Clinical trial NCT04250363: Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Healthy Participants
M5717
Malaria
Plasmodium falciparum
Lead sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2020-01-31
Enrollment: 39
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: PREVENTION

Brief summary: The main purpose of this study was 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.


Eligibility criteria: 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

Primary outcomes:
measure: Early Liver Stage: Number of Participants Over Time With Positive Parasitemia
timeFrame: Early Liver Stage: From Day 1 up to Day 28
measure: Late Liver Stage: Number of Participants Over Time With Positive Parasitemia
timeFrame: Late Liver Stage: From Day 5 up to Day 32
measure: Early Liver Stage: Time to First Positive Parasitemia Based on Quantitative Polymerase Chain Reaction (qPCR)
timeFrame: Early Liver Stage: From Day 1 up to Day 28
measure: Late Liver Stage: Time to First Positive Parasitemia Based on Quantitative Polymerase Chain Reaction (qPCR)
timeFrame: Late Liver Stage: From Day 5 up to Day 32
measure: Early Liver Stage: Number of Participants With Documented Blood Stage Parasite Growth
timeFrame: Early Liver Stage: From Day 1 up to Day 28
measure: Late Liver Stage: Number of Participants With Documented Blood Stage Parasite Growth
timeFrame: Late Liver Stage: From Day 5 up to Day 32
measure: Early Liver Stage: Clinical Symptoms of Malaria Assessed Using Malaria Clinical Score
timeFrame: Early Liver Stage: At Day 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26 and 28
measure: Late Liver Stage: Clinical Symptoms of Malaria Assessed Using Malaria Clinical Score
timeFrame: Late Liver Stage: At Day 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30 and 32
measure: Dose Exposure Response Relationship of M5717 Assessed by Logistic Regression Model
timeFrame: From Day 5 up to Day 32
Secondary outcomes:
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and Treatment-related TEAEs
timeFrame: Early Liver Stage: From Day 1 up to Day 33; Late Liver Stage: From Day 1 up to Day 36
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) Based on Severity
timeFrame: Early Liver Stage: From Day 1 up to Day 33; Late Liver Stage: From Day 1 up to Day 36
measure: Number of Participants With Clinically Significant Change From Baseline in Laboratory Values
timeFrame: Early Liver Stage: From Day 1 up to Day 33; Late Liver Stage: From Day 1 up to Day 36
measure: Number of Participants With Clinically Significant Change From Baseline in Vital Signs
timeFrame: Early Liver Stage: From Day 1 up to Day 33; Late Liver Stage: From Day 1 up to Day 36
measure: Number of Participants With Clinically Significant Change From Baseline in 12-lead Electrocardiogram (ECG) Findings
timeFrame: Early Liver Stage: From Day 1 up to Day 33; Late Liver Stage: From Day 1 up to Day 36
measure: Area Under the Blood Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M5717
timeFrame: Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose
measure: Area Under the Blood Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-tlast) of M5717
timeFrame: Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose
measure: Area Under the Blood Concentration-Time Curve From Time Zero to 24 Hours Post-dose (AUC 0-24) of M5717
timeFrame: Pre-dose, 0.5, 1, 2, 3, 6, 12 and 24 hours post-dose
measure: Area Under the Blood Concentration-Time Curve From Time Zero to 168 Hours Post-dose (AUC 0-168) of M5717
timeFrame: Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120 and 168 hours post-dose
measure: Maximum Observed Blood Concentration (Cmax) of M5717
timeFrame: Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose
measure: Blood Concentration at 24 Hours (C24) of M5717
timeFrame: At 24 hours post-dose
measure: Blood Concentration at 168 Hours (C168) of M5717
timeFrame: At 168 hours post-dose
measure: Time to Reach Maximum Blood Concentration (Tmax) of M5717
timeFrame: Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose
measure: Apparent Terminal Half-life (t1/2) of M5717
timeFrame: Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose
measure: Elimination Rate Constant (Lambda z) of M5717
timeFrame: Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose
measure: Apparent Total Body Clearance From Blood (CL/f) of M5717
timeFrame: Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose
measure: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of M5717
timeFrame: Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose
Other outcomes:
Locations:
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
Study officials:
affiliation: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References: