Trial Outcomes & Findings for A Study Comparing of Two Different Chemotherapy Regimens, in Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer (NCT NCT00606021)

Last Updated: 2011-12-26

Results Overview

Progression free survival is defined as the time from randomization until the date of progression of disease (PD) or death from any cause. PD was determined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria. PD is ≥20% increase in sum of longest diameter of target lesions. PD in maintenance phase uses the last lesion assessment prior to randomization as the baseline assessment.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

106 participants

Primary outcome timeframe

Randomization to progression of disease (PD) or date of death from any cause up to 30.9 months

Results posted on

2011-12-26

Participant Flow

Induction phase (IP) is from first dose of study drug until randomization and entering to maintenance phase (MP) or discontinuation from treatment during IP. 106 participants were treated during IP. MP is from randomization to discontinuation from treatment. Overall period is IP+MP, whereas overall study is MP only.

Participant milestones

Participant milestones
Measure	Pemetrexed Plus Cisplatin (Induction Phase) Pemetrexed, 500 milligrams per square meter (mg/m²), intravenous (IV) followed by Cisplatin, IV, 75 mg/m² on Day 1 of each 21-day cycle for 4 cycles	Pemetrexed Plus Best Supportive Care (Maintenance Phase) Pemetrexed: 500 (mg/m²), IV, Day 1 of each 21-day cycle for 6 cycles Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.	Best Supportive Care (Maintenance Phase) Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.
Induction Phase STARTED	106	0	0
Induction Phase COMPLETED	19	0	0
Induction Phase NOT COMPLETED	87	0	0
Maintenance Phase STARTED	0	28	27
Maintenance Phase COMPLETED	0	5	10
Maintenance Phase NOT COMPLETED	0	23	17

Reasons for withdrawal

Reasons for withdrawal
Measure	Pemetrexed Plus Cisplatin (Induction Phase) Pemetrexed, 500 milligrams per square meter (mg/m²), intravenous (IV) followed by Cisplatin, IV, 75 mg/m² on Day 1 of each 21-day cycle for 4 cycles	Pemetrexed Plus Best Supportive Care (Maintenance Phase) Pemetrexed: 500 (mg/m²), IV, Day 1 of each 21-day cycle for 6 cycles Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.	Best Supportive Care (Maintenance Phase) Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.
Induction Phase Death	73	0	0
Induction Phase Physician Decision	2	0	0
Induction Phase Withdrawal by Subject	2	0	0
Induction Phase Lost to Follow-up	10	0	0
Maintenance Phase Death	0	17	15
Maintenance Phase Physician Decision	0	1	0
Maintenance Phase Lost to Follow-up	0	5	2

