Trial Outcomes & Findings for A Study of BIBW 2992 (Afatinib) in Patients With Metastatic Colorectal Cancer (NCT NCT01152437)

Last Updated: 2014-06-26

Results Overview

Percentage of participants with objective response: complete response (CR) or partial response (PR) according to RECIST (version 1.1) without confirmation criteria applied.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

94 participants

Primary outcome timeframe

Baseline till progression or death, whichever came first, assessed up to 23 months

Results posted on

2014-06-26

Participant Flow

Participant milestones

Participant milestones
Measure	Afatinib (Wild-type) Afatinib tablets once daily in patients with KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) wild-type metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated.	Cetuximab (Wild-type) Cetuximab 400 mg/m² on Day 1 and then 250mg/m² once a week, every week, intravenous (i.v.) in patients with KRAS wild-type metastatic colorectal cancer.	Afatinib (Mutated) Afatinib tablets once daily in patients with KRAS mutated metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated.
Overall Study STARTED	36	15	43
Overall Study COMPLETED	0	0	0
Overall Study NOT COMPLETED	36	15	43

Reasons for withdrawal

Reasons for withdrawal
Measure	Afatinib (Wild-type) Afatinib tablets once daily in patients with KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) wild-type metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated.	Cetuximab (Wild-type) Cetuximab 400 mg/m² on Day 1 and then 250mg/m² once a week, every week, intravenous (i.v.) in patients with KRAS wild-type metastatic colorectal cancer.	Afatinib (Mutated) Afatinib tablets once daily in patients with KRAS mutated metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated.
Overall Study Other Adverse Event	8	1	7
Overall Study Not treated	0	1	2
Overall Study Progressive disease	27	13	32
Overall Study Refusal to continue taking trial medicat	1	0	2

Baseline Characteristics

A Study of BIBW 2992 (Afatinib) in Patients With Metastatic Colorectal Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Afatinib (Wild-type) n=36 Participants Afatinib tablets once daily in patients with KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) wild-type metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated.	Cetuximab (Wild-type) n=14 Participants Cetuximab 400 mg/m² on Day 1 and then 250mg/m² once a week, every week, intravenous (i.v.) in patients with KRAS wild-type metastatic colorectal cancer.	Afatinib (Mutated) n=41 Participants Afatinib tablets once daily in patients with KRAS mutated metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated.	Total n=91 Participants Total of all reporting groups
Age, Continuous	62.5 years STANDARD_DEVIATION 10.4 • n=5 Participants	62.6 years STANDARD_DEVIATION 7.7 • n=7 Participants	60.0 years STANDARD_DEVIATION 11.9 • n=5 Participants	61.4 years STANDARD_DEVIATION 10.8 • n=4 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	5 Participants n=7 Participants	22 Participants n=5 Participants	36 Participants n=4 Participants
Sex: Female, Male Male	27 Participants n=5 Participants	9 Participants n=7 Participants	19 Participants n=5 Participants	55 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline till progression or death, whichever came first, assessed up to 23 months

Population: Randomised set. Primary endpoint for the population of patients with KRAS wildtype tumours.

Percentage of participants with objective response: complete response (CR) or partial response (PR) according to RECIST (version 1.1) without confirmation criteria applied.

Outcome measures

Outcome measures
Measure	Afatinib (Wild-type) n=36 Participants Afatinib tablets once daily in patients with KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) wild-type metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated.	Cetuximab (Wild-type) n=15 Participants Cetuximab 400 mg/m² on Day 1 and then 250mg/m² once a week, every week, intravenous (i.v.) in patients with KRAS wild-type metastatic colorectal cancer.	Afatinib (Mutated) Afatinib tablets once daily in patients with KRAS mutated metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated.
Percentage of Participants With Objective Response	3 Percentage of Participants	20 Percentage of Participants	—

PRIMARY outcome

Timeframe: Baseline till progression or death, whichever came first, assessed up to 23 months

Population: Treated Set. Primary endpoint for the population of patients with KRAS mutated tumours.

Percentage of participants with objective response or stable disease (SD) as determined by RECIST (version 1.1) with confirmation criteria applied.

