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Clinical Trial Results:
A Phase 1/2, Open-Label Study of Neratinib (HKI-272) in Combination with Capecitabine in Subjects with Solid Tumors and ERBB2-Positive Metastatic or Locally Advanced Breast Cancer

Summary
EudraCT number	2008-001662-85
Trial protocol	ES HU
Global end of trial date	01 Jun 2018

Results information
Results version number	v2(current)
This version publication date	06 Jul 2019
First version publication date	31 Dec 2016
Other versions	v1
Version creation reason
Summary report(s)	3144A1-2206 PDS

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

3144A1-2206-WW

ISRCTN number

US NCT number

NCT00741260

WHO universal trial number (UTN)

Sponsor organisation name

Puma Biotechnology, Inc.

Sponsor organisation address

10880 Wilshire Blvd, Suite 2150, Los Angeles, United States, 90024

Public contact

Senior Director, Clinical Operations, Puma Biotechnology, Inc., 1 4242486500, clinicaltrials@pumabiotechnology.com

Scientific contact

Senior Director, Clinical Operations, Puma Biotechnology, Inc., 1 4242486500, clinicaltrials@pumabiotechnology.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

01 Jun 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

01 Jun 2018

Was the trial ended prematurely?

Main objective of the trial

Primary Objectives Part 1: The primary objectives of Part 1 were to assess the safety and tolerability, and to define the MTD of neratinib in combination with capecitabine in subjects with advanced solid tumors. Part 2: The primary objectives of Part 2 of this study were to confirm the MTD identified in Part 1 by collecting further data on the safety and tolerability of the combination of neratinib and capecitabine at the MTD in subjects with erbB-2 positive breast cancer. Secondary Objectives Part 1: The secondary objective of Part 1 was to obtain preliminary anti-tumor activity for neratinib in combination with capecitabine. Part 2: The secondary objectives of Part 2 were to obtain pharmacokinetic (PK) information, and to assess additional efficacy parameters including objective response rate (ORR = complete response [CR] +partial response [PR]), progression-free survival (PFS), clinical benefit rate (CR + PR + stable disease [SD] ≥24 weeks), and duration of response fo

Protection of trial subjects

This study was designed and monitored in accordance with Sponsor procedures, which comply with the ethical principles of the International Council for Harmonisation (ICH) Good Clinical Practice (GCP), including the Declaration of Helsinki and the applicable laws and regulations. The protocol, the investigator’s brochure (IB), and the informed consent form (ICF) for this clinical study were submitted to an institutional review board (IRB) or an independent ethics committee (IEC) for review and written approval. Any subsequent amendments to the protocol or any revisions to the ICF were submitted for IRB or IEC review and written approval. This study was conducted in accordance with the International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice (GCP) and the ethical principles that have their origins in the Declaration of Helsinki. All investigators have provided written commitments to comply with GCP standards and the protocol. Clinical trial data were monitored at regular intervals by the Sponsor or their representative throughout the study to verify compliance to study protocol, completeness, accuracy and consistency of the data and adherence to local regulations on the conduct of clinical research. Patients were discontinued from the study if any of the following occurred: documented disease progression as determined by the investigator (following the definitions provided in the Response Criteria section), patients requiring initiation of bisphosphonate treatment, during the course of the study, were to be discontinued due to progressive disease unless disease progression could be completely ruled out and was clearly documented in the patient’s source documentation, adverse event (AE), symptomatic deterioration, investigator request (with detailed documentation of reasoning), protocol deviation, discontinuation of the study by the sponsor, lost to follow-up, or death.

Background therapy

Evidence for comparator

Actual start date of recruitment

09 Dec 2008

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 7

Country: Number of subjects enrolled

Brazil: 1

Country: Number of subjects enrolled

China: 13

Country: Number of subjects enrolled

Spain: 27

Country: Number of subjects enrolled

Hong Kong: 1

Country: Number of subjects enrolled

Croatia: 4

Country: Number of subjects enrolled

Hungary: 3

Country: Number of subjects enrolled

Korea, Republic of: 14

Country: Number of subjects enrolled

Russian Federation: 8

Country: Number of subjects enrolled

United States: 27

Worldwide total number of subjects

105

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

Screening details

Subjects had to meet all inclusion criteria and not meet any exclusion criteria to participate in this study.