Baseline Characteristics

A Study Comparing of Two Different Chemotherapy Regimens, in Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Pemetrexed Plus Best Supportive Care (Maintenance Phase) n=28 Participants Pemetrexed: 500 mg/m², IV, Day 1 of each 21-day cycle for 6 cycles Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.	Best Supportive Care (Maintenance Phase) n=27 Participants Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.	Total n=55 Participants Total of all reporting groups
Age Continuous	57.4 years STANDARD_DEVIATION 12.52 • n=5 Participants	62.9 years STANDARD_DEVIATION 9.97 • n=7 Participants	60.1 years STANDARD_DEVIATION 11.57 • n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants	10 Participants n=7 Participants	18 Participants n=5 Participants
Sex: Female, Male Male	20 Participants n=5 Participants	17 Participants n=7 Participants	37 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	26 Participants n=5 Participants	26 Participants n=7 Participants	52 Participants n=5 Participants
Race/Ethnicity, Customized African	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Region of Enrollment Egypt	24 participants n=5 Participants	19 participants n=7 Participants	43 participants n=5 Participants
Region of Enrollment Saudi Arabia	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Region of Enrollment Lebanon	4 participants n=5 Participants	7 participants n=7 Participants	11 participants n=5 Participants
Pathological Diagnosis Mixed Cell Carcinoma, Lung	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants
Pathological Diagnosis Large Cells Lung Carcinoma	8 participants n=5 Participants	5 participants n=7 Participants	13 participants n=5 Participants
Pathological Diagnosis Adenocarcinoma	19 participants n=5 Participants	21 participants n=7 Participants	40 participants n=5 Participants
Stage of Disease at The Time of Entry into This Study Stage III B - Locally advanced	9 participants n=5 Participants	10 participants n=7 Participants	19 participants n=5 Participants
Stage of Disease at The Time of Entry into This Study Stage IV - Metastasized	19 participants n=5 Participants	17 participants n=7 Participants	36 participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status at randomization of maintenance phase 0 - Fully active	6 participants n=5 Participants	8 participants n=7 Participants	14 participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status at randomization of maintenance phase 1 - Ambulatory, restricted strenuous activity	20 participants n=5 Participants	17 participants n=7 Participants	37 participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status at randomization of maintenance phase 2 - Ambulatory, unable to carry out work activity	2 participants n=5 Participants	2 participants n=7 Participants	4 participants n=5 Participants
Lesion Response to induction phase Complete Response (CR)	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Lesion Response to induction phase Partial Response (PR)	10 participants n=5 Participants	11 participants n=7 Participants	21 participants n=5 Participants
Lesion Response to induction phase Stable Disease (SD)	17 participants n=5 Participants	13 participants n=7 Participants	30 participants n=5 Participants
Lesion Response to induction phase Unknown	1 participants n=5 Participants	2 participants n=7 Participants	3 participants n=5 Participants

PRIMARY outcome

Timeframe: Randomization to progression of disease (PD) or date of death from any cause up to 30.9 months

Population: Participants who were randomized into maintenance phase and had measurable or evaluable lesions at baseline (last assessment before randomization) and post-baseline.

Outcome measures

Outcome measures
Measure	Pemetrexed Plus Best Supportive Care (Maintenance Phase) n=28 Participants Pemetrexed: 500 mg/m², IV, Day 1 of each 21-day cycle for 6 cycles Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.	Best Supportive Care (Maintenance Phase) n=27 Participants Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.	Pemetrexed Plus Cisplatin (Induction Phase) Pemetrexed, 500 milligrams per square meter (mg/m²), intravenous (IV) followed by Cisplatin, IV, 75 mg/m² on Day 1 of each 21-day cycle for 4 cycles
Progression Free Survival During Maintenance Phase	3.2 months Interval 2.9 to 6.1	3.2 months Interval 2.2 to 4.3	—

SECONDARY outcome

Timeframe: First dose of study drug during IP to PD or date of death from any cause up to 33.6 months

Population: Participants who took at least one dose of study drug during IP and had measurable or evaluable lesions at baseline (assessment before induction phase) and post baseline.

Progression-free survival in overall period is defined as the time from the date of first dose of study drug during IP until the date of PD or death from any cause. PD was determined using RECIST criteria. PD is ≥20% increase in sum of longest diameter of target lesions. PD in overall period uses the screening lesion assessment prior to the induction phase as the baseline assessment.

Outcome measures

Outcome measures
Measure	Pemetrexed Plus Best Supportive Care (Maintenance Phase) n=28 Participants Pemetrexed: 500 mg/m², IV, Day 1 of each 21-day cycle for 6 cycles Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.	Best Supportive Care (Maintenance Phase) n=27 Participants Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.	Pemetrexed Plus Cisplatin (Induction Phase) Pemetrexed, 500 milligrams per square meter (mg/m²), intravenous (IV) followed by Cisplatin, IV, 75 mg/m² on Day 1 of each 21-day cycle for 4 cycles
Progression Free Survival During Overall Period (Induction Phase [IP] + Maintenance Phase [MP])	6.2 months Interval 6.0 to 8.3	6.0 months Interval 4.6 to 6.9	—

SECONDARY outcome

Timeframe: Randomization to PD or date of death from any cause up to 31.3 months

Population: Participants who were randomized into maintenance phase and had measurable or evaluable lesions at baseline (last assessment before randomization) and post-baseline.

Overall survival in maintenance phase is defined as the time from randomization to death. Participants who were alive were censored at the last contact.

