Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model

Healthy Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04250363
• Other study ID #: MS201618_0003
• Secondary ID: 2019-003414-1420
• Status: Completed
• Phase: Phase 1
• Start date: February 17, 2020
• Est. completion date: August 18, 2021

Study information

• Verified date: November 2023
• Source: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 39
• Est. completion date: August 18, 2021
• Est. primary completion date: August 18, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• Healthy

Intervention

Biological:
• PfSPZ Challenge
Participants received 3200 units of Plasmodium falciparum sporozoites by DVI on Day 1.

Drug:
• Palcebo
Participants received single oral dose of placebo matched to M5717 capsule on Day 1.
• M5717 30 mg
Participants received 30 mg single oral dose of M5717 capsule on Day 1.
• M5717 60 mg
Participants received 60 mg single oral dose of M5717 capsule on Day 1.
• M5717 80 mg
Participants received 80 mg single oral dose of M5717 capsule on Day 1.
• M5717 100 mg
Participants received 100 mg single oral dose of M5717 capsule on Day 1.
• M5717 200 mg
Participants received 200 mg single oral dose of M5717 capsule on Day 1.
• Placebo
Participants received single oral dose of placebo matched to M5717 capsule on Day 5.
• M5717 60 mg
Participants received 60 mg single oral dose of M5717 capsule on Day 5.
• M5717 100 mg
Participants received 100 mg single oral dose of M5717 capsule on Day 5.
• M5717 200 mg
Participants received 200 mg single oral dose of M5717 capsule on Day 5.

Locations

Country	Name	City	State
Netherlands	Leiden University Medical Center	Leiden

Sponsors (1)

