Trial Outcomes & Findings for Study to Assess the Effect of AZD9291 on the Blood Levels of Simvastatin in Patients With EGFRm+ NSCLC (NCT NCT02197234)

NCT ID: NCT02197234

Last Updated: 2025-11-20

Results Overview

Pharmacokinetics of simvastatin by assessment of maximum plasma simvastatin concentration

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 52 participants
• Primary outcome timeframe: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A
• Results posted on: 2025-11-20

Participant Flow

First patient enrolled: 22 December 2014; Last Subject Last Visit Part A: 30 April 2015 and Part B: 13 May 2016. Study performed at 17 sites across Asia, North America and Western Europe. Part A assessed effect of multiple doses of AZD9291 on PK of simvastatin; Part B allowed subjects further access to AZD9291 and provided additional safety data.

57 patients were enrolled (signed informed consent). Patients were assigned to treatment if they met all the inclusion and none of the exclusion criteria. 5 patients were enrolled but failed inclusion/exclusion criteria and so were not eligible to be assigned treatment. The remaining 52 patients started Period 1 and received treatment.

Participant milestones

Measure	Simvastatin and AZD9291 (Part A); AZD9291 Alone (Part B) In Part A of the study, sequential treatments of simvastatin alone followed by AZD9291 alone, followed by simvastatin + AZD9291. Each patient received 80 mg oral doses of AZD9291 tablets once daily for 30 days (Days 3 to 32) and single 40 mg oral doses of simvastatin on Day 1 and Day 31. In Part B of the study, each patient received 80 mg oral AZD9291 tablet formulation once daily, for the duration of their participation.
Part A: Day 1-2 (Simvastatin Alone) STARTED	52
Part A: Day 1-2 (Simvastatin Alone) COMPLETED	52
Part A: Day 1-2 (Simvastatin Alone) NOT COMPLETED	0
Part A: Day 3-30 (AZD9291 Alone) STARTED	52
Part A: Day 3-30 (AZD9291 Alone) COMPLETED	50
Part A: Day 3-30 (AZD9291 Alone) NOT COMPLETED	2
Part A: Day 31-32 (Simvastatin+AZD9291) STARTED	49
Part A: Day 31-32 (Simvastatin+AZD9291) COMPLETED	49
Part A: Day 31-32 (Simvastatin+AZD9291) NOT COMPLETED	0
Part B: Day 33 to End Part B (AZD9291) STARTED	50
Part B: Day 33 to End Part B (AZD9291) COMPLETED	20
Part B: Day 33 to End Part B (AZD9291) NOT COMPLETED	30

Reasons for withdrawal

Measure	Simvastatin and AZD9291 (Part A); AZD9291 Alone (Part B) In Part A of the study, sequential treatments of simvastatin alone followed by AZD9291 alone, followed by simvastatin + AZD9291. Each patient received 80 mg oral doses of AZD9291 tablets once daily for 30 days (Days 3 to 32) and single 40 mg oral doses of simvastatin on Day 1 and Day 31. In Part B of the study, each patient received 80 mg oral AZD9291 tablet formulation once daily, for the duration of their participation.
Part A: Day 3-30 (AZD9291 Alone) Condition under investigation worsened	1
Part A: Day 3-30 (AZD9291 Alone) Withdrawal by Subject	1
Part B: Day 33 to End Part B (AZD9291) Adverse Event	1
Part B: Day 33 to End Part B (AZD9291) Withdrawal by Subject	1
Part B: Day 33 to End Part B (AZD9291) Death	6
Part B: Day 33 to End Part B (AZD9291) Condition under investigation worsened	22

Baseline Characteristics

Study to Assess the Effect of AZD9291 on the Blood Levels of Simvastatin in Patients With EGFRm+ NSCLC

Baseline characteristics by cohort

Measure	Simvastatin and AZD9291 (Part A); AZD9291 Alone (Part B) n=52 Participants In Part A of the study, sequential treatments of simvastatin alone followed by AZD9291 alone, followed by simvastatin + AZD9291. Each patient received 80 mg oral doses of AZD9291 tablets once daily for 30 days (Days 3 to 32) and single 40 mg oral doses of simvastatin on Day 1 and Day 31. In Part B of the study, each patient received 80 mg oral AZD9291 tablet formulation once daily, for the duration of their participation.
Age, Continuous	63.5 years STANDARD_DEVIATION 11.28
Sex: Female, Male Female	37 Participants
Sex: Female, Male Male	15 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	17 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Black or African American	0 Participants
Race (NIH/OMB) White	35 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants

PRIMARY outcome

Timeframe: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Population: Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.

