Trial Outcomes & Findings for E7050 in Combination With Cisplatin and Capecitabine Versus Cisplatin and Capecitabine Alone in Patients With Advanced or Metastatic Solid Tumors and Previously Untreated Gastric Cancer (NCT NCT01355302)

Last Updated: 2017-05-15

Results Overview

On days when pharmacokinetic (PK) samples were to be drawn, a predose blood sample was obtained prior to administration of golvatinib and capecitabine. After administration of study drugs, a second postdose blood sample was taken. The amount of golvatinib in the participant's blood was analyzed and the AUC was calculated. The AUC reflects the actual body exposure to drug after administration of a dose of the drug and is dependent on the rate of elimination of the drug from the body and the dose administered. Predose samples that were below the limit of quantitation (BLQ) or missing were assigned a numerical value of zero for the calculation of AUC. Any other BLQ concentrations were assigned a value of zero. Results were expressed in nanograms·hour/milliter (ng·h/mL).

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

7 participants

Primary outcome timeframe

Cycle 1 (Day -2); predose, 30 minutes, 1, 2, 3, 4, 8, 12 (if feasible), 24, and 48 hours after study treatment. Cycle 2 (Day 1); predose, 30 minutes, 1, 2, 3, 4, 8, 12 (if feasible), and 24 hours after study treatment.

Results posted on

2017-05-15

Participant Flow

Subjects were to only participate in either the Phase 1b or Phase 2 portion of the study.

Participant milestones

Participant milestones
Measure	Phase 1b: Golvatinib+Capecitabine+Cisplatin Oral golvatinib (200 mg) was taken at about the same time each day of every 21-day treatment cycle, with or without food. Oral capecitabine (1000 mg/m\^2 tablet) was taken twice a day (2000 mg/m\^2 total daily) with food at about the same time (after golvatinib), on Days 1 through 14 of each 21-day cycle. At least 2 hours after capecitabine was taken, cisplatin (80 mg/m\^2) was administered by intravenous (IV) infusion over 60 minutes (after appropriate hydration or according to the institutional guidelines), on Day 1 of each 21-day cycle. Pretreatment hydration included 1 liter of normal saline by IV infusion over 120 minutes. Posttreatment hydration included 500 mL normal saline over 60 minutes. The dose level of golvatinib was to be escalated (to 300 and 400 mg) for additional cohorts after 3 participants enrolled into a given cohort unless there was a dose-limiting toxicity (DLT) in the first 3 participants.	Phase 2: Golvatinib+Capecitabine+Cisplatin The dose of golvatinib was to be the maximum tolerated dose (MTD) as determined during the Phase 1b portion of the study in combination with capecitabine and cisplatin as described for Phase 1b. The study was terminated prior to Phase 2.	Phase 2: Capecitabine + Cisplatin Oral capecitabine (1000 mg/m\^2 tablet) was taken twice a day (2000 mg/m\^2 total daily) with food at about the same time (after golvatinib), on Days 1 through 14 of each 21-day cycle. At least 2 hours after capecitabine was taken, cisplatin (80 mg/m\^2) was administered by intravenous (IV) infusion over 60 minutes (after appropriate hydration or according to the institutional guidelines), on Day 1 of each 21-day cycle. Pretreatment hydration included 1 liter of normal saline by IV infusion over 120 minutes. Posttreatment hydration included 500 mL normal saline over 60 minutes.
Phase 1b STARTED	7	0	0
Phase 1b COMPLETED	1	0	0
Phase 1b NOT COMPLETED	6	0	0
Phase 2 STARTED	0	0	0
Phase 2 COMPLETED	0	0	0
Phase 2 NOT COMPLETED	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Phase 1b: Golvatinib+Capecitabine+Cisplatin Oral golvatinib (200 mg) was taken at about the same time each day of every 21-day treatment cycle, with or without food. Oral capecitabine (1000 mg/m\^2 tablet) was taken twice a day (2000 mg/m\^2 total daily) with food at about the same time (after golvatinib), on Days 1 through 14 of each 21-day cycle. At least 2 hours after capecitabine was taken, cisplatin (80 mg/m\^2) was administered by intravenous (IV) infusion over 60 minutes (after appropriate hydration or according to the institutional guidelines), on Day 1 of each 21-day cycle. Pretreatment hydration included 1 liter of normal saline by IV infusion over 120 minutes. Posttreatment hydration included 500 mL normal saline over 60 minutes. The dose level of golvatinib was to be escalated (to 300 and 400 mg) for additional cohorts after 3 participants enrolled into a given cohort unless there was a dose-limiting toxicity (DLT) in the first 3 participants.	Phase 2: Golvatinib+Capecitabine+Cisplatin The dose of golvatinib was to be the maximum tolerated dose (MTD) as determined during the Phase 1b portion of the study in combination with capecitabine and cisplatin as described for Phase 1b. The study was terminated prior to Phase 2.	Phase 2: Capecitabine + Cisplatin Oral capecitabine (1000 mg/m\^2 tablet) was taken twice a day (2000 mg/m\^2 total daily) with food at about the same time (after golvatinib), on Days 1 through 14 of each 21-day cycle. At least 2 hours after capecitabine was taken, cisplatin (80 mg/m\^2) was administered by intravenous (IV) infusion over 60 minutes (after appropriate hydration or according to the institutional guidelines), on Day 1 of each 21-day cycle. Pretreatment hydration included 1 liter of normal saline by IV infusion over 120 minutes. Posttreatment hydration included 500 mL normal saline over 60 minutes.
Phase 1b Death	4	0	0
Phase 1b Study terminated by sponsor	2	0	0