Outcome measures

Outcome measures
Measure	Afatinib (Wild-type) n=41 Participants Afatinib tablets once daily in patients with KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) wild-type metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated.	Cetuximab (Wild-type) Cetuximab 400 mg/m² on Day 1 and then 250mg/m² once a week, every week, intravenous (i.v.) in patients with KRAS wild-type metastatic colorectal cancer.	Afatinib (Mutated) Afatinib tablets once daily in patients with KRAS mutated metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated.
Percentage of Participants With Disease Control (DC)	12 Percentage of Participants Interval 4.9 to 23.9	—	—

SECONDARY outcome

Timeframe: Baseline till progression or death, whichever came first, assessed up to 23 months

Population: Randomised set for wild-type group and treated set for mutated group.

PFS time is defined as time from randomisation (wild-type group) or start of treatment (mutated group) to tumor progression evaluated according to RECIST (version 1.1) or death whichever occurs earlier. Median and confidence interval estimated using product-limit Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Afatinib (Wild-type) n=36 Participants Afatinib tablets once daily in patients with KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) wild-type metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated.	Cetuximab (Wild-type) n=15 Participants Cetuximab 400 mg/m² on Day 1 and then 250mg/m² once a week, every week, intravenous (i.v.) in patients with KRAS wild-type metastatic colorectal cancer.	Afatinib (Mutated) n=41 Participants Afatinib tablets once daily in patients with KRAS mutated metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated.
Progression Free Survival (PFS)	46.0 Days Interval 43.0 to 49.0	144.5 Days Interval 24.0 to 233.0	41.0 Days Interval 39.0 to 46.0

SECONDARY outcome

Timeframe: Baseline till death, assessed up to 23 months

Population: Randomised set for wild-type group and treated set for mutated group.

OS time is defined as time from the date of randomisation (wild-type group) or date of start of treatment (mutated group) to the date of death. Median and confidence interval estimated using product-limit Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Afatinib (Wild-type) n=36 Participants Afatinib tablets once daily in patients with KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) wild-type metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated.	Cetuximab (Wild-type) n=15 Participants Cetuximab 400 mg/m² on Day 1 and then 250mg/m² once a week, every week, intravenous (i.v.) in patients with KRAS wild-type metastatic colorectal cancer.	Afatinib (Mutated) n=41 Participants Afatinib tablets once daily in patients with KRAS mutated metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated.
Overall Survival (OS) Time	355.0 Days Interval 211.0 to 449.0	NA Days Interval 204.0 to NA - This was not calculable due to the low number of deaths observed in this group.	173.0 Days Interval 106.0 to 214.0

SECONDARY outcome

Timeframe: day 8

Population: Randomised set for wild-type group and treated set for mutated group.

Cpre,ss,8 represents the pre-dose concentration of afatinib in plasma at steady state on day 8.

Outcome measures

Outcome measures
Measure	Afatinib (Wild-type) n=28 Participants Afatinib tablets once daily in patients with KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) wild-type metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated.	Cetuximab (Wild-type) n=24 Participants Cetuximab 400 mg/m² on Day 1 and then 250mg/m² once a week, every week, intravenous (i.v.) in patients with KRAS wild-type metastatic colorectal cancer.	Afatinib (Mutated) Afatinib tablets once daily in patients with KRAS mutated metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated.
Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 8 (Cpre,ss,8)	16.6 ng/mL Geometric Coefficient of Variation 80.3 • Interval 211.0 to 449.0	21.4 ng/mL Geometric Coefficient of Variation 91.0 • Interval 106.0 to 214.0	—

Adverse Events

Afatinib (Wild-type)

Serious events: 15 serious events

Other events: 35 other events

Deaths: 0 deaths

Cetuximab (Wild-type)

Serious events: 5 serious events

Other events: 14 other events

Deaths: 0 deaths

Afatinib (Mutated)

Serious events: 18 serious events

Other events: 40 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim Pharmaceuticals