Pharmacokinetics of simvastatin by assessment of maximum plasma simvastatin concentration

Outcome measures

Measure	Simvastatin Alone n=46 Participants Simvastatin (CYP substrate) 40mg taken as single dose on Day 1.	AZD9291 + Simvastatin n=43 Participants AZD9291 80 mg once daily on Days 3 to 32; Simvastatin 40 mg on Day 31.
Cmax of Simvastatin	24.54 ng/mL Interval 2.69 to 75.5	18.65 ng/mL Interval 3.87 to 141.0

PRIMARY outcome

Timeframe: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Population: Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.

Pharmacokinetics of simvastatin by assessment of area under the plasma concentration time curve from zero to infinity

Outcome measures

Measure	Simvastatin Alone n=46 Participants Simvastatin (CYP substrate) 40mg taken as single dose on Day 1.	AZD9291 + Simvastatin n=41 Participants AZD9291 80 mg once daily on Days 3 to 32; Simvastatin 40 mg on Day 31.
AUC of Simvastatin	80.25 ng.h/mL Interval 23.9 to 289.0	73.54 ng.h/mL Interval 25.2 to 488.0

SECONDARY outcome

Timeframe: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Population: Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.

Pharmacokinetics of simvastatin and simvastatin acid by time to Cmax

Outcome measures

Measure	Simvastatin Alone n=46 Participants Simvastatin (CYP substrate) 40mg taken as single dose on Day 1.	AZD9291 + Simvastatin n=43 Participants AZD9291 80 mg once daily on Days 3 to 32; Simvastatin 40 mg on Day 31.
Tmax of Simvastatin and Simvastatin Acid Simvastatin	1.50 hours Interval 0.45 to 4.0	1.50 hours Interval 0.5 to 10.0
Tmax of Simvastatin and Simvastatin Acid Simvastatin acid	3.08 hours Interval 0.5 to 10.0	3.08 hours Interval 1.5 to 12.45

SECONDARY outcome

Timeframe: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Population: Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.

Rate and extent of absorption of simvastatin by assessment of apparent clearance following oral administration

Outcome measures

Measure	Simvastatin Alone n=46 Participants Simvastatin (CYP substrate) 40mg taken as single dose on Day 1.	AZD9291 + Simvastatin n=41 Participants AZD9291 80 mg once daily on Days 3 to 32; Simvastatin 40 mg on Day 31.
CL/F of Simvastatin	498.3 L/h Interval 138.0 to 1670.0	543.9 L/h Interval 82.0 to 1590.0

SECONDARY outcome

Timeframe: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Population: Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.

Pharmacokinetics of simvastatin acid by assessment of maximum plasma simvastatin acid concentration

Outcome measures

Measure	Simvastatin Alone n=46 Participants Simvastatin (CYP substrate) 40mg taken as single dose on Day 1.	AZD9291 + Simvastatin n=43 Participants AZD9291 80 mg once daily on Days 3 to 32; Simvastatin 40 mg on Day 31.
Cmax of Simvastatin Acid	4.187 ng/mL Interval 0.482 to 68.5	4.161 ng/mL Interval 0.849 to 66.9

SECONDARY outcome

Timeframe: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Population: Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.

Pharmacokinetics of simvastatin acid by assessment of area under the plasma concentration time curve from zero to infinity

Outcome measures

Measure	Simvastatin Alone n=42 Participants Simvastatin (CYP substrate) 40mg taken as single dose on Day 1.	AZD9291 + Simvastatin n=37 Participants AZD9291 80 mg once daily on Days 3 to 32; Simvastatin 40 mg on Day 31.
AUC of Simvastatin Acid	31.18 ng.h/mL Interval 6.19 to 436.0	30.16 ng.h/mL Interval 6.69 to 443.0

SECONDARY outcome

Timeframe: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Population: Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.

Pharmacokinetics of simvastatin and simvastatin acid by assessment of area under the plasma concentration time curve from time zero to last quantifiable dose

Outcome measures

Measure	Simvastatin Alone n=46 Participants Simvastatin (CYP substrate) 40mg taken as single dose on Day 1.	AZD9291 + Simvastatin n=43 Participants AZD9291 80 mg once daily on Days 3 to 32; Simvastatin 40 mg on Day 31.
AUC(0-t) of Simvastatin and Simvastatin Acid Simvastatin acid	29.25 ng.h/mL Interval 5.71 to 435.0	29.60 ng.h/mL Interval 6.34 to 442.0
AUC(0-t) of Simvastatin and Simvastatin Acid Simvastatin	77.97 ng.h/mL Interval 21.6 to 279.0	70.17 ng.h/mL Interval 24.9 to 470.0