Baseline Characteristics

E7050 in Combination With Cisplatin and Capecitabine Versus Cisplatin and Capecitabine Alone in Patients With Advanced or Metastatic Solid Tumors and Previously Untreated Gastric Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase 1b: Golvatinib+Capecitabine+Cisplatin n=7 Participants Oral golvatinib (200 mg) was taken at about the same time each day of every 21-day treatment cycle, with or without food. Oral capecitabine (1000 mg/m\^2 tablet) was taken twice a day (2000 mg/m\^2 total daily) with food at about the same time (after golvatinib), on Days 1 through 14 of each 21-day cycle. At least 2 hours after capecitabine was taken, cisplatin (80 mg/m\^2) was administered by intravenous (IV) infusion over 60 minutes (after appropriate hydration or according to the institutional guidelines), on Day 1 of each 21-day cycle. Pretreatment hydration included 1 liter of normal saline by IV infusion over 120 minutes. Posttreatment hydration included 500 mL normal saline over 60 minutes. The dose level of golvatinib was to be escalated (to 300 and 400 mg) for additional cohorts after 3 participants enrolled into a given cohort unless there was a dose-limiting toxicity (DLT) in the first 3 participants.
Age, Customized Age range 47 to 80 years	7 Participants n=5 Participants
Sex: Female, Male Female	4 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants

PRIMARY outcome

Timeframe: Cycle 1 (Day -2); predose, 30 minutes, 1, 2, 3, 4, 8, 12 (if feasible), 24, and 48 hours after study treatment. Cycle 2 (Day 1); predose, 30 minutes, 1, 2, 3, 4, 8, 12 (if feasible), and 24 hours after study treatment.

Population: Pharmacokinetic (PK) population: All participants in the Safety Population who had sufficient concentration data to derive one or more of the PK parameters. Participants with partial data were evaluated on a case-by-case basis to determine if sufficient data were available for meaningful PK analysis.

