	1	1	-	-	-
Lost to follow-up	-	-	-	1	4	-	1	-	-	-

Baseline characteristics

Top of page

Reporting group title

Venetoclax 200 mg +R-CHOP

Reporting group description

Reporting group title

Venetoclax 400 mg +R-CHOP

Reporting group description

Reporting group title

Venetoclax 600 mg +R-CHOP

Reporting group description

Reporting group title

Venetoclax 800 mg +R-CHOP

Reporting group description

Reporting group title

Venetoclax 800 mg +R-CHOP Phase II

Reporting group description

Reporting group title

Venetoclax 200 mg +G-CHOP

Reporting group description

Reporting group title

Venetoclax 400 mg +G-CHOP

Reporting group description

Reporting group title

Venetoclax 600 mg +G-CHOP

Reporting group description

Reporting group title

Venetoclax 800 mg +G-CHOP A

Reporting group description

Reporting group title

Venetoclax 800 mg +G-CHOP B

Reporting group description

Phase I: Subjects received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. In this arm venetoclax was administered as follows: Cycle 1 Days 4-8; Cycles 2-8 Days 1-5. Subjects who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

Reporting group values	Venetoclax 200 mg +R-CHOP	Venetoclax 400 mg +R-CHOP	Venetoclax 600 mg +R-CHOP	Venetoclax 800 mg +R-CHOP	Venetoclax 800 mg +R-CHOP Phase II	Venetoclax 200 mg +G-CHOP	Venetoclax 400 mg +G-CHOP	Venetoclax 600 mg +G-CHOP	Venetoclax 800 mg +G-CHOP A	Venetoclax 800 mg +G-CHOP B	Total
Number of subjects	7	3	8	6	208	7	7	6	6	6	264
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0	0	0	0
Adults (18-64 years)	3	2	7	5	101	5	6	3	3	2	137
From 65-84 years	4	1	1	1	106	2	1	3	3	4	126
85 years and over	0	0	0	0	1	0	0	0	0	0	1
Age Continuous
Units: Years
arithmetic mean (standard deviation)	67.0 ± 9.2	61.0 ± 13.1	57.0 ± 9.5	56.3 ± 11.9	61.4 ± 12.8	52.1 ± 16.2	60.9 ± 6.3	66.7 ± 4.2	60.5 ± 13.7	66.8 ± 6.7	-
Sex: Female, Male
Units: Subjects
Female	3	2	2	2	94	2	5	4	4	2	120
Male	4	1	6	4	114	5	2	2	2	4	144
Race
Units: Subjects
Asian	0	0	0	0	5	0	1	0	0	0	6
Black or African American	0	0	0	0	4	0	0	0	0	0	4
Native Hawaiian or other Pacific Islande	0	0	0	0	3	0	0	0	0	0	3
White	6	1	2	2	154	7	2	4	5	4	187
Unknown	1	2	6	4	42	0	4	2	1	2	64
Ethnicity
Units: Subjects
Hispanic or Latino	0	0	0	0	4	0	0	0	0	0	4
Not Hispanic or Latino	6	1	2	3	151	6	3	4	5	6	187
Not Stated	1	2	6	2	45	1	4	1	0	0	62
Unknown	0	0	0	1	8	0	0	1	1	0	11

End points

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Reporting group title

Venetoclax 200 mg +R-CHOP

Reporting group description

Reporting group title

Venetoclax 400 mg +R-CHOP

Reporting group description

Reporting group title

Venetoclax 600 mg +R-CHOP

Reporting group description

Reporting group title

Venetoclax 800 mg +R-CHOP

Reporting group description

Reporting group title

Venetoclax 800 mg +R-CHOP Phase II

Reporting group description

Reporting group title

Venetoclax 200 mg +G-CHOP

Reporting group description

Reporting group title

Venetoclax 400 mg +G-CHOP

Reporting group description

Reporting group title

Venetoclax 600 mg +G-CHOP

Reporting group description

Reporting group title

Venetoclax 800 mg +G-CHOP A

Reporting group description

Reporting group title

Venetoclax 800 mg +G-CHOP B

Reporting group description

Phase I: Subjects received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. In this arm venetoclax was administered as follows: Cycle 1 Days 4-8; Cycles 2-8 Days 1-5. Subjects who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

Subject analysis set title

Venetoclax + R-CHOP 100 mg

Subject analysis set type

Safety analysis

Subject analysis set description

One participant in Venetoclax + R-CHOP 200mg arm mistakenly received only 100 mg instead of the planned 200 mg dose and was reported in a separate arm for PK outcome measures.

Subject analysis set title

Venetoclax + G-CHOP 800 mg A+B

Subject analysis set type

Per protocol

Subject analysis set description

All participants who received Venetoclax + G-CHOP 800 mg.

Subject analysis set title

Venetoclax + R-CHOP 800 mg Phase I and II

Subject analysis set type

Per protocol

Subject analysis set description

All participants who received Venetoclax + R-CHOP 800 mg.

Subject analysis set title

Venetoclax PK population

Subject analysis set type

Per protocol

Subject analysis set description

All participants who received Venetoclax and provided at least one post-treatment PK sample.

Subject analysis set title

Venetoclax 800 mg PK population

Subject analysis set type

Per protocol

Subject analysis set description

All participants in the study, who received 800 mg venetoclax and provided at least one post-treatment PK sample for whom data were available.

Subject analysis set title

Venetoclax + R-CHOP Arm

Subject analysis set type

Per protocol

Subject analysis set description

All participants who received Venetoclax + R-CHOP.

Subject analysis set title

Venetoclax + R-CHOP

Subject analysis set type

Per protocol

Subject analysis set description

All participants who received Venetoclax + R-CHOP.

Subject analysis set title

Venetoclax 800 mg +R-CHOP Phase II ITT population

Subject analysis set type

Intention-to-treat

Subject analysis set description

All participants who were randomized into Venetoclax 800 mg +R-CHOP Phase II arm.

Primary: Safety: Number of Participants With Dose-Limiting Toxicities (DLTs)

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End point title

Safety: Number of Participants With Dose-Limiting Toxicities (DLTs) ^[1] ^[2]

End point description

DLTs were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0). Decrease in B cells, lymphopenia, and leukopenia caused by lymphopenia were not considered DLTs but instead were expected outcomes of study treatment. Any Grade >/= 3 adverse event, that was attributed to having a reasonable possibility of being related to the combined administration of venetoclax plus R-CHOP or G-CHOP, that could not be attributed by the investigator to an alternative, clearly identifiable cause such as tumor progression, concurrent illness or medical condition, or concomitant medication and that occurred during the DLT observation period (start of venetoclax treatment through end of Cycle 2) was considered a DLT for dose-escalation purposes. Grade 3 or 4 neutropenia or thrombocytopenia identified on Day 1 of Cycle 2 or 3, resulting in dose delay were considered DLTs.

End point type

Primary

End point timeframe

Start of venetoclax administration (Cycle 1 Day 4 or 3 days after first CHOP dose) up to end of Cycle 2 (cycle length = 21 days)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis provided
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis performed on specified subject analysis sets

End point values	Venetoclax 200 mg +R-CHOP	Venetoclax 400 mg +R-CHOP	Venetoclax 600 mg +R-CHOP	Venetoclax 800 mg +R-CHOP	Venetoclax 200 mg +G-CHOP	Venetoclax 400 mg +G-CHOP	Venetoclax 600 mg +G-CHOP	Venetoclax 800 mg +G-CHOP A	Venetoclax 800 mg +G-CHOP B
Number of subjects analysed	7	3	8	6	7	7	6	6	6
Units: Participants	1	0	1	0	2	1	1	0	0

No statistical analyses for this end point

Primary: Percentage of Previously Untreated DLBCL Participants With Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET-CT) Scan Using the Modified Lugano Classification assessed by Independent Review Committee (IRC)

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End point title

Percentage of Previously Untreated DLBCL Participants With Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET-CT) Scan Using the Modified Lugano Classification assessed by Independent Review Committee (IRC) ^[3]

End point description

CR was defined as follows according to modified Lugano classification for PET-CT-based response: Lymph nodes and extra-lymphatic sites with score 1, 2, or 3 with or without a residual mass on 5-point scale with 1) no uptake above background; 2) uptake </= mediastinum; 3) uptake < mediastinum but </= liver. No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy. Intent-to-treat. All participants who enrolled in the study were included in the ITT population.