Outcome measures

Outcome measures
Measure	Pemetrexed Plus Best Supportive Care (Maintenance Phase) n=28 Participants Pemetrexed: 500 mg/m², IV, Day 1 of each 21-day cycle for 6 cycles Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.	Best Supportive Care (Maintenance Phase) n=27 Participants Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.	Pemetrexed Plus Cisplatin (Induction Phase) Pemetrexed, 500 milligrams per square meter (mg/m²), intravenous (IV) followed by Cisplatin, IV, 75 mg/m² on Day 1 of each 21-day cycle for 4 cycles
Overall Survival During Maintenance Phase	12.2 months Interval 5.6 to 20.6	11.8 months Interval 6.3 to 25.6	—

SECONDARY outcome

Timeframe: First dose of study drug during IP to PD or date of death from any cause up to 34.1 months

Population: Participants who took at least one dose of study drug during IP and had measurable or evaluable lesions at baseline (assessment before induction phase) and post baseline.

Overall survival in overall period is defined as the time from first dose of study drug during IP to death. Participants who were alive were censored at the last contact.

Outcome measures

Outcome measures
Measure	Pemetrexed Plus Best Supportive Care (Maintenance Phase) n=28 Participants Pemetrexed: 500 mg/m², IV, Day 1 of each 21-day cycle for 6 cycles Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.	Best Supportive Care (Maintenance Phase) n=27 Participants Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.	Pemetrexed Plus Cisplatin (Induction Phase) Pemetrexed, 500 milligrams per square meter (mg/m²), intravenous (IV) followed by Cisplatin, IV, 75 mg/m² on Day 1 of each 21-day cycle for 4 cycles
Overall Survival During Overall Period (IP + MP)	15.4 months Interval 8.4 to 23.7	16.4 months Interval 9.1 to 28.5	—

SECONDARY outcome

Timeframe: First dose of study drug during IP through overall study completion (up to 34.3) months

Population: Participants who took at least one dose of study drug during IP, and randomized to maintenance phase.

The list of serious adverse events (SAEs) and other non-serious adverse events (AEs) are in Adverse Events Section.

Outcome measures

Outcome measures
Measure	Pemetrexed Plus Best Supportive Care (Maintenance Phase) n=28 Participants Pemetrexed: 500 mg/m², IV, Day 1 of each 21-day cycle for 6 cycles Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.	Best Supportive Care (Maintenance Phase) n=27 Participants Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.	Pemetrexed Plus Cisplatin (Induction Phase) n=106 Participants Pemetrexed, 500 milligrams per square meter (mg/m²), intravenous (IV) followed by Cisplatin, IV, 75 mg/m² on Day 1 of each 21-day cycle for 4 cycles
Number of Participants With Adverse Events (AEs) During Overall Period Adverse Events (AE)	15 participants	16 participants	74 participants
Number of Participants With Adverse Events (AEs) During Overall Period Serious Adverse Events (SAE)	1 participants	1 participants	13 participants

SECONDARY outcome

Timeframe: Randomization to measured PD up to 31.4 months

Population: Participants who were randomized into maintenance phase and had measurable or evaluable lesions at baseline (last assessment before randomization) and post-baseline.

Tumor response rate (%) is the number of responders (participants with best response of CR or PR) divided by the number of participants qualified for tumor response according to RECIST criteria multiplied by 100. Disease control rate is percentage of participants with a best response of stable disease \[SD\], PR, or CR. CR=disappearance of all target lesions; PR=30% decrease in sum of longest diameter of target lesions; PD is≥20% increase in sum of longest diameter of target lesions. SD= neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Outcome measures

