Trial Outcomes & Findings for A Study of Prasugrel in Pediatric Participants With Sickle Cell Disease (SCD) (NCT NCT01794000)

Last Updated: 2019-09-25

Results Overview

The VOC is a composite endpoint of painful crisis or acute chest syndrome. Events that occurred within 7 days from the prior event onset date were not counted as a new episode. Data collected through the primary completion date reported below.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

341 participants

Primary outcome timeframe

Randomization through 24 Months

Results posted on

2019-09-25

Participant Flow

Participant milestones

Participant milestones
Measure	Prasugrel Participants (Pts.) will be titrated from initial daily dose of 0.08 milligram per kilogram (mg/kg) of orally administered prasugrel monotherapy at randomization to a dose that will achieve a P2Y12 reaction units (PRU) level of 231 to 136, as measured by VerifyNow instrument. This corresponds to a range of platelet inhibition of approximately 30% to 60%. The maximum possible dose allowed is 0.12 mg/kg daily, not to exceed 10 mg daily.	Placebo Participants in this treatment group will receive daily orally administered placebo and will follow visit schedule identical to that in the active treatment group.
Double-Blind Phase (DBP) STARTED	171	170
Double-Blind Phase (DBP) Received at Least One Dose of Drug	170	170
Double-Blind Phase (DBP) Discontinued During Double Blind Phase	169	166
Double-Blind Phase (DBP) COMPLETED	2	4
Double-Blind Phase (DBP) NOT COMPLETED	169	166
Open-Label Extension Phase (OLE) STARTED	3	0
Open-Label Extension Phase (OLE) COMPLETED	0	0
Open-Label Extension Phase (OLE) NOT COMPLETED	3	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Prasugrel Participants (Pts.) will be titrated from initial daily dose of 0.08 milligram per kilogram (mg/kg) of orally administered prasugrel monotherapy at randomization to a dose that will achieve a P2Y12 reaction units (PRU) level of 231 to 136, as measured by VerifyNow instrument. This corresponds to a range of platelet inhibition of approximately 30% to 60%. The maximum possible dose allowed is 0.12 mg/kg daily, not to exceed 10 mg daily.	Placebo Participants in this treatment group will receive daily orally administered placebo and will follow visit schedule identical to that in the active treatment group.
Double-Blind Phase (DBP) Adverse Event	5	2
Double-Blind Phase (DBP) Death	1	2
Double-Blind Phase (DBP) Entry Criteria Not Met	2	0
Double-Blind Phase (DBP) Parent/Caregiver Decision	5	2
Double-Blind Phase (DBP) Physician Decision	2	0
Double-Blind Phase (DBP) Sponsor Decision	148	149
Double-Blind Phase (DBP) Withdrawal by Subject	6	11
Open-Label Extension Phase (OLE) Sponsor Decision	3	0