End point type

Primary

End point timeframe

Baseline up to end of treatment (up to approximately 6 months)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis provided

End point values	Venetoclax 800 mg +R-CHOP Phase II ITT population
Number of subjects analysed	211
Units: Percentage of participants
number (confidence interval 95%)	68.2 (61.50 to 74.47)

No statistical analyses for this end point

Primary: Percentage of Participants With CR Defined by PET/CT Scan in Previously Untreated DLBCL Co‑expressing Both Bcl‑2 and c‑Myc Proteins (DE-DLBCL) Participants Assessed by IRC

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End point title

Percentage of Participants With CR Defined by PET/CT Scan in Previously Untreated DLBCL Co‑expressing Both Bcl‑2 and c‑Myc Proteins (DE-DLBCL) Participants Assessed by IRC ^[4]

End point description

CR was defined as follows according to modified Lugano classification for PET/CT-based response: Lymph nodes and extra-lymphatic sites with score 1, 2, or 3 with or without a residual mass on 5-point scale with 1) no uptake above background; 2) uptake </= mediastinum; 3) uptake < mediastinum but </= liver. No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy. PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample.

End point type

Primary

End point timeframe

Baseline up to end of treatment (up to approximately 6 months)

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis provided

End point values	Venetoclax 800 mg +R-CHOP Phase II ITT population
Number of subjects analysed	81
Units: Percentage of participants
number (confidence interval 95%)	66.7 (55.32 to 76.76)

No statistical analyses for this end point

Secondary: Venetoclax Plasma PK: Area Under the Plasma Concentration-Time Curve (AUC)

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End point title

Venetoclax Plasma PK: Area Under the Plasma Concentration-Time Curve (AUC) ^[5]

End point description

AUC was calculated based on measurement of venetoclax concentration in plasma over time. Data are reported as hour*micrograms per milliliter (hr*mcg/mL). PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample. 99999=N/A

End point type

Secondary

End point timeframe

Predose (within 30 minutes) & 2, 4, 6, 8 hours (Hr) postdose on Cycle 1 Day 4; predose (within 30 minutes) and 8 Hr postdose on Cycle 1 Day 8; predose (within 30 minutes) on Cycle 2, 3, 4 Day 10 (cycle length = 21 days)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis performed on specified subject analysis sets

End point values	Venetoclax 200 mg +R-CHOP	Venetoclax 400 mg +R-CHOP	Venetoclax 600 mg +R-CHOP	Venetoclax 200 mg +G-CHOP	Venetoclax 400 mg +G-CHOP	Venetoclax 600 mg +G-CHOP	Venetoclax + R-CHOP 100 mg	Venetoclax + G-CHOP 800 mg A+B	Venetoclax + R-CHOP 800 mg Phase I and II
Number of subjects analysed	6	3	8	7	7	6	1	10	124
Units: hr*mcg/mL
arithmetic mean (standard deviation)	2.51 ± 0.97	3.87 ± 2.41	3.70 ± 1.59	2.55 ± 1.13	4.33 ± 1.31	5.13 ± 2.41	0.66 ± 9999	6.20 ± 1.71	4.51 ± 2.32

No statistical analyses for this end point

Secondary: Venetoclax Plasma PK: Time to Maximum Observed Plasma Concentration (Tmax)

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End point title

Venetoclax Plasma PK: Time to Maximum Observed Plasma Concentration (Tmax) ^[6]

End point description

Tmax was determined based on measurement of venetoclax concentrations in plasma over time. PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample. 99999=N/A

End point type

Secondary

End point timeframe

Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4; predose (within 30 minutes) and 8 Hr postdose on Cycle 1 Day 8; predose (within 30 minutes) on Cycle 2, 3, 4 Day 10 (cycle length = 21 days)

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis performed on specified subject analysis sets

End point values	Venetoclax 200 mg +R-CHOP	Venetoclax 400 mg +R-CHOP	Venetoclax 600 mg +R-CHOP	Venetoclax 200 mg +G-CHOP	Venetoclax 400 mg +G-CHOP	Venetoclax 600 mg +G-CHOP	Venetoclax + R-CHOP 100 mg	Venetoclax + G-CHOP 800 mg A+B	Venetoclax + R-CHOP 800 mg Phase I and II
Number of subjects analysed	6	3	8	7	7	6	1	10	124
Units: Hour
arithmetic mean (standard deviation)	4.59 ± 1.08	6.50 ± 1.91	5.52 ± 2.07	5.72 ± 1.42	6.56 ± 1.51	5.30 ± 2.38	4.0 ± 9999	5.79 ± 1.47	5.53 ± 1.55

No statistical analyses for this end point

Secondary: Venetoclax Plasma PK: Maximum Observed Plasma Concentration (Cmax)

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End point title

Venetoclax Plasma PK: Maximum Observed Plasma Concentration (Cmax) ^[7]

End point description

Cmax was determined based on measurement of venetoclax concentrations in plasma over time. Data are reported as micrograms per milliliter. PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample. 99999=N/A

End point type

Secondary

End point timeframe

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis performed on specified subject analysis sets

End point values	Venetoclax 200 mg +R-CHOP	Venetoclax 400 mg +R-CHOP	Venetoclax 600 mg +R-CHOP	Venetoclax 200 mg +G-CHOP	Venetoclax 400 mg +G-CHOP	Venetoclax 600 mg +G-CHOP	Venetoclax + R-CHOP 100 mg	Venetoclax + G-CHOP 800 mg A+B	Venetoclax + R-CHOP 800 mg Phase I and II
Number of subjects analysed	6	3	8	7	7	6	1	10	124
Units: Ug/ML
arithmetic mean (standard deviation)	0.58 ± 0.32	0.92 ± 0.64	0.85 ± 0.33	0.52 ± 0.21	1.26 ± 0.3	1.0 ± 0.58	0.09 ± 9999	1.54 ± 0.37	1.15 ± 0.48

No statistical analyses for this end point

Secondary: Venetoclax Plasma PK: Minimum Plasma Concentration (Cmin) within the Dosing Interval

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End point title

Venetoclax Plasma PK: Minimum Plasma Concentration (Cmin) within the Dosing Interval ^[8]

End point description

Cmin was determined based on measurement of venetoclax concentrations in plasma over time. PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample.

End point type

Secondary

End point timeframe

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis performed on specified subject analysis sets

End point values	Venetoclax 200 mg +R-CHOP	Venetoclax 400 mg +R-CHOP	Venetoclax 600 mg +R-CHOP	Venetoclax 200 mg +G-CHOP	Venetoclax 400 mg +G-CHOP	Venetoclax 600 mg +G-CHOP	Venetoclax + R-CHOP 100 mg	Venetoclax + G-CHOP 800 mg A+B	Venetoclax + R-CHOP 800 mg Phase I and II
Number of subjects analysed	3	2	4	7	5	5	1	6	124
Units: mcg/mL
arithmetic mean (standard deviation)	0.522 ± 0.441	0.253 ± 0.247	0.387 ± 0.141	0.134 ± 0.107	0.395 ± 0.381	0.612 ± 0.535	0.0714 ± 9999	0.628 ± 0.395	0.640 ± 0.451

No statistical analyses for this end point

Secondary: Prednisone Plasma PK: AUC

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End point title

Prednisone Plasma PK: AUC

End point description

AUC was determined based on measurement of Predisone concentrations in plasma over time. PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample.

End point type

Secondary

End point timeframe

Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days)

End point values	Venetoclax PK population
Number of subjects analysed	52
Units: hr*mcg/mL
arithmetic mean (standard deviation)
Cycle 1, Day 1\|	195 ± 72.8
Cycle 2, Day 1\|	184 ± 81.2

No statistical analyses for this end point

Secondary: Prednisone Plasma PK: Tmax

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End point title

Prednisone Plasma PK: Tmax

End point description

Tmax was determined based on measurement of Predisone concentrations in plasma over time. PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample.

End point type

Secondary

End point timeframe

Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days)

End point values	Venetoclax PK population
Number of subjects analysed	54
Units: Hour
arithmetic mean (standard deviation)
Cycle 1, Day 1\|	2.19 ± 1.61
Cycle 2, Day 1\|	3.80 ± 2.52

No statistical analyses for this end point

Secondary: Prednisone Plasma PK: Cmax

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End point title

Prednisone Plasma PK: Cmax

End point description

Cmax was determined based on measurement of Predisone concentrations in plasma over time. PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample.

