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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04072302
• Collaborator: (none)
• Enrollment: 86
• Location: 1
• Arms: 12
• Actual Duration (Months): 38.5
• Patients Per Site Per Month: 2.2

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Malaria	Drug: KAF156; Drug: Placebo	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 86 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: 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
• Actual Study Start Date: Sep 15, 2014
• Actual Primary Completion Date: Nov 29, 2017
• Actual Study Completion Date: Nov 29, 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Number of subjects with parasitemia after single dose oral administration of KAF156 either prior to, or following, exposure to P. falciparum sporozoite-infected mosquitoes [From Day 1 to Day 43]

   The number of subjects that became infected with malaria at each dose

2. 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 [From Day 1 to Day 43]

   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

Secondary Outcome Measures

1. Number of subjects with adverse events, serious adverse events, and death [From screening to Day 43]

   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.

2. Pharmacokinetics of KAF156: Area under the plasma concentration-time curve from time zero to infinity (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]

   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

3. Pharmacokinetics of KAF156: Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (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]

   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

4. Pharmacokinetics of KAF156: Area under teh plasma concentration-time curve from time zero to time 24 h (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]

   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

5. Pharmacokinetics of KAF156: Terminal elimination half life (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]

   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.

6. Pharmacokinetics of KAF156: Apparent systemic clearance from plasma following oral administration (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]

   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

7. Pharmacokinetics of KAF156: Apparent volume of distribution during the terminal phase following oral administration (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]

   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

8. Pharmacokinetics of KAF156: Observed maximum plasma concentration (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]

   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

9. Pharmacokinetics of KAF156: Time to reach the maximum concentration (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]

   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

10. Parasite growth Kinetics by qRT-PCR [Pre-dose, days 7-23, Day 29, Day 43]

    Parasitemia levels as measured by qRT-PCR will be summarized and displayed graphically over time.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 40 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Seattle	Washington	United States	98109

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04072302
• Other Study ID Numbers: CKAF156X2202
• First Posted: Aug 28, 2019
• Last Update Posted: Aug 28, 2019
• Last Verified: Aug 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Malaria; KAF156; P. falciparum
• Additional relevant MeSH terms: Malaria

Study Results

No Results Posted as of Aug 28, 2019