Safety and Causal Prophylactic Efficacy of KAF156 in a Controlled Human Malaria Challenge Model

Study Overview
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Brief Summary
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This study is designed to investigate the safety and causal prophylactic efficacy of KAF156 in healthy subjects using a controlled human malaria infection model.

Official Title
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A Two-part, Randomized, Double-blind, Placebo-controlled, Single-center Study to Evaluate the Safety and Causal Prophylactic Efficacy of KAF156 in a Controlled Human Malaria Challenge Model

Conditions
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Malaria

Intervention / Treatment
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* Drug: KAF156
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Healthy male subjects,aged 18 to 40 years of age included and in good health as determined by past medical history, physical examination, vital signs, ECG, and laboratory tests Exclusion Criteria: History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes. Known history or current clinically significant ECG abnormalities or arrhythmias. Symptoms, physical signs and laboratory values suggestive of systemic disorders including renal, hepatic, cardiovascular, pulmonary, skin, immunodeficiency, psychiatric, or other conditions which could interfere with the interpretation of the study results or compromise the health of the subjects. Sexually active males must use a condom during intercourse while taking drug and for al least 4 weeks after stopping study medication and should not father a child during this period. History of malaria or residence in a malaria-endemic area over a period of 6 months before study entry. - Any condition that would, in the opinion of the site investigator, place the subject at an unacceptable risk or render the subject unable to meet requirements of the protocol. Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KAF156 800 mg pre-challenge<br>Single dose 800 mg KAF156 oral administration in healthy subjects, prior to exposure to P. falciparum sporozoite-infected mosquitos | Drug: KAF156<br>* 100 mg tablet, 20 mg tablet, 50 mg tablet<br>|
| Placebo Comparator: Placebo 800 mg pre-challenge<br>Single dose 800 mg placebo oral administration in healthy subjects, prior to exposure to P. falciiparum sporozoite-infected mosquitos | Drug: Placebo<br>* 100 mg tablet, 20 mg tablet, 50 mg tablet<br>|
| Experimental: KAF156 800 mg post-challenge<br>Single dose 800 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos | Drug: KAF156<br>* 100 mg tablet, 20 mg tablet, 50 mg tablet<br>|
| Placebo Comparator: Placebo 800 mg post-challenge<br>Single dose 800 mg placebo oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos | Drug: Placebo<br>* 100 mg tablet, 20 mg tablet, 50 mg tablet<br>|
| Experimental: KAF156 300 mg post-challenge<br>Single dose 300 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos | Drug: KAF156<br>* 100 mg tablet, 20 mg tablet, 50 mg tablet<br>|
| Placebo Comparator: Placebo 300 mg post-challenge<br>Single dose 300 mg placebo oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos | Drug: Placebo<br>* 100 mg tablet, 20 mg tablet, 50 mg tablet<br>|
| Experimental: KAF156 100 mg post-challenge<br>Single dose 100 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos | Drug: KAF156<br>* 100 mg tablet, 20 mg tablet, 50 mg tablet<br>|
| Placebo Comparator: Placebo 100 mg post-challenge<br>Single dose 100 mg placebo oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos | Drug: Placebo<br>* 100 mg tablet, 20 mg tablet, 50 mg tablet<br>|
| Experimental: KAF156 20 mg post-challenge<br>Single dose 20 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos | Drug: KAF156<br>* 100 mg tablet, 20 mg tablet, 50 mg tablet<br>|
| Placebo Comparator: Placebo 20 mg post-challenge<br>Single dose 20 mg Placebo oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos | Drug: Placebo<br>* 100 mg tablet, 20 mg tablet, 50 mg tablet<br>|
| Experimental: KAF156 50 mg post-challenge<br>Single dose 50 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos | Drug: KAF156<br>* 100 mg tablet, 20 mg tablet, 50 mg tablet<br>|
| Placebo Comparator: Placebo 50 mg post-challenge<br>Single dose 50 mg Placebo oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos | Drug: Placebo<br>* 100 mg tablet, 20 mg tablet, 50 mg tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with parasitemia after single dose oral administration of KAF156 either prior to, or following, exposure to P. falciparum sporozoite-infected mosquitoes | The number of subjects that became infected with malaria at each dose | From Day 1 to Day 43 | 