End point type

Secondary

End point timeframe

Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days)

End point values	Venetoclax PK population
Number of subjects analysed	54
Units: Ng/ML
arithmetic mean (standard deviation)
Cycle 1, Day 1\|	49.9 ± 28.7
Cycle 2, Day 1\|	43.2 ± 17.6

No statistical analyses for this end point

Secondary: Rituximab PK: Cmax

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End point title

Rituximab PK: Cmax

End point description

Cmax was determined based on measurement of Rituximab concentrations in plasma over time. PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample.

End point type

Secondary

End point timeframe

Predose (within 30 minutes) on Day 1 of Cycles 1-8; end of infusion (infusion duration = 2-3 hours) on Cycle 1 Day 1; anytime during end of treatment (6-9 weeks after Cycle 8 Day 1) (cycle length = 21 days)

End point values	Venetoclax 800 mg PK population
Number of subjects analysed	7
Units: mcg/mL
arithmetic mean (standard deviation)	173 ± 39.4

No statistical analyses for this end point

Secondary: Rituximab PK: Cmin within the Dosing Interval

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End point title

Rituximab PK: Cmin within the Dosing Interval

End point description

Cmin was determined based on measurement of Rituximab concentrations in plasma over time. PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample.

End point type

Secondary

End point timeframe

Predose (within 30 minutes) on Day 1 of Cycles 1-8; end of infusion (infusion duration = 2-3 hours) on Cycle 1 Day 1 (cycle length = 21 days)

End point values	Venetoclax 800 mg PK population
Number of subjects analysed	8
Units: mcg/mL
arithmetic mean (standard deviation)	26.1 ± 13

No statistical analyses for this end point

Secondary: Obinutuzumab PK: Cmax

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End point title

Obinutuzumab PK: Cmax

End point description

Cmax was determined based on measurement of Obinutuzumab concentrations in plasma over time. PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample.

End point type

Secondary

End point timeframe

Predose (within 30 minutes) on Day 1 of Cycles 1-8; predose (within 30 minutes) and end of infusion (infusion duration = 3 Hr) on Day 1 of Cycles 1 and 2; anytime during end of treatment (6-9 weeks after Cycle 8 Day 1) (cycle length = 21 days)

End point values	Venetoclax 800 mg PK population
Number of subjects analysed	10
Units: mcg/mL
arithmetic mean (standard deviation)	326 ± 76

No statistical analyses for this end point

Secondary: Cyclophosphamide PK: Cmax

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End point title

Cyclophosphamide PK: Cmax

End point description

Cmax was determined based on measurement of Cyclophosphamide concentrations in plasma over time. PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample.

End point type

Secondary

End point timeframe

Predose (within 30 minutes) and end of infusion (infusion duration = 30 minutes) on Day 1 of Cycles 1 and 2 (cycle length = 21 days)

End point values	Venetoclax PK population
Number of subjects analysed	36
Units: mcg/mL
arithmetic mean (standard deviation)	32.1 ± 7.51

No statistical analyses for this end point

Secondary: Doxorubicin PK: Cmax

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End point title

Doxorubicin PK: Cmax

End point description

Cmax was determined based on measurement of Doxorubicin concentrations in plasma over time. PK evaluable population: All patients who received study drug and provided at least one post-treatment PK sample.

End point type

Secondary

End point timeframe

Predose (within 30 minutes) and end of infusion (infusion duration = 15-30 minutes) on Day 1 of Cycles 1 and 2 (cycle length = 21 days)

End point values	Venetoclax PK population
Number of subjects analysed	24
Units: mcg/mL
arithmetic mean (standard deviation)	1260 ± 911

No statistical analyses for this end point

Secondary: Vincristine PK: Cmax

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End point title

Vincristine PK: Cmax

End point description

End point type

Secondary

End point timeframe

Predose (within 30 minutes) and end of infusion (infusion duration = 10 minutes) on Day 1 of Cycles 1 and 2 (cycle length = 21 days)

End point values	Venetoclax PK population
Number of subjects analysed	28
Units: mcg/mL
arithmetic mean (standard deviation)	54.0 ± 44.6

No statistical analyses for this end point

Secondary: Percentage of Participants With Objective Response Defined as Partial Response (PR) or Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET/CT) Using the Modified Lugano Classification assessed by IRC

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End point title

Percentage of Participants With Objective Response Defined as Partial Response (PR) or Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET/CT) Using the Modified Lugano Classification assessed by IRC

End point description

Objective Response defined as PR (partial response) or CR (complete response) at end of treatment. CR: Lymph nodes and extra-lymphatic sites with score 1, 2 or 3 on a 5-point scale (with a higher score being a worse outcome). No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy. PR: Lymph nodes and extralymphatic sites with score of 4 or 5 on the 5-point scale with reduced uptake compared with baseline and residual mass(es) of any size. CT-based response criteria for PR must also be met. No new lesions. In bone marrow residual uptake could be higher than in normal marrow but must be reduced compared with baseline; persistent focal changes in the marrow to be considered for further evaluation with magnetic resonance imaging (MRI) or biopsy or an interval scan. OR=PR+CR

End point type

Secondary

End point timeframe

Baseline to end of treatment (up to approximately 6 months)

End point values	Venetoclax 800 mg +R-CHOP Phase II ITT population
Number of subjects analysed	211
Units: Percentage of Participants
number (confidence interval 95%)	81.5 (75.61 to 86.51)

No statistical analyses for this end point

Secondary: Percentage of Participants who are Alive and Without Disease Progression at Month 12

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End point title

Percentage of Participants who are Alive and Without Disease Progression at Month 12 ^[9]

End point description

Progressive disease (PD) was determined using the modified Lugano classification criteria. For PET-CT-based PD: Score 4 (uptake moderately > liver) or 5 (uptake markedly higher than liver and/or new lesions) with an increase in intensity of uptake from baseline in target nodes and nodal lesions, new FDG-uptake foci of extranodal lesions consistent with lymphoma at interim or end-of-treatment assessment, no non-measured lesions, new FDG-uptake foci consistent with lymphoma, new or recurrent FDG-uptake foci in bone marrow. For CT-based PD: >/= 50% decrease in SPD of up to 6 target measureable nodes and extranodal sites; non-measured lesion should be absent/normal, have regressed, but not increased; no new lesions. All participants who enrolled in the study were included in the ITT population

End point type

Secondary

End point timeframe

Month 12

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis performed on specified subject analysis sets

End point values	Venetoclax 200 mg +R-CHOP	Venetoclax 400 mg +R-CHOP	Venetoclax 600 mg +R-CHOP	Venetoclax 800 mg +R-CHOP	Venetoclax 200 mg +G-CHOP	Venetoclax 400 mg +G-CHOP	Venetoclax 600 mg +G-CHOP	Venetoclax 800 mg +G-CHOP A	Venetoclax 800 mg +G-CHOP B	Venetoclax 800 mg +R-CHOP Phase II ITT population
Number of subjects analysed	7	3	8	6	7	7	6	6	6	211
Units: Percentage of Participants
number (confidence interval 95%)	85.71 (59.79 to 100)	100 (100 to 100)	87.50 (64.58 to 100)	66.67 (28.95 to 100)	100 (100 to 100)	75.00 (32.75 to 100)	100 (100 to 100)	100 (100 to 100)	100 (100 to 100)	88.99 (82.65 to 92.10)

No statistical analyses for this end point

Secondary: Percentage of Participants With CR Defined by Computed Tomography (CT) Scan Using the Modified Lugano Classification

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End point title

Percentage of Participants With CR Defined by Computed Tomography (CT) Scan Using the Modified Lugano Classification

End point description

CR was defined as follows according to modified Lugano classification for CT-based response: Target nodes/nodal masses must have regressed to </= 1.5 cm in longest transverse diameter of a lesion (LDi), no extra-lymphatic sites of disease, absence of non-measured lesions, organ enlargement must have regressed to normal, no new lesions, and if the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy. All participants who enrolled in the study were included in the ITT population

End point type

Secondary

End point timeframe

Baseline up to end of treatment (approx. 6 months)

End point values	Venetoclax 800 mg +R-CHOP Phase II ITT population
Number of subjects analysed	211
Units: Percentage of Participants
number (confidence interval 95%)	37.4 (30.89 to 44.35)

No statistical analyses for this end point

Secondary: Safety: Percentage of Participants With Adverse Events

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End point title

Safety: Percentage of Participants With Adverse Events

End point description

An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. All patients who enrolled in the study and received any amount of venetoclax or R-CHOP/G-CHOP were included in the safety population.

