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

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Primary Purpose

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

KAF156

Placebo

About this trial

This is an interventional prevention trial for Malaria focused on measuring Malaria, KAF156, P. falciparum

Eligibility Criteria

18 Years - 40 Years (Adult)MaleAccepts Healthy Volunteers

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.

Sites / Locations

Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm 10

Arm 11

Arm 12

Arm Type

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Arm Label

KAF156 800 mg pre-challenge

Placebo 800 mg pre-challenge

KAF156 800 mg post-challenge

Placebo 800 mg post-challenge

KAF156 300 mg post-challenge

Placebo 300 mg post-challenge

KAF156 100 mg post-challenge

Placebo 100 mg post-challenge

KAF156 20 mg post-challenge

Placebo 20 mg post-challenge

KAF156 50 mg post-challenge

Placebo 50 mg post-challenge

Arm Description

Single dose 800 mg KAF156 oral administration in healthy subjects, prior to exposure to P. falciparum sporozoite-infected mosquitos

Single dose 800 mg placebo oral administration in healthy subjects, prior to exposure to P. falciiparum sporozoite-infected mosquitos

Single dose 800 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos

Single dose 800 mg placebo oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos

Single dose 300 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos

Single dose 300 mg placebo oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos

Single dose 100 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos

Single dose 100 mg placebo oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos

Single dose 20 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos

Single dose 20 mg Placebo oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos

Single dose 50 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos

Single dose 50 mg Placebo oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos

Outcomes

Primary Outcome Measures

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

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

Secondary Outcome Measures

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.

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

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

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

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.

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

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

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

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

Parasite growth Kinetics by qRT-PCR

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

Full Information

NCT ID

NCT04072302

First Posted

August 20, 2019

Last Updated

August 26, 2019

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT04072302

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2019

Overall Recruitment Status

Completed

Study Start Date

September 15, 2014 (Actual)

Primary Completion Date

November 29, 2017 (Actual)

Study Completion Date

November 29, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

No

Data Monitoring Committee

Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Malaria

Keywords

Malaria, KAF156, P. falciparum

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

86 (Actual)

8. Arms, Groups, and Interventions

Arm Title

KAF156 800 mg pre-challenge

Arm Type

Experimental

Arm Description

Single dose 800 mg KAF156 oral administration in healthy subjects, prior to exposure to P. falciparum sporozoite-infected mosquitos

Arm Title

Placebo 800 mg pre-challenge

Arm Type

Placebo Comparator

Arm Description

Single dose 800 mg placebo oral administration in healthy subjects, prior to exposure to P. falciiparum sporozoite-infected mosquitos

Arm Title

KAF156 800 mg post-challenge

Arm Type

Experimental

Arm Description

Single dose 800 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos

Arm Title

Placebo 800 mg post-challenge

Arm Type

Placebo Comparator

Arm Description

Single dose 800 mg placebo oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos

Arm Title

KAF156 300 mg post-challenge

Arm Type

Experimental

Arm Description

Single dose 300 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos

Arm Title

Placebo 300 mg post-challenge

Arm Type

Placebo Comparator

Arm Description

Single dose 300 mg placebo oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos

Arm Title

KAF156 100 mg post-challenge

Arm Type

Experimental

Arm Description

Single dose 100 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos

Arm Title

Placebo 100 mg post-challenge

Arm Type

Placebo Comparator

Arm Description

Single dose 100 mg placebo oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos

Arm Title

KAF156 20 mg post-challenge

Arm Type

Experimental

Arm Description

Single dose 20 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos

Arm Title

Placebo 20 mg post-challenge

Arm Type

Placebo Comparator

Arm Description

Single dose 20 mg Placebo oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos

Arm Title

KAF156 50 mg post-challenge

Arm Type

Experimental

Arm Description

Single dose 50 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos

Arm Title

Placebo 50 mg post-challenge

Arm Type

Placebo Comparator

Arm Description

Single dose 50 mg Placebo oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos

Intervention Type

Drug

Intervention Name(s)

KAF156

Intervention Description

100 mg tablet, 20 mg tablet, 50 mg tablet

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

100 mg tablet, 20 mg tablet, 50 mg tablet

Primary Outcome Measure Information:

Title

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

Description

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

Time Frame

From Day 1 to Day 43

Title

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

Description

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

Time Frame

From Day 1 to Day 43

Secondary Outcome Measure Information:

Title

Number of subjects with adverse events, serious adverse events, and death

Description

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.

Time Frame

From screening to Day 43

Title

Pharmacokinetics of KAF156: Area under the plasma concentration-time curve from time zero to infinity (AUCinf)

Description

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

Time Frame