Baseline Characteristics

A Study of Prasugrel in Pediatric Participants With Sickle Cell Disease (SCD)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Prasugrel n=171 Participants Participants will be titrated from initial daily dose of 0.08 milligram per kilogram (mg/kg) of orally administered prasugrel monotherapy at randomization to a dose that will achieve a P2Y12 reaction units (PRU) level of 231 to 136, as measured by VerifyNow instrument. This corresponds to a range of platelet inhibition of approximately 30% to 60%. The maximum possible dose allowed is 0.12 mg/kg daily, not to exceed 10 mg daily.	Placebo n=170 Participants Participants in this treatment group will receive daily orally administered placebo and will follow visit schedule identical to that in the active treatment group.	Total n=341 Participants Total of all reporting groups
Age, Continuous	10.606 years STANDARD_DEVIATION 4.334 • n=5 Participants	10.580 years STANDARD_DEVIATION 4.349 • n=7 Participants	10.593 years STANDARD_DEVIATION 4.335 • n=5 Participants
Sex: Female, Male Female	87 Participants n=5 Participants	86 Participants n=7 Participants	173 Participants n=5 Participants
Sex: Female, Male Male	84 Participants n=5 Participants	84 Participants n=7 Participants	168 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	94 Participants n=5 Participants	98 Participants n=7 Participants	192 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	75 Participants n=5 Participants	71 Participants n=7 Participants	146 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	113 Participants n=5 Participants	109 Participants n=7 Participants	222 Participants n=5 Participants
Race (NIH/OMB) White	58 Participants n=5 Participants	58 Participants n=7 Participants	116 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment United States	23 participants n=5 Participants	25 participants n=7 Participants	48 participants n=5 Participants
Region of Enrollment Egypt	23 participants n=5 Participants	22 participants n=7 Participants	45 participants n=5 Participants
Region of Enrollment United Kingdom	5 participants n=5 Participants	4 participants n=7 Participants	9 participants n=5 Participants
Region of Enrollment Ghana	29 participants n=5 Participants	28 participants n=7 Participants	57 participants n=5 Participants
Region of Enrollment Kenya	47 participants n=5 Participants	44 participants n=7 Participants	91 participants n=5 Participants
Region of Enrollment Oman	2 participants n=5 Participants	4 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment Lebanon	8 participants n=5 Participants	8 participants n=7 Participants	16 participants n=5 Participants
Region of Enrollment Saudi Arabia	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Region of Enrollment Canada	4 participants n=5 Participants	4 participants n=7 Participants	8 participants n=5 Participants
Region of Enrollment Turkey	20 participants n=5 Participants	22 participants n=7 Participants	42 participants n=5 Participants
Region of Enrollment Belgium	1 participants n=5 Participants	2 participants n=7 Participants	3 participants n=5 Participants
Region of Enrollment Brazil	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants
Region of Enrollment Italy	7 participants n=5 Participants	7 participants n=7 Participants	14 participants n=5 Participants
Hydroxyurea Use at Baseline Yes	77 participants n=5 Participants	76 participants n=7 Participants	153 participants n=5 Participants
Hydroxyurea Use at Baseline No	94 participants n=5 Participants	94 participants n=7 Participants	188 participants n=5 Participants

PRIMARY outcome

Timeframe: Randomization through 24 Months

Population: All randomized participants.

Outcome measures

Outcome measures
Measure	Prasugrel n=171 Participants Participants will be titrated from initial daily dose of 0.08 milligram per kilogram (mg/kg) of orally administered prasugrel monotherapy at randomization to a dose that will achieve a P2Y12 reaction units (PRU) level of 231 to 136, as measured by VerifyNow instrument. This corresponds to a range of platelet inhibition of approximately 30% to 60%. The maximum possible dose allowed is 0.12 mg/kg daily, not to exceed 10 mg daily.	Placebo n=170 Participants Participants in this treatment group will receive daily orally administered placebo and will follow visit schedule identical to that in the active treatment group.
Number of Vaso-Occlusive Crisis (VOC) Events Per Participant Per Year (Rate of VOC)	2.295 Number of Events per Participant-Year	2.767 Number of Events per Participant-Year

SECONDARY outcome

Timeframe: Randomization through 9 Months

Population: All randomized participants who are 7 years or older and have both baseline and at least one post-baseline monthly outcome measure in any month. This is the Sickle cell population in which content validity has been established for the FPS-R.

Monthly rate of days with pain was measured through participant diaries using a modified version of the Faces Pain Scale-Revised (FPS-R). Each day participants selected the face on the scale that reflected their worst pain related to sickle cell disease (SCD) on that day. This pain scale contains six faces corresponding to the pain intensity of 0, 2, 4, 6, 8 or 10, in which 0 denotes no pain and 10 denotes the worst pain possible. Any day the participant selected a face other than face 0 was considered a day with pain. Monthly rate of days with pain was calculated for each participant by summing the number of days reported with any pain divided by the number of non-missing diary entries completed in the month. A month was defined as 4 weeks (28 days).The monthly rate was set to missing if there were more than 14 missing entries for the FPS-R in a specific month. Data collected through the primary completion date are present below.

Outcome measures

Outcome measures
Measure	Prasugrel n=127 Participants Participants will be titrated from initial daily dose of 0.08 milligram per kilogram (mg/kg) of orally administered prasugrel monotherapy at randomization to a dose that will achieve a P2Y12 reaction units (PRU) level of 231 to 136, as measured by VerifyNow instrument. This corresponds to a range of platelet inhibition of approximately 30% to 60%. The maximum possible dose allowed is 0.12 mg/kg daily, not to exceed 10 mg daily.	Placebo n=127 Participants Participants in this treatment group will receive daily orally administered placebo and will follow visit schedule identical to that in the active treatment group.
Monthly Rate of Days With Pain	17.457 Percentage of Days in a Month Standard Error 1.558	17.699 Percentage of Days in a Month Standard Error 1.551