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Afatinib (Wild-type) n=36 participants at risk Afatinib tablets once daily in patients with KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) wild-type metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated.	Cetuximab (Wild-type) n=14 participants at risk Cetuximab 400 mg/m² on Day 1 and then 250mg/m² once a week, every week, intravenous (i.v.) in patients with KRAS wild-type metastatic colorectal cancer.	Afatinib (Mutated) n=41 participants at risk Afatinib tablets once daily in patients with KRAS mutated metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated.
General disorders Disease progression	2.8% 1/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	9.8% 4/41 • First administration of trial medication until 28 days after last administration of trial medication
General disorders Fatigue	2.8% 1/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	2.4% 1/41 • First administration of trial medication until 28 days after last administration of trial medication
General disorders Malaise	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
General disorders Pyrexia	2.8% 1/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	2.4% 1/41 • First administration of trial medication until 28 days after last administration of trial medication
Hepatobiliary disorders Bile duct obstruction	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	14.3% 2/14 • First administration of trial medication until 28 days after last administration of trial medication	2.4% 1/41 • First administration of trial medication until 28 days after last administration of trial medication
Hepatobiliary disorders Jaundice	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	2.4% 1/41 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Catheter site infection	2.8% 1/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Clostridium difficile colitis	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Device related infection	2.8% 1/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Escherichia sepsis	2.8% 1/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Lower respiratory tract infection	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	2.4% 1/41 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Lung infection	2.8% 1/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Pneumonia	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	4.9% 2/41 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Sepsis	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	2.4% 1/41 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Ureteritis	2.8% 1/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Urinary tract infection	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Urinary tract infection enterococcal	2.8% 1/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Injury, poisoning and procedural complications Post procedural haemorrhage	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	2.4% 1/41 • First administration of trial medication until 28 days after last administration of trial medication
Investigations Blood calcium increased	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	2.4% 1/41 • First administration of trial medication until 28 days after last administration of trial medication
Blood and lymphatic system disorders Anaemia	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	4.9% 2/41 • First administration of trial medication until 28 days after last administration of trial medication
Cardiac disorders Atrial fibrillation	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	2.4% 1/41 • First administration of trial medication until 28 days after last administration of trial medication
Cardiac disorders Bradycardia	2.8% 1/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Cardiac disorders Tachycardia	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	2.4% 1/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Abdominal pain	5.6% 2/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Abdominal pain upper	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	2.4% 1/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Ascites	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	2.4% 1/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Constipation	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	4.9% 2/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Diarrhoea	11.1% 4/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	9.8% 4/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Intestinal obstruction	2.8% 1/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Nausea	11.1% 4/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	12.2% 5/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Small intestinal obstruction	2.8% 1/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Vomiting	13.9% 5/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	7.3% 3/41 • First administration of trial medication until 28 days after last administration of trial medication
General disorders Condition aggravated	2.8% 1/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Investigations Quality of life decreased	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	2.4% 1/41 • First administration of trial medication until 28 days after last administration of trial medication
Investigations Weight decreased	2.8% 1/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Metabolism and nutrition disorders Decreased appetite	2.8% 1/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Metabolism and nutrition disorders Dehydration	5.6% 2/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	4.9% 2/41 • First administration of trial medication until 28 days after last administration of trial medication
Metabolism and nutrition disorders Hypercalcaemia	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	2.4% 1/41 • First administration of trial medication until 28 days after last administration of trial medication
Musculoskeletal and connective tissue disorders Pain in extremity	2.8% 1/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to bone	2.8% 1/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	2.4% 1/41 • First administration of trial medication until 28 days after last administration of trial medication

