Chemoprophylactic Activity of M5717 in PfSPZ Challenge Model

NCT04250363 | Completed Phase 1 Results

• 3 other identifiers: MS201618_00032019-003414-14203481/Z/16/Z
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy

Keywords

Healthy Participants; M5717; Malaria; Plasmodium falciparum

Outcome Measures

Primary Outcomes (9)

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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 Outcomes (17)

• Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and Treatment-related TEAEs

  Early Liver Stage: From Day 1 up to Day 33; Late Liver Stage: From Day 1 up to Day 36

• Number of Participants With Treatment Emergent Adverse Events (TEAEs) Based on Severity

  Early Liver Stage: From Day 1 up to Day 33; Late Liver Stage: From Day 1 up to Day 36

• Number of Participants With Clinically Significant Change From Baseline in Laboratory Values

  Early Liver Stage: From Day 1 up to Day 33; Late Liver Stage: From Day 1 up to Day 36

• Number of Participants With Clinically Significant Change From Baseline in Vital Signs

  Early Liver Stage: From Day 1 up to Day 33; Late Liver Stage: From Day 1 up to Day 36

• Number of Participants With Clinically Significant Change From Baseline in 12-lead Electrocardiogram (ECG) Findings

  Early Liver Stage: From Day 1 up to Day 33; Late Liver Stage: From Day 1 up to Day 36

Study Arms (10)

Early liver stage: Pooled Placebo

PLACEBO COMPARATOR

Participants received single dose of placebo matched to M5717 capsule on Day 1 after 2 hours of Plasmodium falciparum Sporozoite (PfSPZ) (3200 sporozoites per injection) intravenous (IV) inoculation administration on Day 1.

Biological: PfSPZ Challenge; Drug: Palcebo

Early liver stage: 30 mg M5717

EXPERIMENTAL

Participants received single dose of M5717 30 mg capsule on Day 1 after 2 hours of PfSPZ (3200 sporozoites per injection) IV inoculation administration on Day 1.

Biological: PfSPZ Challenge; Drug: M5717 30 mg

Early liver stage: 60 mg M5717

EXPERIMENTAL

Participants received single dose of M5717 60 mg capsule on Day 1 after 2 hours of PfSPZ (3200 sporozoites per injection) IV inoculation administration on Day 1.

Biological: PfSPZ Challenge; Drug: M5717 60 mg

Early liver stage: 80 mg M5717

EXPERIMENTAL

Participants received single dose of M5717 80 mg capsule on Day 1 after 2 hours of PfSPZ (3200 sporozoites per injection) IV inoculation administration on Day 1.

Biological: PfSPZ Challenge; Drug: M5717 80 mg

Early liver stage: 100 mg M5717

EXPERIMENTAL

Participants received single dose of M5717 100 mg capsule on Day 1 after 2 hours of PfSPZ (3200 sporozoites per injection) IV inoculation administration on Day 1.

Biological: PfSPZ Challenge; Drug: M5717 100 mg

Early liver stage: 200 mg M5717

EXPERIMENTAL

Participants received single dose of M5717 200 mg capsule on Day 1 after 2 hours of PfSPZ (3200 sporozoites per injection) IV inoculation administration on Day 1.

Biological: PfSPZ Challenge; Drug: M5717 200 mg

Late liver stage: Pooled Placebo

EXPERIMENTAL

Participants received single dose of placebo matched to M5717 capsule on Day 5 after 96 hours of PfSPZ (3200 sporozoites per injection) IV inoculation administration on Day 1.

Biological: PfSPZ Challenge; Drug: Placebo

Late liver stage: 60 mg M5717

EXPERIMENTAL

Participants received single dose of M5717 60 mg capsule on Day 5 after 96 hours of PfSPZ (3200 sporozoites per injection) IV inoculation administration on Day 1.