Outcome measures

Outcome measures
Measure	Phase 1b: Golvatinib+Capecitabine+Cisplatin n=7 Participants Oral golvatinib (200 mg) was taken at about the same time each day of every 21-day treatment cycle, with or without food. Oral capecitabine (1000 mg/m\^2 tablet) was taken twice a day (2000 mg/m\^2 total daily) with food at about the same time (after golvatinib), on Days 1 through 14 of each 21-day cycle. At least 2 hours after capecitabine was taken, cisplatin (80 mg/m\^2) was administered by intravenous (IV) infusion over 60 minutes (after appropriate hydration or according to the institutional guidelines), on Day 1 of each 21-day cycle. Pretreatment hydration included 1 liter of normal saline by IV infusion over 120 minutes. Posttreatment hydration included 500 mL normal saline over 60 minutes. The dose level of golvatinib was to be escalated (to 300 and 400 mg) for additional cohorts after 3 participants enrolled into a given cohort unless there was a dose-limiting toxicity (DLT) in the first 3 participants.	Phase 2: Capecitabine + Cisplatin The dose of golvatinib was to be the MTD as determined during the Phase 1b portion of the study in combination with capecitabine and cisplatin as described for Phase 1b. The study was terminated prior to Phase 2.
Area Under The Concentration-Time Curve (AUC) From 0 to 24 Hours of Golvatinib Cycle 1, Day -2	23400 ng·h/mL Interval 5000.0 to 56100.0	—
Area Under The Concentration-Time Curve (AUC) From 0 to 24 Hours of Golvatinib Cycle 2, Day 1	26300 ng·h/mL Interval 17400.0 to 62400.0	—

PRIMARY outcome

Blood samples were drawn to analyze the amount of golvatinib in the participant's serum. Maximum concentration refers to the maximum (or peak) serum concentration of study drug in the participant's system after administration of the study drug and prior to the administration of a second dose of the study drug. Results were expressed in nanograms/milliliter (ng/mL).

Outcome measures

Outcome measures
Measure	Phase 1b: Golvatinib+Capecitabine+Cisplatin n=7 Participants Oral golvatinib (200 mg) was taken at about the same time each day of every 21-day treatment cycle, with or without food. Oral capecitabine (1000 mg/m\^2 tablet) was taken twice a day (2000 mg/m\^2 total daily) with food at about the same time (after golvatinib), on Days 1 through 14 of each 21-day cycle. At least 2 hours after capecitabine was taken, cisplatin (80 mg/m\^2) was administered by intravenous (IV) infusion over 60 minutes (after appropriate hydration or according to the institutional guidelines), on Day 1 of each 21-day cycle. Pretreatment hydration included 1 liter of normal saline by IV infusion over 120 minutes. Posttreatment hydration included 500 mL normal saline over 60 minutes. The dose level of golvatinib was to be escalated (to 300 and 400 mg) for additional cohorts after 3 participants enrolled into a given cohort unless there was a dose-limiting toxicity (DLT) in the first 3 participants.	Phase 2: Capecitabine + Cisplatin The dose of golvatinib was to be the MTD as determined during the Phase 1b portion of the study in combination with capecitabine and cisplatin as described for Phase 1b. The study was terminated prior to Phase 2.
Maximum Concentration (Cmax) of Golvatinib Cycle 1, Day -2	1680 ng/mL Interval 268.0 to 3890.0	—
Maximum Concentration (Cmax) of Golvatinib Cycle 2, Day 1	1620 ng/mL Interval 834.0 to 3430.0	—

PRIMARY outcome

Timeframe: From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month.

Population: Safety Population included all participants who received at least one dose of study drug and who had at least one safety assessment after the first dose of study drug.

Safety assessments consisted of monitoring and recording all adverse events (AEs) and serious AEs; regular monitoring of hematology, blood chemistry, and urine values; periodic measurement of vital signs and electrocardiograms (ECGs); and performance of physical examinations. A TEAE was defined as an adverse event (AE) that had an onset date, or a worsening in severity from Baseline (pretreatment), on or after the first dose of study drug up to 30 days after the date of last study treatment.