Outcome measures
Measure	Pemetrexed Plus Best Supportive Care (Maintenance Phase) n=28 Participants Pemetrexed: 500 mg/m², IV, Day 1 of each 21-day cycle for 6 cycles Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.	Best Supportive Care (Maintenance Phase) n=27 Participants Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.	Pemetrexed Plus Cisplatin (Induction Phase) Pemetrexed, 500 milligrams per square meter (mg/m²), intravenous (IV) followed by Cisplatin, IV, 75 mg/m² on Day 1 of each 21-day cycle for 4 cycles
Tumor Response Rate and Disease Control Rate After Induction Phase (IP) CR	0 percentage of participants Interval 0.0 to 12.3	0 percentage of participants Interval 0.0 to 12.8	—
Tumor Response Rate and Disease Control Rate After Induction Phase (IP) Disease Control Rate	57.1 percentage of participants Interval 37.2 to 75.5	44.4 percentage of participants Interval 25.5 to 64.7	—
Tumor Response Rate and Disease Control Rate After Induction Phase (IP) Early Death From Toxicity	0 percentage of participants Interval 0.0 to 12.3	0 percentage of participants Interval 0.0 to 12.8	—
Tumor Response Rate and Disease Control Rate After Induction Phase (IP) Early Death From other cause	3.6 percentage of participants Interval 0.1 to 18.3	0 percentage of participants Interval 0.0 to 12.8	—
Tumor Response Rate and Disease Control Rate After Induction Phase (IP) Best Overall Response Rate	0 percentage of participants Interval 0.0 to 12.3	0 percentage of participants Interval 0.0 to 12.8	—
Tumor Response Rate and Disease Control Rate After Induction Phase (IP) PR	0 percentage of participants Interval 0.0 to 12.3	0 percentage of participants Interval 0.0 to 12.8	—
Tumor Response Rate and Disease Control Rate After Induction Phase (IP) SD	57.1 percentage of participants Interval 37.2 to 75.5	44.4 percentage of participants Interval 25.5 to 64.7	—
Tumor Response Rate and Disease Control Rate After Induction Phase (IP) PD	32.1 percentage of participants Interval 15.9 to 52.4	37.0 percentage of participants Interval 19.4 to 57.6	—
Tumor Response Rate and Disease Control Rate After Induction Phase (IP) Early Death From Malignant Disease	7.1 percentage of participants Interval 0.9 to 23.5	0 percentage of participants Interval 0.0 to 12.8	—
Tumor Response Rate and Disease Control Rate After Induction Phase (IP) Unknown	0 percentage of participants Interval 0.0 to 12.3	18.5 percentage of participants Interval 6.3 to 38.1	—

Adverse Events

Pemetrexed Plus Best Supportive Care - Maintenance Phase

Serious events: 1 serious events

Other events: 15 other events

Deaths: 0 deaths

Best Supportive Care - Maintenance Phase

Serious events: 1 serious events

Other events: 16 other events

Deaths: 0 deaths

Pemetrexed + Cisplatin - Induction Phase

Serious events: 13 serious events

Other events: 74 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 800-545-5979