Period 1 title

Treatment Period (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

N160+C1500

Arm description

Part 1 of the study. Neratinib 160 mg / day in combination with Capecitabine 1500 mg/m2/day (750 mg/m2 bid)

Arm type

Experimental

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

750 mg/m2 bid, for a total of 1500 mg/m2 daily, on days 1-14 of each 21 day cycle.

Investigational medicinal product name

Neratinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Neratinib 4 40-mg tablets, qd, p.o., preferably with food in the morning.

N240+C1500

Arm description

Part 1 of the study. Neratinib 240 mg / day in combination with Capecitabine 1500 mg/m2/day (750 mg/m2 bid)

Arm type

Experimental

Investigational medicinal product name

Neratinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Neratinib 240 mg qd po, preferably with food in the morning.

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

750 mg/m2 bid, for a total of 1500 mg/m2 daily, on days 1-14 of each 21 day cycle.

N240+C2000

Arm description

Part 1 of the study. Neratinib 240 mg / day in combination with Capecitabine 2000 mg/m2/day (1000 mg/m2 bid)

Arm type

Experimental

Investigational medicinal product name

Neratinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Neratinib 240 mg qd po, preferably with food in the morning.

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

1000 mg/m2 bid, for a total of 2000 mg/m2 daily, on days 1-14 of each 21 day cycle.

N200+C2000

Arm description

Part 1 of the study. Neratinib 200 mg / day in combination with Capecitabine 2000 mg/m2/day (1000 mg/m2 bid)

Arm type

Experimental

Investigational medicinal product name

Neratinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

5 neratinib 40 mg tablets qd, preferably with food, in morning.

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capecitabine 1000 (mg/m2) BID (2000 mg/m2/day) on days 1 – 14 of each 21-day cycle

N160+C2000

Arm description

Part 1 of the study. Neratinib 160 mg / day in combination with Capecitabine 2000 mg/m2/day (1000 mg/m2 bid)

Arm type

Experimental

Investigational medicinal product name

Neratinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Neratinib 4 40-mg tablets, qd, p.o., preferably with food in the morning.

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capecitabine 1000 mg/m2/day BID (2000 mg/m2/day) on days 1-14 of each 21 day cycle.

P2 N240+C1500 NPL

Arm description

Part 2 of the study. Neratinib 240 mg / day in combination with Capecitabine 1500mg/m2/day (750mg/m2 bid), for subjects who have not received prior lapatinib.

Arm type

Experimental

Investigational medicinal product name

Neratinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Neratinib 240 mg qd po, preferably with food in the morning.

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

750 mg/m2 bid, for a total of 1500 mg/m2 daily, on days 1-14 of each 21 day cycle.

P2 N240+C1500 PL

Arm description

Part 2 of the study. Neratinib 240 mg / day in combination with Capecitabine 1500mg/m2/day (750mg/m2 bid), for subjects who have received prior lapatinib.

Arm type

Experimental

Investigational medicinal product name

Neratinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Neratinib 240 mg qd po, preferably with food in the morning.

Investigational medicinal product name

Capecitabine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

750 mg/m2 bid, for a total of 1500 mg/m2 daily, on days 1-14 of each 21 day cycle.

Number of subjects in period 1	N160+C1500	N240+C1500	N240+C2000	N200+C2000	N160+C2000	P2 N240+C1500 NPL	P2 N240+C1500 PL
Started	6	8	4	6	9	65	7
Completed	0	0	0	0	0	0	0
Not completed	6	8	4	6	9	65	7
Started new anti-cancer medication	-	-	-	1	1	-	-
Physician decision	1	2	-	-	-	2	-
Consent withdrawn by subject	-	-	-	-	1	4	1
Adverse event, non-fatal	1	-	1	1	-	2	-
Death	-	1	-	1	2	4	-
Discontinuation of study by sponsor	-	-	-	-	-	4	-
Disease Progression	4	5	3	3	5	49	6

Baseline characteristics

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Reporting group title

Treatment Period

Reporting group description

Reporting group values	Treatment Period	Total
Number of subjects	105	105
Age categorical
Units: Subjects
Adults (18-64 years)	91	91
From 65-84 years	14	14
85 years and over	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	52.4 ± 10.8	-
Gender categorical
Units: Subjects
Female	93	93
Male	12	12

End points

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Reporting group title

N160+C1500

Reporting group description

Part 1 of the study. Neratinib 160 mg / day in combination with Capecitabine 1500 mg/m2/day (750 mg/m2 bid)

