Trial Outcomes & Findings for Pyronaridine Artesunate 3:1 Granule Formulation vs. Coartem© Crushed Tablets in P. Falciparum Malaria Pediatric Patients (NCT NCT00541385)

Last Updated: 2021-11-22

Results Overview

Percentage of patients with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 28. The PCR-corrected ACPR on Day 28 is defined as the absence of parasitaemia on Day 28 without the patient's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

535 participants

Primary outcome timeframe

Day 28

Results posted on

2021-11-22

Participant Flow

Participant milestones

Participant milestones
Measure	PA Group Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	AL Group Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.
Overall Study STARTED	355	180
Overall Study COMPLETED	274	142
Overall Study NOT COMPLETED	81	38

Reasons for withdrawal

Reasons for withdrawal
Measure	PA Group Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	AL Group Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.
Overall Study Adverse Event	6	3
Overall Study Withdrawal by Subject	2	2
Overall Study Lost to Follow-up	6	1
Overall Study Parasite reappearance/malaria	67	32

Baseline Characteristics

Pyronaridine Artesunate 3:1 Granule Formulation vs. Coartem© Crushed Tablets in P. Falciparum Malaria Pediatric Patients

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	PA Group n=355 Participants Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	AL Group n=180 Participants Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	Total n=535 Participants Total of all reporting groups
Age, Continuous	4.9 years STANDARD_DEVIATION 2.47 • n=5 Participants	5.3 years STANDARD_DEVIATION 2.52 • n=7 Participants	5.0 years STANDARD_DEVIATION 2.49 • n=5 Participants
Age, Customized <1 year	12 Participants n=5 Participants	3 Participants n=7 Participants	15 Participants n=5 Participants
Age, Customized 1-<5 years	148 Participants n=5 Participants	69 Participants n=7 Participants	217 Participants n=5 Participants
Age, Customized 5-12 years	195 Participants n=5 Participants	108 Participants n=7 Participants	303 Participants n=5 Participants
Sex: Female, Male Female	178 Participants n=5 Participants	96 Participants n=7 Participants	274 Participants n=5 Participants
Sex: Female, Male Male	177 Participants n=5 Participants	84 Participants n=7 Participants	261 Participants n=5 Participants
Race/Ethnicity, Customized Black	342 Participants n=5 Participants	172 Participants n=7 Participants	514 Participants n=5 Participants
Race/Ethnicity, Customized Asian/Oriental	13 Participants n=5 Participants	8 Participants n=7 Participants	21 Participants n=5 Participants
Region of Enrollment Gabon	53 participants n=5 Participants	27 participants n=7 Participants	80 participants n=5 Participants
Region of Enrollment Burkina Faso	19 participants n=5 Participants	9 participants n=7 Participants	28 participants n=5 Participants
Region of Enrollment Mali	86 participants n=5 Participants	44 participants n=7 Participants	130 participants n=5 Participants
Region of Enrollment Philippines	13 participants n=5 Participants	7 participants n=7 Participants	20 participants n=5 Participants
Region of Enrollment Congo, The Democratic Republic of the	56 participants n=5 Participants	28 participants n=7 Participants	84 participants n=5 Participants
Region of Enrollment Côte D'Ivoire	72 participants n=5 Participants	35 participants n=7 Participants	107 participants n=5 Participants
Region of Enrollment Kenya	56 participants n=5 Participants	30 participants n=7 Participants	86 participants n=5 Participants

PRIMARY outcome

Timeframe: Day 28

Population: Efficacy evaluable population: patients who completed a full course of study medication and had a known primary efficacy endpoint at D28; did not miss a dose; did not use concomitant medication, except acetaminophen; did not have a concomitant disease which may interfere with the clear classification of the treatment outcome; did not have a major protocol deviation.C

Outcome measures

Outcome measures
Measure	PA Group n=337 Participants Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	AL Group n=167 Participants Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.
Percentage of Participants With PCR-Corrected ACPR on Day 28	97.6 percentage of cured subjects Interval 95.4 to 99.0	98.8 percentage of cured subjects Interval 95.7 to 99.9