SECONDARY outcome

Timeframe: Randomization through 9 Months

Each day participants selected the face on the FPS-R scale that reflected their worst pain related to sickle cell disease (SCD) on that day. Monthly mean in FPS-R score was calculated for each participant by summing the FPS-R score divided by the number of non-missing diary entries completed in the month. This pain scale contains six faces corresponding to the pain intensity of 0, 2, 4, 6, 8 or 10, in which 0 denotes no pain and 10 denotes the worst pain possible. A month was defined as 4 weeks (28 days). The monthly mean in FPS-R score was set to missing if there were more than 14 missing entries for the FPS-R in a specific month. Data collected through the primary completion date are presented below.

Outcome measures

Outcome measures
Measure	Prasugrel n=127 Participants Participants will be titrated from initial daily dose of 0.08 milligram per kilogram (mg/kg) of orally administered prasugrel monotherapy at randomization to a dose that will achieve a P2Y12 reaction units (PRU) level of 231 to 136, as measured by VerifyNow instrument. This corresponds to a range of platelet inhibition of approximately 30% to 60%. The maximum possible dose allowed is 0.12 mg/kg daily, not to exceed 10 mg daily.	Placebo n=127 Participants Participants in this treatment group will receive daily orally administered placebo and will follow visit schedule identical to that in the active treatment group.
Monthly Mean in Faces Pain Scale-Revised Score	0.7116 Units on a Scale Standard Error 0.0757	0.6148 Units on a Scale Standard Error 0.0753

SECONDARY outcome

Timeframe: Randomization through 24 Months

Population: All randomized participants.

A painful crisis is defined as an onset of moderate to severe pain that lasts at least 2 hours for which there is no explanation other than vaso-occlusion and which requires therapy with oral or parenteral opioids, ketorolac, or other analgesics prescribed by a health care provider (HCP) in a medical setting such as a hospital, clinic, emergency room visit, or telephone management. The painful crisis that occurred within 7 days from the prior event onset date was not counted as a new episode. Data collected through the primary completion date are presented below.

Outcome measures

Outcome measures
Measure	Prasugrel n=171 Participants Participants will be titrated from initial daily dose of 0.08 milligram per kilogram (mg/kg) of orally administered prasugrel monotherapy at randomization to a dose that will achieve a P2Y12 reaction units (PRU) level of 231 to 136, as measured by VerifyNow instrument. This corresponds to a range of platelet inhibition of approximately 30% to 60%. The maximum possible dose allowed is 0.12 mg/kg daily, not to exceed 10 mg daily.	Placebo n=170 Participants Participants in this treatment group will receive daily orally administered placebo and will follow visit schedule identical to that in the active treatment group.
Number of Painful Crisis Events Per Participant Per Year (Rate of Painful Crisis)	2.239 Number of Events per Participant-Year	2.720 Number of Events per Participant-Year

SECONDARY outcome

Timeframe: Randomization through 24 Months

Population: All randomized participants.

Hospitalization that occurred within 7 days of the prior event onset date were not counted as a new episode. Data collected through the primary completion date are presented below.

Outcome measures

Outcome measures
Measure	Prasugrel n=171 Participants Participants will be titrated from initial daily dose of 0.08 milligram per kilogram (mg/kg) of orally administered prasugrel monotherapy at randomization to a dose that will achieve a P2Y12 reaction units (PRU) level of 231 to 136, as measured by VerifyNow instrument. This corresponds to a range of platelet inhibition of approximately 30% to 60%. The maximum possible dose allowed is 0.12 mg/kg daily, not to exceed 10 mg daily.	Placebo n=170 Participants Participants in this treatment group will receive daily orally administered placebo and will follow visit schedule identical to that in the active treatment group.
Number of Hospitalizations for VOC Per Participant Per Year (Rate of Hospitalizations)	1.064 Number of Events per Participant-Year	1.126 Number of Events per Participant-Year

SECONDARY outcome

Timeframe: Randomization through 24 Months

Population: All randomized participants.

Acute chest syndrome was defined as an acute illness characterized by fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on a chest X-ray. Acute chest syndrome that occurred within 7 days of the prior event onset date was not counted as a new episode. Data collected through the primary completion date are presented below.

