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

• ClinicalTrials.gov Identifier: NCT04072302
• Recruitment Status: Completed
• First Posted: August 28, 2019
• Last Update Posted: August 28, 2019
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: August 20, 2019
• First Posted Date: August 28, 2019
• Last Update Posted Date: August 28, 2019
• Actual Study Start Date: September 15, 2014
• Actual Primary Completion Date: November 29, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 26, 2019)

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

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: August 26, 2019)

• Number of subjects with adverse events, serious adverse events, and death [ Time Frame: 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.
• Pharmacokinetics of KAF156: Area under the plasma concentration-time curve from time zero to infinity (AUCinf) [ Time Frame: 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
• Pharmacokinetics of KAF156: Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast) [ Time Frame: 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
• Pharmacokinetics of KAF156: Area under teh plasma concentration-time curve from time zero to time 24 h (AUC0-24) [ Time Frame: 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
• Pharmacokinetics of KAF156: Terminal elimination half life (T1/2) [ Time Frame: 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.
• Pharmacokinetics of KAF156: Apparent systemic clearance from plasma following oral administration (CL/F) [ Time Frame: 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
• Pharmacokinetics of KAF156: Apparent volume of distribution during the terminal phase following oral administration (Vz/F) [ Time Frame: 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
• Pharmacokinetics of KAF156: Observed maximum plasma concentration (Cmax) [ Time Frame: 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
• Pharmacokinetics of KAF156: Time to reach the maximum concentration (Tmax) [ Time Frame: 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
• Parasite growth Kinetics by qRT-PCR [ Time Frame: Pre-dose, days 7-23, Day 29, Day 43 ]
  Parasitemia levels as measured by qRT-PCR will be summarized and displayed graphically over time.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention
• Condition: Malaria

Intervention

• Drug: KAF156
  100 mg tablet, 20 mg tablet, 50 mg tablet
• Drug: Placebo
  100 mg tablet, 20 mg tablet, 50 mg tablet

Study Arms

• 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
  Intervention: Drug: KAF156
• 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
  Intervention: Drug: Placebo
• Experimental: KAF156 800 mg post-challenge
  Single dose 800 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos
  Intervention: Drug: KAF156
• 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
  Intervention: Drug: Placebo
• Experimental: KAF156 300 mg post-challenge
  Single dose 300 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos
  Intervention: Drug: KAF156
• 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
  Intervention: Drug: Placebo
• Experimental: KAF156 100 mg post-challenge
  Single dose 100 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos
  Intervention: Drug: KAF156
• 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
  Intervention: Drug: Placebo
• Experimental: KAF156 20 mg post-challenge
  Single dose 20 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos
  Intervention: Drug: KAF156
• 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
  Intervention: Drug: Placebo
• Experimental: KAF156 50 mg post-challenge
  Single dose 50 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos
  Intervention: Drug: KAF156
• 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
  Intervention: Drug: Placebo

• Publications *: Kublin JG, Murphy SC, Maenza J, Seilie AM, Jain JP, Berger D, Spera D, Zhao R, Soon RL, Czartoski JL, Potochnic MA, Duke E, Chang M, Vaughan A, Kappe SHI, Leong FJ, Pertel P, Prince WT; KAF156 Study Team. Safety, Pharmacokinetics, and Causal Prophylactic Efficacy of KAF156 in a Plasmodium falciparum Human Infection Study. Clin Infect Dis. 2021 Oct 5;73(7):e2407-e2414. doi: 10.1093/cid/ciaa952.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 26, 2019): 86
• Original Actual Enrollment: Same as current
• Actual Study Completion Date: November 29, 2017
• Actual Primary Completion Date: November 29, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years to 40 Years (Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04072302
• Other Study ID Numbers: CKAF156X2202
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: August 2019