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Clinical Trial Results:
A Phase 1b/2 Study of Safety and Efficacy of MLN0128 (Dual TORC1/2 Inhibitor) in Combination With Exemestane or Fulvestrant Therapy in Postmenopausal Women With ER+/HER2- Advanced or Metastatic Breast Cancer That Has Progressed on Treatment With Everolimus in Combination With Exemestane or Fulvestrant

Summary
EudraCT number	2014-001921-34
Trial protocol	BE FR
Global end of trial date	03 Jul 2018

Results information
Results version number	v2(current)
This version publication date	08 May 2020
First version publication date	14 Jul 2019
Other versions	v1
Version creation reason

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

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Trial information

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Sponsor protocol code

C31001

ISRCTN number

US NCT number

NCT02049957

WHO universal trial number (UTN)

U1111-1195-3894

Sponsor organisation name

Takeda Oncology

Sponsor organisation address

40 Landsdowne Street, Cambridge, United States, 02139

Public contact

Medical Director, Takeda Oncology, +1 8778253327, clinicaltrialregistry@tpna.com

Scientific contact

Medical Director, Takeda Oncology, +1 8778253327, clinicaltrialregistry@tpna.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

03 Jul 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

03 Jul 2018

Was the trial ended prematurely?

Main objective of the trial

Phase 1b - To evaluate the safety and tolerability of MLN0128 in combination with either exemestane or fulvestrant. Phase 2 - To evaluate the antitumor activity by clinical benefit rate (CBR) at 16 weeks (CBR-16 is defined as the proportion of patients who achieve complete response [CR] or partial response of any duration, or have stable disease [SD] at 16 weeks) of treatment with MLN0128 in combination with either exemestane or fulvestrant.

Protection of trial subjects

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

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Feb 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 95

Country: Number of subjects enrolled

France: 16

Country: Number of subjects enrolled

Belgium: 7

Worldwide total number of subjects

118

EEA total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants took part in the study at 40 investigative sites in Belgium, France and the United States from 13 February 2014 to 03 July 2019.

Screening details

Postmenopausal women with estrogen receptor positive/human epidermal growth factor receptor-2 negative advanced/metastatic breast cancer who progressed with everolimus (everolimus sensitive-achieved CR/PR of any duration/stable disease for ≥6 months; resistant-without CR/PR/SD < 6 months) were enrolled to receive MLN0128+exemestane/fulvestrant.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane

Arm description

Sapanisertib 5 mg, unmilled active pharmaceutical ingredient (API) capsule, once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 12 cycles).

Arm type

Experimental

Investigational medicinal product name

Sapanisertib

Investigational medicinal product code

Other name

MLN0128

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Sapanisertib capsules

Investigational medicinal product name

Exemestane

Investigational medicinal product code

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

Exemestane coated tablets

Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant

Arm description

Sapanisertib 5 mg, unmilled API capsule, once daily in a 28-day cycle plus fulvestrant 500 mg, injection, intramuscularly (IM), once on Day 1 of each cycle (Up to 57 cycles).

Arm type

Experimental

Investigational medicinal product name

Sapanisertib

Investigational medicinal product code

Other name

MLN0128

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Sapanisertib capsules

Investigational medicinal product name

Fulvestrant

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Fulvestrant Intramuscular (IM) injection

Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane

Arm description

Sapanisertib 3 mg, milled API capsule, once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 8 cycles).

Arm type

Experimental

Investigational medicinal product name

Sapanisertib

Investigational medicinal product code

Other name

MLN0128

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Sapanisertib capsules

Investigational medicinal product name

Exemestane

Investigational medicinal product code

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

Exemestane coated tablets

Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant

Arm description

Sapanisertib 3 mg, milled API capsule, once daily in a 28-day cycle up to 14 cycles plus fulvestrant 500 mg, injection, IM, once on Day 1 of each cycle (Up to 14 cycles).

Arm type

Experimental

Investigational medicinal product name

Sapanisertib

Investigational medicinal product code

Other name

MLN0128

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Sapanisertib capsules

Investigational medicinal product name

Fulvestrant

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Fulvestrant Intramuscular (IM) injection

Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane

Arm description

Sapanisertib 4 mg, milled API capsule, once daily, in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 18 cycles).

Arm type

Experimental

Investigational medicinal product name

Sapanisertib

Investigational medicinal product code

Other name

MLN0128

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Sapanisertib capsules

Investigational medicinal product name

Exemestane

Investigational medicinal product code

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

Exemestane coated tablets

Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive)

Arm description

Sapanisertib 4 mg, milled API capsule once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 14 cycles) in everolimus sensitive participants.

Arm type

Experimental

Investigational medicinal product name

Sapanisertib

Investigational medicinal product code

Other name

MLN0128

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Sapanisertib capsules

Investigational medicinal product name

Exemestane

Investigational medicinal product code

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

Exemestane coated tablets

Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive)

Arm description

Sapanisertib 4 mg, milled API capsule once daily in a 28-day cycle plus fulvestrant 500 mg, injection IM, once on Day 1 of each cycle (Up to 17 cycles) in everolimus sensitive participants.

Arm type

Experimental

Investigational medicinal product name

Sapanisertib

Investigational medicinal product code

Other name

MLN0128

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Sapanisertib capsules

Investigational medicinal product name

Fulvestrant

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Fulvestrant Intramuscular (IM) injection

Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant)

Arm description

Sapanisertib 4 mg, milled API capsule, once daily, in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 12 cycles) in everolimus resistant participants.

Arm type

Experimental

Investigational medicinal product name

Sapanisertib

Investigational medicinal product code

Other name

MLN0128

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Sapanisertib capsules

Investigational medicinal product name

Exemestane

Investigational medicinal product code

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

Exemestane coated tablets

Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)

Arm description

Sapanisertib 4 mg, milled API capsule, once daily in a 28-day cycle plus fulvestrant 500 mg, injection IM, once on Day 1 of each cycle (Up to 9 cycles) in everolimus resistant participants.