Outcome measures

Outcome measures
Measure	Phase 1b: Golvatinib+Capecitabine+Cisplatin n=7 Participants Oral golvatinib (200 mg) was taken at about the same time each day of every 21-day treatment cycle, with or without food. Oral capecitabine (1000 mg/m\^2 tablet) was taken twice a day (2000 mg/m\^2 total daily) with food at about the same time (after golvatinib), on Days 1 through 14 of each 21-day cycle. At least 2 hours after capecitabine was taken, cisplatin (80 mg/m\^2) was administered by intravenous (IV) infusion over 60 minutes (after appropriate hydration or according to the institutional guidelines), on Day 1 of each 21-day cycle. Pretreatment hydration included 1 liter of normal saline by IV infusion over 120 minutes. Posttreatment hydration included 500 mL normal saline over 60 minutes. The dose level of golvatinib was to be escalated (to 300 and 400 mg) for additional cohorts after 3 participants enrolled into a given cohort unless there was a dose-limiting toxicity (DLT) in the first 3 participants.	Phase 2: Capecitabine + Cisplatin The dose of golvatinib was to be the MTD as determined during the Phase 1b portion of the study in combination with capecitabine and cisplatin as described for Phase 1b. The study was terminated prior to Phase 2.
Number of Participants With a Treatment-Emergent Adverse Event (TEAE)	7 Participants	—

PRIMARY outcome

Tmax was defined as the time at which Cmax was observed for golvatinib in combination with cisplatin and capecitabine.

Outcome measures

Outcome measures
Measure	Phase 1b: Golvatinib+Capecitabine+Cisplatin n=7 Participants Oral golvatinib (200 mg) was taken at about the same time each day of every 21-day treatment cycle, with or without food. Oral capecitabine (1000 mg/m\^2 tablet) was taken twice a day (2000 mg/m\^2 total daily) with food at about the same time (after golvatinib), on Days 1 through 14 of each 21-day cycle. At least 2 hours after capecitabine was taken, cisplatin (80 mg/m\^2) was administered by intravenous (IV) infusion over 60 minutes (after appropriate hydration or according to the institutional guidelines), on Day 1 of each 21-day cycle. Pretreatment hydration included 1 liter of normal saline by IV infusion over 120 minutes. Posttreatment hydration included 500 mL normal saline over 60 minutes. The dose level of golvatinib was to be escalated (to 300 and 400 mg) for additional cohorts after 3 participants enrolled into a given cohort unless there was a dose-limiting toxicity (DLT) in the first 3 participants.	Phase 2: Capecitabine + Cisplatin The dose of golvatinib was to be the MTD as determined during the Phase 1b portion of the study in combination with capecitabine and cisplatin as described for Phase 1b. The study was terminated prior to Phase 2.
Time to Maximum Concentration (Tmax) of Golvatinib Cycle 1, Day -2	3.00 Hours Interval 1.0 to 7.78	—
Time to Maximum Concentration (Tmax) of Golvatinib Cycle 2, Day 1	6.07 Hours Interval 3.0 to 12.82	—

SECONDARY outcome

Timeframe: Until disease progression or death for 3 years

Population: The study was terminated prior to enrollment in Phase 2 so this outcome measure was not conducted.

The study was terminated prior to enrollment in Phase 2 so this outcome measure was not conducted.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Until disease progression or death for 3 years

Population: The study was terminated prior to enrollment in Phase 2 so this outcome measure was not conducted.

The study was terminated prior to enrollment in Phase 2 so this outcome measure was not conducted.

Outcome measures

Outcome data not reported

Adverse Events

Phase 1b: Golvatinib+Capecitabine+Cisplatin

Serious events: 5 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Phase 1b: Golvatinib+Capecitabine+Cisplatin n=7 participants at risk Oral golvatinib (200 mg) was taken at about the same time each day of every 21-day treatment cycle, with or without food. Oral capecitabine (1000 mg/m\^2 tablet) was taken twice a day (2000 mg/m\^2 total daily) with food at about the same time (after golvatinib), on Days 1 through 14 of each 21-day cycle. At least 2 hours after capecitabine was taken, cisplatin (80 mg/m\^2) was administered by intravenous (IV) infusion over 60 minutes (after appropriate hydration or according to the institutional guidelines), on Day 1 of each 21-day cycle. Pretreatment hydration included 1 liter of normal saline by IV infusion over 120 minutes. Posttreatment hydration included 500 mL normal saline over 60 minutes. The dose level of golvatinib was to be escalated (to 300 and 400 mg) for additional cohorts after 3 participants enrolled into a given cohort unless there was a dose-limiting toxicity (DLT) in the first 3 participants.
Musculoskeletal and connective tissue disorders Arthralgia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Infections and infestations Psoas abscess	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Infections and infestations Pneumonia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Vascular disorders Pulmonary embolism	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Nervous system disorders Convulsion	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Gastrointestinal disorders Nausea	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Metabolism and nutrition disorders Dehydration	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Metabolism and nutrition disorders Electrolyte imbalance	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Gastrointestinal disorders Vomiting	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Cardiac disorders Supraventricular tachycardia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Gastrointestinal disorders Stomatitis	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.