Reporting group title

N240+C1500

Reporting group description

Part 1 of the study. Neratinib 240 mg / day in combination with Capecitabine 1500 mg/m2/day (750 mg/m2 bid)

Reporting group title

N240+C2000

Reporting group description

Part 1 of the study. Neratinib 240 mg / day in combination with Capecitabine 2000 mg/m2/day (1000 mg/m2 bid)

Reporting group title

N200+C2000

Reporting group description

Part 1 of the study. Neratinib 200 mg / day in combination with Capecitabine 2000 mg/m2/day (1000 mg/m2 bid)

Reporting group title

N160+C2000

Reporting group description

Part 1 of the study. Neratinib 160 mg / day in combination with Capecitabine 2000 mg/m2/day (1000 mg/m2 bid)

Reporting group title

P2 N240+C1500 NPL

Reporting group description

Part 2 of the study. Neratinib 240 mg / day in combination with Capecitabine 1500mg/m2/day (750mg/m2 bid), for subjects who have not received prior lapatinib.

Reporting group title

P2 N240+C1500 PL

Reporting group description

Part 2 of the study. Neratinib 240 mg / day in combination with Capecitabine 1500mg/m2/day (750mg/m2 bid), for subjects who have received prior lapatinib.

Primary: Objective Response Rate

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End point title

Objective Response Rate ^[1] ^[2]

End point description

Objective response rate was defined as the proportion of subjects archiving a confirmed complete response (CR) or partial response (PR), according to RECIST. To be assigned a status of PR or CR, changes in tumor measurements were confirmed by repeat assessments that were performed no less than 4 weeks after the criteria for response were first met.

End point type

Primary

End point timeframe

From first dose through last tumor assessment.

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: The Objective Response Rate was computed for Part 2 of the study and there were no comparisons to be made. The rate and the corresponding 95% CI were estimated using the Kaplan-Meier method.
[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 considered for only part 2 of the study.

End point values	P2 N240+C1500 NPL	P2 N240+C1500 PL
Number of subjects analysed	65	7
Units: Percentage
number (confidence interval 95%)	63.1 (50.2 to 74.7)	57.1 (18.4 to 90.1)

No statistical analyses for this end point

Secondary: Clinical Benefit Response Rate

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End point title

Clinical Benefit Response Rate ^[3]

End point description

Subjects are considered a responder if their best response is either a complete or partial response. A complete or partial response must be confirmed no less than 4-weeks after the criteria for response are initially met per RECIST. A subject is deemed to have a clinical benefit if the patient is a responder or if stable disease lasted longer than 24 weeks.

End point type

Secondary

End point timeframe

From first dose through the last tumor assessment

Notes
[3] - 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 considered for only part 2 of the study.

End point values	P2 N240+C1500 NPL	P2 N240+C1500 PL
Number of subjects analysed	65	7
Units: Percentage
number (confidence interval 95%)	70.8 (58.2 to 81.4)	57.1 (18.4 to 90.1)

No statistical analyses for this end point

Secondary: Progression Free Survival

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End point title

Progression Free Survival ^[4]

End point description

PFS is defined as the interval from the date of randomization until the earliest date of disease recurrence, progression (per RECIST criteria) or death due to any cause. Symptomatic deterioration is considered as progressive disease (PD). Subjects without documented progression or death will be censored at the date of last valid tumor assessment.

End point type

Secondary

End point timeframe

From date of randomization through earliest of disease recurrence, progression, or death.

Notes
[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 considered for only part 2 of the study.

End point values	P2 N240+C1500 NPL	P2 N240+C1500 PL
Number of subjects analysed	65	7
Units: Months
median (confidence interval 95%)	9.03 (6.87 to 11.1)	8.28 (4.14 to 15.2)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