Arm type

Experimental

Investigational medicinal product name

Sapanisertib

Investigational medicinal product code

Other name

MLN0128

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Sapanisertib capsules

Investigational medicinal product name

Fulvestrant

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Fulvestrant Intramuscular (IM) injection

Number of subjects in period 1	Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane	Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant	Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane	Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant	Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane	Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive)	Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive)	Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant)	Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
Started	6	6	3	3	6	43	8	35	8
Completed	0	0	0	0	0	0	0	0	0
Not completed	6	6	3	3	6	43	8	35	8
Consent withdrawn by subject	-	-	-	1	-	2	-	3	1
Physician decision	-	-	-	-	-	1	-	-	-
Adverse event, non-fatal	1	1	1	-	-	5	-	6	1
Progressive Disease	5	4	2	2	6	35	7	26	6
Study Terminated by Sponsor	-	1	-	-	-	-	1	-	-

Baseline characteristics

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Reporting group title

Overall Study

Reporting group description

All enrolled participants

Reporting group values	Overall Study	Total
Number of subjects	118	118
Age categorical
Units: Subjects
Adults (18-64 years)	83	83
From 65-84 years	35	35
Age Continuous
Units: years
arithmetic mean (full range (min-max))	57.31 (32 to 83)	-
Sex: Female, Male
9999 = Data for this arm group is available in subject analysis set 'Phase 1 (Part 2): Sapanisertib 3 mg QD+Exemestane/Fulvestrant'.
Units: Subjects
Female	118	118
Male	0	0
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	4	4
Not Hispanic or Latino	103	103
Unknown or Not Reported	11	11
Race/Ethnicity, Customized
Units: Subjects
White	98	98
Not Reported	6	6
Black or African American	7	7
Asian	4	4
Other	3	3
Region of Enrollment
Units: Subjects
United States	95	95
Belgium	16	16
France	7	7
Height
Number analyzed is the number of participants with data available for height.
Units: cm
arithmetic mean (full range (min-max))	165.02 (150 to 183)	-
Weight
Number analyzed is the number of participants with data available for weight.
Units: kg
arithmetic mean (full range (min-max))	70.37 (46.5 to 139)	-

End points

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Reporting group title

Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane

Reporting group description

Sapanisertib 5 mg, unmilled active pharmaceutical ingredient (API) capsule, once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 12 cycles).

Reporting group title

Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant

Reporting group description

Sapanisertib 5 mg, unmilled API capsule, once daily in a 28-day cycle plus fulvestrant 500 mg, injection, intramuscularly (IM), once on Day 1 of each cycle (Up to 57 cycles).

Reporting group title

Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane

Reporting group description

Sapanisertib 3 mg, milled API capsule, once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 8 cycles).

Reporting group title

Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant

Reporting group description

Sapanisertib 3 mg, milled API capsule, once daily in a 28-day cycle up to 14 cycles plus fulvestrant 500 mg, injection, IM, once on Day 1 of each cycle (Up to 14 cycles).

Reporting group title

Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane

Reporting group description

Sapanisertib 4 mg, milled API capsule, once daily, in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 18 cycles).

Reporting group title

Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive)

Reporting group description

Sapanisertib 4 mg, milled API capsule once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 14 cycles) in everolimus sensitive participants.

Reporting group title

Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive)

Reporting group description

Sapanisertib 4 mg, milled API capsule once daily in a 28-day cycle plus fulvestrant 500 mg, injection IM, once on Day 1 of each cycle (Up to 17 cycles) in everolimus sensitive participants.

Reporting group title

Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant)

Reporting group description

Sapanisertib 4 mg, milled API capsule, once daily, in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 12 cycles) in everolimus resistant participants.

Reporting group title

Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)

Reporting group description

Sapanisertib 4 mg, milled API capsule, once daily in a 28-day cycle plus fulvestrant 500 mg, injection IM, once on Day 1 of each cycle (Up to 9 cycles) in everolimus resistant participants.

Primary: Phase 1: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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End point title

Phase 1: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) ^[1] ^[2]

End point description

An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product whether or not it is related to the medicinal product. This includes any newly occurring event, or a previous condition that has increased in severity or frequency since the administration of study drug. A SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. Relationship of each AE to study drug will be determined by the Investigator. Safety Population included participants who received at least 1 dose of any study drug.

End point type

Primary

End point timeframe

First dose of study drug through 30 days after the last dose (Up to 52 months)

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: This endpoint was performed in Phase 1 of the study.
[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: This endpoint was performed in Phase 1 of the study.

End point values	Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane	Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant	Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane	Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant	Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane
Number of subjects analysed	6	6	3	3	6
Units: participants
Any AE	6	6	3	3	6
SAEs	1	2	0	0	2

No statistical analyses for this end point

Primary: Phase 2: Clinical Benefit Rate at 16 Weeks (CBR-16)

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End point title

Phase 2: Clinical Benefit Rate at 16 Weeks (CBR-16) ^[3] ^[4]

End point description

CBR-16 was defined as the percentage of participants who achieved confirmed complete response (CR) or partial response (PR) of any duration or had confirmed stable disease (SD) as best response and the first 2 or more post baseline scans had PR/SD and the duration of SD was >112 days. Disease response was assessed for target lesions by computed tomography (CT) or magnetic resonance imaging (MRI) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. CR is disappearance of all target lesions. PR is >=30% decrease in the sum of the longest diameter of target lesions. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression (PD). Response-Evaluable Population included participants who received at least 1 dose of study drug and had measurable disease at baseline.

End point type

Primary

End point timeframe

Week 16

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: This endpoint was performed in Phase 2 of the study.
[4] - 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: This endpoint was performed in Phase 2 of the study.

End point values	Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive)	Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive)	Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant)	Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
Number of subjects analysed	43	8	35	8
Units: percentage of participants
number (confidence interval 95%)	44 (29.1 to 60.1)	50 (15.7 to 84.3)	23 (10.4 to 40.1)	25 (3.2 to 65.1)

No statistical analyses for this end point

Secondary: Phase 2: Clinical Benefit Rate at 24 Weeks (CBR-24)

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End point title

Phase 2: Clinical Benefit Rate at 24 Weeks (CBR-24) ^[5]

End point description

CBR-24 was defined as the percentage of participants who achieved confirmed CR or PR at any time or had confirmed SD as best response and the first 2 or more post baseline scans had PR/SD and the duration of stable disease was >168 days. Disease response was assessed for target lesions by CT or MRI according to RECIST version 1.1 guidelines. CR is disappearance of all target lesions. PR is >=30% decrease in the sum of the longest diameter of target lesions. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Response-Evaluable Population included participants who received at least 1 dose of study drug and had measurable disease at baseline.

End point type

Secondary

End point timeframe

Week 24

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: This endpoint was performed in Phase 2 of the study.