SECONDARY outcome

Timeframe: Day 14

Percentage of subjects with PCR-corrected adequate clinical and parasitological response (ACPR) on Day 14. The PCR-corrected ACPR on Day 14 is defined as the absence of parasitaemia on Day 14 without the subject's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure

Outcome measures

Outcome measures
Measure	PA Group n=337 Participants Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	AL Group n=167 Participants Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.
Percentage of Participants With PCR-Corrected ACPR on Day 14	100.0 percentage of subjects Interval 98.9 to 100.0	100.0 percentage of subjects Interval 97.8 to 100.0

SECONDARY outcome

Timeframe: Days 14 and 28

Percentage of subjects with adequate clinical and parasitological response (ACPR) on Day 14 and 28, without correction by PCR. Crude ACPR on Day 14 and 28 is defined as the absence of parasitaemia on Day 14 and 28 without the subject's meeting any of the criteria of early treatment failure, late clinical failure, or late parasitological failure

Outcome measures

Outcome measures
Measure	PA Group n=337 Participants Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	AL Group n=167 Participants Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.
Crude ACPR (Non-PCR Corrected ACPR) (Crude Cure Rate) on Day 14 and Day 28 Percentage of Participants with ACPR at Day 14	100 percentage of subjects Interval 98.9 to 100.0	100 percentage of subjects Interval 97.8 to 100.0
Crude ACPR (Non-PCR Corrected ACPR) (Crude Cure Rate) on Day 14 and Day 28 Percentage of Participants with ACPR at Day 28	90.2 percentage of subjects Interval 86.5 to 93.2	89.2 percentage of subjects Interval 83.5 to 93.5

SECONDARY outcome

Timeframe: Days 0, 3, 7, 14, 21, 28, 35, and 42 or on any other day if the subject spontaneously returned within the 42-day study period

Parasite clearance time is defined as the time from first dosing to the time of first blood draw with parasite clearance. Parasite clearance was defined as zero presence of asexual parasites for 2 consecutive negative readings taken between 7 and 25 hours apart

Outcome measures

Outcome measures
Measure	PA Group n=337 Participants Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	AL Group n=167 Participants Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.
Parasite Clearance Time	24.1 hours Interval 24.0 to 24.1	24.2 hours Interval 24.0 to 31.8

SECONDARY outcome

Timeframe: Day 0 and every 8 hours over ≥72 hours following first study drug administration or temperature normalization for ≥2 readings between 7 and 25 hours apart, then at each visit and as clinically indicated (within the 42-day study period)

Population: Efficacy evaluable population\*: patients who completed a full course of study medication and had a known primary efficacy endpoint at D28; did not miss a dose; did not use concomitant medication, except acetaminophen; did not have a concomitant disease which may interfere with the clear classification of the treatment outcome; did not have a major protocol deviation. \*does not include subjects initially included on history of fever.

Fever clearance time is defined as the time from first dosing to the first normal reading of temperature for 2 consecutive normal temperature readings taken between 7 and 25 hours apart.

Outcome measures

Outcome measures
Measure	PA Group n=264 Participants Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	AL Group n=126 Participants Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.
Fever Clearance Time	8.1 hours Interval 8.0 to 8.1	8.1 hours Interval 8.0 to 15.8

SECONDARY outcome

Timeframe: Days 1, 2, and 3

Outcome measures

Outcome measures
Measure	PA Group n=337 Participants Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	AL Group n=167 Participants Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.
Proportion of Subjects With Cleared Parasites on Days 1, 2, and 3 Percentage of Participants with parasite clearance at Day 1 (24h after first dose)	49.9 percentage of subjects Interval 44.5 to 55.2	43.7 percentage of subjects Interval 36.2 to 51.2
Proportion of Subjects With Cleared Parasites on Days 1, 2, and 3 Percentage of Participants with parasite clearance at Day 2 (48h after first dose)	95.5 percentage of subjects Interval 93.3 to 97.8	95.2 percentage of subjects Interval 92.0 to 98.4
Proportion of Subjects With Cleared Parasites on Days 1, 2, and 3 Percentage of Participants with parasite clearance at Day 3 (72h after first dose)	97.0 percentage of subjects Interval 95.2 to 98.8	98.8 percentage of subjects Interval 97.2 to 100.0

