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Effect of ACT-451840 Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Subjects

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ClinicalTrials.gov Identifier: NCT02223871
Recruitment Status : Completed
First Posted : August 22, 2014
Results First Posted : August 10, 2016
Last Update Posted : August 22, 2019
Sponsor:
Information provided by (Responsible Party):
Idorsia Pharmaceuticals Ltd.

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Other
Condition Healthy Subjects
Interventions Drug: ACT-451840:
Other: Plasmodium falciparum-infected human erythrocytes:
Drug: Artemether 20 mg and lumefantrine 120mg combination tablet:
Drug: Primaquine:
Enrollment 8
Recruitment Details 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).
Pre-assignment Details  
Arm/Group Title ACT-451840 500 mg
Hide Arm/Group Description 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).
Period Title: Overall Study
Started 8
Completed 8
Not Completed 0
Arm/Group Title ACT-451840 500 mg
Hide Arm/Group Description 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).
Overall Number of Baseline Participants 8
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 8 participants
24.1
(19 to 38)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 8 participants
Female
0
   0.0%
Male
8
 100.0%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 8 participants
Caucasian 4
Indian 2
Asian 1
Native Hawaiian 1
1.Primary Outcome
Title Drug-specific Parasite Reduction Ratio (PRR48) of ACT-451840 Over 48 Hours Using a Standardized Approach
Hide Description

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)

Time Frame 48 hours after study drug administration
Hide Outcome Measure Data
Hide Analysis Population Description
Only subjects with appropriate overall fit (p-value of the overall model F-test <0.001) were taken into account (n = 5)
Arm/Group Title ACT-451840 500 mg
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 5
Mean (95% Confidence Interval)
Unit of Measure: Ratio
234.5
(130.4 to 422.0)
2.Secondary Outcome
Title Maximum Plasma Concentration (Cmax) of ACT-451840
Hide Description Cmax 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.
Time Frame From pre-dose to 144 hours after study drug adminsitration
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title ACT-451840 500 mg
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 8
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng/mL
121.7
(90.6 to 163.5)
3.Secondary Outcome
Title Time to Reach Maximum Plasma Concentration (Tmax) of ACT-451840
Hide Description tmax 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.
Time Frame From pre-dose to144 hours after study drug administration
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title ACT-451840 500 mg
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 8
Median (Full Range)
Unit of Measure: Hours
4.0
(3.0 to 6.0)
4.Secondary Outcome
Title Areas Under the Plasma Concentration-time Curve of ACT-451840
Hide Description

Two 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

Time Frame From pre-dose to144 hours after study drug administration
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title ACT-451840 500 mg
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 8
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng*h/mL
AUC(0-t)
1254.8
(906.8 to 1736.4)
AUC(0-inf)
1284.4
(919.6 to 1794.1)
5.Secondary Outcome
Title Terminal Half-life [t(1/2)]
Hide Description 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
Time Frame From pre-dose to144 hours after study drug adminsitration
Hide Outcome Measure Data
Hide Analysis Population Description
Per protocol set
Arm/Group Title ACT-451840 500 mg
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 8
Geometric Mean (95% Confidence Interval)
Unit of Measure: Hours
36.4
(30.2 to 43.9)
6.Secondary Outcome
Title Change From Baseline in Blood Pressure to End of Study (EOS)
Hide Description 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.
Time Frame Day 28 (EOS)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title ACT-451840 500 mg
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 8
Median (Full Range)
Unit of Measure: mmHg
SBP at baseline (Day 0)
121.0
(110.0 to 136.0)
SBP at EOS (Day 28)
125.5
(117.0 to 139.0)
Change from Day 0 to Day 28 in SBP
2.5
(-5.0 to 20.0)
DBP at baseline (Day 0)
66.0
(51.0 to 73.0)
DBP at EOS (Day 28)
70.5
(57.0 to 75.0)
Change from Day 0 to Day 28 in DBP
0.5
(-3.0 to 12.0)
7.Secondary Outcome
Title Change From Baseline in Body Temperature up to End of Study (EOS)
Hide Description Body temperature was measured orally
Time Frame Day 28 (EOS)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title ACT-451840 500 mg
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 8
Median (Full Range)
Unit of Measure: Degree Celsius
Temperature at baseline (Day 0)
36.3
(36.0 to 36.7)
Temperature at EOS (Day 28)
35.9
(35.8 to 36.4)
Change from Day 0 to Day 28 in temperature
-0.2
(-0.7 to 0.2)
8.Secondary Outcome
Title Change From Baseline in Respiratory Rate to End of Study (EOS)
Hide Description [Not Specified]
Time Frame Day 28 (EOS)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title ACT-451840 500 mg
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 8
Median (Full Range)
Unit of Measure: Breaths/min
Respiratory rate at baseline (Day 0)
14
(12 to 18)
Respiratory rate at EOS (Day 28)
16
(14 to 18)
Change from Day 0 to Day 28 in respiratory rate
1.5
(-4 to 4)
9.Post-Hoc Outcome
Title Drug-specific Parasite Reduction Ratio (PRR48) of ACT-451840 Over 48 Hours Using a New Approach
Hide Description