End point values	Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive)	Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive)	Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant)	Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
Number of subjects analysed	43	8	35	8
Units: percentage of participants
number (confidence interval 95%)	28 (15.3 to 43.7)	38 (8.5 to 75.5)	23 (10.4 to 40.1)	25 (3.2 to 65.1)

No statistical analyses for this end point

Secondary: Phase 2: Overall Response Rate (ORR)

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End point title

Phase 2: Overall Response Rate (ORR) ^[6]

End point description

ORR is defined as the percentage of participants with confirmed CR or PR as per RECIST version1.1 guidelines. CR is disappearance of all target lesions. PR is >=30% decrease in the sum of the longest diameter of target lesions. Response-Evaluable Population included participants who received at least 1 dose of study drug and had measurable disease at baseline.

End point type

Secondary

End point timeframe

Baseline then every 2 cycles from Cycles 2 through 6, and every 3 cycles thereafter in a 28-day cycle up to End of Treatment (EOT) (Up to 24 months)

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: This endpoint was performed in Phase 2 of the study.

End point values	Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive)	Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive)	Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant)	Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
Number of subjects analysed	43	8	35	8
Units: percentage of participants
number (confidence interval 95%)	7 (1.5 to 19.1)	13 (1 to 52.7)	0 (0 to 0)	13 (1 to 52.7)

No statistical analyses for this end point

Secondary: Phase 2: Progression-Free Survival (PFS)

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End point title

Phase 2: Progression-Free Survival (PFS) ^[7]

End point description

PFS is defined as the time in months from the date of first dose of study treatment to the date of the first documented disease progression or death. Disease progression was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; or the appearance of one or more new lesions. Safety Population included participants who received at least 1 dose of study drug. For a participant whose disease had not progressed and was last known to be alive, PFS was censored at the last response assessment that was stable disease or better. 99999: Upper limit of Confidence Interval (CI) was not reached due to low number of participants with events.

End point type

Secondary

End point timeframe

Baseline then every 2 cycles from Cycles 2 through 6, and every 3 cycles thereafter in a 28-day cycle, then every 3 months after EOT until disease progression or death (Up to 24 months)

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: This endpoint was performed in Phase 2 of the study.

End point values	Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive)	Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive)	Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant)	Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
Number of subjects analysed	43	8	35	8
Units: months
median (confidence interval 95%)	4.1 (1.9 to 5.5)	5.5 (1.8 to 99999)	3.3 (1.9 to 3.7)	5.4 (1.7 to 8.3)

No statistical analyses for this end point

Secondary: Phase 2: Overall Survival (OS)

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End point title

Phase 2: Overall Survival (OS) ^[8]

End point description

OS is the time in months from start of study treatment to date of death due to any cause. Data for the analysis of OS included the censored data at the timepoint that the participant was last known to be alive. Safety Population included participants who received at least 1 dose of study drug. Participants without documentation of death at the time of analysis were censored at the date last known to be alive.

End point type

Secondary

End point timeframe

Up to 24 months

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: This endpoint was performed in Phase 2 of the study.

End point values	Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive)	Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive)	Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant)	Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
Number of subjects analysed	43	8	35	8
Units: months
median (confidence interval 95%)	15.9 (14.1 to 19.5)	20.7 (8.6 to 20.7)	14.0 (10.6 to 16.0)	13.0 (4.1 to 21.3)

No statistical analyses for this end point

Secondary: Phase 2: Best Percent Change from Baseline in Tumor Size

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End point title

Phase 2: Best Percent Change from Baseline in Tumor Size ^[9]

End point description

Participants from Safety Population included participants who received at least 1 dose of study drug and provided both baseline and at least one post-baseline disease response.

End point type

Secondary

End point timeframe

Baseline to Month 24

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: This endpoint was performed in Phase 2 of the study.

End point values	Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive)	Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive)	Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant)	Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
Number of subjects analysed	36	7	27	7
Units: percentage change in tumor size
arithmetic mean (standard deviation)	-0.46 ± 34.89	0.96 ± 38.98	1.76 ± 31.14	-18.91 ± 19.71

No statistical analyses for this end point

Secondary: Phase1: Cmax: Maximum Observed Plasma Concentration for Sapanisertib

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End point title

Phase1: Cmax: Maximum Observed Plasma Concentration for Sapanisertib ^[10]

End point description

Pharmacokinetic (PK) Population included participants with sufficient dosing and PK data to reliably estimate PK parameters. PK data was not available for Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant arm group at Cycle 1 Day 15. n= number analyzed is the number of participants with data available for analyses at the given timepoint.

End point type

Secondary

End point timeframe

Cycle 1 Day 15 and Cycle 2 Day 1 pre-dose and multiple timepoints (Up to 8 hours) post-dose

Notes
[10] - 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: This endpoint was performed in Phase 1 of the study.

End point values	Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane	Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant	Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane	Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant	Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane
Number of subjects analysed	6	5	3	3	6
Units: ng/mL
arithmetic mean (standard deviation)
Cycle 1 Day 15 (n=6,0,3,2,6)	57.72 ± 9.927	9999 ± 9999	47.40 ± 6.583	50.90 ± 23.476	45.37 ± 9.644
Cycle 2 Day 1 (n=5,5,3,3,5)	38.68 ± 20.551	44.96 ± 34.459	43.47 ± 0.874	45.30 ± 16.235	44.68 ± 8.636

No statistical analyses for this end point

Secondary: Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Sapanisertib

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End point title

Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Sapanisertib ^[11]

End point description

PK Population included participants with sufficient dosing and PK data to reliably estimate PK parameters. PK data was not available for Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant arm group at Cycle 1 Day 15. n=number analyzed is the number of participants with data available for analyses at the given timepoint.

End point type

Secondary

End point timeframe

Cycle 1 Day 15 and Cycle 2 Day 1 pre-dose and multiple timepoints (Up to 8 hours) post-dose

Notes
[11] - 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: This endpoint was performed in Phase 1 of the study.

