Trial Outcomes & Findings for Effect of ACT-451840 Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Subjects (NCT NCT02223871)
NCT ID: NCT02223871
Last Updated: 2019-08-22
Results Overview
After the blood stage Plasmodium falciparum challenge (BSPC), malaria parasitemia was measured by polymerase chain reaction (PCR) in regularly collected blood samples. The subject-specific and drug-specific parasite reduction rates over a 48 h period (PRR48) were calculated using an objective standardized approach (observed data over 48 h)
Recruitment status
COMPLETED
Study phase
PHASE1
Target enrollment
8 participants
Primary outcome timeframe
48 hours after study drug administration
Results posted on
2019-08-22
Participant Flow
This proof-of-concept study was conducted in 8 subjects at a single center in Australia. All the subjects were screened from June 6, 2014 to June 23, 2014 and all were enrolled in the study on June 25, 2014 (Study Day 0).
Participant milestones
| Measure |
ACT-451840 500 mg
The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required).
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|---|---|
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Overall Study
STARTED
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8
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Overall Study
COMPLETED
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8
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Overall Study
NOT COMPLETED
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0
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Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Effect of ACT-451840 Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Subjects
Baseline characteristics by cohort
| Measure |
ACT-451840 500 mg
n=8 Participants
The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes occurred 16 days after ACT-451840 administration (or earlier if required).
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|---|---|
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Age, Continuous
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24.1 Years
n=5 Participants
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Sex: Female, Male
Female
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0 Participants
n=5 Participants
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Sex: Female, Male
Male
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8 Participants
n=5 Participants
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Race/Ethnicity, Customized
Caucasian
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4 Participants
n=5 Participants
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Race/Ethnicity, Customized
Indian
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2 Participants
n=5 Participants
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Race/Ethnicity, Customized
Asian
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1 Participants
n=5 Participants
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Race/Ethnicity, Customized
Native Hawaiian
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1 Participants
n=5 Participants
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PRIMARY outcome
Timeframe: 48 hours after study drug administrationPopulation: Only subjects with appropriate overall fit (p-value of the overall model F-test \<0.001) were taken into account (n = 5)
After the blood stage Plasmodium falciparum challenge (BSPC), malaria parasitemia was measured by polymerase chain reaction (PCR) in regularly collected blood samples. The subject-specific and drug-specific parasite reduction rates over a 48 h period (PRR48) were calculated using an objective standardized approach (observed data over 48 h)
Outcome measures
| Measure |
ACT-451840 500 mg
n=5 Participants
The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required).
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|---|---|
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Drug-specific Parasite Reduction Ratio (PRR48) of ACT-451840 Over 48 Hours Using a Standardized Approach
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234.5 Ratio
Interval 130.4 to 422.0
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SECONDARY outcome
Timeframe: From pre-dose to 144 hours after study drug adminsitrationCmax was directly derived from the plasma concentrations-time curves of ACT-451840. Blood samples for pharmacokinetic characterization were drawn at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 48, 72, 96, and 144 hours post-dose.
Outcome measures
| Measure |
ACT-451840 500 mg
n=8 Participants
The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required).
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|---|---|
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Maximum Plasma Concentration (Cmax) of ACT-451840
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121.7 ng/mL
Interval 90.6 to 163.5
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SECONDARY outcome
Timeframe: From pre-dose to144 hours after study drug administrationtmax was directly derived from the plasma concentration-time curves of ACT-451840. Blood samples for pharmacokinetic characterization were drawn at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 48, 72, 96, and 144 hours post-dose.
Outcome measures
| Measure |
ACT-451840 500 mg
n=8 Participants
The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required).
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|---|---|
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Time to Reach Maximum Plasma Concentration (Tmax) of ACT-451840
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4.0 Hours
Interval 3.0 to 6.0
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SECONDARY outcome
Timeframe: From pre-dose to144 hours after study drug administrationTwo AUCs were calculated using non-compartmental analysis: AUC(0-t) from pre-dose to last time-point of measure and AUC(0-inf) from pre-dose and extrapolated to infinity. Blood samples for pharmacokinetic characterization were drawn at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 48, 72, 96, and 144 hours post-dose
Outcome measures
| Measure |
ACT-451840 500 mg
n=8 Participants
The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required).
