Trial Outcomes & Findings for Safety and Protective Efficacy of Pb(PfCS@UIS4) (NCT NCT03138096)

Last Updated: 2022-03-04

Results Overview

Frequency and magnitude of adverse events in study groups following one or more exposures to Pb(PfCS@UIS4)-infected mosquitoes.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

24 participants

Primary outcome timeframe

Groups 1&2: from exposure to Pb(PfCS@UIS4)-infected mosquitoes until 28 days thereafter. Group 3: from first exposure until 21 days after fourth/final exposure (=until day immediately prior to CHMI, i.e. approximately 15 weeks after first exposure).

Results posted on

2022-03-04

Participant Flow

Participant milestones

Participant milestones
Measure	Group 1 - Five Pb(PfCS@UIS4)-Infected Mosquitoes (Group 1) will be exposed to bites of five Pb(PfCS@UIS4)-infected mosquitoes Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	Group 2 - 25 Pb(PfCS@UIS4)-Infected Mosquito Bites (group 2) will be exposed to 25 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	Group 3 -25 Pb(PfCS@UIS4)-Infected Mosquito Bites (group 3) will be exposed to 75 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Group 4 - Infectivity Control Group (Phase 1) Infectivity control group (Phase 1) Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes
Overall Study STARTED	3	3	12	6
Overall Study COMPLETED	3	3	12	6
Overall Study NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Group 1 n=3 Participants (Group 1) will be exposed to bites of five Pb(PfCS@UIS4)-infected mosquitoes Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	Group 2 n=3 Participants (group 2) will be exposed to 25 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	Group 3 n=12 Participants (group 3) will be exposed to 75 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Group 4 n=6 Participants Infectivity control group Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Group 5 Infectivity control group Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Total n=24 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=3 Participants	0 Participants n=3 Participants	0 Participants n=12 Participants	0 Participants n=6 Participants	—	0 Participants n=24 Participants
Age, Categorical Between 18 and 65 years	3 Participants n=3 Participants	3 Participants n=3 Participants	12 Participants n=12 Participants	6 Participants n=6 Participants	—	24 Participants n=24 Participants
Age, Categorical >=65 years	0 Participants n=3 Participants	0 Participants n=3 Participants	0 Participants n=12 Participants	0 Participants n=6 Participants	—	0 Participants n=24 Participants
Age, Continuous	21.1 Years n=3 Participants	26.1 Years n=3 Participants	21.5 Years n=12 Participants	22.5 Years n=6 Participants	—	22.5 Years n=24 Participants
Sex: Female, Male Female	3 Participants n=3 Participants	1 Participants n=3 Participants	7 Participants n=12 Participants	4 Participants n=6 Participants	—	15 Participants n=24 Participants
Sex: Female, Male Male	0 Participants n=3 Participants	2 Participants n=3 Participants	5 Participants n=12 Participants	2 Participants n=6 Participants	—	9 Participants n=24 Participants
Race and Ethnicity Not Collected	—	—	—	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment Netherlands	3 participants n=3 Participants	3 participants n=3 Participants	12 participants n=12 Participants	6 participants n=6 Participants	—	24 participants n=24 Participants

PRIMARY outcome

Timeframe: Groups 1&2: from exposure to Pb(PfCS@UIS4)-infected mosquitoes until 28 days thereafter. Group 3: from first exposure until 21 days after fourth/final exposure (=until day immediately prior to CHMI, i.e. approximately 15 weeks after first exposure).

Population: Groups 1-3, immunization phase only (groups 1\&2 underwent only a single immunization; group 3 underwent 4 sequential immunizations). Note: group 4 did NOT undergo immunization. AEs following CHMI with WT-infected mosquitoes (i.e. in group 3\&4) were not a protocol-defined endpoint and are NOT included here. Group 5 was not enrolled, as protective efficacy in group 3 following first CHMI was insufficient (per protocol) to warrant a second CHMI and hence a second infectivity control group.

Frequency and magnitude of adverse events in study groups following one or more exposures to Pb(PfCS@UIS4)-infected mosquitoes.