End point values	Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane	Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant	Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane	Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant	Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane
Number of subjects analysed	6	5	3	3	6
Units: hour
median (full range (min-max))
Cycle 1 Day 15 (n=6,0,3,2,6)	3.005 (0.58 to 7.30)	9999 (9999 to 9999)	0.600 (0.45 to 1.00)	1.035 (1.00 to 1.07)	2.000 (0.50 to 3.55)
Cycle 2 Day 1 (n=5,5,3,3,5)	2.280 (0.85 to 3.58)	3.500 (0.92 to 4.03)	0.980 (0.68 to 1.00)	1.000 (0.48 to 1.12)	2.000 (0.50 to 3.77)

No statistical analyses for this end point

Secondary: Phase 1: AUC(0-24): Area under the Plasma Concentration-time Curve from Time 0 to Time 24 Hours, Calculated using the Observed Value of the Last Quantifiable Concentration Over the Dosing Interval for Sapanisertib

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End point title

Phase 1: AUC(0-24): Area under the Plasma Concentration-time Curve from Time 0 to Time 24 Hours, Calculated using the Observed Value of the Last Quantifiable Concentration Over the Dosing Interval for Sapanisertib ^[12]

End point description

AUC(0-24) is the area under the plasma concentration-time curve of the samples collected up to 8 hours and extrapolated up to 24 hours. Participants from PK Population included participants with sufficient dosing and PK data to reliably estimate PK parameters. PK data was not available for Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant arm group at Cycle 1 Day 15. Number analyzed is the number of participants with data available for analyses at the given timepoint.

End point type

Secondary

End point timeframe

Cycle 1 Day 15 pre-dose and multiple timepoints (Up to 8 hours) post-dose, extrapolated to 24 hours post-dose

Notes
[12] - 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: This endpoint was performed in Phase 1 of the study.

End point values	Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane	Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant	Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane	Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant	Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane
Number of subjects analysed	6	0 ^[13]	3	2	5
Units: h*ng/mL
arithmetic mean (standard deviation)	577.081 ± 331.9813	±	178.063 ± 46.1416	332.618 ± 228.5641	277.626 ± 64.0661

Notes
[13] - PK data was not available at Cycle 1 Day 15.

No statistical analyses for this end point

Secondary: Phase 1: AUC(0-last): Area under the Plasma Concentration-time Curve from Time 0 to Time tau Over the Dosing Interval for MLN0128

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End point title

Phase 1: AUC(0-last): Area under the Plasma Concentration-time Curve from Time 0 to Time tau Over the Dosing Interval for MLN0128 ^[14]

End point description

AUC(0-last) is the area under the plasma concentration-time curve of the samples collected up to 8 hours and extrapolated up to last time point. PK Population included participants with sufficient dosing and PK data to reliably estimate PK parameters. PK data was not available for Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant arm group at Cycle 1 Day 15. n=number analyzed is the number of participants with data available for analyses at the given timepoint.

End point type

Secondary

End point timeframe

Cycle 1 Day 15 pre-dose and multiple timepoints (Up to 8 hours) post-dose, extrapolated to last timepoint

Notes
[14] - 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: This endpoint was performed in Phase 1 of the study.

End point values	Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane	Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant	Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane	Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant	Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane
Number of subjects analysed	6	5	3	3	6
Units: h*ng/mL
arithmetic mean (standard deviation)
Cycle 1 Day 15 (n=6,0,3,2,6)	577.081 ± 331.9813	9999 ± 9999	164.123 ± 52.6287	332.618 ± 228.5641	251.165 ± 83.7121
Cycle 1 Day 2 (n=5,5,3,3,5)	101.599 ± 51.0248	109.496 ± 82.3968	89.576 ± 15.0117	109.548 ± 52.8500	116.557 ± 8.6059

No statistical analyses for this end point

Secondary: Phase 1: Terminal Elimination Half-life (T1/2) for Sapanisertib

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End point title

Phase 1: Terminal Elimination Half-life (T1/2) for Sapanisertib ^[15]

End point description

Participants from PK Population, participants with sufficient dosing and PK data to reliably estimate PK parameters. PK data was not available for Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant arm group at Cycle 1 Day 15.

End point type

Secondary

End point timeframe

Cycle 1 Day 15 pre-dose and multiple timepoints (Up to 8 hours) post-dose

Notes
[15] - 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: This endpoint was performed in Phase 1 of the study.

End point values	Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane	Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant	Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane	Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant	Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane
Number of subjects analysed	2	0 ^[16]	3	2	4
Units: hour
arithmetic mean (standard deviation)	6.639 ± 1.2176	±	3.161 ± 1.6585	7.777 ± 2.9177	5.370 ± 1.4638

Notes
[16] - PK data was not available at Cycle 1 Day 15.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

First dose up to 30 days post last dose of study drug (Up to 52 months)

Adverse event reporting additional description

At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane

Reporting group description

Sapanisertib 5 mg, unmilled active pharmaceutical ingredient (API) capsule, once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 12 cycles).

Reporting group title

Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant

Reporting group description

Sapanisertib 5 mg, unmilled API capsule, once daily in a 28-day cycle plus fulvestrant 500 mg, injection, intramuscularly (IM), once on Day 1 of each cycle (Up to 57 cycles).

Reporting group title

Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane

Reporting group description

Sapanisertib 3 mg, milled API capsule, once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 8 cycles).

Reporting group title

Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant

Reporting group description

Sapanisertib 3 mg, milled API capsule, once daily in a 28-day cycle up to 14 cycles plus fulvestrant 500 mg, injection, IM, once on Day 1 of each cycle (Up to 14 cycles).

Reporting group title

Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane

Reporting group description

Sapanisertib 4 mg, milled API capsule, once daily, in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 18 cycles).

Reporting group title

Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive)

Reporting group description

Sapanisertib 4 mg, milled API capsule once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 14 cycles) in everolimus sensitive participants.

Reporting group title

Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant)

Reporting group description

Sapanisertib 4 mg, milled API capsule, once daily, in a 28-day cycle plus fulvestrant 500 mg, injection IM, once on Day 1 of each cycle (Up to 12 cycles) in everolimus resistant participants.

Reporting group title

Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive)

Reporting group description

Sapanisertib 4 mg, milled API capsule once daily in a 28-day cycle plus fulvestrant 500 mg, injection IM, once on Day 1 of each cycle (Up to 17 cycles) in everolimus sensitive participants.

Reporting group title

Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)

Reporting group description

Sapanisertib 4 mg, milled API capsule, once daily in a 28-day cycle plus fulvestrant 500 mg, injection IM, once on Day 1 of each cycle (Up to 9 cycles) in everolimus resistant participants.