Other adverse events
Measure	Afatinib (Wild-type) n=36 participants at risk Afatinib tablets once daily in patients with KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) wild-type metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated.	Cetuximab (Wild-type) n=14 participants at risk Cetuximab 400 mg/m² on Day 1 and then 250mg/m² once a week, every week, intravenous (i.v.) in patients with KRAS wild-type metastatic colorectal cancer.	Afatinib (Mutated) n=41 participants at risk Afatinib tablets once daily in patients with KRAS mutated metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated.
Eye disorders Conjunctivitis	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Eye disorders Eye irritation	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Eye disorders Eye pain	5.6% 2/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Eye disorders Lacrimation increased	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Eye disorders Scintillating scotoma	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Abdominal pain	5.6% 2/36 • First administration of trial medication until 28 days after last administration of trial medication	21.4% 3/14 • First administration of trial medication until 28 days after last administration of trial medication	17.1% 7/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Abdominal pain lower	2.8% 1/36 • First administration of trial medication until 28 days after last administration of trial medication	14.3% 2/14 • First administration of trial medication until 28 days after last administration of trial medication	2.4% 1/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Constipation	27.8% 10/36 • First administration of trial medication until 28 days after last administration of trial medication	28.6% 4/14 • First administration of trial medication until 28 days after last administration of trial medication	9.8% 4/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Diarrhoea	69.4% 25/36 • First administration of trial medication until 28 days after last administration of trial medication	28.6% 4/14 • First administration of trial medication until 28 days after last administration of trial medication	61.0% 25/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Dry mouth	5.6% 2/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	7.3% 3/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Dyspepsia	5.6% 2/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	7.3% 3/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Gingival pain	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	4.9% 2/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Intestinal obstruction	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Nausea	33.3% 12/36 • First administration of trial medication until 28 days after last administration of trial medication	21.4% 3/14 • First administration of trial medication until 28 days after last administration of trial medication	41.5% 17/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Oral pain	19.4% 7/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	7.3% 3/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Rectal haemorrhage	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	9.8% 4/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Rectal tenesmus	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Stomatitis	16.7% 6/36 • First administration of trial medication until 28 days after last administration of trial medication	21.4% 3/14 • First administration of trial medication until 28 days after last administration of trial medication	19.5% 8/41 • First administration of trial medication until 28 days after last administration of trial medication
Gastrointestinal disorders Vomiting	16.7% 6/36 • First administration of trial medication until 28 days after last administration of trial medication	14.3% 2/14 • First administration of trial medication until 28 days after last administration of trial medication	34.1% 14/41 • First administration of trial medication until 28 days after last administration of trial medication
General disorders Chills	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	2.4% 1/41 • First administration of trial medication until 28 days after last administration of trial medication
General disorders Fatigue	33.3% 12/36 • First administration of trial medication until 28 days after last administration of trial medication	21.4% 3/14 • First administration of trial medication until 28 days after last administration of trial medication	36.6% 15/41 • First administration of trial medication until 28 days after last administration of trial medication
General disorders Influenza like illness	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
General disorders Mucosal inflammation	8.3% 3/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	7.3% 3/41 • First administration of trial medication until 28 days after last administration of trial medication
General disorders Oedema peripheral	5.6% 2/36 • First administration of trial medication until 28 days after last administration of trial medication	14.3% 2/14 • First administration of trial medication until 28 days after last administration of trial medication	12.2% 5/41 • First administration of trial medication until 28 days after last administration of trial medication
General disorders Pain	5.6% 2/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	7.3% 3/41 • First administration of trial medication until 28 days after last administration of trial medication
General disorders Pyrexia	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	14.3% 2/14 • First administration of trial medication until 28 days after last administration of trial medication	2.4% 1/41 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Device related infection	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Localised infection	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Nasopharyngitis	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	14.3% 2/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Oral candidiasis	5.6% 2/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	7.3% 3/41 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Oral herpes	2.8% 1/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Paronychia	2.8% 1/36 • First administration of trial medication until 28 days after last administration of trial medication	14.3% 2/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Infections and infestations Urinary tract infection	11.1% 4/36 • First administration of trial medication until 28 days after last administration of trial medication	21.4% 3/14 • First administration of trial medication until 28 days after last administration of trial medication	14.6% 6/41 • First administration of trial medication until 28 days after last administration of trial medication
Investigations Weight decreased	5.6% 2/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	7.3% 3/41 • First administration of trial medication until 28 days after last administration of trial medication
Metabolism and nutrition disorders Decreased appetite	30.6% 11/36 • First administration of trial medication until 28 days after last administration of trial medication	42.9% 6/14 • First administration of trial medication until 28 days after last administration of trial medication	31.7% 13/41 • First administration of trial medication until 28 days after last administration of trial medication
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Metabolism and nutrition disorders Hypomagnesaemia	2.8% 1/36 • First administration of trial medication until 28 days after last administration of trial medication	28.6% 4/14 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/41 • First administration of trial medication until 28 days after last administration of trial medication
Musculoskeletal and connective tissue disorders Back pain	5.6% 2/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	9.8% 4/41 • First administration of trial medication until 28 days after last administration of trial medication
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/36 • First administration of trial medication until 28 days after last administration of trial medication	7.1% 1/14 • First administration of trial medication until 28 days after last administration of trial medication	2.4% 1/41 • First administration of trial medication until 28 days after last administration of trial medication
Nervous system disorders Dysgeusia	13.9% 5/36 • First administration of trial medication until 28 days after last administration of trial medication	0.00% 0/14 • First administration of trial medication until 28 days after last administration of trial medication	9.8% 4/41 • First administration of trial medication until 28 days after last administration of trial medication