1st dose through 28 days after last dose

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

N160+C1500

Reporting group description

Part 1: Neratinib 160 mg qd + Capecitabine 1500 mg

Reporting group title

N240+C2000

Reporting group description

Part 1: Neratinib 240 mg qd + Capecitabine 2000 mg

Reporting group title

N240+C1500

Reporting group description

Part 1: Neratinib 240 mg qd + Capecitabine 1500 mg

Reporting group title

N200+C2000

Reporting group description

Part 1: Neratinib 200 mg qd + Capecitabine 2000 mg

Reporting group title

N160+C2000

Reporting group description

Part 1: Neratinib 160 mg qd + Capecitabine 2000 mg

Reporting group title

P2 N240+C1500 NPL

Reporting group description

Part 2: Neratinib 240 mg qd + Capecitabine 1500 mg No Prior Lapatinib

Reporting group title

P2 N240+C1500 PL

Reporting group description

Part 2: Neratinib 240 mg qd + Capecitabine 1500 mg Prior Lapatinb

Serious adverse events	N160+C1500	N240+C2000	N240+C1500	N200+C2000	N160+C2000	P2 N240+C1500 NPL	P2 N240+C1500 PL
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 6 (83.33%)	2 / 4 (50.00%)	4 / 8 (50.00%)	3 / 6 (50.00%)	3 / 9 (33.33%)	19 / 65 (29.23%)	2 / 7 (28.57%)
number of deaths (all causes)	0	0	3	2	2	7	1
number of deaths resulting from adverse events	0	0	2	2	1	4	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast neoplasm
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Vascular disorders
Hypotension
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Shock haemorrhagic
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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 / 1	0 / 0	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
General disorders and administration site conditions
Chills
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Disease progression
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	1 / 6 (16.67%)	0 / 9 (0.00%)	2 / 65 (3.08%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 2	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	1 / 1	0 / 0
Pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Pyrexia
subjects affected / exposed	2 / 6 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Reproductive system and breast disorders
Breast pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood alkaline phosphatase abnormal
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Cardiac disorders
Pericardial effusion
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Tachycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Nervous system disorders
Ataxia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Lacunar infarction
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	1 / 7 (14.29%)
occurrences causally related to treatment / all	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
Nerve root compression
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Seizure
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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 / 1	0 / 0
Spinal cord compression
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Febrile neutropenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Thrombocytopenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	2 / 7 (28.57%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Melaena
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Proctitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Vomiting
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	1 / 7 (14.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Biloma
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Hyperbilirubinaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Ureteric stenosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Ureterolithiasis
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Infections and infestations
Acarodermatitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Cystitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Herpes zoster
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Hypokalaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	2 / 7 (28.57%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	N160+C1500	N240+C2000	N240+C1500	N200+C2000	N160+C2000	P2 N240+C1500 NPL	P2 N240+C1500 PL
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 6 (100.00%)	4 / 4 (100.00%)	8 / 8 (100.00%)	6 / 6 (100.00%)	9 / 9 (100.00%)	62 / 65 (95.38%)	7 / 7 (100.00%)
Vascular disorders
Arteriosclerosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	1
Haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	1
Hot flush
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	4 / 65 (6.15%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	6	0
Hypertension
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 9 (22.22%)	3 / 65 (4.62%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	8	0
Hypotension
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences all number	0	0	0	4	0	1	0
Lymphoedema
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 9 (0.00%)	5 / 65 (7.69%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	5	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 6 (33.33%)	2 / 4 (50.00%)	4 / 8 (50.00%)	2 / 6 (33.33%)	5 / 9 (55.56%)	12 / 65 (18.46%)	0 / 7 (0.00%)
occurrences all number	4	3	14	6	6	23	0
Chills
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	2
Early satiety
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 65 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1	0	1
Fatigue
subjects affected / exposed	1 / 6 (16.67%)	1 / 4 (25.00%)	3 / 8 (37.50%)	1 / 6 (16.67%)	4 / 9 (44.44%)	15 / 65 (23.08%)	2 / 7 (28.57%)