Serious adverse events	Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane	Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant	Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane	Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant	Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane	Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive)	Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant)	Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive)	Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	11 / 43 (25.58%)	5 / 35 (14.29%)	3 / 8 (37.50%)	2 / 8 (25.00%)
number of deaths (all causes)	0	0	0	0	1	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer metastatic
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	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
Cancer pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Generalised oedema
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Pulmonary embolism
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Mental status changes
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Investigations
Clostridium test positive
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Alcohol poisoning
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Ataxia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoaesthesia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Diplopia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	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
Gastritis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences causally related to treatment / all	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
Nausea
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences causally related to treatment / all	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
Hepatobiliary disorders
Hepatic failure
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Pain in extremity
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 43 (4.65%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	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
Infections and infestations
Pneumonia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	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 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	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
Viral infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast cellulitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (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
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	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

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	Phase 1 (Part 1): Sapanisertib 5 mg + Exemestane	Phase 1 (Part 1): Sapanisertib 5 mg + Fulvestrant	Phase 1 (Part 2): Sapanisertib 3 mg + Exemestane	Phase 1 (Part 2): Sapanisertib 3 mg + Fulvestrant	Phase 1 (Part 2): Sapanisertib 4 mg + Exemestane	Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Sensitive)	Phase 2: Sapanisertib 4 mg + Exemestane (Everolimus Resistant)	Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Sensitive)	Phase 2: Sapanisertib 4 mg+Fulvestrant (Everolimus Resistant)
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 6 (100.00%)	6 / 6 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	6 / 6 (100.00%)	43 / 43 (100.00%)	35 / 35 (100.00%)	8 / 8 (100.00%)	8 / 8 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Seborrhoeic keratosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Tumour pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Vascular disorders
Hot flush
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	2 / 43 (4.65%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	2	0	1	0	3	0	0	0
Hypotension
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	1 / 35 (2.86%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	2	0	0	0	1	1	1	0
Hypertension
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 43 (6.98%)	4 / 35 (11.43%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	7	5	0	0
Flushing
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Lymphoedema
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Thrombophlebitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Venous thrombosis limb
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	4 / 6 (66.67%)	6 / 6 (100.00%)	1 / 3 (33.33%)	3 / 3 (100.00%)	4 / 6 (66.67%)	19 / 43 (44.19%)	16 / 35 (45.71%)	6 / 8 (75.00%)	2 / 8 (25.00%)
occurrences all number	7	6	1	3	4	30	16	6	2
Pyrexia
subjects affected / exposed	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 43 (6.98%)	3 / 35 (8.57%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	2	0	0	0	3	3	0	0
Injection site pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Injection site rash
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Non-cardiac chest pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	2 / 35 (5.71%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	2	0	0
Oedema peripheral
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1	0	0	0	1	0	0	1
Asthenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 43 (6.98%)	4 / 35 (11.43%)	1 / 8 (12.50%)	2 / 8 (25.00%)
occurrences all number	0	0	0	0	0	5	4	1	2
Chest pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 43 (6.98%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	4	0	0	0
Influenza like illness
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	2 / 35 (5.71%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0
Peripheral swelling
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	1	0	1
Gait disturbance
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	3	0	0	0
General physical health deterioration
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Malaise
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	5	0	0	0
Pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Immune system disorders
Contrast media allergy
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Reproductive system and breast disorders
Breast pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 43 (6.98%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	3	0	0	0
Vulvovaginal dryness
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 43 (4.65%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	3	0	0	0
Genital rash
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Pelvic pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 6 (16.67%)	3 / 6 (50.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	8 / 43 (18.60%)	2 / 35 (5.71%)	2 / 8 (25.00%)	0 / 8 (0.00%)
occurrences all number	1	4	0	0	1	11	2	2	0
Cough
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	7 / 43 (16.28%)	4 / 35 (11.43%)	3 / 8 (37.50%)	2 / 8 (25.00%)
occurrences all number	1	1	0	0	1	9	4	4	2
Hypoxia
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0
Nasal congestion
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 43 (4.65%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	1	2	1	0	0
Atelectasis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Dysphonia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1	0	0	0	0	1	0	1
Pleural effusion
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 43 (2.33%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	1	1	0	0
Pleurisy
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Rhinorrhoea
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 43 (4.65%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	2	0	0	0
Sleep apnoea syndrome
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Wheezing
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Epistaxis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	2 / 35 (5.71%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	2	0	0
Sinus congestion
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	2 / 35 (5.71%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0
Upper-airway cough syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0
Dyspnoea exertional
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Nasal dryness
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Pleuritic pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Productive cough
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Pulmonary embolism
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Respiration abnormal
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	3 / 43 (6.98%)	3 / 35 (8.57%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	1	3	4	1	0
Insomnia
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	2	0	0	0	3	0	0	0
Confusional state
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1	0	0	0	0	1	0	1
Dysphoria
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Stress
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Depression
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 43 (4.65%)	2 / 35 (5.71%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	2	2	0	0
Irritability
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	1	0	1
Hallucination
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Hallucinations, mixed
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Initial insomnia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Panic attack
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Product issues
Thrombosis in device
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Investigations
Weight decreased
subjects affected / exposed	2 / 6 (33.33%)	2 / 6 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 6 (50.00%)	6 / 43 (13.95%)	4 / 35 (11.43%)	2 / 8 (25.00%)	0 / 8 (0.00%)
occurrences all number	2	2	0	2	3	8	5	2	0
Aspartate aminotransferase increased
subjects affected / exposed	2 / 6 (33.33%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	6 / 43 (13.95%)	5 / 35 (14.29%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	2	1	0	0	0	8	6	0	2
Alanine aminotransferase increased
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 43 (4.65%)	4 / 35 (11.43%)	0 / 8 (0.00%)	2 / 8 (25.00%)
occurrences all number	2	0	0	0	0	2	5	0	3
Amylase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	1 / 43 (2.33%)	2 / 35 (5.71%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	1	1	1	3	0	1
Blood creatinine increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	3 / 43 (6.98%)	6 / 35 (17.14%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	1	0	3	7	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 6 (16.67%)	4 / 43 (9.30%)	1 / 35 (2.86%)	0 / 8 (0.00%)	2 / 8 (25.00%)
occurrences all number	0	0	1	0	1	4	2	0	2
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 43 (9.30%)	2 / 35 (5.71%)	0 / 8 (0.00%)	2 / 8 (25.00%)
occurrences all number	1	0	0	0	0	5	2	0	2
