Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model

Study Overview
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Brief Summary
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The main purpose of this study is to assess the chemoprophylactic activity and dose-exposure-response relationship of single oral dose of M5717 administered after direct intravenous inoculation (DVI) of Plasmodium falciparum sporozoite (PfSPZ) challenge in healthy participants.

Official Title
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A Phase Ib, Randomized, Double-Blind, Placebo Controlled, Sequential Study of Single Oral Doses of M5717 to Explore the Chemoprophylactic Activity of M5717 in a Controlled PISPZ Challenge Model in Healthy Participants

Conditions
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Healthy

Intervention / Treatment
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* Drug: M5717
* Biological: PfSPZ Challenge
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants who are overtly healthy as determined by medical evaluation, including no clinically significant abnormality identified on physical examination or laboratory evaluation and no active clinically significant disorder, condition, infection or disease that would pose a risk to participant safety or interfere with the study evaluation, procedures or completion Participants who have a body weight within 50 to 100 kilograms (kg) and body mass index within the range 19.0 to 29.9 kilograms per meter square (kg/m2) (inclusive) Male participants, during the study intervention period and for at least 120 days after the day of the study intervention dose (covering a full sperm cycle of 90 days starting after 5 half lives of last dose of study intervention: - refrain from donating sperm plus, either - abstain from intercourse with a woman of childbearing potential (WOCBP) or - use a male condom, when having sexual intercourse with a WOCBP, who is not currently pregnant, and advise her to use a highly effective contraceptive method with a failure rate of less than (<) 1 percent (%) per year, since a condom may break or leak Female participants who are: - not a WOCBP; - at least 1 year post-menopausal (amenorrhea greater than or equal to [>=] 12 months and follicle-stimulating hormone [FSH] >= 40 milli-international units per milliliter [mIU/mL]) at screening; - surgically sterile (bilateral oophorectomy, hysterectomy or bilateral salpingectomy; tubal ligation alone is not sufficient) Participants who are capable of giving signed informed consent, which includes compliance with the requirements (including mandatory intake of rescue medication to participants who have been administered the investigational Plasmodium falciparum sporozoite challenge) and restrictions listed in the informed consent form (ICF) and this protocol Other protocol defined inclusion criteria could apply Exclusion Criteria: Participants with 12-Lead electrocardiogram (ECG) outside normal range (QTcF greater than [>] 450 milli seconds [ms], pulse rate [PR] > 215 ms, or QRS > 120 ms) and deemed clinically relevant by the Investigator Supine systolic blood pressure > 140 or < 90 millimeter of mercury (mmHg), diastolic blood pressure > 90 or < 50 mmHg, and pulse rate > 90 or < 50 beats per minute (min) at screening and at admission on Day -1 (any abnormal blood pressure or pulse rate results may be repeated once and if the repeat result is within the normal range, it is not considered to have met the exclusion criterion) Seropositive for human immunodeficiency virus (HIV) I and II antibody or antigen), hepatitis B virus (HBV; hepatitis B surface antigen [HBsAg]), or hepatitis C virus (HCV; antibody) tests Liver function tests above the upper limit of normal (ULN) (> 3 x ULN) the day before DVI / study intervention administration (Day -1) History or presence of diagnosed food or known drug allergies (including but not limited to allergy to any of the antimalarial rescue medications to be used in the study), or history of anaphylaxis or other severe allergic reactions Participant with a whole blood donation or loss of > 450 mL within 60 days before administration of study drug or unwilling to defer blood donations for 6 months Other protocol defined exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

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: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: M5717<br>Participants will receive single ascending oral dose of M5717 powder in capsule after DVI of PfSPZ challenge on Day 1 (early liver stage) or on Day 4 (late liver stage). | Drug: M5717<br>* Participants will receive single ascending oral dose of M5717 powder in capsule on Day 1 (early liver stage) or on Day 4 (late liver stage).<br>Biological: PfSPZ Challenge<br>* Participants will receive 3200 units of Plasmodium falciparum sporozoites by DVI.<br>|
| Placebo Comparator: Placebo<br>Participants will receive placebo matched to M5717 after DIV of PfSPZ challenge on Day 1 (early liver stage) or on Day 4 (late liver stage). | Biological: PfSPZ Challenge<br>* Participants will receive 3200 units of Plasmodium falciparum sporozoites by DVI.<br>Drug: Placebo<br>* Participants will receive placebo matched to M5717 on Day 1 (early liver stage) or on Day 4 (late liver stage).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Positive Parasitemia | Positive parasitemia is defined as first positive quantitative polymerase chain reaction (qPCR) outcome equal or greater than 100 asexual parasites per milliliter (mL) of blood within 28 days of PfSPZ challenge. | From Day 1 up to Day 28 | 
| Time to Parasitemia | Time to parasitemia is defined as time from PfSPZ DIV to the first qPCR outcome equal or greater than 100 asexual parasites per mL of blood. | From Day 1 up to Day 28 | 
| Number of Participants With Documented Blood Stage Parasite Growth | Blood stage parasite growth is defined as an increase of qPCR measured asexual parasites per mL compared to the first parasitemia measurement. | From Day 1 up to Day 28 | 
| Clinical Symptoms of Malaria Using Malaria Clinical Score |  | From Day 1 up to Day 28 | 
| Number of Participants With Dose Exposure Response Relationship of M5717 Assessed by Pharmacokinetic/Pharmacodynamic Modeling |  | From baseline up to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and Treatment-related Adverse Events |  | Baseline up to end of study visit (approximately 33 days) | 
| Number of Participants With Clinically Significant Change From Baseline in Safety Laboratory Parameters, Vital Signs and 12-lead Electrocardiogram (ECG) Findings | Number of participants with clinically significant change from baseline in safety laboratory parameters, vital signs and 12-lead ECG findings will be reported. | Baseline up to end of study visit (approximately 33 days) | 
| Area Under the Blood Concentration Concentration-Time Curve (AUC) After Single Dose Administration of M5717 |  | Pre-dose up to 768 hours post-dose | 
| Area Under the Blood Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M5717 |  | Pre-dose up to 768 hours post-dose | 
| Area Under the Blood Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of M5717 |  | Pre-dose up to 768 hours post-dose | 
| Area Under the Blood Concentration-Time Curve From Time Zero to 24 Hours Post-dose (AUC 0-24) of M5717 |  | Pre-dose up to 24 hours post-dose | 
| Area Under the Blood Concentration-Time Curve From Time Zero to 168 Hours Post-dose (AUC 0-168) of M5717 |  | Pre-dose up to 168 hours post-dose | 
| Maximum Observed Blood Concentration (Cmax) of M5717 |  | Pre-dose up to 768 hours post-dose | 
| Blood Concentration at 24 Hours (C24) of M5717 |  | 24 hours post-dose | 
| Blood Concentration at 168 Hours (C168) of M5717 |  | 168 hours post-dose | 
| Time to Reach Maximum Blood Concentration (tmax) of M5717 |  | Pre-dose up to 24 hours post-dose | 
| Apparent Terminal Half-life (t1/2) of M5717 |  | Pre-dose up to 768 hours post-dose | 
| Elimination Rate Constant (lambda z) of M5717 |  | Pre-dose up to 768 hours post-dose | 
| Apparent Total Body Clearance From Blood (CL/f) of M5717 |  | Pre-dose up to 768 hours post-dose | 
| Apparent Volume of Distribution During Terminal Phase Following Extravascular Administration (Vz/F) of M5717 |  | Pre-dose up to 768 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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M5717, Healthy Participants, Malaria, Plasmodium falciparum