End point type

Secondary

End point timeframe

Baseline up to approximately 36 months

End point values	Venetoclax 200 mg +R-CHOP	Venetoclax 400 mg +R-CHOP	Venetoclax 600 mg +R-CHOP	Venetoclax 800 mg +R-CHOP	Venetoclax 800 mg +R-CHOP Phase II	Venetoclax 200 mg +G-CHOP	Venetoclax 400 mg +G-CHOP	Venetoclax 600 mg +G-CHOP	Venetoclax 800 mg +G-CHOP A	Venetoclax 800 mg +G-CHOP B
Number of subjects analysed	7	3	8	6	206	7	7	6	6	6
Units: Percentage of Participants
number (not applicable)	100.00	100.00	100.00	100.00	99.0	100.00	100.00	100.00	100.00	100.00

No statistical analyses for this end point

Secondary: Safety: Percentage of Participants Maintaining Relative Dose Intensity of CHOP Chemotherapy

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End point title

Safety: Percentage of Participants Maintaining Relative Dose Intensity of CHOP Chemotherapy

End point description

Maintenance of relative dose intensity was defined as a dose intensity of >/= 90%. All patients who enrolled in the study and received any amount of venetoclax or R-CHOP/G-CHOP were included in the safety population.

End point type

Secondary

End point timeframe

Baseline up to Cycle 6 (cycle length = 21 days)

End point values	Venetoclax + R-CHOP Arm	Venetoclax + R-CHOP
Number of subjects analysed	232	32
Units: Percentage of participants
number (not applicable)
Cyclophosphamide\|	89.5	77.4
Doxorubicin\|	88.6	77.4
Vincristine\|	86.6	78.1
Prednisone\|	87.4	81.3

No statistical analyses for this end point

Secondary: Relative Dose Intensity of Venetoclax

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End point title

Relative Dose Intensity of Venetoclax

End point description

Dose intensity was categorized as < 80%, 80% to < 85%, 85% to < 90%, or >/= 90%. All patients who enrolled in the study and received any amount of venetoclax or R-CHOP/G-CHOP were included in the safety population

End point type

Secondary

End point timeframe

Baseline up to Cycle 8 (cycle length = 21 days)

End point values	Venetoclax 200 mg +R-CHOP	Venetoclax 400 mg +R-CHOP	Venetoclax 600 mg +R-CHOP	Venetoclax 800 mg +R-CHOP	Venetoclax 800 mg +R-CHOP Phase II	Venetoclax 200 mg +G-CHOP	Venetoclax 400 mg +G-CHOP	Venetoclax 600 mg +G-CHOP	Venetoclax 800 mg +G-CHOP A	Venetoclax 800 mg +G-CHOP B
Number of subjects analysed	7	3	8	6	208	7	7	6	6	6
Units: Percentage of Partcipants
number (not applicable)
<80%\|	71.4	0.00	12.5	0.00	26.0	100	14.3	50.0	83.3	100
80-<85%\|	0.00	0.00	12.5	0.00	3.4	0.00	14.3	16.7	0.00	0.00
85-<90%\|	0.00	0.00	12.5	0.00	2.9	0.00	0.00	0.00	16.7	0.00
>=90%\|	28.6	100	62.5	100	67.6	0.00	71.4	33.3	0.00	0.00

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to approximately 67 months.

Adverse event reporting additional description

Safety population: All participants, who were enrolled in the study and received any amount of venetoclax or R-CHOP/G-CHOP were included in the safety population.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

Venetoclax+R-CHOP 200 mg

Reporting group description

Reporting group title

Venetoclax+R-CHOP 400 mg

Reporting group description

Reporting group title

Venetoclax+R-CHOP 600 mg

Reporting group description

Reporting group title

Venetoclax+R-CHOP 800 mg

Reporting group description

Reporting group title

Venetoclax+R-CHOP 800 mg Phase II

Reporting group description

Reporting group title

Venetoclax+G-CHOP 200 mg

Reporting group description

Reporting group title

Venetoclax+G-CHOP 400 mg

Reporting group description

Reporting group title

Venetoclax+G-CHOP 600 mg

Reporting group description

Reporting group title

Venetoclax+G-CHOP 800 mg A

Reporting group description

Reporting group title

Venetoclax+G-CHOP 800 mg B

Reporting group description

Phase I: Subjects received 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle consisted of 21 days. In this arm venetoclax was administered as follows: Cycle 1 Days 4-8; Cycles 2-8 Days 1-5. Subjects who experienced ongoing response without excessive toxicity could receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor.