occurrences all number	1	4	3	1	8	27	3
Impaired healing
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	2	0	0	0	0	0	0
Implant site pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Inflammation
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Influenza like illness
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	6 / 65 (9.23%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	9	0
Injection site extravasation
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Mucosal inflammation
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	3 / 8 (37.50%)	2 / 6 (33.33%)	0 / 9 (0.00%)	9 / 65 (13.85%)	0 / 7 (0.00%)
occurrences all number	0	1	5	6	0	32	0
Oedema
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	2 / 65 (3.08%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	3	1
Oedema peripheral
subjects affected / exposed	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	2 / 65 (3.08%)	0 / 7 (0.00%)
occurrences all number	1	1	0	0	0	2	0
Pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 9 (22.22%)	3 / 65 (4.62%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	3	3	0
Pyrexia
subjects affected / exposed	2 / 6 (33.33%)	1 / 4 (25.00%)	2 / 8 (25.00%)	1 / 6 (16.67%)	2 / 9 (22.22%)	6 / 65 (9.23%)	0 / 7 (0.00%)
occurrences all number	3	1	2	1	2	8	0
Xerosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Seasonal allergy
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Reproductive system and breast disorders
Breast swelling
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Metrorrhagia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 6 (33.33%)	1 / 4 (25.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	1 / 9 (11.11%)	4 / 65 (6.15%)	0 / 7 (0.00%)
occurrences all number	2	1	2	0	1	5	0
Dyspnoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	3 / 9 (33.33%)	10 / 65 (15.38%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	6	15	0
Epistaxis
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	5 / 65 (7.69%)	1 / 7 (14.29%)
occurrences all number	1	0	0	0	0	8	2
Productive cough
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 9 (0.00%)	2 / 65 (3.08%)	0 / 7 (0.00%)
occurrences all number	0	0	2	0	0	3	0
Rhinorrhoea
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	1 / 7 (14.29%)
occurrences all number	0	1	0	0	0	1	1
Sinus congestion
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	1	0
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 6 (16.67%)	1 / 4 (25.00%)	1 / 8 (12.50%)	1 / 6 (16.67%)	0 / 9 (0.00%)	3 / 65 (4.62%)	0 / 7 (0.00%)
occurrences all number	1	1	1	2	0	3	0
Depression
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	1 / 6 (16.67%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	3	0	0	0
Insomnia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	4 / 8 (50.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	9 / 65 (13.85%)	0 / 7 (0.00%)
occurrences all number	0	0	4	0	0	12	0
Investigations
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 8 (12.50%)	2 / 6 (33.33%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences all number	0	2	1	4	0	7	0
Alanine aminotransferase increased
subjects affected / exposed	2 / 6 (33.33%)	1 / 4 (25.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	2 / 9 (22.22%)	11 / 65 (16.92%)	2 / 7 (28.57%)
occurrences all number	4	7	0	1	2	19	2
Aspartate aminotransferase increased
subjects affected / exposed	2 / 6 (33.33%)	1 / 4 (25.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	2 / 9 (22.22%)	10 / 65 (15.38%)	2 / 7 (28.57%)
occurrences all number	4	4	0	1	2	17	2
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	3 / 9 (33.33%)	3 / 65 (4.62%)	0 / 7 (0.00%)
occurrences all number	1	1	0	0	4	5	0
Blood bilirubin increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	1 / 9 (11.11%)	6 / 65 (9.23%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	2	14	0
Blood creatinine increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 9 (0.00%)	2 / 65 (3.08%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	9	0
Blood glucose increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	3 / 65 (4.62%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	4	0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	6 / 65 (9.23%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	13	3
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 9 (22.22%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences all number	1	1	0	0	4	1	0
Haemoglobin decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	3 / 65 (4.62%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	12	0
International normalised ratio increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	1 / 9 (11.11%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences all number	1	0	1	0	1	1	0
Liver function test increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	1	0	0	0
Weight decreased
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	7 / 65 (10.77%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	1	14	0
Weight increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	4	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	1	0
Eye contusion
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	1
Fall
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	1	1
Ligament sprain
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Nasal injury
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Radius fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Cardiac disorders
Tachycardia
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Nervous system disorders