Biological: PfSPZ Challenge; Drug: M5717 60 mg

Late liver stage: 100 mg M5717

EXPERIMENTAL

Participants received single dose of M5717 100 mg capsule on Day 5 after 96 hours of PfSPZ (3200 sporozoites per injection) IV inoculation administration on Day 1.

Biological: PfSPZ Challenge; Drug: M5717 100 mg

Late liver stage: 200 mg M5717

EXPERIMENTAL

Participants received single dose of M5717 200 mg capsule on Day 5 after 96 hours of PfSPZ (3200 sporozoites per injection) IV inoculation administration on Day 1.

Biological: PfSPZ Challenge; Drug: M5717 200 mg

Interventions

PfSPZ Challenge BIOLOGICAL

Participants received 3200 units of Plasmodium falciparum sporozoites by DVI on Day 1.

Early liver stage: 100 mg M5717; Early liver stage: 200 mg M5717; Early liver stage: 30 mg M5717; Early liver stage: 60 mg M5717; Early liver stage: 80 mg M5717; Early liver stage: Pooled Placebo; Late liver stage: 100 mg M5717; Late liver stage: 200 mg M5717; Late liver stage: 60 mg M5717; Late liver stage: Pooled Placebo

Palcebo DRUG

Participants received single oral dose of placebo matched to M5717 capsule on Day 1.

Early liver stage: Pooled Placebo

M5717 30 mg DRUG

Participants received 30 mg single oral dose of M5717 capsule on Day 1.

Early liver stage: 30 mg M5717

M5717 60 mg DRUG

Participants received 60 mg single oral dose of M5717 capsule on Day 1.

Early liver stage: 60 mg M5717

M5717 80 mg DRUG

Participants received 80 mg single oral dose of M5717 capsule on Day 1.

Early liver stage: 80 mg M5717

M5717 100 mg DRUG

Participants received 100 mg single oral dose of M5717 capsule on Day 1.

Early liver stage: 100 mg M5717

M5717 200 mg DRUG

Participants received 200 mg single oral dose of M5717 capsule on Day 1.

Early liver stage: 200 mg M5717

Placebo DRUG

Participants received single oral dose of placebo matched to M5717 capsule on Day 5.

Late liver stage: Pooled Placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany: lead

Study Sites (1)

Leiden University Medical Center

Leiden, Netherlands

Location

Related Publications (1)

• van der Plas JL, Kuiper VP, Bagchus WM, Bodding M, Yalkinoglu O, Tappert A, Seitzinger A, Spangenberg T, Bezuidenhout D, Wilkins J, Oeuvray C, Dhingra SK, Thathy V, Fidock DA, Smidt LCA, Roozen GVT, Koopman JPR, Lamers OAC, Sijtsma J, van Schuijlenburg R, Wessels E, Meij P, Kamerling IMC, Roestenberg M, Khandelwal A. Causal chemoprophylactic activity of cabamiquine against Plasmodium falciparum in a controlled human malaria infection: a randomised, double-blind, placebo-controlled study in the Netherlands. Lancet Infect Dis. 2023 Oct;23(10):1164-1174. doi: 10.1016/S1473-3099(23)00212-8. Epub 2023 Jul 3.

  PMID: 37414066 DERIVED

Related Links

• Trial Awareness and Transparency website
• Medical Information Location Map - Med Info Contacts

MeSH Terms

Conditions

Malaria; Malaria, Falciparum

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Results Point of Contact

• Title: Communication Center
• Organization: Merck Healthcare KGaA, Darmstadt Germany, an affiliate of Merck KGaA, Darmstadt, Germany

service@emdgroup.com

+49-6151-72-5200

Study Officials

• Medical Responsible

  Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 29, 2020
• First Posted: January 31, 2020
• Study Start: February 17, 2020
• Primary Completion: August 18, 2021
• Study Completion: August 18, 2021
• Last Updated: May 1, 2024
• Results First Posted: May 1, 2024

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)