Serious adverse events	Venetoclax+R-CHOP 200 mg	Venetoclax+R-CHOP 400 mg	Venetoclax+R-CHOP 600 mg	Venetoclax+R-CHOP 800 mg	Venetoclax+R-CHOP 800 mg Phase II	Venetoclax+G-CHOP 200 mg	Venetoclax+G-CHOP 400 mg	Venetoclax+G-CHOP 600 mg	Venetoclax+G-CHOP 800 mg A	Venetoclax+G-CHOP 800 mg B
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 7 (71.43%)	2 / 3 (66.67%)	4 / 8 (50.00%)	3 / 6 (50.00%)	116 / 208 (55.77%)	5 / 7 (71.43%)	4 / 7 (57.14%)	3 / 6 (50.00%)	5 / 6 (83.33%)	5 / 6 (83.33%)
number of deaths (all causes)	1	0	1	2	33	1	1	0	0	0
number of deaths resulting from adverse events	0	0	0	0	3	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ACUTE MYELOID LEUKAEMIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	3 / 208 (1.44%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	3 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ADENOLYMPHOMA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GLIOBLASTOMA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HISTIOCYTOSIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LUNG NEOPLASM MALIGNANT
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MYELODYSPLASTIC SYNDROME
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
EMBOLISM
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPOTENSION
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FATIGUE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INFLAMMATION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PYREXIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	7 / 208 (3.37%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	6 / 7	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SUDDEN CARDIAC DEATH
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
HYPOGAMMAGLOBULINAEMIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COUGH
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DYSPNOEA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HAEMOPTYSIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INTERSTITIAL LUNG DISEASE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ORGANISING PNEUMONIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PLEURAL EFFUSION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMOTHORAX
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PRODUCTIVE COUGH
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PULMONARY EMBOLISM
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
CONFUSIONAL STATE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PSYCHOTIC DISORDER
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
BLOOD POTASSIUM INCREASED
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
C-REACTIVE PROTEIN INCREASED
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
CONTUSION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INFUSION RELATED REACTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LIGAMENT RUPTURE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
POST LUMBAR PUNCTURE SYNDROME
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SPINAL FRACTURE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TOXICITY TO VARIOUS AGENTS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
ACUTE CORONARY SYNDROME
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ATRIAL FIBRILLATION
subjects affected / exposed	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 6 (0.00%)	6 / 208 (2.88%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0	3 / 6	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ATRIOVENTRICULAR BLOCK
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CARDIAC ARREST
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CARDIAC FAILURE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CARDIAC FAILURE CONGESTIVE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CARDIOGENIC SHOCK
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CARDIOMYOPATHY
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LEFT VENTRICULAR FAILURE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MYOCARDIAL ISCHAEMIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SINUS TACHYCARDIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SUPRAVENTRICULAR TACHYCARDIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TACHYCARDIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
CAROTID SINUS SYNDROME
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
EPILEPSY
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPOGLOSSAL NERVE PARESIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
POLYNEUROPATHY
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PRESYNCOPE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SYNCOPE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TRANSIENT ISCHAEMIC ATTACK
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
AGRANULOCYTOSIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ANAEMIA
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 6 (0.00%)	4 / 208 (1.92%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	4 / 4	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FEBRILE NEUTROPENIA
subjects affected / exposed	3 / 7 (42.86%)	0 / 3 (0.00%)	1 / 8 (12.50%)	2 / 6 (33.33%)	57 / 208 (27.40%)	1 / 7 (14.29%)	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	5 / 5	0 / 0	2 / 2	3 / 3	85 / 89	1 / 1	2 / 2	0 / 0	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HAEMOLYTIC ANAEMIA
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LEUKOPENIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NEUTROPENIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	19 / 208 (9.13%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	24 / 24	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
THROMBOCYTOPENIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	4 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
OPTIC NEUROPATHY
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
DIARRHOEA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	4 / 208 (1.92%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	3 / 4	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIVERTICULAR PERFORATION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DUODENAL STENOSIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DYSPHAGIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ENTEROCOLITIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTRIC DILATATION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTRIC PERFORATION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTRIC STENOSIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTRIC ULCER
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTRIC ULCER PERFORATION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL PAIN
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HAEMATEMESIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ILEAL PERFORATION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ILEUS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NAUSEA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OBSTRUCTION GASTRIC
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OESOPHAGEAL STENOSIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PANCREATITIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RECTAL HAEMORRHAGE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SMALL INTESTINAL OBSTRUCTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
STOMATITIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
UPPER GASTROINTESTINAL HAEMORRHAGE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VOMITING
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 6 (0.00%)	5 / 208 (2.40%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	4 / 5	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
BILE DUCT STONE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CHOLECYSTITIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CHOLECYSTITIS ACUTE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DRUG-INDUCED LIVER INJURY
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
RASH MACULO-PAPULAR
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
ACUTE KIDNEY INJURY
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
BACK PAIN
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
JOINT SWELLING
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PAIN IN EXTREMITY
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SPONDYLOLISTHESIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
ACUTE SINUSITIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ATYPICAL PNEUMONIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BACTERIAL SEPSIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BRONCHITIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CELLULITIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CLOSTRIDIUM COLITIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CLOSTRIDIUM DIFFICILE INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DEVICE RELATED INFECTION
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIVERTICULITIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
EMPYEMA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ESCHERICHIA PYELONEPHRITIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ESCHERICHIA URINARY TRACT INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTROENTERITIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTROENTERITIS NOROVIRUS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HERPES SIMPLEX
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	4 / 208 (1.92%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 5	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INFLUENZA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LOWER RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LUNG INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	3 / 208 (1.44%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	3 / 4	0 / 0	1 / 1	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MENINGITIS VIRAL
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NASOPHARYNGITIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OOPHORITIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ORAL CANDIDIASIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ORAL HERPES
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMOCYSTIS JIROVECII INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMOCYSTIS JIROVECII PNEUMONIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	9 / 208 (4.33%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	7 / 9	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA RESPIRATORY SYNCYTIAL VIRAL
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PSEUDOMONAL SEPSIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	3 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RECTAL ABSCESS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RHINOVIRUS INFECTION
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SEPSIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	6 / 208 (2.88%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	5 / 6	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SIALOADENITIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SINUSITIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SKIN INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
STAPHYLOCOCCAL SEPSIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
URINARY TRACT INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
URINARY TRACT INFECTION PSEUDOMONAL
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VASCULAR DEVICE INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
DECREASED APPETITE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DEHYDRATION
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIABETES MELLITUS INADEQUATE CONTROL
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPERKALAEMIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPOKALAEMIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPONATRAEMIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TUMOUR LYSIS SYNDROME
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Venetoclax+R-CHOP 200 mg	Venetoclax+R-CHOP 400 mg	Venetoclax+R-CHOP 600 mg	Venetoclax+R-CHOP 800 mg	Venetoclax+R-CHOP 800 mg Phase II	Venetoclax+G-CHOP 200 mg	Venetoclax+G-CHOP 400 mg	Venetoclax+G-CHOP 600 mg	Venetoclax+G-CHOP 800 mg A	Venetoclax+G-CHOP 800 mg B
Total subjects affected by non serious adverse events
subjects affected / exposed	7 / 7 (100.00%)	3 / 3 (100.00%)	8 / 8 (100.00%)	6 / 6 (100.00%)	204 / 208 (98.08%)	7 / 7 (100.00%)	7 / 7 (100.00%)	6 / 6 (100.00%)	6 / 6 (100.00%)	6 / 6 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
SQUAMOUS CELL CARCINOMA
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0	0	0
SQUAMOUS CELL CARCINOMA OF SKIN
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Vascular disorders
HOT FLUSH
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	2	0	0	0	1	0
HYPOTENSION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	13 / 208 (6.25%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	15	1	0	0	2	0
THROMBOPHLEBITIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	3 / 208 (1.44%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	3	1	0	0	0	0