Outcome measures

Outcome measures
Measure	Prasugrel n=171 Participants Participants will be titrated from initial daily dose of 0.08 milligram per kilogram (mg/kg) of orally administered prasugrel monotherapy at randomization to a dose that will achieve a P2Y12 reaction units (PRU) level of 231 to 136, as measured by VerifyNow instrument. This corresponds to a range of platelet inhibition of approximately 30% to 60%. The maximum possible dose allowed is 0.12 mg/kg daily, not to exceed 10 mg daily.	Placebo n=170 Participants Participants in this treatment group will receive daily orally administered placebo and will follow visit schedule identical to that in the active treatment group.
Number of Acute Chest Syndrome Per Participant Per Year (Rate of Acute Chest Syndrome)	0.112 Number of Events per Participant-Year	0.115 Number of Events per Participant-Year

SECONDARY outcome

Timeframe: Randomization through 24 Months

Population: All randomized participants.

RBC transfusions that occurred within 7 days of the prior event onset date were not counted as a new episode. Data collected through the primary completion date are presented below.

Outcome measures

Outcome measures
Measure	Prasugrel n=171 Participants Participants will be titrated from initial daily dose of 0.08 milligram per kilogram (mg/kg) of orally administered prasugrel monotherapy at randomization to a dose that will achieve a P2Y12 reaction units (PRU) level of 231 to 136, as measured by VerifyNow instrument. This corresponds to a range of platelet inhibition of approximately 30% to 60%. The maximum possible dose allowed is 0.12 mg/kg daily, not to exceed 10 mg daily.	Placebo n=170 Participants Participants in this treatment group will receive daily orally administered placebo and will follow visit schedule identical to that in the active treatment group.
Number of Red Blood Cell (RBC) Transfusions Due to Sickle Cell Disease (SCD) Per Participant Per Year (Rate of RBC Transfusions)	0.497 Number of Events per Participant-Year	0.420 Number of Events per Participant-Year

SECONDARY outcome

Timeframe: Randomization through 9 Months

Population: All randomized participants who are 4 years or older and have baseline and at least one post-baseline monthly outcome measure in any month. Diaries were only provided to participants 4 years and older.

Monthly rate of days of analgesic use was measured through participant diaries and was calculated for each participant by summing the number of days they reported analgesic use divided by the number of diary entries completed in the month. A month was defined as 4 weeks (28 days). The monthly rate was set to missing if there were more than 14 missing entries for analgesic use in a specific month. Data collected through the primary completion date are presented below.

Outcome measures

Outcome measures
Measure	Prasugrel n=153 Participants Participants will be titrated from initial daily dose of 0.08 milligram per kilogram (mg/kg) of orally administered prasugrel monotherapy at randomization to a dose that will achieve a P2Y12 reaction units (PRU) level of 231 to 136, as measured by VerifyNow instrument. This corresponds to a range of platelet inhibition of approximately 30% to 60%. The maximum possible dose allowed is 0.12 mg/kg daily, not to exceed 10 mg daily.	Placebo n=153 Participants Participants in this treatment group will receive daily orally administered placebo and will follow visit schedule identical to that in the active treatment group.
Monthly Rate of Days of Analgesic Use	24.270 Percentage of Days in a Month Standard Error 2.290	22.757 Percentage of Days in a Month Standard Error 2.337

SECONDARY outcome

Timeframe: Randomization through 9 Months

Population: All Randomized participants who are 4 years or older and have both baseline and at least one post-baseline quarterly outcome measure in any quarter. Diaries were only provided to participants 4 years and older.

Quarterly rate of school absence due to sickle cell pain was measured through participant diaries and was calculated for each participant by summing the number of days with school absence due to sickle cell pain divided by the number of school dates in the quarter. A quarter was defined as 12 weeks. The quarterly rate was set to missing if there were more than 6 weeks of missing diary entries during a specific quarter. Data collected through the primary completion date are presented below.