Lead Sponsor	Collaborator
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Early Liver Stage: Number of Participants Over Time With Positive Parasitemia	Number of participants with positive parasitemia 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.	Early Liver Stage: From Day 1 up to Day 28
Primary	Late Liver Stage: Number of Participants Over Time With Positive Parasitemia	Number of participants with positive parasitemia 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.	Late Liver Stage: From Day 5 up to Day 32
Primary	Early Liver Stage: Time to First Positive Parasitemia Based on Quantitative Polymerase Chain Reaction (qPCR)	Time to first positive parasitemia was defined as the time (i.e., number of days) from the PfSPZ DVI (i.e., date of DVI PfSPZ) to the first qPCR outcome greater than or equal to (>=) 100 asexual parasites per milliliter (mL) of blood.	Early Liver Stage: From Day 1 up to Day 28
Primary	Late Liver Stage: Time to First Positive Parasitemia Based on Quantitative Polymerase Chain Reaction (qPCR)	Time to first positive parasitemia was defined as the time (i.e., number of days) from the PfSPZ DVI (i.e., date of DVI PfSPZ) to the first qPCR outcome greater than or equal to (>=) 100 asexual parasites per milliliter (mL) of blood.	Late Liver Stage: From Day 5 up to Day 32
Primary	Early Liver Stage: Number of Participants With Documented Blood Stage Parasite Growth	Documented blood stage parasite growth was defined as an increase of qPCR measured asexual parasites per mL compared to the first parasitemia measurement, within 28 days of PfSPZ DVI.	Early Liver Stage: From Day 1 up to Day 28
Primary	Late Liver Stage: Number of Participants With Documented Blood Stage Parasite Growth	Documented blood stage parasite growth was defined as an increase of qPCR measured asexual parasites per mL compared to the first parasitemia measurement, within 28 days of PfSPZ DVI.	Late Liver Stage: From Day 5 up to Day 32
Primary	Early Liver Stage: Clinical Symptoms of Malaria Assessed Using Malaria Clinical Score	The malaria clinical score consisted of 14 signs/symptoms frequently associated with malaria and graded using a 4-point scale (absent: 0; mild: 1; moderate: 2; severe: 3) and summed to generate a total malaria clinical score (maximum score possible is 42): headache, myalgia (muscle ache), arthralgia (joint ache), fatigue/lethargy, malaise (general discomfort/uneasiness), chills/shivering/rigors, sweating/hot spells, anorexia, nausea, vomiting, abdominal discomfort, fever, tachycardia and hypotension. The minimum score was 0 (no symptoms) and the maximum score was 42 (maximum symptoms). Total scores are reported here.	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
Primary	Late Liver Stage: Clinical Symptoms of Malaria Assessed Using Malaria Clinical Score	The malaria clinical score consisted of 14 signs/symptoms frequently associated with malaria and graded using a 4-point scale (absent: 0; mild: 1; moderate: 2; severe: 3) and summed to generate a total malaria clinical score (maximum score possible is 42): headache, myalgia (muscle ache), arthralgia (joint ache), fatigue/lethargy, malaise (general discomfort/uneasiness), chills/shivering/rigors, sweating/hot spells, anorexia, nausea, vomiting, abdominal discomfort, fever, tachycardia and hypotension. The minimum score was 0 (no symptoms) and the maximum score was 42 (maximum symptoms). Total scores are reported here.	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
Primary	Dose Exposure Response Relationship of M5717 Assessed by Logistic Regression Model	Exposure efficacy relationship was analyzed using logistic regression model. Different exposure matrices (AUC0-24, AUC0-168, AUC0-inf, C24 and C168) were analyzed using logistic regression model.	From Day 5 up to Day 32
Secondary	Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and Treatment-related TEAEs	An adverse event (AE) was defined as any untoward medical occurrence in a participant administered with study drug which does not necessarily had a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE was defined as AEs starting or worsening after the first intake of the study drug. TEAEs included both serious TEAEs and non-serious TEAEs. Treatment-related TEAEs: reasonably related to study intervention.	Early Liver Stage: From Day 1 up to Day 33; Late Liver Stage: From Day 1 up to Day 36
Secondary	Number of Participants With Treatment Emergent Adverse Events (TEAEs) Based on Severity	Severity of adverse events (AE) were assessed by the investigator per the Qualitative Toxicity Scale. Grade 1= Mild, Grade 2=Moderate, Grade 3=Severe. The number of participants that experienced at least one solicited local TEAE were summarized by grade. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs include both Serious TEAEs and non-serious TEAEs. Number of participants with Grade=1, Grade=2 and 3 were reported.	Early Liver Stage: From Day 1 up to Day 33; Late Liver Stage: From Day 1 up to Day 36
Secondary	Number of Participants With Clinically Significant Change From Baseline in Laboratory Values	Laboratory assessments included hematology, biochemistry, urinalysis, and coagulation. Number of participants with clinically significant changes from baseline in laboratory values which were deemed clinically significant by the investigator were reported.	Early Liver Stage: From Day 1 up to Day 33; Late Liver Stage: From Day 1 up to Day 36
Secondary	Number of Participants With Clinically Significant Change From Baseline in Vital Signs	Vital signs included oral body temperature, height, weight, systolic blood pressure, diastolic blood pressure, and pulse rate. Number of participants with clinically significant changes from baseline in Vital signs which were deemed clinically significant by the investigator were reported.	Early Liver Stage: From Day 1 up to Day 33; Late Liver Stage: From Day 1 up to Day 36
Secondary	Number of Participants With Clinically Significant Change From Baseline in 12-lead Electrocardiogram (ECG) Findings	Single 12-lead ECG was obtained as outlined using an ECG machine that automatically calculates the heart rate and measures PR, QRS, and QT intervals. Number of participants with clinically significant changes from baseline in ECG which were deemed clinically significant by the investigator were reported.	Early Liver Stage: From Day 1 up to Day 33; Late Liver Stage: From Day 1 up to Day 36
Secondary	Area Under the Blood Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M5717	AUC0-inf was calculated by combining AUC0-t and AUCextra. AUC extra represents an extrapolated value obtained by Clast/ ?z, where Clast is the calculated blood concentration at the last sampling time point at which the measured blood concentration is at or above the Lower Limit of quantification (LLQ) and ?z is the apparent terminal rate constant determined by log-linear regression analysis of the measured blood concentrations of the terminal log-linear phase.	Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose
Secondary	Area Under the Blood Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-tlast) of M5717	Area under the blood concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule.	Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose
Secondary	Area Under the Blood Concentration-Time Curve From Time Zero to 24 Hours Post-dose (AUC 0-24) of M5717	AUC from time zero to 24 hours post dose, calculated using the mixed log linear trapezoidal rule (linear up, log down) using the nominal dosing interval.	Pre-dose, 0.5, 1, 2, 3, 6, 12 and 24 hours post-dose
Secondary	Area Under the Blood Concentration-Time Curve From Time Zero to 168 Hours Post-dose (AUC 0-168) of M5717	AUC from time zero to 168 hours post dose. Calculated using the mixed log linear trapezoidal rule (linear up, log down) using the nominal dosing interval.	Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120 and 168 hours post-dose
Secondary	Maximum Observed Blood Concentration (Cmax) of M5717	Cmax was obtained directly from the concentration versus time curve.	Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose
Secondary	Blood Concentration at 24 Hours (C24) of M5717	Blood samples for PK analysis of C24 of M5717 was reported.	At 24 hours post-dose
Secondary	Blood Concentration at 168 Hours (C168) of M5717	C168 is the calculated blood concentration at 168 hours post-dose at which the measured blood concentration is at or above the Lower Limit of quantification (LLQ).	At 168 hours post-dose
Secondary	Time to Reach Maximum Blood Concentration (Tmax) of M5717	Time to reach the maximum blood concentration (Tmax) was obtained directly from the concentration versus time curve.	Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose
Secondary	Apparent Terminal Half-life (t1/2) of M5717	Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by lambda z.	Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose
Secondary	Elimination Rate Constant (Lambda z) of M5717	Elimination rate constant determined from the terminal slope of the log-transformed concentration curve using linear regression on terminal data points of the curve.	Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose
Secondary	Apparent Total Body Clearance From Blood (CL/f) of M5717	Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent body clearance of the drug from blood, CL= Dose/AUC0-inf	Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose
Secondary	Apparent Volume of Distribution (Vz/F) During the Terminal Phase of M5717	The Vz/f was defined as the theoretical volume in which the total amount of required to uniformly distribute to produce the desired plasma concentration. Apparent volume of distribution after oral dose (Vz/F) was influenced by the fraction absorbed. The Vz/f was calculated by dividing the dose with area under the concentration time curve from time zero to infinity multiplied with terminal elimination rate constant Lambda(z). Vz/f=Dose/AUC(0-inf) multiply Lambda(z).	Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose

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