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	2 / 7 (28.57%)	1 / 3 (33.33%)	2 / 8 (25.00%)	0 / 6 (0.00%)	33 / 208 (15.87%)	2 / 7 (28.57%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	2	2	0	41	2	0	1	0	0
CHEST PAIN
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	12 / 208 (5.77%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	12	0	0	0	0	1
CHILLS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	12 / 208 (5.77%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	15	0	0	0	0	0
FATIGUE
subjects affected / exposed	5 / 7 (71.43%)	0 / 3 (0.00%)	3 / 8 (37.50%)	2 / 6 (33.33%)	81 / 208 (38.94%)	5 / 7 (71.43%)	2 / 7 (28.57%)	2 / 6 (33.33%)	3 / 6 (50.00%)	1 / 6 (16.67%)
occurrences all number	5	0	3	4	104	7	2	2	4	1
FEELING ABNORMAL
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0
GAIT DISTURBANCE
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	3 / 208 (1.44%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	3	0	0	0	0	0
INFLUENZA LIKE ILLNESS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	3 / 208 (1.44%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	4	1	0	0	0	0
INFUSION SITE EXTRAVASATION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
MALAISE
subjects affected / exposed	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	5 / 208 (2.40%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	0	0	0	5	2	0	0	0	0
MUCOSAL INFLAMMATION
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	2 / 8 (25.00%)	1 / 6 (16.67%)	19 / 208 (9.13%)	1 / 7 (14.29%)	3 / 7 (42.86%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	1	0	2	1	28	1	3	0	1	1
NON-CARDIAC CHEST PAIN
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
OEDEMA
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	3 / 208 (1.44%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	4	0	0	0	0	0
OEDEMA PERIPHERAL
subjects affected / exposed	2 / 7 (28.57%)	0 / 3 (0.00%)	2 / 8 (25.00%)	0 / 6 (0.00%)	23 / 208 (11.06%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	3 / 6 (50.00%)	1 / 6 (16.67%)
occurrences all number	2	0	2	0	26	0	1	0	3	1
PAIN
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	7 / 208 (3.37%)	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)
occurrences all number	0	0	0	0	8	1	1	0	1	2
PYREXIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	2 / 6 (33.33%)	50 / 208 (24.04%)	0 / 7 (0.00%)	5 / 7 (71.43%)	2 / 6 (33.33%)	1 / 6 (16.67%)	2 / 6 (33.33%)
occurrences all number	0	0	1	2	68	0	7	2	1	2
UNEVALUABLE EVENT
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Immune system disorders
HYPERSENSITIVITY
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
HYPOGAMMAGLOBULINAEMIA
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	1	0	0	0	0	0
Reproductive system and breast disorders
BREAST PAIN
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
TESTICULAR PAIN
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
VAGINAL DISCHARGE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
VULVOVAGINAL DRYNESS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
Respiratory, thoracic and mediastinal disorders
COUGH
subjects affected / exposed	2 / 7 (28.57%)	0 / 3 (0.00%)	3 / 8 (37.50%)	1 / 6 (16.67%)	51 / 208 (24.52%)	3 / 7 (42.86%)	2 / 7 (28.57%)	0 / 6 (0.00%)	3 / 6 (50.00%)	2 / 6 (33.33%)
occurrences all number	2	0	4	1	67	3	2	0	5	2
DYSPNOEA
subjects affected / exposed	2 / 7 (28.57%)	1 / 3 (33.33%)	0 / 8 (0.00%)	1 / 6 (16.67%)	22 / 208 (10.58%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	3	2	0	1	24	0	1	0	1	1
DYSPNOEA EXERTIONAL
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	1 / 6 (16.67%)	4 / 208 (1.92%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	1	1	4	0	0	0	0	0
EPISTAXIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	3 / 208 (1.44%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	3	1	0	0	1	0
HICCUPS
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	4 / 208 (1.92%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	5	0	0	0	0	0
NASAL CONGESTION
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 8 (12.50%)	1 / 6 (16.67%)	11 / 208 (5.29%)	2 / 7 (28.57%)	1 / 7 (14.29%)	0 / 6 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)
occurrences all number	1	0	1	1	11	2	1	0	4	1
OROPHARYNGEAL PAIN
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	10 / 208 (4.81%)	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	13	1	1	0	0	0
PLEURAL EFFUSION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0	0
PLEURITIC PAIN
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
PRODUCTIVE COUGH
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	8 / 208 (3.85%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	8	0	0	0	0	1
RHINORRHOEA
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	11 / 208 (5.29%)	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	0	0	0	11	1	0	1	0	1
SINUS PAIN
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	1	0
VOCAL CORD DYSFUNCTION
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
WHEEZING
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	1	0	0	0	0	0
Psychiatric disorders
ANXIETY
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	9 / 208 (4.33%)	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1	9	3	1	0	0	1
DEPRESSION
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	4 / 208 (1.92%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	5	0	1	0	0	0
INSOMNIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	2 / 8 (25.00%)	1 / 6 (16.67%)	14 / 208 (6.73%)	2 / 7 (28.57%)	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	3	1	17	2	3	0	0	1
MOOD SWINGS
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
Investigations
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0
ASPARTATE AMINOTRANSFERASE INCREASED
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
BLOOD MAGNESIUM DECREASED
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
BLOOD POTASSIUM INCREASED
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
COMPUTERISED TOMOGRAM THORAX ABNORMAL
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
EJECTION FRACTION DECREASED
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	2	1	0	0	0	0
URINE OUTPUT DECREASED
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
WEIGHT DECREASED
subjects affected / exposed	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	32 / 208 (15.38%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)
occurrences all number	3	0	0	1	33	0	1	0	2	1
WEIGHT INCREASED
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	3 / 208 (1.44%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	3	0	0	0	1	0
WHITE BLOOD CELL COUNT DECREASED
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
Injury, poisoning and procedural complications
FALL
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	4 / 208 (1.92%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	4	0	0	0	1	0
HAND FRACTURE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
INFUSION RELATED REACTION
subjects affected / exposed	1 / 7 (14.29%)	2 / 3 (66.67%)	1 / 8 (12.50%)	2 / 6 (33.33%)	44 / 208 (21.15%)	4 / 7 (57.14%)	1 / 7 (14.29%)	2 / 6 (33.33%)	2 / 6 (33.33%)	3 / 6 (50.00%)
occurrences all number	1	2	1	3	48	4	1	2	3	4
MUSCLE STRAIN
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
PROCEDURAL PAIN
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
THERMAL BURN
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
TRACHEAL OBSTRUCTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Congenital, familial and genetic disorders
ICHTHYOSIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
Cardiac disorders
ANGINA PECTORIS
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0	0	0	1	0	0
ATRIAL FIBRILLATION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	7 / 208 (3.37%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1	0	8	1	0	0	0	1
CARDIAC FAILURE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0
PALPITATIONS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	8 / 208 (3.85%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	8	0	1	0	0	0
TACHYCARDIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	3 / 208 (1.44%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1	0	3	0	0	0	0	1
Nervous system disorders
AGEUSIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0
CAROTID SINUS SYNDROME
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
COGNITIVE DISORDER
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0
DISTURBANCE IN ATTENTION
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	1	1	0	0	0	0
DIZZINESS
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	2 / 8 (25.00%)	1 / 6 (16.67%)	24 / 208 (11.54%)	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)
occurrences all number	1	0	2	1	33	1	1	0	0	2
DYSGEUSIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	1 / 6 (16.67%)	19 / 208 (9.13%)	1 / 7 (14.29%)	3 / 7 (42.86%)	1 / 6 (16.67%)	2 / 6 (33.33%)	4 / 6 (66.67%)
occurrences all number	0	0	1	1	19	1	3	1	2	4
HEADACHE
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	3 / 8 (37.50%)	1 / 6 (16.67%)	28 / 208 (13.46%)	3 / 7 (42.86%)	3 / 7 (42.86%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	3	1	31	5	3	1	0	0
HYPOAESTHESIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	4 / 208 (1.92%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	4	1	0	0	0	0
LETHARGY
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	1	0	0	0	1
MEMORY IMPAIRMENT
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	3 / 208 (1.44%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	3	0	0	0	0	0
NEUROPATHY PERIPHERAL
subjects affected / exposed	2 / 7 (28.57%)	1 / 3 (33.33%)	3 / 8 (37.50%)	3 / 6 (50.00%)	28 / 208 (13.46%)	0 / 7 (0.00%)	2 / 7 (28.57%)	1 / 6 (16.67%)	1 / 6 (16.67%)	2 / 6 (33.33%)
occurrences all number	2	2	3	3	33	0	2	1	1	3
PARAESTHESIA
subjects affected / exposed	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	18 / 208 (8.65%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	0	0	1	26	0	1	0	0	0
PERIPHERAL MOTOR NEUROPATHY
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	2	0	0	0	1	1
PERIPHERAL SENSORY NEUROPATHY
subjects affected / exposed	3 / 7 (42.86%)	1 / 3 (33.33%)	2 / 8 (25.00%)	2 / 6 (33.33%)	14 / 208 (6.73%)	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	3	1	2	2	14	0	1	1	1	1
POST HERPETIC NEURALGIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
PRESYNCOPE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	1 / 208 (0.48%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	1	1	0	0	0	0
SYNCOPE
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	4 / 208 (1.92%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	8	0	0	0	0	0
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	4 / 7 (57.14%)	0 / 3 (0.00%)	1 / 8 (12.50%)	2 / 6 (33.33%)	73 / 208 (35.10%)	1 / 7 (14.29%)	1 / 7 (14.29%)	1 / 6 (16.67%)	5 / 6 (83.33%)	4 / 6 (66.67%)
occurrences all number	9	0	1	2	117	1	1	4	8	5
FEBRILE NEUTROPENIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	1 / 6 (16.67%)	9 / 208 (4.33%)	0 / 7 (0.00%)	4 / 7 (57.14%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	1	3	10	0	7	0	1	0
HAEMOLYTIC ANAEMIA
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
LEUKOPENIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	23 / 208 (11.06%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	47	0	0	1	0	0
NEUTROPENIA
subjects affected / exposed	4 / 7 (57.14%)	2 / 3 (66.67%)	6 / 8 (75.00%)	3 / 6 (50.00%)	134 / 208 (64.42%)	2 / 7 (28.57%)	4 / 7 (57.14%)	5 / 6 (83.33%)	6 / 6 (100.00%)	2 / 6 (33.33%)
occurrences all number	9	8	18	10	409	2	17	13	16	10
PANCYTOPENIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	1 / 6 (16.67%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0	0	0
THROMBOCYTOPENIA
subjects affected / exposed	4 / 7 (57.14%)	1 / 3 (33.33%)	3 / 8 (37.50%)	0 / 6 (0.00%)	52 / 208 (25.00%)	2 / 7 (28.57%)	3 / 7 (42.86%)	2 / 6 (33.33%)	4 / 6 (66.67%)	2 / 6 (33.33%)
occurrences all number	7	2	5	0	89	3	7	6	15	5
Ear and labyrinth disorders
EAR PAIN
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0	0	0
TINNITUS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0
Eye disorders
DRY EYE
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	4 / 208 (1.92%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	4	0	0	0	0	0
EYE PAIN
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	1	0
LACRIMATION INCREASED
subjects affected / exposed	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	3 / 208 (1.44%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	0	0	0	3	0	0	1	0	0
PHOTOPHOBIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
VISION BLURRED
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	7 / 208 (3.37%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	1	0	7	0	0	0	0	0
VITREOUS FLOATERS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	1	0
Gastrointestinal disorders
ABDOMINAL DISCOMFORT
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	4 / 208 (1.92%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	4	0	0	0	1	0
ABDOMINAL DISTENSION
subjects affected / exposed	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	14 / 208 (6.73%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	2	0	0	0	15	0	1	0	1	0
ABDOMINAL PAIN
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	1 / 6 (16.67%)	30 / 208 (14.42%)	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	3 / 6 (50.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1	1	38	0	1	1	4	1