Other adverse events

Other adverse events
Measure	Phase 1b: Golvatinib+Capecitabine+Cisplatin n=7 participants at risk Oral golvatinib (200 mg) was taken at about the same time each day of every 21-day treatment cycle, with or without food. Oral capecitabine (1000 mg/m\^2 tablet) was taken twice a day (2000 mg/m\^2 total daily) with food at about the same time (after golvatinib), on Days 1 through 14 of each 21-day cycle. At least 2 hours after capecitabine was taken, cisplatin (80 mg/m\^2) was administered by intravenous (IV) infusion over 60 minutes (after appropriate hydration or according to the institutional guidelines), on Day 1 of each 21-day cycle. Pretreatment hydration included 1 liter of normal saline by IV infusion over 120 minutes. Posttreatment hydration included 500 mL normal saline over 60 minutes. The dose level of golvatinib was to be escalated (to 300 and 400 mg) for additional cohorts after 3 participants enrolled into a given cohort unless there was a dose-limiting toxicity (DLT) in the first 3 participants.
Gastrointestinal disorders Nausea	100.0% 7/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Metabolism and nutrition disorders Dehydration	71.4% 5/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
General disorders Fatigue	71.4% 5/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Gastrointestinal disorders Vomiting	71.4% 5/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Metabolism and nutrition disorders Decreased appetite	57.1% 4/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Skin and subcutaneous tissue disorders Palmar-Plantar erythrodysaesthesia Syndrome	57.1% 4/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Blood and lymphatic system disorders Anaemia	42.9% 3/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Gastrointestinal disorders Constipation	42.9% 3/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Gastrointestinal disorders Diarrhoea	42.9% 3/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Nervous system disorders Headache	42.9% 3/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Metabolism and nutrition disorders Hypocalcaemia	42.9% 3/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Blood and lymphatic system disorders Leukopenia	42.9% 3/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Blood and lymphatic system disorders Neutropenia	42.9% 3/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Psychiatric disorders Anxiety	28.6% 2/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
General disorders Asthenia	28.6% 2/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
General disorders Chest pain	28.6% 2/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
General disorders Chills	28.6% 2/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Injury, poisoning and procedural complications Contusion	28.6% 2/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Metabolism and nutrition disorders Dizziness	28.6% 2/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Metabolism and nutrition disorders Hypoalbuminaemia	28.6% 2/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Metabolism and nutrition disorders Hypokalaemia	28.6% 2/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Metabolism and nutrition disorders Hypomagnesaemia	28.6% 2/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Metabolism and nutrition disorders Hyponatraemia	28.6% 2/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Psychiatric disorders Insomnia	28.6% 2/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Musculoskeletal and connective tissue disorders Pain in extremity	28.6% 2/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
General disorders Pyrexia	28.6% 2/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Skin and subcutaneous tissue disorders Rash	28.6% 2/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Blood and lymphatic system disorders Thrombocytopenia	28.6% 2/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Investigations Weight decreased	28.6% 2/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Gastrointestinal disorders Abdominal discomfort	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Gastrointestinal disorders Abdominal distension	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Gastrointestinal disorders Abdominal pain	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Gastrointestinal disorders Abdominal pain upper	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Gastrointestinal disorders Abdominal tenderness	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Nervous system disorders Ageusia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Nervous system disorders Amnesia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Cardiac disorders Arteriosclerosis coronary artery	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Musculoskeletal and connective tissue disorders Arthralgia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Musculoskeletal and connective tissue disorders Back pain	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Nervous system disorders Balance disorder	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Investigations Blood alkaline phosphatase increased	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Investigations Breath sounds abnormal	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Psychiatric disorders Catatonia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