Outcome measures

Outcome measures
Measure	Prasugrel n=105 Participants Participants will be titrated from initial daily dose of 0.08 milligram per kilogram (mg/kg) of orally administered prasugrel monotherapy at randomization to a dose that will achieve a P2Y12 reaction units (PRU) level of 231 to 136, as measured by VerifyNow instrument. This corresponds to a range of platelet inhibition of approximately 30% to 60%. The maximum possible dose allowed is 0.12 mg/kg daily, not to exceed 10 mg daily.	Placebo n=115 Participants Participants in this treatment group will receive daily orally administered placebo and will follow visit schedule identical to that in the active treatment group.
Quarterly Rate of School Absence Due to Sickle Cell Pain	11.527 Percentage of Days in a Quarter Standard Error 1.525	10.255 Percentage of Days in a Quarter Standard Error 1.466

SECONDARY outcome

Timeframe: Randomization through 24 Months

Population: No participants had a TIA or ischemic stroke at time of analysis.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Randomization through 24 Months

Population: All randomized participants who were hospitalized for VOC.

The total length of hospitalization in days for VOC was calculated for each participant. Data collected through the primary completion date are presented below.

Outcome measures

Outcome measures
Measure	Prasugrel n=69 Participants Participants will be titrated from initial daily dose of 0.08 milligram per kilogram (mg/kg) of orally administered prasugrel monotherapy at randomization to a dose that will achieve a P2Y12 reaction units (PRU) level of 231 to 136, as measured by VerifyNow instrument. This corresponds to a range of platelet inhibition of approximately 30% to 60%. The maximum possible dose allowed is 0.12 mg/kg daily, not to exceed 10 mg daily.	Placebo n=76 Participants Participants in this treatment group will receive daily orally administered placebo and will follow visit schedule identical to that in the active treatment group.
Number of Days Hospitalized for VOC	12.9 Days Standard Error 1.72	12.0 Days Standard Error 1.63

SECONDARY outcome

Timeframe: Randomization to First VOC and Second VOC respectively (up to 24 Months)

Population: All randomized participants.

Data collected through the primary completion date are presented below.

Outcome measures

Outcome measures
Measure	Prasugrel n=171 Participants Participants will be titrated from initial daily dose of 0.08 milligram per kilogram (mg/kg) of orally administered prasugrel monotherapy at randomization to a dose that will achieve a P2Y12 reaction units (PRU) level of 231 to 136, as measured by VerifyNow instrument. This corresponds to a range of platelet inhibition of approximately 30% to 60%. The maximum possible dose allowed is 0.12 mg/kg daily, not to exceed 10 mg daily.	Placebo n=170 Participants Participants in this treatment group will receive daily orally administered placebo and will follow visit schedule identical to that in the active treatment group.
Time From Randomization to First and Second VOC Time from Randomization to the First VOC	90.0 Days Interval 71.0 to 151.0	87.0 Days Interval 65.0 to 106.0
Time From Randomization to First and Second VOC Time from Randomization to the Second VOC	338.0 Days Interval 240.0 to Upper limit of 95% Confidence Interval could not be calculated due to limited data	238.0 Days Interval 177.0 to 300.0

SECONDARY outcome

Timeframe: First Dose through 24 Months

Population: All randomized participants who received at least one dose of drug.

Medical intervention was defined as any medical evaluation resulting in therapy or further investigation, as determined by a trained medical professional. Data collected from the first dose of study medication through 10 days after last dose of study medication during the double blind study period are presented below.

Outcome measures

Outcome measures
Measure	Prasugrel n=170 Participants Participants will be titrated from initial daily dose of 0.08 milligram per kilogram (mg/kg) of orally administered prasugrel monotherapy at randomization to a dose that will achieve a P2Y12 reaction units (PRU) level of 231 to 136, as measured by VerifyNow instrument. This corresponds to a range of platelet inhibition of approximately 30% to 60%. The maximum possible dose allowed is 0.12 mg/kg daily, not to exceed 10 mg daily.	Placebo n=170 Participants Participants in this treatment group will receive daily orally administered placebo and will follow visit schedule identical to that in the active treatment group.
Percentage of Participants With Hemorrhagic Events Requiring Medical Intervention	6.5 Percentage of Participants	4.7 Percentage of Participants