Blood cholesterol increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	3 / 43 (6.98%)	2 / 35 (5.71%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	1	3	2	0	1
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0	0
Electrocardiogram QT prolonged
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Glycosylated haemoglobin increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	3 / 43 (6.98%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0	3	1	0	0
International normalised ratio increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	1 / 35 (2.86%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	1	2	1	0
White blood cells urine positive
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Lymphocyte count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 43 (9.30%)	2 / 35 (5.71%)	0 / 8 (0.00%)	2 / 8 (25.00%)
occurrences all number	0	0	0	0	0	9	2	0	2
White blood cell count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 43 (9.30%)	1 / 35 (2.86%)	1 / 8 (12.50%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	6	1	1	1
Neutrophil count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 43 (9.30%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	5	0	1	0
Blood phosphorus increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 43 (4.65%)	1 / 35 (2.86%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	2	1	0	1
Blood phosphorus decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 43 (6.98%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	3	0	0	0
Blood triglycerides increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	2 / 35 (5.71%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	2	0	0
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0
Blood urea increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0
Amylase decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Blood albumin decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Blood calcium increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Blood glucose increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	4	0	0
Blood potassium increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Blood sodium decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Haemoglobin decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
International normalised ratio decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Low density lipoprotein increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Platelet count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Protein total increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Protein urine
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Transaminases increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Injury, poisoning and procedural complications
Upper limb fracture
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0	0
Humerus fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Rib fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0
Contusion
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	1	0
Animal bite
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Fall
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Procedural nausea
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Procedural pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Spinal compression fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Thoracic vertebral fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 43 (6.98%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	3	1	0	0
Tachycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 43 (4.65%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Atrial fibrillation
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Sinus tachycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Tachyarrhythmia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Nervous system disorders
Dysgeusia
subjects affected / exposed	3 / 6 (50.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	8 / 43 (18.60%)	4 / 35 (11.43%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	4	1	0	0	0	9	4	0	0
Dizziness
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	7 / 43 (16.28%)	3 / 35 (8.57%)	2 / 8 (25.00%)	0 / 8 (0.00%)
occurrences all number	1	1	0	0	1	11	3	3	0
Headache
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	11 / 43 (25.58%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	2	0	0	0	1	13	0	1	0
Tremor
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	5 / 43 (11.63%)	1 / 35 (2.86%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	1	1	0	0	1	6	2	1	0
Paraesthesia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	2	0	1	0	0	0	0	0	0
Ataxia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Disturbance in attention
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Hyperaesthesia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Hypoaesthesia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Restless legs syndrome
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Serotonin syndrome
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
VIth nerve paralysis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Cognitive disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 43 (4.65%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Ageusia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Dystonia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Hypoglossal nerve disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Neuropathy peripheral
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Sciatica
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	6 / 43 (13.95%)	6 / 35 (17.14%)	0 / 8 (0.00%)	2 / 8 (25.00%)
occurrences all number	0	0	0	0	1	8	8	0	2
Leukocytosis
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Lymphopenia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0
Thrombocytopenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	2 / 35 (5.71%)	2 / 8 (25.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	2	2	1
Eosinophilia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0
Lymphadenopathy
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 43 (4.65%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Leukopenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Ear and labyrinth disorders
Deafness neurosensory
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Ear pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Tinnitus
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Eye disorders
Cataract
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Diplopia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Dry eye
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	2 / 43 (4.65%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0	3	0	1	0
Eye pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	1	0
Vision blurred
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	1 / 35 (2.86%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	2	1	1	0
Visual impairment
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 43 (4.65%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Vitreous floaters
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0
Conjunctival haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Retinal scar
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	3 / 6 (50.00%)	5 / 6 (83.33%)	2 / 3 (66.67%)	2 / 3 (66.67%)	4 / 6 (66.67%)	17 / 43 (39.53%)	9 / 35 (25.71%)	3 / 8 (37.50%)	6 / 8 (75.00%)
occurrences all number	5	11	2	4	5	27	10	3	9
Nausea
subjects affected / exposed	6 / 6 (100.00%)	4 / 6 (66.67%)	1 / 3 (33.33%)	2 / 3 (66.67%)	3 / 6 (50.00%)	23 / 43 (53.49%)	15 / 35 (42.86%)	7 / 8 (87.50%)	4 / 8 (50.00%)
occurrences all number	7	5	1	2	5	29	21	8	5
Stomatitis
subjects affected / exposed	5 / 6 (83.33%)	3 / 6 (50.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	10 / 43 (23.26%)	8 / 35 (22.86%)	3 / 8 (37.50%)	2 / 8 (25.00%)
occurrences all number	10	5	0	0	3	11	11	3	2
Vomiting
subjects affected / exposed	1 / 6 (16.67%)	2 / 6 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 6 (50.00%)	10 / 43 (23.26%)	10 / 35 (28.57%)	1 / 8 (12.50%)	5 / 8 (62.50%)
occurrences all number	1	2	2	0	4	13	13	2	7
Constipation
subjects affected / exposed	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	6 / 43 (13.95%)	5 / 35 (14.29%)	1 / 8 (12.50%)	2 / 8 (25.00%)
occurrences all number	1	2	0	1	1	7	5	1	2
Abdominal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 6 (16.67%)	5 / 43 (11.63%)	2 / 35 (5.71%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	2	0	1	5	2	1	0
Toothache
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	2 / 35 (5.71%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	2	0	0	0	1	2	0	1
Dyspepsia
subjects affected / exposed	2 / 6 (33.33%)	1 / 6 (16.67%)	3 / 3 (100.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 43 (9.30%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	2	1	3	0	0	4	1	0	0
Abdominal distension
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1	0	0	1	0	0	0	1
Dysphagia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 43 (4.65%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	2	0	0	0
Flatulence
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	2 / 43 (4.65%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0	3	0	0	0
Gastroesophageal reflux disease
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 43 (2.33%)	2 / 35 (5.71%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0	1	2	0	0
Gingival pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Glossodynia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Mouth ulceration
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0	0
Dry mouth
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	7 / 43 (16.28%)	3 / 35 (8.57%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	7	3	0	0
Abdominal pain upper
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 43 (4.65%)	1 / 35 (2.86%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	2	1	1	0
Abdominal discomfort
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Colitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Eructation
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Gastrointestinal disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Lip dry
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	3 / 6 (50.00%)	3 / 6 (50.00%)	1 / 3 (33.33%)	3 / 3 (100.00%)	3 / 6 (50.00%)	11 / 43 (25.58%)	6 / 35 (17.14%)	1 / 8 (12.50%)	1 / 8 (12.50%)
occurrences all number	4	3	1	4	3	14	8	1	1
Rash maculo-papular
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 6 (33.33%)	5 / 43 (11.63%)	3 / 35 (8.57%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	8	1	1	1	6	6	3	1	0
Rash pruritic
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	1	0	0	1	0	1	0	0
Rash
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	4 / 35 (11.43%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	2	0	0	0	1	5	0	0