Ataxia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	2	1	0
Balance disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	3
Dizziness
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	3 / 8 (37.50%)	0 / 6 (0.00%)	0 / 9 (0.00%)	7 / 65 (10.77%)	2 / 7 (28.57%)
occurrences all number	1	0	3	0	0	14	3
Dysarthria
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	1
Dysgeusia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 9 (0.00%)	4 / 65 (6.15%)	0 / 7 (0.00%)
occurrences all number	0	0	0	2	0	6	0
Headache
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 9 (22.22%)	12 / 65 (18.46%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	3	28	0
Hypoaesthesia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	1 / 6 (16.67%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Monoparesis
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Nervous system disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	1
Neuralgia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	4	0	0	0	0
Neuropathy peripheral
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	5 / 65 (7.69%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	9	1
Neurotoxicity
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	1	1
Peripheral sensory neuropathy
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	6 / 65 (9.23%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	11	0
Somnolence
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 9 (0.00%)	2 / 65 (3.08%)	1 / 7 (14.29%)
occurrences all number	0	0	1	0	0	2	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	1 / 9 (11.11%)	6 / 65 (9.23%)	0 / 7 (0.00%)
occurrences all number	3	0	5	0	3	36	0
Leukopenia
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	1 / 9 (11.11%)	4 / 65 (6.15%)	1 / 7 (14.29%)
occurrences all number	2	0	0	1	1	15	2
Lymphopenia
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 8 (12.50%)	1 / 6 (16.67%)	0 / 9 (0.00%)	2 / 65 (3.08%)	0 / 7 (0.00%)
occurrences all number	0	2	1	1	0	2	0
Neutropenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	2 / 9 (22.22%)	11 / 65 (16.92%)	1 / 7 (14.29%)
occurrences all number	0	0	0	6	2	31	2
Thrombocytopenia
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	2 / 6 (33.33%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences all number	0	1	0	3	0	9	0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	4 / 65 (6.15%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	6	0
Eye disorders
Lacrimation increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	2 / 65 (3.08%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	2	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	1	1
Abdominal distension
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	2 / 6 (33.33%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences all number	0	0	1	2	0	1	0
Abdominal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	2 / 8 (25.00%)	2 / 6 (33.33%)	0 / 9 (0.00%)	8 / 65 (12.31%)	0 / 7 (0.00%)
occurrences all number	0	0	5	4	0	12	0
Abdominal pain upper
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	1 / 6 (16.67%)	0 / 9 (0.00%)	6 / 65 (9.23%)	0 / 7 (0.00%)
occurrences all number	0	0	1	1	0	11	0
Cheilitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	1 / 6 (16.67%)	0 / 9 (0.00%)	2 / 65 (3.08%)	0 / 7 (0.00%)
occurrences all number	0	0	1	2	0	2	0
Constipation
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	2 / 8 (25.00%)	1 / 6 (16.67%)	0 / 9 (0.00%)	8 / 65 (12.31%)	2 / 7 (28.57%)
occurrences all number	0	0	4	1	0	11	3
Dental caries
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences all number	0	0	2	0	0	1	0
Diarrhoea
subjects affected / exposed	5 / 6 (83.33%)	4 / 4 (100.00%)	7 / 8 (87.50%)	6 / 6 (100.00%)	8 / 9 (88.89%)	59 / 65 (90.77%)	7 / 7 (100.00%)
occurrences all number	10	25	26	25	27	651	29
Dry mouth
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 8 (12.50%)	1 / 6 (16.67%)	0 / 9 (0.00%)	3 / 65 (4.62%)	0 / 7 (0.00%)
occurrences all number	1	0	1	1	0	4	0
Dyspepsia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	2 / 8 (25.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	11 / 65 (16.92%)	2 / 7 (28.57%)
occurrences all number	0	0	3	0	1	14	2
Faeces soft
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Gastrointestinal disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	1
Haematemesis
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Intestinal obstruction
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	1
Lip dry
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Mouth ulceration
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	2 / 65 (3.08%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	2	1
Nausea
subjects affected / exposed	2 / 6 (33.33%)	2 / 4 (50.00%)	4 / 8 (50.00%)	3 / 6 (50.00%)	3 / 9 (33.33%)	25 / 65 (38.46%)	4 / 7 (57.14%)
occurrences all number	4	3	5	6	9	50	6
Stomatitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 9 (0.00%)	12 / 65 (18.46%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	20	0
Vomiting
subjects affected / exposed	1 / 6 (16.67%)	2 / 4 (50.00%)	6 / 8 (75.00%)	1 / 6 (16.67%)	3 / 9 (33.33%)	21 / 65 (32.31%)	3 / 7 (42.86%)
occurrences all number	3	5	7	4	11	42	3
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	2 / 65 (3.08%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	3	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	1 / 7 (14.29%)
occurrences all number	1	0	0	0	0	1	1
Dermatitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	2
Dry skin
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	2 / 8 (25.00%)	2 / 6 (33.33%)	0 / 9 (0.00%)	7 / 65 (10.77%)	0 / 7 (0.00%)