Outcome measures

Outcome measures
Measure	Group 1 n=3 Participants (Group 1) will be exposed to bites of five Pb(PfCS@UIS4)-infected mosquitoes Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	Group 2 n=3 Participants (group 2) will be exposed to 25 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	Group 3 n=12 Participants (group 3) will be exposed to 75 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Group 4 Infectivity control group Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes
Adverse Events in Study Groups Following Exposure to Pb(PfCS@UIS4)-Infected Mosquitoes [Safety] Immunization 1: Numbers of local adverse events (grade 1/2)	0 numbers of adverse events	3 numbers of adverse events	10 numbers of adverse events	—
Adverse Events in Study Groups Following Exposure to Pb(PfCS@UIS4)-Infected Mosquitoes [Safety] Immunization 2: Numbers of local adverse events (grade 1/2)	—	—	9 numbers of adverse events	—
Adverse Events in Study Groups Following Exposure to Pb(PfCS@UIS4)-Infected Mosquitoes [Safety] Immunization 3: Numbers of local adverse events (grade 1/2)	—	—	12 numbers of adverse events	—
Adverse Events in Study Groups Following Exposure to Pb(PfCS@UIS4)-Infected Mosquitoes [Safety] Immunization 4: Numbers of local adverse events (grade 1/2)	—	—	11 numbers of adverse events	—
Adverse Events in Study Groups Following Exposure to Pb(PfCS@UIS4)-Infected Mosquitoes [Safety] Immunization 1: Numbers of systemic adverse events (grade 1/2)	7 numbers of adverse events	5 numbers of adverse events	9 numbers of adverse events	—
Adverse Events in Study Groups Following Exposure to Pb(PfCS@UIS4)-Infected Mosquitoes [Safety] Immunization 2: Numbers of systemic adverse events (grade 1/2)	—	—	2 numbers of adverse events	—
Adverse Events in Study Groups Following Exposure to Pb(PfCS@UIS4)-Infected Mosquitoes [Safety] Immunization 3: Numbers of systemic adverse events (grade 1/2)	—	—	4 numbers of adverse events	—
Adverse Events in Study Groups Following Exposure to Pb(PfCS@UIS4)-Infected Mosquitoes [Safety] Immunization 4: Numbers of systemic adverse events (grade 1/2)	—	—	4 numbers of adverse events	—

PRIMARY outcome

Timeframe: Groups 1-3: from (first) exposure until 28 days thereafter.

Population: Groups 1-3 only. Note: For group 3, only immunisation (exposure) #1 is included here, as immunisations #2-4 fell in phase 2 of the trial, during which this outcome was no longer classified as an endpoint. Group 4 was not exposed to Pb(PfCS@UIS4)-infected mosquitoes (only to CHMI with WT-infected mosquitoes) and group 5 was not enrolled, as protective efficacy in group 3 following first CHMI was insufficient (per protocol) to warrant a second CHMI and hence a second infectivity control group.

Presence of breakthrough parasitemia following (first) exposure to Pb(PfCS@UIS4)-infected mosquito bites, as determined by thick blood smear microscopy

Outcome measures

Outcome measures
Measure	Group 1 n=3 Participants (Group 1) will be exposed to bites of five Pb(PfCS@UIS4)-infected mosquitoes Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	Group 2 n=3 Participants (group 2) will be exposed to 25 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	Group 3 n=12 Participants (group 3) will be exposed to 75 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Group 4 Infectivity control group Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes
Presence of Breakthrough Parasitemia Following Exposure to Pb(PfCS@UIS4)-Infected Mosquito Bites	0 Participants	0 Participants	0 Participants	—

PRIMARY outcome

Timeframe: Groups 3&4: from day of CHMI until 28 days thereafter

Population: Groups 3\&4 only. Note: Groups 1 \& 2 did not undergo CHMI and group 5 was not enrolled, as protective efficacy in group 3 following first CHMI was insufficient (per protocol) to warrant a second CHMI and hence a second infectivity control group

Time to parasitemia after CHMI with the wild-type NF54 P. falciparum strain, as detected by qPCR \[Efficacy\]

Outcome measures

Outcome measures
Measure	Group 1 (Group 1) will be exposed to bites of five Pb(PfCS@UIS4)-infected mosquitoes Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	Group 2 (group 2) will be exposed to 25 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	Group 3 n=12 Participants (group 3) will be exposed to 75 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Group 4 n=6 Participants Infectivity control group Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes
Time to Parasitemia After CHMI [Efficacy]	—	—	9.9 days to P. falciparum parasitemia Interval 7.0 to 14.0	7.7 days to P. falciparum parasitemia Interval 7.0 to 11.0

SECONDARY outcome

Timeframe: Group 3: from baseline until day prior to CHMI (approximately 15 weeks after first Pb(PfCS@UIS4) immunization)

Population: Group 3 only. Note: no analysis of humoral immune responses was performed for Groups 1 \& 2 (single immunization only) or group 4 (no immunization); group 5 was not enrolled.

Immunogenicity of repeated Pb(PfCS@UIS4) immunization as assessed by fold change in anti-P. falciparum IgG from baseline to post-immunization (day prior to CHMI), as measured by ELISA.

Outcome measures

Outcome measures
Measure	Group 1 (Group 1) will be exposed to bites of five Pb(PfCS@UIS4)-infected mosquitoes Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	Group 2 (group 2) will be exposed to 25 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	Group 3 n=12 Participants (group 3) will be exposed to 75 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Group 4 Infectivity control group Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes
Immunogenicity of Pb(PfCS@UIS4) as Assessed by ELISA	—	—	3.5 Fold increase in anti-P. falciparum IgG Standard Deviation 0.3	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Group 3: from baseline until day prior to CHMI (approximately 15 weeks after first Pb(PfCS@UIS4) immunization)

Population: Group 3 only. Note: no analysis of cellular immune responses was performed for Groups 1 \& 2 (single immunization only) or group 4 (no immunizsation); group 5 was not enrolled.