SECONDARY outcome

Timeframe: Days 1, 2, and 3

Fever clearance time is defined as the time from first dosing to the first normal reading of temperature for 2 consecutive normal temperature readings taken between 7 and 25 hours apart

Outcome measures

Outcome measures
Measure	PA Group n=264 Participants Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	AL Group n=126 Participants Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.
Proportion of Subjects With Fever Cleared on Days 1, 2, and 3 Percentage of Participants with fever clearance at Day 1 (24h after first dose)	87.1 percentage of subjects Interval 83.1 to 91.2	81.0 percentage of subjects Interval 74.1 to 87.8
Proportion of Subjects With Fever Cleared on Days 1, 2, and 3 Percentage of Participants with fever clearance at Day 2 (48h after first dose)	98.5 percentage of subjects Interval 97.0 to 100.0	96.8 percentage of subjects Interval 93.8 to 99.9
Proportion of Subjects With Fever Cleared on Days 1, 2, and 3 Percentage of Participants with fever clearance at Day 3 (48h after first dose)	99.6 percentage of subjects Interval 98.9 to 100.0	98.4 percentage of subjects Interval 96.2 to 100.0

SECONDARY outcome

Timeframe: Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier

Population: Safety population: all randomized subjects who received any amount of study medication. Subjects were analyzed as treated

Outcome measures

Outcome measures
Measure	PA Group n=355 Participants Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.	AL Group n=180 Participants Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology based on body weight ranges.
Number of Subjects With ≥1 Adverse Event Nr subj. with ≥1 AE	285 Participants	143 Participants
Number of Subjects With ≥1 Adverse Event Nr subj. with ≥1 treatment-related AE	132 Participants	80 Participants
Number of Subjects With ≥1 Adverse Event Nr subj. with ≥1 SAE	1 Participants	0 Participants
Number of Subjects With ≥1 Adverse Event Nr subj. with ≥1 treatment-related SAE	0 Participants	0 Participants
Number of Subjects With ≥1 Adverse Event Nr subj. with ≥1 severe or life-threatening AE	2 Participants	2 Participants
Number of Subjects With ≥1 Adverse Event Nr subj. with ≥1 AE leading to death	0 Participants	0 Participants
Number of Subjects With ≥1 Adverse Event Nr subj. ≥1 AE leading to drug discontinuation	6 Participants	3 Participants
Number of Subjects With ≥1 Adverse Event Nr subj. with ≥1 AE leading to study withdrawal	6 Participants	3 Participants

Adverse Events

PA Group

Serious events: 1 serious events

Other events: 285 other events

Deaths: 0 deaths

AL Group

Serious events: 0 serious events

Other events: 143 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	PA Group n=355 participants at risk Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology was based on body weight ranges. Subjects were randomized in a 2:1 ratio to receive either PA or AL.	AL Group n=180 participants at risk Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology was based on body weight ranges. Subjects were randomized in a 2:1 ratio to receive either PA or AL.
Infections and infestations Malaria	0.28% 1/355 • Number of events 1 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	0.00% 0/180 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier

Other adverse events

Additional Information

Stephan Duparc, MD, Chief Medical Officer

Medicines for Malaria Venture (MMV)