ABDOMINAL PAIN UPPER
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	0 / 6 (0.00%)	7 / 208 (3.37%)	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	1	1	0	12	1	1	0	1	0
CONSTIPATION
subjects affected / exposed	1 / 7 (14.29%)	2 / 3 (66.67%)	3 / 8 (37.50%)	2 / 6 (33.33%)	67 / 208 (32.21%)	6 / 7 (85.71%)	3 / 7 (42.86%)	2 / 6 (33.33%)	2 / 6 (33.33%)	1 / 6 (16.67%)
occurrences all number	1	2	3	2	78	7	3	2	2	1
DENTAL CARIES
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	1	0	0	0	0	1
DENTAL CYST
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
DIARRHOEA
subjects affected / exposed	3 / 7 (42.86%)	2 / 3 (66.67%)	2 / 8 (25.00%)	3 / 6 (50.00%)	79 / 208 (37.98%)	5 / 7 (71.43%)	3 / 7 (42.86%)	2 / 6 (33.33%)	2 / 6 (33.33%)	1 / 6 (16.67%)
occurrences all number	10	4	2	5	133	5	6	3	4	1
DRY MOUTH
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	5 / 208 (2.40%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	5	0	0	2	1	0
DYSPEPSIA
subjects affected / exposed	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 8 (0.00%)	1 / 6 (16.67%)	22 / 208 (10.58%)	1 / 7 (14.29%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	0	1	27	1	1	1	0	0
DYSPHAGIA
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	7 / 208 (3.37%)	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	1	9	1	1	0	0	0
FLATULENCE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	4 / 208 (1.92%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	4	0	1	0	0	0
GASTRIC ULCER
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
GASTROINTESTINAL DISORDER
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
GASTROOESOPHAGEAL REFLUX DISEASE
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 8 (12.50%)	2 / 6 (33.33%)	6 / 208 (2.88%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	0	1	2	7	0	0	0	1	0
GINGIVAL PAIN
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	1	0
HAEMORRHOIDS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	15 / 208 (7.21%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	17	0	1	0	0	0
MOUTH ULCERATION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	7 / 208 (3.37%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	2	0	7	0	0	0	0	0
NAUSEA
subjects affected / exposed	3 / 7 (42.86%)	2 / 3 (66.67%)	1 / 8 (12.50%)	5 / 6 (83.33%)	108 / 208 (51.92%)	3 / 7 (42.86%)	4 / 7 (57.14%)	3 / 6 (50.00%)	5 / 6 (83.33%)	4 / 6 (66.67%)
occurrences all number	3	4	1	7	172	5	7	4	10	6
ORAL PAIN
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	3 / 208 (1.44%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	1	3	0	0	0	0	0
PROCTALGIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	2	0	0	0	0	0
STOMATITIS
subjects affected / exposed	2 / 7 (28.57%)	1 / 3 (33.33%)	1 / 8 (12.50%)	2 / 6 (33.33%)	24 / 208 (11.54%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	1	1	2	29	0	0	1	0	0
TOOTHACHE
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	2	1	0	0	0	0
VOMITING
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	1 / 8 (12.50%)	2 / 6 (33.33%)	64 / 208 (30.77%)	5 / 7 (71.43%)	4 / 7 (57.14%)	0 / 6 (0.00%)	4 / 6 (66.67%)	1 / 6 (16.67%)
occurrences all number	0	1	1	6	111	5	8	0	6	1
Hepatobiliary disorders
CHOLELITHIASIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
HYPERBILIRUBINAEMIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	3 / 208 (1.44%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	5	1	0	0	0	0
Skin and subcutaneous tissue disorders
ALOPECIA
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	3 / 6 (50.00%)	28 / 208 (13.46%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	0	0	3	29	0	0	1	0	0
DRY SKIN
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 6 (0.00%)	8 / 208 (3.85%)	0 / 7 (0.00%)	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	9	0	2	0	0	0
ECCHYMOSIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
HYPERHIDROSIS
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	3 / 208 (1.44%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	2	0	0	1	3	0	0	0	1	0
NAIL DISCOLOURATION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	1 / 6 (16.67%)	3 / 208 (1.44%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	1	3	0	1	0	0	0
NIGHT SWEATS
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	4 / 208 (1.92%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	4	0	0	0	0	0
PIGMENTATION DISORDER
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
PRURITUS
subjects affected / exposed	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 8 (0.00%)	0 / 6 (0.00%)	6 / 208 (2.88%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	1	1	0	0	8	0	0	1	2	0
PURPURA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	1	0	0	0	0	1
RASH
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	9 / 208 (4.33%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	1	0	9	0	0	0	0	0
RASH MACULO-PAPULAR
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	5 / 208 (2.40%)	1 / 7 (14.29%)	0 / 7 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	1	5	1	0	2	0	0
SKIN HYPERPIGMENTATION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	1	0	0	0	0	1
Renal and urinary disorders
BLADDER HYPERTROPHY
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
DYSURIA
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	1 / 6 (16.67%)	3 / 208 (1.44%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	1	3	0	0	0	0	0
HAEMATURIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	1	0
NOCTURIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	1	0
POLLAKIURIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0
RENAL FAILURE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
URINARY INCONTINENCE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	2	0	1	0	0	0
URINARY TRACT PAIN
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	1	0	0	0	0	0
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	22 / 208 (10.58%)	1 / 7 (14.29%)	2 / 7 (28.57%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	4	0	0	1	23	1	3	2	0	0
BACK PAIN
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	2 / 6 (33.33%)	29 / 208 (13.94%)	0 / 7 (0.00%)	2 / 7 (28.57%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1	2	34	0	2	1	0	1
BONE PAIN
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 8 (0.00%)	1 / 6 (16.67%)	9 / 208 (4.33%)	2 / 7 (28.57%)	1 / 7 (14.29%)	2 / 6 (33.33%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	1	0	1	10	2	2	2	0	1
MUSCLE SPASMS
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	5 / 208 (2.40%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	1	0	5	0	0	0	0	0
MUSCULAR WEAKNESS
subjects affected / exposed	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	10 / 208 (4.81%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	2	0	0	1	10	0	1	0	1	1
MUSCULOSKELETAL CHEST PAIN
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	3 / 208 (1.44%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	3	0	0	0	0	1
MYALGIA
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 8 (12.50%)	1 / 6 (16.67%)	12 / 208 (5.77%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	1	0	1	1	18	1	0	0	1	1
PAIN IN EXTREMITY
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	5 / 208 (2.40%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1	5	0	0	0	0	1
PAIN IN JAW
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 208 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0	0	0
Infections and infestations
ANORECTAL INFECTION
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
BRONCHITIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	16 / 208 (7.69%)	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	2	0	18	0	1	1	0	1
CAMPYLOBACTER GASTROENTERITIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0
CANDIDA INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	3 / 208 (1.44%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	3	0	1	0	0	0
CELLULITIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0	0	0
CELLULITIS ORBITAL
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
CLOSTRIDIUM DIFFICILE COLITIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	3 / 208 (1.44%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	3	0	0	0	1	0
CLOSTRIDIUM DIFFICILE INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0	0	0
CONJUNCTIVITIS
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	2	0	0	0	0	0
DEVICE RELATED INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	1	0
ENTEROVIRUS INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0
ERYSIPELAS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
FURUNCLE
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
HERPES SIMPLEX
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	1	0	0	0	0	0
HERPES ZOSTER
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	1	0	1	1	0	0
INFLUENZA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	1	0
LUNG INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	4 / 208 (1.92%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	5	1	0	0	0	0
NASOPHARYNGITIS
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	8 / 208 (3.85%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	0	0	0	9	0	1	0	0	1
ORAL CANDIDIASIS
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	8 / 208 (3.85%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	1	0	0	0	9	0	0	1	1	1
ORAL FUNGAL INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	2	0	0	0	0	1
ORAL HERPES
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	5 / 208 (2.40%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	6	0	0	0	1	0
PNEUMOCYSTIS JIROVECII PNEUMONIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 208 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	0
PNEUMONIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	5 / 208 (2.40%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	5	0	0	0	1	0
PSEUDOMONAL BACTERAEMIA
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
RHINITIS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	7 / 208 (3.37%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	7	0	0	2	0	0
SEPSIS
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
SINUSITIS BACTERIAL
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0
SKIN INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	3 / 208 (1.44%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	3	0	1	0	0	0
STAPHYLOCOCCAL INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0	0	0
TOOTH ABSCESS
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	1	0
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	12 / 208 (5.77%)	2 / 7 (28.57%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	1	0	0	1	15	2	0	1	2	1
URINARY TRACT INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	16 / 208 (7.69%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	22	0	0	0	0	0
VASCULAR DEVICE INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	1	0	0	0	0	1
VIRAL UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	1	0	0	0	0	0
VULVOVAGINAL CANDIDIASIS
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
Metabolism and nutrition disorders
DECREASED APPETITE
subjects affected / exposed	1 / 7 (14.29%)	1 / 3 (33.33%)	1 / 8 (12.50%)	1 / 6 (16.67%)	42 / 208 (20.19%)	2 / 7 (28.57%)	2 / 7 (28.57%)	1 / 6 (16.67%)	2 / 6 (33.33%)	1 / 6 (16.67%)
occurrences all number	1	1	1	1	45	2	2	1	2	1
DEHYDRATION
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	7 / 208 (3.37%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	11	0	0	0	0	0
FLUID RETENTION
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	3	0	0	0	1	0
GOUT
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	2	0	0	0	0	1
HYPERKALAEMIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	4 / 208 (1.92%)	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	4	0	1	1	0	0
HYPERPHOSPHATAEMIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 208 (0.96%)	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	2	1	0	1	0	0
HYPERURICAEMIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	2 / 208 (0.96%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	2	0	0	0	0	0
HYPOCALCAEMIA
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	3 / 208 (1.44%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	4	0	0	0	0	0
HYPOCHLORAEMIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 208 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
HYPOKALAEMIA
subjects affected / exposed	3 / 7 (42.86%)	1 / 3 (33.33%)	2 / 8 (25.00%)	0 / 6 (0.00%)	35 / 208 (16.83%)	1 / 7 (14.29%)	2 / 7 (28.57%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)
occurrences all number	4	1	2	0	44	1	2	0	1	1
HYPOMAGNESAEMIA
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	10 / 208 (4.81%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	6	0	0	0	12	0	0	0	0	0
HYPONATRAEMIA
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	4 / 208 (1.92%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)
occurrences all number	2	0	0	0	4	0	0	0	0	1
HYPOPHOSPHATAEMIA
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	7 / 208 (3.37%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0	9	0	0	0	0	0
TUMOUR LYSIS SYNDROME
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 208 (0.48%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	1	0