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	Pemetrexed Plus Best Supportive Care - Maintenance Phase n=28 participants at risk Pemetrexed: 500 mg/m², IV, Day 1 of each 21-day cycle for 6 cycles Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.	Best Supportive Care - Maintenance Phase n=27 participants at risk Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.	Pemetrexed + Cisplatin - Induction Phase n=106 participants at risk Pemetrexed, 500 milligrams per square meter (mg/m²), intravenous (IV) followed by Cisplatin, IV, 75 mg/m² on Day 1 of each 21-day cycle for 4 cycles.
Blood and lymphatic system disorders Anaemia	0.00% 0/28 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	0.94% 1/106 • Number of events 1 Adverse events include pre-existing conditions.
Cardiac disorders Acute myocardial infarction	0.00% 0/28 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	0.94% 1/106 • Number of events 1 Adverse events include pre-existing conditions.
Cardiac disorders Cardiac arrest	3.6% 1/28 • Number of events 1 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	0.00% 0/106 Adverse events include pre-existing conditions.
Ear and labyrinth disorders Deafness	0.00% 0/28 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	0.94% 1/106 • Number of events 1 Adverse events include pre-existing conditions.
Gastrointestinal disorders Diarrhoea	0.00% 0/28 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	0.94% 1/106 • Number of events 1 Adverse events include pre-existing conditions.
Gastrointestinal disorders Vomiting	0.00% 0/28 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	0.94% 1/106 • Number of events 1 Adverse events include pre-existing conditions.
General disorders Death	0.00% 0/28 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	0.94% 1/106 • Number of events 1 Adverse events include pre-existing conditions.
General disorders Sudden death	0.00% 0/28 Adverse events include pre-existing conditions.	3.7% 1/27 • Number of events 1 Adverse events include pre-existing conditions.	1.9% 2/106 • Number of events 2 Adverse events include pre-existing conditions.
Investigations Weight decreased	0.00% 0/28 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	0.94% 1/106 • Number of events 1 Adverse events include pre-existing conditions.
Nervous system disorders Altered state of consciousness	0.00% 0/28 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	0.94% 1/106 • Number of events 1 Adverse events include pre-existing conditions.
Nervous system disorders Cerebrovascular accident	0.00% 0/28 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	0.94% 1/106 • Number of events 1 Adverse events include pre-existing conditions.
Nervous system disorders Convulsion	0.00% 0/28 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	0.94% 1/106 • Number of events 1 Adverse events include pre-existing conditions.
Nervous system disorders Diabetic ketoacidotic hyperglycaemic coma	0.00% 0/28 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	0.94% 1/106 • Number of events 1 Adverse events include pre-existing conditions.
Psychiatric disorders Depression	0.00% 0/28 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	0.94% 1/106 • Number of events 1 Adverse events include pre-existing conditions.
Reproductive system and breast disorders Ovarian cyst	0.00% 0/28 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	0.94% 1/106 • Number of events 1 Adverse events include pre-existing conditions.
Respiratory, thoracic and mediastinal disorders Respiratory arrest	0.00% 0/28 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	0.94% 1/106 • Number of events 1 Adverse events include pre-existing conditions.
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.00% 0/28 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	0.94% 1/106 • Number of events 1 Adverse events include pre-existing conditions.
Vascular disorders Arterial thrombosis limb	0.00% 0/28 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	0.94% 1/106 • Number of events 1 Adverse events include pre-existing conditions.
Vascular disorders Circulatory collapse	0.00% 0/28 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	0.94% 1/106 • Number of events 1 Adverse events include pre-existing conditions.