Rash macular
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	2	0	0	1	0	0	0	0
Acne
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	3 / 43 (6.98%)	1 / 35 (2.86%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	1	0	4	1	0	1
Dermatitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Dermatitis acneiform
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	4 / 43 (9.30%)	1 / 35 (2.86%)	1 / 8 (12.50%)	1 / 8 (12.50%)
occurrences all number	0	0	0	1	0	5	1	1	1
Drug reaction with eosinophilia and systemic symptoms
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Dry skin
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 43 (6.98%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	3	1	0	0
Ingrowing nail
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Night sweats
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	1	0	0	0	0	0	0	1
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Pruritus generalised
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	2 / 35 (5.71%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	1	2	0	0
Psoriasis
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Rash papular
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	0	1	0	4	0
Skin exfoliation
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Skin irritation
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	0
Skin ulcer
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Alopecia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 43 (4.65%)	2 / 35 (5.71%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	3	2	0	0
Erythema
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	2	0	0
Nail ridging
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	2 / 35 (5.71%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0
Onychoclasis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 43 (4.65%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Skin lesion
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0
Urticaria
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0
Decubitus ulcer
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Ecchymosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Eczema
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Pain of skin
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Rash erythematous
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Skin hyperpigmentation
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Swelling face
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Renal and urinary disorders
Proteinuria
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	1	0	0	0	1	0	0	0
Acute kidney injury
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Dysuria
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	1	1	0
Haematuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 43 (2.33%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	1	1	0	0
Oliguria
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Pollakiuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	1 / 35 (2.86%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	1	1	0	1
Azotaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Chronic kidney disease
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Leukocyturia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Micturition urgency
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Urinary incontinence
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Urinary tract pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Endocrine disorders
Thyroid disorder
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 6 (33.33%)	1 / 6 (16.67%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 43 (6.98%)	2 / 35 (5.71%)	2 / 8 (25.00%)	1 / 8 (12.50%)
occurrences all number	2	2	2	0	0	3	2	2	1
Pain in extremity
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 43 (4.65%)	1 / 35 (2.86%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	2	1	0	1	2	1	0	1
Joint swelling
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0
Muscle spasms
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	1	1	0	1	0	0
Myalgia
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 43 (6.98%)	1 / 35 (2.86%)	0 / 8 (0.00%)	2 / 8 (25.00%)
occurrences all number	2	0	0	0	0	3	1	0	2
Back pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	8 / 43 (18.60%)	4 / 35 (11.43%)	0 / 8 (0.00%)	2 / 8 (25.00%)
occurrences all number	1	0	0	0	0	12	5	0	2
Muscle fatigue
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	3 / 43 (6.98%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	1	3	0	0	0
Neck pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 43 (4.65%)	2 / 35 (5.71%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	1	0	0	0	0	2	2	0	1
Osteonecrosis of jaw
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	1	0	0
Osteopenia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Pain in jaw
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	1	2	0	0
Musculoskeletal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	6 / 43 (13.95%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	6	0	0	0
Bone pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	1 / 35 (2.86%)	1 / 8 (12.50%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	1	1	1	1
Muscular weakness
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	2	2	0	0
Bursitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Flank pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Joint range of motion decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Joint stiffness
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Muscle twitching
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Musculoskeletal stiffness
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Pathological fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Synovial cyst
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0
Tenosynovitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Infections and infestations
Urinary tract infection
subjects affected / exposed	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	7 / 43 (16.28%)	5 / 35 (14.29%)	3 / 8 (37.50%)	1 / 8 (12.50%)
occurrences all number	2	0	0	0	1	8	5	3	1
Rhinitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Sinusitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0	0
Skin infection
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	1	0	1	0	0	1
Oral candidiasis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0
Tooth infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0
Arthritis infective
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Bacteraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Bacterial infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Bronchitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Catheter site infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Diverticulitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Fungal infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Fungal skin infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Hepatic infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Otitis media
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Pharyngitis streptococcal
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	0	0	0	1
Rash pustular
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	3	0	0	0
Respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Sphingomonas paucimobilis infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Streptococcal infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Vulvovaginal candidiasis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Vulvovaginal mycotic infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 6 (33.33%)	3 / 6 (50.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 6 (16.67%)	16 / 43 (37.21%)	9 / 35 (25.71%)	1 / 8 (12.50%)	2 / 8 (25.00%)
occurrences all number	2	4	1	2	1	19	10	1	2
Hyperglycaemia
subjects affected / exposed	3 / 6 (50.00%)	4 / 6 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	11 / 43 (25.58%)	16 / 35 (45.71%)	0 / 8 (0.00%)	4 / 8 (50.00%)
occurrences all number	3	5	0	0	2	25	29	0	8
Dehydration
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 43 (6.98%)	3 / 35 (8.57%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	2	1	0	0	0	3	4	0	0
Hypercholesterolaemia
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	3 / 35 (8.57%)	1 / 8 (12.50%)	1 / 8 (12.50%)
occurrences all number	0	2	0	0	0	1	3	1	1
Hypokalaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	7 / 43 (16.28%)	1 / 35 (2.86%)	1 / 8 (12.50%)	1 / 8 (12.50%)
occurrences all number	0	1	0	0	1	8	1	1	1
Hypophosphataemia
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 43 (6.98%)	1 / 35 (2.86%)	1 / 8 (12.50%)	0 / 8 (0.00%)
occurrences all number	1	1	0	0	0	3	1	1	0
Hypercalcaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	1	1	0	0
Hyperlipidaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0
Hyponatraemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	3 / 35 (8.57%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	1	0	0	0	0	0	4	0	0
Lactic acidosis
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 43 (0.00%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Hypomagnesaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 43 (6.98%)	3 / 35 (8.57%)	0 / 8 (0.00%)	3 / 8 (37.50%)
occurrences all number	0	0	0	0	0	3	3	0	3
Hypertriglyceridaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 43 (6.98%)	2 / 35 (5.71%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	3	2	0	1
Hypoalbuminaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 43 (6.98%)	1 / 35 (2.86%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	4	1	0	1
Hyperkalaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	3 / 35 (8.57%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	2	3	0	0
Hypernatraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 43 (4.65%)	1 / 35 (2.86%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	2	1	0	0
Hyperuricaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	1 / 35 (2.86%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	1	1	0	1
Hypoglycaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	1 / 35 (2.86%)	0 / 8 (0.00%)	1 / 8 (12.50%)
occurrences all number	0	0	0	0	0	1	2	0	1
Hypocalcaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 43 (4.65%)	1 / 35 (2.86%)	0 / 8 (0.00%)	2 / 8 (25.00%)
occurrences all number	0	0	0	0	0	2	2	0	3
Food intolerance
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Hypermagnesaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Vitamin D deficiency
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 43 (2.33%)	0 / 35 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0