General disorders Cold sweat	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Nervous system disorders Convulsion	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Respiratory, thoracic and mediastinal disorders Cough	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Skin and subcutaneous tissue disorders Decubitus ulcer	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Psychiatric disorders Depression	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Respiratory, thoracic and mediastinal disorders Diaphragmatic paralysis	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Gastrointestinal disorders Dry mouth	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Skin and subcutaneous tissue disorders Dry skin	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Gastrointestinal disorders Dyspepsia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Gastrointestinal disorders Dysphagia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Respiratory, thoracic and mediastinal disorders Dyspnoea	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Investigations Electrocardiogram st segment elevation	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Metabolism and nutrition disorders Electrolyte imbalance	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Gastrointestinal disorders Enteritis	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Respiratory, thoracic and mediastinal disorders Epistaxis	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Skin and subcutaneous tissue disorders Erythema	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Eye disorders Eye discharge	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
General disorders Feeling cold	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
General disorders Feeling hot	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Gastrointestinal disorders Glossodynia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Renal and urinary disorders Haematuria	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Respiratory, thoracic and mediastinal disorders Hiccups	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Metabolism and nutrition disorders Hyperglycaemia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Nervous system disorders Hypoaesthesia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Metabolism and nutrition disorders Hypoglycaemia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Metabolism and nutrition disorders Hypophosphataemia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Vascular disorders Hypotension	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Respiratory, thoracic and mediastinal disorders Hypoxia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Respiratory, thoracic and mediastinal disorders Increased upper airway secretion	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Eye disorders Lacrimation increased	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Blood and lymphatic system disorders Leukocytosis	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
General disorders Malaise	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Psychiatric disorders Mood swings	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
General disorders Mucosal inflammation	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Musculoskeletal and connective tissue disorders Muscle spasms	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Respiratory, thoracic and mediastinal disorders Nasal dryness	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Infections and infestations Nasopharyngitis	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Nervous system disorders Neuralgia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Nervous system disorders Neuropathy peripheral	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Renal and urinary disorders Nocturia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
General disorders Oedema peripheral	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Gastrointestinal disorders Oral pain	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Infections and infestations Oropharyngeal candidiasis	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
General disorders Pain	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
General disorders Pallor	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Cardiac disorders Palpitations	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Nervous system disorders Paraesthesia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Respiratory, thoracic and mediastinal disorders Paranasal sinus hypersecretion	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Nervous system disorders Peripheral sensory neuropathy	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Infections and infestations Pneumonia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Gastrointestinal disorders Proctalgia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Musculoskeletal and connective tissue disorders Psoas abscess	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Vascular disorders Pulmonary embolism	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Skin and subcutaneous tissue disorders Rash generalised	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Renal and urinary disorders Renal failure acute	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Psychiatric disorders Restlessness	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Skin and subcutaneous tissue disorders Scab	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Musculoskeletal and connective tissue disorders Scoliosis	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Musculoskeletal and connective tissue disorders Spinal osteoarthritis	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Gastrointestinal disorders Stomatitis	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Infections and infestations Streptococcal bacteraemia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Cardiac disorders Supraventricular tachycardia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Respiratory, thoracic and mediastinal disorders Tachypnoea	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Nervous system disorders Trigeminal neuralgia	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Infections and infestations Urinary tract infection	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Eye disorders Vision blurred	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.
Respiratory, thoracic and mediastinal disorders Wheezing	14.3% 1/7 • From date of first dose up to 30 days after the last dose of study treatment, up to approximately 1 year 1 month. Safety population included all participants enrolled in Phase 1b of this study, except for those who (a) dropped out prior to receiving study drug, or (b) were without any safety assessments after the first dose of study drug. Treatment-emergent AEs, (onset date or worsening in severity from baseline after first dose of study drug), were reported.

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