occurrences all number	0	0	2	3	0	7	0
Hyperhidrosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	2 / 65 (3.08%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	2	0
Nail disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	4 / 65 (6.15%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	5	0
Nail dystrophy
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Night sweats
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Onychoclasis
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	2 / 8 (25.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences all number	0	0	2	0	0	1	0
Onycholysis
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	3 / 65 (4.62%)	0 / 7 (0.00%)
occurrences all number	0	2	0	0	0	3	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	2 / 6 (33.33%)	3 / 4 (75.00%)	2 / 8 (25.00%)	1 / 6 (16.67%)	4 / 9 (44.44%)	41 / 65 (63.08%)	5 / 7 (71.43%)
occurrences all number	3	6	8	3	13	107	14
Pigmentation disorder
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	2 / 8 (25.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences all number	0	3	2	0	0	1	0
Rash
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	1 / 6 (16.67%)	0 / 9 (0.00%)	13 / 65 (20.00%)	2 / 7 (28.57%)
occurrences all number	0	0	1	1	0	27	5
Skin fissures
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	1	0
Skin lesion
subjects affected / exposed	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences all number	1	1	0	0	0	1	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	4 / 65 (6.15%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	5	0
Haematuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 9 (0.00%)	3 / 65 (4.62%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	3	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	5 / 65 (7.69%)	0 / 7 (0.00%)
occurrences all number	3	0	0	0	0	7	0
Back pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	3 / 8 (37.50%)	1 / 6 (16.67%)	0 / 9 (0.00%)	7 / 65 (10.77%)	0 / 7 (0.00%)
occurrences all number	0	0	3	4	0	10	0
Muscle spasms
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 9 (0.00%)	5 / 65 (7.69%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	9	0
Muscular weakness
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	2	1	0	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	1 / 9 (11.11%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	1	2	0
Musculoskeletal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	7 / 65 (10.77%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	8	2
Myalgia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	4 / 65 (6.15%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	4	0
Neck pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	2 / 65 (3.08%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	3	1
Pain in extremity
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	1 / 6 (16.67%)	0 / 9 (0.00%)	8 / 65 (12.31%)	0 / 7 (0.00%)
occurrences all number	0	0	2	1	0	10	0
Posture abnormal
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	0	0	2
Infections and infestations
Candida infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Gastroenteritis
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	1	0	0	0	0
Gastroenteritis viral
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Nail infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	3 / 65 (4.62%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	4	0
Paronychia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	8 / 65 (12.31%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	17	0
Pneumonia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	1 / 9 (11.11%)	2 / 65 (3.08%)	0 / 7 (0.00%)
occurrences all number	0	0	2	0	1	2	0
Rhinitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	4 / 65 (6.15%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	4	0
Skin infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	2 / 9 (22.22%)	10 / 65 (15.38%)	1 / 7 (14.29%)
occurrences all number	0	1	0	0	2	16	1
Urinary tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 9 (0.00%)	4 / 65 (6.15%)	0 / 7 (0.00%)
occurrences all number	0	0	0	1	0	6	0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	5 / 65 (7.69%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	0	6	0
Wound infection pseudomonas
subjects affected / exposed	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 6 (0.00%)	3 / 4 (75.00%)	2 / 8 (25.00%)	4 / 6 (66.67%)	2 / 9 (22.22%)	19 / 65 (29.23%)	2 / 7 (28.57%)
occurrences all number	0	3	4	6	4	24	3
Dehydration
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	3 / 8 (37.50%)	0 / 6 (0.00%)	1 / 9 (11.11%)	3 / 65 (4.62%)	0 / 7 (0.00%)
occurrences all number	0	0	7	0	1	3	0
Hypercholesterolaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences all number	0	1	0	0	0	1	0
Hyperglycaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 9 (0.00%)	5 / 65 (7.69%)	0 / 7 (0.00%)
occurrences all number	0	1	1	0	0	11	0
Hyperphosphataemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Hypoglycaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 65 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Hypokalaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	3 / 65 (4.62%)	1 / 7 (14.29%)
occurrences all number	0	0	0	0	1	3	1
Hypomagnesaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 4 (25.00%)	1 / 8 (12.50%)	1 / 6 (16.67%)	1 / 9 (11.11%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences all number	0	1	1	3	1	21	0
Hyponatraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 9 (0.00%)	1 / 65 (1.54%)	0 / 7 (0.00%)
occurrences all number	0	0	0	5	0	2	0