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Were there any global substantial amendments to the protocol? Yes

16 Jun 2014

• The primary purpose of this amendment was to expand the number of investigative sites to include sites in the US, Belgium, and France. In conjunction with this expansion, the sponsor agreed to provide exemestane and fulvestrant to sites outside of the US, and references to the Summary of Product Characteristics (SmPC) for each agent were added. • This amendment also incorporated procedural clarifications contained in prior administrative letters and clarified posttreatment follow-up procedures, including a specification for an overall study ending timepoint no later than 6 months after the last patient completed the end of treatment (EOT) visit. • To optimize analysis of the phase 2 exploratory endpoint of changes in tumor volume, collection of the most recent prebaseline computed tomography (CT) scan (if available) was added to the screening procedures; availability of the historical prebaseline scan was not a prerequisite for study eligibility. • Several eligibility criteria were clarified: the inclusion criterion for HER2- status was simplified to reference the updated ASCO/CAP testing criteria, and the exclusion criterion for treatment with cytochrome P450 (CYP) inhibitors was aligned with prohibited concomitant medications.

15 Sep 2014

• The primary purpose of Amendment 2 was to evaluate the safety, tolerability, and pharmacokinetic (PK) of a new sapanisertib capsule based on milled API before initiation of the phase 2 portion of the study. The new capsules based on milled API were to be taken on an empty stomach.

12 Mar 2015

• The primary purpose of Amendment 3 was to clarify that enrolled patients in France or Belgium would not have had prior combination therapy with fulvestrant and everolimus and would not receive this combination in the study. Additionally, this amendment clarified the timing of sapanisertib and exemestane administration to allow for exemestane to be administered after a meal in accordance with the product label. A guide for managing patients with noninfectious pneumonitis was added, and the vendor and contact information to report product complaints was updated.

22 Oct 2015

• The primary purpose of Amendment 4 was to modify the eligibility criteria to expand the pool of potential study participants and clarify disease status confirmation requirements, and to decrease the number of PK samples required in phase 2. This amendment also revised the excluded medications section of the protocol based on characterization of PK from the phase 1 portion of this study and other clinical studies in the sapanisertib development program. The starting dose for the phase 2 portion of this study was confirmed as 4 mg (milled) sapanisertib + either exemestane 25 mg or fulvestrant 500 mg, based on a safety and tolerability review of patients in cohort 2 of phase 1b part 2. It was not anticipated that these modifications would affect the scientific integrity of the study or the safety of study participants. Administrative changes were also made, such as introducing the new compound code for the study drug, adding the suspected unexpected serious adverse reactions (SUSAR) language, and • revising the product complaints vendor and contact information.

12 May 2017

• The primary purpose of Amendment 5 was to allow the use of ondansetron and granisetron for antiemetic therapy and prophylaxis, update the definition of the response-evaluable population, and remove the PK/tumor-pharmacodynamic cohort.

26 Oct 2017

• The primary purpose of Amendment 6 was to update sections affected by new nonclinical data for sapanisertib metabolism by specific cytochrome P450 (CYP) isoforms. Exclusion criteria, the list of prohibited concomitant medications and CYP inhibitors, dietary restrictions related to CYP inhibitors and inducers, the use of contrast with MRI, and the description of potential DDIs were updated accordingly.

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

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Clinical trials

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Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Primary: Phase 1: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Primary: Phase 2: Clinical Benefit Rate at 16 Weeks (CBR-16)

Primary: Phase 2: Clinical Benefit Rate at 16 Weeks (CBR-16)

Secondary: Phase 2: Clinical Benefit Rate at 24 Weeks (CBR-24)

Secondary: Phase 2: Clinical Benefit Rate at 24 Weeks (CBR-24)

Secondary: Phase 2: Overall Response Rate (ORR)

Secondary: Phase 2: Overall Response Rate (ORR)

Secondary: Phase 2: Progression-Free Survival (PFS)

Secondary: Phase 2: Progression-Free Survival (PFS)

Secondary: Phase 2: Overall Survival (OS)

Secondary: Phase 2: Overall Survival (OS)

Secondary: Phase 2: Best Percent Change from Baseline in Tumor Size

Secondary: Phase 2: Best Percent Change from Baseline in Tumor Size

Secondary: Phase1: Cmax: Maximum Observed Plasma Concentration for Sapanisertib

Secondary: Phase1: Cmax: Maximum Observed Plasma Concentration for Sapanisertib

Secondary: Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Sapanisertib

Secondary: Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Sapanisertib

Secondary: Phase 1: AUC(0-24): Area under the Plasma Concentration-time Curve from Time 0 to Time 24 Hours, Calculated using the Observed Value of the Last Quantifiable Concentration Over the Dosing Interval for Sapanisertib

Secondary: Phase 1: AUC(0-24): Area under the Plasma Concentration-time Curve from Time 0 to Time 24 Hours, Calculated using the Observed Value of the Last Quantifiable Concentration Over the Dosing Interval for Sapanisertib

Secondary: Phase 1: AUC(0-last): Area under the Plasma Concentration-time Curve from Time 0 to Time tau Over the Dosing Interval for MLN0128

Secondary: Phase 1: AUC(0-last): Area under the Plasma Concentration-time Curve from Time 0 to Time tau Over the Dosing Interval for MLN0128

Secondary: Phase 1: Terminal Elimination Half-life (T1/2) for Sapanisertib

Secondary: Phase 1: Terminal Elimination Half-life (T1/2) for Sapanisertib

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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