Adverse Events

Overall Safety Population

Serious events: 11 serious events

Other events: 50 other events

Deaths: 5 deaths

Part A Safety Population

Serious events: 4 serious events

Other events: 39 other events

Deaths: 0 deaths

Part B Safety Population

Serious events: 8 serious events

Other events: 45 other events

Deaths: 8 deaths

Serious adverse events

Measure	Overall Safety Population n=52 participants at risk Parts A and B of the study combined.	Part A Safety Population n=52 participants at risk In Part A of the study, each patient received 80 mg oral doses of AZD9291 tablets once daily for 30 days (Days 3 to 32) and single 40 mg oral doses of simvastatin on Day 1 and Day 31.	Part B Safety Population n=50 participants at risk In Part B of the study, each patient received 80 mg oral AZD9291 tablet formulation once daily, for the duration of their participation.
Cardiac disorders Bundle branch block left	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/50 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Cardiac disorders Left ventricular dysfunction	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/52 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	2.0% 1/50 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Gastrointestinal disorders Pancreatitis acute	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/52 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	2.0% 1/50 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Infections and infestations Infectious pleural effusion	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/50 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Injury, poisoning and procedural complications Pneumonitis chemical	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/52 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	2.0% 1/50 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Injury, poisoning and procedural complications Spinal compression fracture	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/52 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	2.0% 1/50 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Investigations General physical condition abnormal	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/52 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	2.0% 1/50 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Myelodysplastic syndrome	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/50 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Nervous system disorders Thrombotic stroke	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/52 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	2.0% 1/50 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Respiratory, thoracic and mediastinal disorders Acute pulmonary oedema	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/52 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	2.0% 1/50 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/52 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	2.0% 1/50 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Respiratory, thoracic and mediastinal disorders Respiratory failure	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/52 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	2.0% 1/50 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Vascular disorders Thrombophlebitis	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/50 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Vascular disorders Vasculitis	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/52 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	2.0% 1/50 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).