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Were there any global substantial amendments to the protocol? Yes

21 Jan 2014

Changes that allow for symmetry in the treatment of patients receiving rituximab or obinutuzumab in case of hepatitis B reactivation. Changes to clarify that either antibody should be held in case of serious infection. clarification that patients with mantle cell lymphoma (MCL) and small lymphocytic lymphoma (SLL) were not eligible for the dose escalation portion of the study for safety reasons.

23 May 2014

Changes amended following identification of higher incidence of thrombocytopenia and hemorrhagic events in patients receiving obinutuzumab. Guidelines for management of patients with thrombocytopenia, especially during the first cycle have been added.

01 Oct 2014

An exploratory analysis of minimal residual disease has been added. Language has been added indicating the possibility of continued cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) treatment for up to eight cycles in selected patients who are tolerating therapy well and for whom it is felt by the investigator to be appropriate. Response criteria have been updated to be consistent with the 2014 Lugano Classification. Safety language has been updated.

24 Apr 2015

GDC-0199 dosing schedule updated. Characterization of the pharmacokinetics of the cyclophosphamide, doxorubicin and vincristine (CHO) components was deleted from the Pharmacokinetic Objectives as detailed characterization cannot be achieved with the current PK sampling scheme.

07 Dec 2015

An interim safety analysis has been added after 20 patients in the R-CHOP arm in the Phase II portion of the study have completed two cycles of treatment in order to confirm the safety and tolerability of the combination therapy at the venetoclax. The primary objectives of Phase II of the study have been modified to include assessment of efficacy of R-CHOP+ Venetoclax in patients with co-expression of both Bcl-2 and c-Myc. The term PET/CT will be replaced with PET-CT throughout the protocol.

10 Oct 2016

Venetoclax nonclinical toxicology section updated based on recent data findings. Twelve month Progression Free Survival (PFS) was added as a secondary efficacy objective. Information was added regarding the decision to not open Arm B in Phase II in DLBCL on the basis of information from the GOYA study results.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

http://www.ncbi.nlm.nih.gov/pubmed/30850381

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Safety: Number of Participants With Dose-Limiting Toxicities (DLTs)

Primary: Safety: Number of Participants With Dose-Limiting Toxicities (DLTs)

Primary: Percentage of Previously Untreated DLBCL Participants With Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET-CT) Scan Using the Modified Lugano Classification assessed by Independent Review Committee (IRC)

Primary: Percentage of Previously Untreated DLBCL Participants With Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET-CT) Scan Using the Modified Lugano Classification assessed by Independent Review Committee (IRC)

Primary: Percentage of Participants With CR Defined by PET/CT Scan in Previously Untreated DLBCL Co‑expressing Both Bcl‑2 and c‑Myc Proteins (DE-DLBCL) Participants Assessed by IRC

Primary: Percentage of Participants With CR Defined by PET/CT Scan in Previously Untreated DLBCL Co‑expressing Both Bcl‑2 and c‑Myc Proteins (DE-DLBCL) Participants Assessed by IRC

Secondary: Venetoclax Plasma PK: Area Under the Plasma Concentration-Time Curve (AUC)

Secondary: Venetoclax Plasma PK: Area Under the Plasma Concentration-Time Curve (AUC)

Secondary: Venetoclax Plasma PK: Time to Maximum Observed Plasma Concentration (Tmax)

Secondary: Venetoclax Plasma PK: Time to Maximum Observed Plasma Concentration (Tmax)

Secondary: Venetoclax Plasma PK: Maximum Observed Plasma Concentration (Cmax)

Secondary: Venetoclax Plasma PK: Maximum Observed Plasma Concentration (Cmax)

Secondary: Venetoclax Plasma PK: Minimum Plasma Concentration (Cmin) within the Dosing Interval

Secondary: Venetoclax Plasma PK: Minimum Plasma Concentration (Cmin) within the Dosing Interval

Secondary: Prednisone Plasma PK: AUC

Secondary: Prednisone Plasma PK: AUC

Secondary: Prednisone Plasma PK: Tmax

Secondary: Prednisone Plasma PK: Tmax

Secondary: Prednisone Plasma PK: Cmax

Secondary: Prednisone Plasma PK: Cmax

Secondary: Rituximab PK: Cmax

Secondary: Rituximab PK: Cmax

Secondary: Rituximab PK: Cmin within the Dosing Interval

Secondary: Rituximab PK: Cmin within the Dosing Interval

Secondary: Obinutuzumab PK: Cmax

Secondary: Obinutuzumab PK: Cmax

Secondary: Cyclophosphamide PK: Cmax

Secondary: Cyclophosphamide PK: Cmax

Secondary: Doxorubicin PK: Cmax

Secondary: Doxorubicin PK: Cmax

Secondary: Vincristine PK: Cmax

Secondary: Vincristine PK: Cmax

Secondary: Percentage of Participants With Objective Response Defined as Partial Response (PR) or Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET/CT) Using the Modified Lugano Classification assessed by IRC

Secondary: Percentage of Participants With Objective Response Defined as Partial Response (PR) or Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET/CT) Using the Modified Lugano Classification assessed by IRC

Secondary: Percentage of Participants who are Alive and Without Disease Progression at Month 12

Secondary: Percentage of Participants who are Alive and Without Disease Progression at Month 12

Secondary: Percentage of Participants With CR Defined by Computed Tomography (CT) Scan Using the Modified Lugano Classification

Secondary: Percentage of Participants With CR Defined by Computed Tomography (CT) Scan Using the Modified Lugano Classification

Secondary: Safety: Percentage of Participants With Adverse Events

Secondary: Safety: Percentage of Participants With Adverse Events

Secondary: Safety: Percentage of Participants Maintaining Relative Dose Intensity of CHOP Chemotherapy

Secondary: Safety: Percentage of Participants Maintaining Relative Dose Intensity of CHOP Chemotherapy

Secondary: Relative Dose Intensity of Venetoclax

Secondary: Relative Dose Intensity of Venetoclax

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

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