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Were there any global substantial amendments to the protocol? Yes

27 Aug 2008

Revised Part 2 of the study from a 3 treatment arm comparison to a single treatment arm study; Removed the following treatment arms: ARM A: neratinib (240 mg), and ARM C: lapatinib (1250 mg) + capecitabine (2000 mg/m2). The remaining study arm (neratinib and capecitabine at administered as determined in Part 1 [MTD]) was retained as a single arm. Consistent with the removal of Part 2 treatment arms A and C, the procedure for assignment to treatment group was clarified to indicate that subjects would not be randomized to treatment in Part 1 or Part 2. In Part 1, subjects were enrolled in a non-random manner according to a pre-specified dose escalation scheme. In Part 2, subjects were enrolled at the MTD established in Part 1; hence, randomization to treatment was not required. The major inclusion criterion specifying prior treatment with a both a taxane and an anthracycline was changed from a requirement of a specific number of cycles (at least 4 cycles in the absence of disease progression and a least 2 cycles if disease progresses during treatment) to a requirement of prior treatment only. Additionally, the locally advanced disease treatment setting was added to the list of treatment settings for inclusion. Consistent with the removal of Part 2 treatment arms A and C, the specification that the study would continue without the neratinib + capecitabine (MTD) treatment arm if dose level 1 was not tolerated was removed from the dose escalation scheme discussion. The secondary endpoint of overall survival (OS) was removed. The involvement of an independent radiology vendor for primary analysis was cancelled. The plasma collection for capecitabine metabolites PK dosing was removed.

03 Mar 2009

Added LVEF monitoring time points to the active study period; data were to be collected for any stool culture that was performed to exclude infectious etiologies; subject exposure to unnecessary exposure to radiographic materials was reduced; allowance of radiotherapy was removed; clarification regarding subjects who were not able to give consent for themselves but needed a legally authorized representative; a 2-week washout period between trastuzumab treatment and first dose of the test article was added; anthracycline requirement was removed; skin lesions could be measurable lesions (per RECIST) on CT/MRI scan, and therefore, could be included as long as skin lesions were measurable by CT/MRI scan; definition of modest elevated total bilirubin (≤1.5 × ULN) was amended; the number of subjects in Part 2 was increased to include a subgroup of subjects with prior lapatinib exposure; washout period was shortened to allow subjects with CNS metastases who had been shown to be stable off of steroids and anticonvulsants for 4 weeks; clarified requirements for birth control during the study and exclusion criteria related to pregnant; breast-feeding or women of childbearing potential who were not using effective contraception; amended permitted bisphosphonate use for subjects with bone lesions present at screening that required bisphosphonate therapy, neratinib administration instructions, diarrhea management instructions, dose adjustment guidelines; Neratinib dose re-escalation was removed; use of diary cards was deleted; clarification of lymph nodes as a new site of disease was added to the evaluation of overall response; overdose definitions were revised.

03 Dec 2009

Added radiation therapy for palliative use; explored two additional dosing cohorts (Dose level 4: neratinib 200 mg/capecitabine 2000 mg/m2 and Dose level 5: neratinib 160 mg/capecitabine 2000 mg/m2); updated PK monitoring, review of laboratory values at the beginning of each cycle, ECHO and MUGA assessment schedule, inclusion criteria regarding gender of subjects; exclusion of prior erbB-2 targeted agents; clarified use of concomitant steroids for subjects with CNS metastases, added additional dose reductions to the table for Part 1, cohort 4 subjects (neratinib starting dose 200 mg [Dose level -1: 160 mg and Dose level -2: 120 mg]); added guidelines for potential liver toxicity; corrected a typographical error to accurately reflect that LVEF monitoring was to occur every 12 weeks instead of every 9 weeks; removed allowance of neratinib re-escalation to the previous dose in case of certain events.

05 Sep 2017

Added guidance to monitor for the signs and symptoms of pancreatitis to the dose adjustment guidelines and minor corrections and clarifications.

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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A Phase 1/2, Open-Label Study of Neratinib (HKI-272) in Combination with Capecitabine in Subjects with Solid Tumors and ERBB2-Positive Metastatic or Locally Advanced Breast Cancer

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Clinical Trial Results: A Phase 1/2, Open-Label Study of Neratinib (HKI-272) in Combination with Capecitabine in Subjects with Solid Tumors and ERBB2-Positive Metastatic or Locally Advanced Breast Cancer

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Primary: Objective Response Rate

Primary: Objective Response Rate

Secondary: Clinical Benefit Response Rate

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Clinical Trial Results:
A Phase 1/2, Open-Label Study of Neratinib (HKI-272) in Combination with Capecitabine in Subjects with Solid Tumors and ERBB2-Positive Metastatic or Locally Advanced Breast Cancer