Other adverse events

Measure	Overall Safety Population n=52 participants at risk Parts A and B of the study combined.	Part A Safety Population n=52 participants at risk In Part A of the study, each patient received 80 mg oral doses of AZD9291 tablets once daily for 30 days (Days 3 to 32) and single 40 mg oral doses of simvastatin on Day 1 and Day 31.	Part B Safety Population n=50 participants at risk In Part B of the study, each patient received 80 mg oral AZD9291 tablet formulation once daily, for the duration of their participation.
Blood and lymphatic system disorders Anaemia	11.5% 6/52 • Number of events 8 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	3.8% 2/52 • Number of events 2 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	10.0% 5/50 • Number of events 6 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Blood and lymphatic system disorders Lymphopenia	7.7% 4/52 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	6.0% 3/50 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Blood and lymphatic system disorders Neutropenia	9.6% 5/52 • Number of events 7 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	3.8% 2/52 • Number of events 2 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	6.0% 3/50 • Number of events 5 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Gastrointestinal disorders Abdominal pain upper	9.6% 5/52 • Number of events 6 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	8.0% 4/50 • Number of events 5 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Gastrointestinal disorders Constipation	17.3% 9/52 • Number of events 12 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	7.7% 4/52 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	12.0% 6/50 • Number of events 8 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Gastrointestinal disorders Diarrhoea	40.4% 21/52 • Number of events 22 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	15.4% 8/52 • Number of events 9 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	26.0% 13/50 • Number of events 13 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Gastrointestinal disorders Nausea	21.2% 11/52 • Number of events 14 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	11.5% 6/52 • Number of events 6 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	16.0% 8/50 • Number of events 8 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Gastrointestinal disorders Stomatitis	7.7% 4/52 • Number of events 6 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	5.8% 3/52 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	4.0% 2/50 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Gastrointestinal disorders Vomiting	11.5% 6/52 • Number of events 6 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	10.0% 5/50 • Number of events 5 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
General disorders Asthenia	21.2% 11/52 • Number of events 22 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	7.7% 4/52 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	18.0% 9/50 • Number of events 18 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
General disorders Fatigue	19.2% 10/52 • Number of events 11 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	7.7% 4/52 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	14.0% 7/50 • Number of events 7 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
General disorders Non-cardiac chest pain	7.7% 4/52 • Number of events 5 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	3.8% 2/52 • Number of events 2 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	6.0% 3/50 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
General disorders Oedema peripheral	13.5% 7/52 • Number of events 9 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	5.8% 3/52 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	8.0% 4/50 • Number of events 6 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
General disorders Xerosis	9.6% 5/52 • Number of events 5 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	9.6% 5/52 • Number of events 5 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/50 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Infections and infestations Bronchitis	7.7% 4/52 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	6.0% 3/50 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Infections and infestations Nasopharyngitis	13.5% 7/52 • Number of events 7 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	3.8% 2/52 • Number of events 2 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	10.0% 5/50 • Number of events 5 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Infections and infestations Paronychia	21.2% 11/52 • Number of events 16 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	5.8% 3/52 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	16.0% 8/50 • Number of events 13 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Infections and infestations Respiratory tract infection	7.7% 4/52 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/52 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	8.0% 4/50 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Infections and infestations Upper respiratory tract infection	9.6% 5/52 • Number of events 5 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	8.0% 4/50 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Investigations Alanine aminotransferase increased	7.7% 4/52 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	6.0% 3/50 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Investigations Blood creatine phosphokinase increased	5.8% 3/52 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/52 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	6.0% 3/50 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Investigations Blood creatinine increased	9.6% 5/52 • Number of events 5 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	5.8% 3/52 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	4.0% 2/50 • Number of events 2 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Metabolism and nutrition disorders Decreased appetite	23.1% 12/52 • Number of events 15 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	9.6% 5/52 • Number of events 5 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	14.0% 7/50 • Number of events 10 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Metabolism and nutrition disorders Hyperglycaemia	5.8% 3/52 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/52 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	6.0% 3/50 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Musculoskeletal and connective tissue disorders Arthralgia	13.5% 7/52 • Number of events 8 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	12.0% 6/50 • Number of events 7 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Musculoskeletal and connective tissue disorders Back pain	9.6% 5/52 • Number of events 5 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	8.0% 4/50 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Musculoskeletal and connective tissue disorders Muscle spasms	19.2% 10/52 • Number of events 10 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	18.0% 9/50 • Number of events 9 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	7.7% 4/52 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	6.0% 3/50 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Musculoskeletal and connective tissue disorders Musculoskeletal pain	5.8% 3/52 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/52 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	6.0% 3/50 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Musculoskeletal and connective tissue disorders Neck pain	9.6% 5/52 • Number of events 5 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/52 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	10.0% 5/50 • Number of events 5 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Nervous system disorders Headache	15.4% 8/52 • Number of events 8 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	3.8% 2/52 • Number of events 2 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	12.0% 6/50 • Number of events 6 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Nervous system disorders Hypoaesthesia	5.8% 3/52 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/52 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	6.0% 3/50 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Nervous system disorders Paraesthesia	5.8% 3/52 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/52 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	6.0% 3/50 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Psychiatric disorders Insomnia	9.6% 5/52 • Number of events 5 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	5.8% 3/52 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	4.0% 2/50 • Number of events 2 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Renal and urinary disorders Dysuria	5.8% 3/52 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/52 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	6.0% 3/50 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Respiratory, thoracic and mediastinal disorders Cough	32.7% 17/52 • Number of events 21 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	7.7% 4/52 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	28.0% 14/50 • Number of events 17 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Respiratory, thoracic and mediastinal disorders Dyspnoea	11.5% 6/52 • Number of events 6 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	5.8% 3/52 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	6.0% 3/50 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Respiratory, thoracic and mediastinal disorders Epistaxis	9.6% 5/52 • Number of events 6 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	3.8% 2/52 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	6.0% 3/50 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Respiratory, thoracic and mediastinal disorders Nasal inflammation	5.8% 3/52 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/52 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	6.0% 3/50 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Respiratory, thoracic and mediastinal disorders Productive cough	9.6% 5/52 • Number of events 5 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/52 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	10.0% 5/50 • Number of events 5 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	11.5% 6/52 • Number of events 6 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	0.00% 0/52 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	12.0% 6/50 • Number of events 6 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Skin and subcutaneous tissue disorders Dermatitis acneiform	13.5% 7/52 • Number of events 12 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	7.7% 4/52 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	10.0% 5/50 • Number of events 8 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Skin and subcutaneous tissue disorders Dry skin	21.2% 11/52 • Number of events 19 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	11.5% 6/52 • Number of events 6 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	18.0% 9/50 • Number of events 13 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Skin and subcutaneous tissue disorders Pruritus	17.3% 9/52 • Number of events 9 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	7.7% 4/52 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	10.0% 5/50 • Number of events 5 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Skin and subcutaneous tissue disorders Rash macular	7.7% 4/52 • Number of events 6 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	3.8% 2/52 • Number of events 2 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	8.0% 4/50 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Skin and subcutaneous tissue disorders Rash papular	5.8% 3/52 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	1.9% 1/52 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	6.0% 3/50 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).
Vascular disorders Hypertension	7.7% 4/52 • Number of events 4 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	5.8% 3/52 • Number of events 3 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).	2.0% 1/50 • Number of events 1 • Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined). Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A. Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).

Additional Information

Dr Karen So

AstraZeneca

Email: ClinicalTrialTransparency@astrazeneca.com

Results disclosure agreements

• Principal investigator is a sponsor employee The Principal Investigator (PI) agrees to collaborate on the contents and formation of any publication and to pay due consideration to comments and opinions offered. AstraZeneca have 30 days for final manuscript review and may require that submission for publication be delayed in order to file patent application.
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