Adverse Events

Prasugrel - Double Blind Phase

Serious events: 100 serious events

Other events: 148 other events

Deaths: 0 deaths

Placebo - Double Blind Phase

Serious events: 106 serious events

Other events: 154 other events

Deaths: 0 deaths

Prasugrel - Open Label Phase

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 800-545-5979

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	Prasugrel - Double Blind Phase n=170 participants at risk Participants will be titrated from initial daily dose of 0.08 milligram per kilogram (mg/kg) of orally administered prasugrel monotherapy at randomization to a dose that will achieve a P2Y12 reaction units (PRU) level of 231 to 136, as measured by VerifyNow instrument. This corresponds to a range of platelet inhibition of approximately 30% to 60%. The maximum possible dose allowed is 0.12 mg/kg daily, not to exceed 10 mg daily.	Placebo - Double Blind Phase n=170 participants at risk Participants in this treatment group will receive daily orally administered placebo and will follow visit schedule identical to that in the active treatment group.	Prasugrel - Open Label Phase n=3 participants at risk Participants who continued to meet eligibility criteria, who were not permanently discontinued from study drug, and who concluded their participation in 24 months of double blind treatment were to be considered eligible to enter the open label phase.
Blood and lymphatic system disorders Anaemia	3.5% 6/170 • Number of events 8 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	6.5% 11/170 • Number of events 13 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
Blood and lymphatic system disorders Sickle cell anaemia with crisis	52.9% 90/170 • Number of events 223 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	60.0% 102/170 • Number of events 272 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	33.3% 1/3 • Number of events 1 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
Gastrointestinal disorders Abdominal pain	10.0% 17/170 • Number of events 23 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	11.8% 20/170 • Number of events 28 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
Gastrointestinal disorders Abdominal pain upper	1.8% 3/170 • Number of events 3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	6.5% 11/170 • Number of events 14 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
Gastrointestinal disorders Constipation	5.3% 9/170 • Number of events 10 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	7.1% 12/170 • Number of events 16 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
Gastrointestinal disorders Diarrhoea	3.5% 6/170 • Number of events 8 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	6.5% 11/170 • Number of events 12 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
Gastrointestinal disorders Gastritis	5.9% 10/170 • Number of events 13 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	5.9% 10/170 • Number of events 19 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
Gastrointestinal disorders Vomiting	4.1% 7/170 • Number of events 11 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	7.1% 12/170 • Number of events 19 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
General disorders Nodule	0.00% 0/170 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/170 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	33.3% 1/3 • Number of events 1 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
General disorders Pain	10.6% 18/170 • Number of events 31 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	11.2% 19/170 • Number of events 30 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
General disorders Pyrexia	20.6% 35/170 • Number of events 54 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	25.3% 43/170 • Number of events 69 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	33.3% 1/3 • Number of events 1 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
Infections and infestations Malaria	19.4% 33/170 • Number of events 62 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	19.4% 33/170 • Number of events 53 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
Infections and infestations Nasopharyngitis	8.8% 15/170 • Number of events 19 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	10.6% 18/170 • Number of events 34 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
Infections and infestations Pharyngitis	2.4% 4/170 • Number of events 4 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	5.9% 10/170 • Number of events 11 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
Infections and infestations Rhinitis	6.5% 11/170 • Number of events 12 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	4.1% 7/170 • Number of events 10 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
Infections and infestations Tonsillitis	11.8% 20/170 • Number of events 26 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	14.1% 24/170 • Number of events 31 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
Infections and infestations Upper respiratory tract infection	25.9% 44/170 • Number of events 76 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	21.8% 37/170 • Number of events 69 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
Infections and infestations Urinary tract infection	10.0% 17/170 • Number of events 26 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	10.0% 17/170 • Number of events 17 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
Musculoskeletal and connective tissue disorders Arthralgia	4.7% 8/170 • Number of events 11 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	5.9% 10/170 • Number of events 11 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
Musculoskeletal and connective tissue disorders Back pain	11.8% 20/170 • Number of events 32 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	17.1% 29/170 • Number of events 54 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
Musculoskeletal and connective tissue disorders Pain in extremity	16.5% 28/170 • Number of events 45 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	27.6% 47/170 • Number of events 84 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
Nervous system disorders Headache	14.7% 25/170 • Number of events 32 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	17.1% 29/170 • Number of events 43 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
Respiratory, thoracic and mediastinal disorders Cough	8.2% 14/170 • Number of events 19 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	10.0% 17/170 • Number of events 19 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	33.3% 1/3 • Number of events 1 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
Respiratory, thoracic and mediastinal disorders Epistaxis	13.5% 23/170 • Number of events 48 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	12.4% 21/170 • Number of events 29 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	5.3% 9/170 • Number of events 13 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	4.7% 8/170 • Number of events 8 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.	0.00% 0/3 • Adverse events reported below reflect the entire study safety information through the supplemental data base lock (the study completion date). All randomized participants who received at least one dose of drug.