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.

Time Frame 48 hours after study drug administration
Hide Outcome Measure Data
Hide Analysis Population Description
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)
Arm/Group Title ACT-451840 500 mg
Hide Arm/Group Description:
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).
Overall Number of Participants Analyzed 8
Mean (95% Confidence Interval)
Unit of Measure: Ratio
73.6
(56.1 to 96.5)
Time Frame From baseline to end of study
Adverse Event Reporting Description 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
 
Arm/Group Title ACT-451840 500 mg
Hide Arm/Group Description 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.
All-Cause Mortality
ACT-451840 500 mg
Affected / at Risk (%)
Total   --/--    
Hide Serious Adverse Events
ACT-451840 500 mg
Affected / at Risk (%) # Events
Total   0/8 (0.00%)    
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
ACT-451840 500 mg
Affected / at Risk (%) # Events
Total   8/8 (100.00%)    
Blood and lymphatic system disorders   
Neutropenia  1  1/8 (12.50%)  1
Thrombocytopenia  1  1/8 (12.50%)  1
Gastrointestinal disorders   
Lip ulcer  1  1/8 (12.50%)  1
Nausea  1  1/8 (12.50%)  1
General disorders   
Pyrexia  1  5/8 (62.50%)  5
Injection site erythema  1  1/8 (12.50%)  2
Malaise  1  1/8 (12.50%)  1
Pain injection site  1  3/8 (37.50%)  3
Rigors  1  1/8 (12.50%)  1
Vessel puncture site pain  1  1/8 (12.50%)  1
Infections and infestations   
Upper respiratory tract infection (not otherwise specified)  1  2/8 (25.00%)  2
Investigations   
Alanine aminotransferase increased  1  1/8 (12.50%)  1
Rhesus antibodies positive  1  1/8 (12.50%)  1
Musculoskeletal and connective tissue disorders   
Myalgia  1  5/8 (62.50%)  5
Nervous system disorders   
Headache  1  7/8 (87.50%)  10
Lethargy  1  3/8 (37.50%)  3
Psychiatric disorders   
Anxiety  1  1/8 (12.50%)  1
Insomnia  1  1/8 (12.50%)  1
Respiratory, thoracic and mediastinal disorders   
Cough  1  1/8 (12.50%)  1
Skin and subcutaneous tissue disorders   
Dermatitis contact  1  1/8 (12.50%)  1
Night sweats  1  1/8 (12.50%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 17.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Clinical Trial Disclosure desk
Organization: Idorsia Pharmaceuticals Ltd
EMail: clinical-trials-disclosure@idorsia.com
Layout table for additonal information
Responsible Party: Idorsia Pharmaceuticals Ltd.
ClinicalTrials.gov Identifier: NCT02223871    
Other Study ID Numbers: AC-071-102
First Submitted: August 21, 2014
First Posted: August 22, 2014
Results First Submitted: July 1, 2016
Results First Posted: August 10, 2016
Last Update Posted: August 22, 2019