Phone: +41 22 555 0300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	PA Group n=355 participants at risk Oral pyronaridine/artesunate (PA, 60:20mg granules) once a day for 3 consecutive days (Days 0, 1, and 2). Posology was based on body weight ranges. Subjects were randomized in a 2:1 ratio to receive either PA or AL.	AL Group n=180 participants at risk Oral artemether/lumefantrine (AL, 20:120mg crushed tablets) twice a day for 3 consecutive days (Days 0, 1, and 2). Posology was based on body weight ranges. Subjects were randomized in a 2:1 ratio to receive either PA or AL.
Blood and lymphatic system disorders Anaemia	9.6% 34/355 • Number of events 36 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	7.8% 14/180 • Number of events 14 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Blood and lymphatic system disorders Splenomegaly	2.3% 8/355 • Number of events 8 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	2.2% 4/180 • Number of events 5 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Gastrointestinal disorders Vomiting	7.0% 25/355 • Number of events 27 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	4.4% 8/180 • Number of events 9 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Gastrointestinal disorders Abdominal pain	3.1% 11/355 • Number of events 11 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	4.4% 8/180 • Number of events 8 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
General disorders Pyrexia	6.5% 23/355 • Number of events 24 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	4.4% 8/180 • Number of events 8 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
General disorders Influenza like illness	5.4% 19/355 • Number of events 19 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	4.4% 8/180 • Number of events 8 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Infections and infestations Upper respiratory tract infection	11.8% 42/355 • Number of events 44 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	10.6% 19/180 • Number of events 19 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Infections and infestations Bronchitis	7.9% 28/355 • Number of events 31 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	5.6% 10/180 • Number of events 10 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Infections and infestations Helminthic infection	3.1% 11/355 • Number of events 11 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	1.7% 3/180 • Number of events 4 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Infections and infestations Nasopharyngitis	2.5% 9/355 • Number of events 10 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	1.7% 3/180 • Number of events 3 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Infections and infestations Rhinitis	2.3% 8/355 • Number of events 10 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	1.7% 3/180 • Number of events 3 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Infections and infestations Tinea capitis	2.0% 7/355 • Number of events 7 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	0.56% 1/180 • Number of events 1 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Infections and infestations Pneumonia	1.1% 4/355 • Number of events 4 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	2.8% 5/180 • Number of events 5 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Infections and infestations Tonsillitis	0.56% 2/355 • Number of events 2 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	2.2% 4/180 • Number of events 4 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Investigations Platelet count increased	9.3% 33/355 • Number of events 33 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	10.6% 19/180 • Number of events 19 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Investigations Blood glucose decreased	9.0% 32/355 • Number of events 32 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	10.6% 19/180 • Number of events 19 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Investigations Blood albumin decreased	5.9% 21/355 • Number of events 21 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	8.9% 16/180 • Number of events 16 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Investigations Aspartate aminotransferase increased	4.8% 17/355 • Number of events 17 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	4.4% 8/180 • Number of events 8 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Investigations Blood potassium increased	4.5% 16/355 • Number of events 16 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	3.3% 6/180 • Number of events 6 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Investigations Haematocrit decreased	4.5% 16/355 • Number of events 16 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	2.8% 5/180 • Number of events 5 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Investigations Haemoglobin decreased	4.2% 15/355 • Number of events 15 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	2.8% 5/180 • Number of events 5 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Investigations White blood cell count increased	2.5% 9/355 • Number of events 9 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	1.1% 2/180 • Number of events 2 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Investigations Alanine aminotransferase increased	2.0% 7/355 • Number of events 7 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	1.1% 2/180 • Number of events 2 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Investigations Blood creatinine decreased	2.0% 7/355 • Number of events 7 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	3.9% 7/180 • Number of events 7 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Investigations Platelet count decreased	2.0% 7/355 • Number of events 7 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	0.56% 1/180 • Number of events 1 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Nervous system disorders Headache	3.7% 13/355 • Number of events 14 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	2.8% 5/180 • Number of events 5 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Respiratory, thoracic and mediastinal disorders Cough	12.4% 44/355 • Number of events 48 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	15.6% 28/180 • Number of events 30 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier
Respiratory, thoracic and mediastinal disorders Productive cough	1.7% 6/355 • Number of events 6 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier	2.2% 4/180 • Number of events 4 • Day 0 to 42. Subjects experiencing AEs at Day 42 were followed for up to 30 days after the end of study or resolution of the event, whichever was earlier