Cellular immune responses after repeated exposure to Pb(PfCS@UIS4), as determined by increase in %-age IFNg+ lymphocytes following in vitro stimulation of PBMCs with WT P. falciparum sporozoites measured by flow cytometry at baseline and following immunization (day prior to CHMI)

Outcome measures

Outcome measures
Measure	Group 1 (Group 1) will be exposed to bites of five Pb(PfCS@UIS4)-infected mosquitoes Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	Group 2 (group 2) will be exposed to 25 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	Group 3 n=12 Participants (group 3) will be exposed to 75 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Group 4 Infectivity control group Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes
Cellular Immune Responses After Exposure to Pb(PfCS@UIS4) [Exploratory Endpoint]	—	—	0.510 change in %-age IFNg+ lymphocytes Standard Deviation 1.102	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Group 3: from baseline until day prior to CHMI (approximately 15 weeks after first Pb(PfCS@UIS4) immunization)

Population: Group 3 only. Note: no analysis of humoral immune responses was performed for Groups 1 \& 2 (single immunizsation only) or group 4 (no immunization); group 5 was not enrolled.

Humoral immune responses after repeated exposure to Pb(PfCS@UIS4) as determined by increase in %-age inhibition of WT P. falciparum sporozoite invasion in HC-04 cells by purified plasma IgG collected at baseline and following immunization (day prior to CHMI).

Outcome measures

Outcome measures
Measure	Group 1 (Group 1) will be exposed to bites of five Pb(PfCS@UIS4)-infected mosquitoes Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	Group 2 (group 2) will be exposed to 25 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	Group 3 n=12 Participants (group 3) will be exposed to 75 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Group 4 Infectivity control group Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes
Humoral Immune Responses After Exposure to Pb(PfCS@UIS4) [Exploratory Endpoint]	—	—	48.8 % change in inhibition of spz invasion Standard Deviation 17.5	—

Adverse Events

Group 1

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Group 2

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Group 3

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Group 4

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Dr. M.B.B. McCall

Radboud University Medical Center

Phone: +31642166480

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Other adverse events
Measure	Group 1 n=3 participants at risk (Group 1) will be exposed to bites of five Pb(PfCS@UIS4)-infected mosquitoes Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	Group 2 n=3 participants at risk (group 2) will be exposed to 25 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes	Group 3 n=12 participants at risk (group 3) will be exposed to 75 Pb(PfCS@UIS4)-infected mosquito bites Pb(PfCS@UIS4)-infected mosquitoes: Pb(PfCS@UIS4)-infected mosquitoes Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes	Group 4 n=6 participants at risk Infectivity control group Challenge infection P. falciparum: Challenge infection with bites of five infected Pf mosquitoes
Skin and subcutaneous tissue disorders Pruritis	0.00% 0/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	100.0% 3/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	83.3% 10/12 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	16.7% 1/6 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.
Skin and subcutaneous tissue disorders Edema arms	0.00% 0/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	8.3% 1/12 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/6 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.
Skin and subcutaneous tissue disorders Painful skin arms	0.00% 0/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	8.3% 1/12 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/6 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.
Blood and lymphatic system disorders Hematoma / Pain after venapuncture	0.00% 0/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	33.3% 1/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/12 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	16.7% 1/6 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.
General disorders Headache	66.7% 2/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	66.7% 2/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	58.3% 7/12 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	100.0% 6/6 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.
General disorders Abdominal pain	33.3% 1/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	8.3% 1/12 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/6 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.
General disorders Nausea	66.7% 2/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	50.0% 6/12 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	66.7% 4/6 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.
General disorders Diarrhoea	33.3% 1/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	33.3% 1/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	8.3% 1/12 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/6 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.
General disorders Stomach pain	0.00% 0/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	33.3% 1/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	8.3% 1/12 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/6 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.
General disorders Malaise	0.00% 0/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	33.3% 4/12 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	33.3% 2/6 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.
General disorders Fatigue	0.00% 0/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	33.3% 1/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	33.3% 4/12 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/6 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.
General disorders Angio-oedema	0.00% 0/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	8.3% 1/12 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/6 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.
General disorders Dizziness	33.3% 1/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/12 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/6 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.
General disorders Night sweating	0.00% 0/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	8.3% 1/12 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/6 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.
General disorders Chills	0.00% 0/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	8.3% 1/12 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/6 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.
General disorders Myalgia	0.00% 0/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	0.00% 0/3 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	8.3% 1/12 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.	16.7% 1/6 • 79 days Blood was drawn for routine haematological and biochemical analysis and peripheral thick blood smears. Signs and symptoms were recorded and graded by a physician. An independent Safety Monitoring Committee was appointed to assess safety data as presented by the study team in periodic safety reports. These reports included comprehensive lists of adverse events and any safety laboratory values outside the normal range.