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|---|---|
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Areas Under the Plasma Concentration-time Curve of ACT-451840
AUC(0-t)
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1254.8 ng*h/mL
Interval 906.8 to 1736.4
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Areas Under the Plasma Concentration-time Curve of ACT-451840
AUC(0-inf)
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1284.4 ng*h/mL
Interval 919.6 to 1794.1
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SECONDARY outcome
Timeframe: From pre-dose to144 hours after study drug adminsitrationPopulation: Per protocol set
Blood samples for pharmacokinetic characterization were drawn at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, 48, 72, 96, and 144 hours post-dose
Outcome measures
| Measure |
ACT-451840 500 mg
n=8 Participants
The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required).
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|---|---|
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Terminal Half-life [t(1/2)]
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36.4 Hours
Interval 30.2 to 43.9
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SECONDARY outcome
Timeframe: Day 28 (EOS)Vital signs, including diastolic and systolic blood pressure (DBP/SBP), were measured at each outpatient visit up to 7 days after ACT-451840 administration, every day during confinement or when malaria symptoms were presented and at the end of study visit (EOS). Other measures were performed if required.
Outcome measures
| Measure |
ACT-451840 500 mg
n=8 Participants
The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required).
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|---|---|
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Change From Baseline in Blood Pressure to End of Study (EOS)
SBP at baseline (Day 0)
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121.0 mmHg
Interval 110.0 to 136.0
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Change From Baseline in Blood Pressure to End of Study (EOS)
SBP at EOS (Day 28)
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125.5 mmHg
Interval 117.0 to 139.0
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Change From Baseline in Blood Pressure to End of Study (EOS)
Change from Day 0 to Day 28 in SBP
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2.5 mmHg
Interval -5.0 to 20.0
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Change From Baseline in Blood Pressure to End of Study (EOS)
DBP at baseline (Day 0)
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66.0 mmHg
Interval 51.0 to 73.0
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Change From Baseline in Blood Pressure to End of Study (EOS)
DBP at EOS (Day 28)
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70.5 mmHg
Interval 57.0 to 75.0
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Change From Baseline in Blood Pressure to End of Study (EOS)
Change from Day 0 to Day 28 in DBP
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0.5 mmHg
Interval -3.0 to 12.0
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SECONDARY outcome
Timeframe: Day 28 (EOS)Body temperature was measured orally
Outcome measures
| Measure |
ACT-451840 500 mg
n=8 Participants
The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required).
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|---|---|
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Change From Baseline in Body Temperature up to End of Study (EOS)
Temperature at baseline (Day 0)
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36.3 Degree Celsius
Interval 36.0 to 36.7
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Change From Baseline in Body Temperature up to End of Study (EOS)
Temperature at EOS (Day 28)
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35.9 Degree Celsius
Interval 35.8 to 36.4
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Change From Baseline in Body Temperature up to End of Study (EOS)
Change from Day 0 to Day 28 in temperature
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-0.2 Degree Celsius
Interval -0.7 to 0.2
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SECONDARY outcome
Timeframe: Day 28 (EOS)Outcome measures
| Measure |
ACT-451840 500 mg
n=8 Participants
The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required).
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|---|---|
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Change From Baseline in Respiratory Rate to End of Study (EOS)
Respiratory rate at baseline (Day 0)
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14 Breaths/min
Interval 12.0 to 18.0
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Change From Baseline in Respiratory Rate to End of Study (EOS)
Respiratory rate at EOS (Day 28)
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16 Breaths/min
Interval 14.0 to 18.0
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Change From Baseline in Respiratory Rate to End of Study (EOS)
Change from Day 0 to Day 28 in respiratory rate
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1.5 Breaths/min
Interval -4.0 to 4.0
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POST_HOC outcome
Timeframe: 48 hours after study drug administrationPopulation: Only subjects with appropriate overall fit (p-value of the overall model F-test \<0.001) were taken into account (n = 8 with the method described by Marquart et al., 2015)
After the blood stage Plasmodium falciparum challenge (BSPC), malaria parasitemia was measured by polymerase chain reaction (PCR) in regularly collected blood samples. The subject-specific and drug-specific parasite reduction rates over a 48 h period (PRR48) were calculated following the data-driven method by Marquart et al. (2015), removing potential lag and tail phases prior to log-linear regression modeling.