| Relationship between pharmacokinetics (i.e., Maximum Plasma Concentration [Cmax], Area Under Curve [AUC]) of KAF156 and number of subjects with parasitemia, after oral administration of single descending doses of KAF156 in healthy subjects with CHMI | The exposure-response relationship of KAF156 was explored in a PK/PD model to relate drug exposure to prophylactic efficacy using standard statistical methods such as CART or non-linear regression. Summary statistics were also provided for the malaria incidence rate by cohort and treatment arm | From Day 1 to Day 43 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with adverse events, serious adverse events, and death | All information obtained on adverse events will be displayed by arm, treatment, and subject. The number and percentage of subjects with adverse events will be tabulated by body system and preferred term with a breakdown by cohort and treatment. | From screening to Day 43 | 
| Pharmacokinetics of KAF156: Area under the plasma concentration-time curve from time zero to infinity (AUCinf) | KAF156 plasma concentration data will be listed by arm, subject, and sampling time point. Descriptive summary statistics will be provided by arm and sampling time point. These values will be used to calculate AUCinf | Pre-dose, and Post-dose: 1 hour, 3 hours, 6 hours, 9 hours, 12 hours, 24 hours, 96 hours, 144 hours, 110 hours, 216 hours, 240 hours | 
| Pharmacokinetics of KAF156: Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) | KAF156 plasma concentration data will be listed by arm, subject, and sampling time point. Descriptive summary statistics will be provided by arm and sampling time point. These values will be used to calculate AUClast | Pre-dose, and Post-dose: 1 hour, 3 hours, 6 hours, 9 hours, 12 hours, 24 hours, 96 hours, 144 hours, 110 hours, 216 hours, 240 hours | 
| Pharmacokinetics of KAF156: Area under teh plasma concentration-time curve from time zero to time 24 h (AUC0-24) | KAF156 plasma concentration data will be listed by arm, subject, and sampling time point. Descriptive summary statistics will be provided by arm and sampling time point. These values will be used to calculate AUC0-24 | Pre-dose, and Post-dose: 1 hour, 3 hours, 6 hours, 9 hours, 12 hours, 24 hours, 96 hours, 144 hours, 110 hours, 216 hours, 240 hours | 
| Pharmacokinetics of KAF156: Terminal elimination half life (T1/2) | KAF156 plasma concentration data will be listed by arm, subject, and sampling time point. Descriptive summary statistics will be provided by arm and sampling time point. These values will be used to calculate T1/2. | Pre-dose, and Post-dose: 1 hour, 3 hours, 6 hours, 9 hours, 12 hours, 24 hours, 96 hours, 144 hours, 110 hours, 216 hours, 240 hours | 
| Pharmacokinetics of KAF156: Apparent systemic clearance from plasma following oral administration (CL/F) | KAF156 plasma concentration data will be listed by arm, subject, and sampling time point. Descriptive summary statistics will be provided by arm and sampling time point. These values will be used to calculate CL/F | Pre-dose, and Post-dose: 1 hour, 3 hours, 6 hours, 9 hours, 12 hours, 24 hours, 96 hours, 144 hours, 110 hours, 216 hours, 240 hours | 
| Pharmacokinetics of KAF156: Apparent volume of distribution during the terminal phase following oral administration (Vz/F) | KAF156 plasma concentration data will be listed by arm, subject, and sampling time point. Descriptive summary statistics will be provided by arm and sampling time point. These values will be used to calculate Vz/F | Pre-dose, and Post-dose: 1 hour, 3 hours, 6 hours, 9 hours, 12 hours, 24 hours, 96 hours, 144 hours, 110 hours, 216 hours, 240 hours | 
| Pharmacokinetics of KAF156: Observed maximum plasma concentration (Cmax) | KAF156 plasma concentration data will be listed by arm, subject, and sampling time point. Descriptive summary statistics will be provided by arm and sampling time point. These values will be used to calculate Cmax | Pre-dose, and Post-dose: 1 hour, 3 hours, 6 hours, 9 hours, 12 hours, 24 hours, 96 hours, 144 hours, 110 hours, 216 hours, 240 hours | 
| Pharmacokinetics of KAF156: Time to reach the maximum concentration (Tmax) | KAF156 plasma concentration data will be listed by arm, subject, and sampling time point. Descriptive summary statistics will be provided by arm and sampling time point. These values will be used to calculate Tmax | Pre-dose, and Post-dose: 1 hour, 3 hours, 6 hours, 9 hours, 12 hours, 24 hours, 96 hours, 144 hours, 110 hours, 216 hours, 240 hours | 
| Parasite growth Kinetics by qRT-PCR | Parasitemia levels as measured by qRT-PCR will be summarized and displayed graphically over time. | Pre-dose, days 7-23, Day 29, Day 43 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Malaria, KAF156, P. falciparum