Measure	Pemetrexed Plus Best Supportive Care - Maintenance Phase n=28 participants at risk Pemetrexed: 500 mg/m², IV, Day 1 of each 21-day cycle for 6 cycles Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.	Best Supportive Care - Maintenance Phase n=27 participants at risk Best Supportive Care: Patients will receive best supportive care (dose, frequency, duration) as judged by their treating physician.	Pemetrexed + Cisplatin - Induction Phase n=106 participants at risk Pemetrexed, 500 milligrams per square meter (mg/m²), intravenous (IV) followed by Cisplatin, IV, 75 mg/m² on Day 1 of each 21-day cycle for 4 cycles.
Blood and lymphatic system disorders Anaemia	17.9% 5/28 • Number of events 6 Adverse events include pre-existing conditions.	11.1% 3/27 • Number of events 3 Adverse events include pre-existing conditions.	13.2% 14/106 • Number of events 16 Adverse events include pre-existing conditions.
Blood and lymphatic system disorders Lymphopenia	0.00% 0/28 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	5.7% 6/106 • Number of events 6 Adverse events include pre-existing conditions.
Blood and lymphatic system disorders Neutropenia	10.7% 3/28 • Number of events 11 Adverse events include pre-existing conditions.	3.7% 1/27 • Number of events 1 Adverse events include pre-existing conditions.	10.4% 11/106 • Number of events 16 Adverse events include pre-existing conditions.
Ear and labyrinth disorders Tinnitus	7.1% 2/28 • Number of events 2 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	1.9% 2/106 • Number of events 2 Adverse events include pre-existing conditions.
Gastrointestinal disorders Gastritis	7.1% 2/28 • Number of events 2 Adverse events include pre-existing conditions.	3.7% 1/27 • Number of events 1 Adverse events include pre-existing conditions.	7.5% 8/106 • Number of events 10 Adverse events include pre-existing conditions.
Gastrointestinal disorders Nausea	7.1% 2/28 • Number of events 4 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	14.2% 15/106 • Number of events 20 Adverse events include pre-existing conditions.
Gastrointestinal disorders Vomiting	7.1% 2/28 • Number of events 3 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	33.0% 35/106 • Number of events 65 Adverse events include pre-existing conditions.
General disorders Chest pain	14.3% 4/28 • Number of events 5 Adverse events include pre-existing conditions.	11.1% 3/27 • Number of events 3 Adverse events include pre-existing conditions.	7.5% 8/106 • Number of events 9 Adverse events include pre-existing conditions.
General disorders Fatigue	10.7% 3/28 • Number of events 3 Adverse events include pre-existing conditions.	14.8% 4/27 • Number of events 4 Adverse events include pre-existing conditions.	23.6% 25/106 • Number of events 30 Adverse events include pre-existing conditions.
Hepatobiliary disorders Hyperbilirubinaemia	0.00% 0/28 Adverse events include pre-existing conditions.	7.4% 2/27 • Number of events 2 Adverse events include pre-existing conditions.	0.00% 0/106 Adverse events include pre-existing conditions.
Investigations Alanine aminotransferase increased	7.1% 2/28 • Number of events 2 Adverse events include pre-existing conditions.	3.7% 1/27 • Number of events 1 Adverse events include pre-existing conditions.	0.00% 0/106 Adverse events include pre-existing conditions.
Metabolism and nutrition disorders Decreased appetite	7.1% 2/28 • Number of events 2 Adverse events include pre-existing conditions.	11.1% 3/27 • Number of events 3 Adverse events include pre-existing conditions.	24.5% 26/106 • Number of events 36 Adverse events include pre-existing conditions.
Metabolism and nutrition disorders Diabetes mellitus	3.6% 1/28 • Number of events 1 Adverse events include pre-existing conditions.	7.4% 2/27 • Number of events 2 Adverse events include pre-existing conditions.	4.7% 5/106 • Number of events 5 Adverse events include pre-existing conditions.
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/28 Adverse events include pre-existing conditions.	7.4% 2/27 • Number of events 2 Adverse events include pre-existing conditions.	7.5% 8/106 • Number of events 9 Adverse events include pre-existing conditions.
Metabolism and nutrition disorders Hyperkalaemia	0.00% 0/28 Adverse events include pre-existing conditions.	3.7% 1/27 • Number of events 1 Adverse events include pre-existing conditions.	5.7% 6/106 • Number of events 7 Adverse events include pre-existing conditions.
Metabolism and nutrition disorders Hypokalaemia	7.1% 2/28 • Number of events 2 Adverse events include pre-existing conditions.	0.00% 0/27 Adverse events include pre-existing conditions.	0.94% 1/106 • Number of events 1 Adverse events include pre-existing conditions.
Metabolism and nutrition disorders Hyponatraemia	3.6% 1/28 • Number of events 1 Adverse events include pre-existing conditions.	3.7% 1/27 • Number of events 1 Adverse events include pre-existing conditions.	7.5% 8/106 • Number of events 9 Adverse events include pre-existing conditions.
Respiratory, thoracic and mediastinal disorders Cough	3.6% 1/28 • Number of events 1 Adverse events include pre-existing conditions.	14.8% 4/27 • Number of events 4 Adverse events include pre-existing conditions.	9.4% 10/106 • Number of events 12 Adverse events include pre-existing conditions.
Respiratory, thoracic and mediastinal disorders Dyspnoea	10.7% 3/28 • Number of events 3 Adverse events include pre-existing conditions.	14.8% 4/27 • Number of events 4 Adverse events include pre-existing conditions.	8.5% 9/106 • Number of events 9 Adverse events include pre-existing conditions.
Vascular disorders Hypertension	7.1% 2/28 • Number of events 2 Adverse events include pre-existing conditions.	3.7% 1/27 • Number of events 1 Adverse events include pre-existing conditions.	4.7% 5/106 • Number of events 5 Adverse events include pre-existing conditions.