Outcome measures
| Measure |
ACT-451840 500 mg
n=8 Participants
The subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes. When the parasitemia reached 1000 counts/mL, the subjects received 500 mg of ACT-451840 as an oral single dose. Compulsory commencement of treatment with Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, occurred 16 days after ACT-451840 administration (or earlier if required).
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|---|---|
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Drug-specific Parasite Reduction Ratio (PRR48) of ACT-451840 Over 48 Hours Using a New Approach
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73.6 Ratio
Interval 56.1 to 96.5
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Adverse Events
ACT-451840 500 mg
Serious events: 0 serious events
Other events: 8 other events
Deaths: 0 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
ACT-451840 500 mg
n=8 participants at risk
The eight subjects were infected with Plasmodium falciparum parasites (malaria) using malaria-infected human erythrocytes on Day 0 and received 500 mg of ACT-451840 on Day 7. All of them received six doses of Riamet® (artemether-lumefantrine) to ensure complete clearance of any gametocytes, as per protocol.
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General disorders
Pyrexia
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62.5%
5/8 • Number of events 5 • From baseline to end of study
None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum
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General disorders
Injection site erythema
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12.5%
1/8 • Number of events 2 • From baseline to end of study
None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum
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General disorders
Malaise
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12.5%
1/8 • Number of events 1 • From baseline to end of study
None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum
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General disorders
Pain injection site
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37.5%
3/8 • Number of events 3 • From baseline to end of study
None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum
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General disorders
Rigors
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12.5%
1/8 • Number of events 1 • From baseline to end of study
None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum
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General disorders
Vessel puncture site pain
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12.5%
1/8 • Number of events 1 • From baseline to end of study
None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum
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Nervous system disorders
Headache
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87.5%
7/8 • Number of events 10 • From baseline to end of study
None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum
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Nervous system disorders
Lethargy
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37.5%
3/8 • Number of events 3 • From baseline to end of study
None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum
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Musculoskeletal and connective tissue disorders
Myalgia
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62.5%
5/8 • Number of events 5 • From baseline to end of study
None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum
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Gastrointestinal disorders
Lip ulcer
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12.5%
1/8 • Number of events 1 • From baseline to end of study
None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum
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Gastrointestinal disorders
Nausea
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12.5%
1/8 • Number of events 1 • From baseline to end of study
None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum
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Infections and infestations
Upper respiratory tract infection (not otherwise specified)
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25.0%
2/8 • Number of events 2 • From baseline to end of study
None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum
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Investigations
Alanine aminotransferase increased
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12.5%
1/8 • Number of events 1 • From baseline to end of study
None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum
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Investigations
Rhesus antibodies positive
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12.5%
1/8 • Number of events 1 • From baseline to end of study
None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum
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Psychiatric disorders
Anxiety
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12.5%
1/8 • Number of events 1 • From baseline to end of study
None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum
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Psychiatric disorders
Insomnia
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12.5%
1/8 • Number of events 1 • From baseline to end of study
None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum
|
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Blood and lymphatic system disorders
Neutropenia
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12.5%
1/8 • Number of events 1 • From baseline to end of study
None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum
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Blood and lymphatic system disorders
Thrombocytopenia
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12.5%
1/8 • Number of events 1 • From baseline to end of study
None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum
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Respiratory, thoracic and mediastinal disorders
Cough
|
12.5%
1/8 • Number of events 1 • From baseline to end of study
None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum
|
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Skin and subcutaneous tissue disorders
Dermatitis contact
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12.5%
1/8 • Number of events 1 • From baseline to end of study
None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum
|
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Skin and subcutaneous tissue disorders
Night sweats
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12.5%
1/8 • Number of events 1 • From baseline to end of study
None of the treatment-emergent advserse events reported below were considered related to ACT-451840, one (nausea) was related to Riamet, and all the other ones were related to malaria inoculum
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Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee Publication of the data is under the responsibility of Actelion Pharmaceuticals Ltd. The PI has the opportunity to review the analysis of the data and to discuss with the sponsor the interpretation of the study results prior to publication.
- Publication restrictions are in place
Restriction type: OTHER