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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 39
- 试验地点
- 1
- 主要终点
- Early Liver Stage: Time to First Positive Parasitemia Based on Quantitative Polymerase Chain Reaction (qPCR)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Prevention
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Early liver stage: Pooled Placebo
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.
干预措施: PfSPZ Challenge (Biological)
Early liver stage: Pooled Placebo
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.
干预措施: Palcebo (Drug)
Early liver stage: 30 mg M5717
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.
干预措施: PfSPZ Challenge (Biological)
Early liver stage: 30 mg M5717
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.
干预措施: M5717 30 mg (Drug)
Early liver stage: 60 mg M5717
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.
干预措施: PfSPZ Challenge (Biological)
Early liver stage: 60 mg M5717
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.
干预措施: M5717 60 mg (Drug)
Early liver stage: 80 mg M5717
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.
干预措施: PfSPZ Challenge (Biological)
Early liver stage: 80 mg M5717
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.
干预措施: M5717 80 mg (Drug)
Early liver stage: 100 mg M5717
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.
干预措施: PfSPZ Challenge (Biological)
Early liver stage: 100 mg M5717
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.
干预措施: M5717 100 mg (Drug)
Early liver stage: 200 mg M5717
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.
干预措施: PfSPZ Challenge (Biological)
Early liver stage: 200 mg M5717
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.
干预措施: M5717 200 mg (Drug)
Late liver stage: Pooled Placebo
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.
干预措施: PfSPZ Challenge (Biological)
Late liver stage: Pooled Placebo
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.
干预措施: Placebo (Drug)
Late liver stage: 60 mg M5717
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.
干预措施: PfSPZ Challenge (Biological)
Late liver stage: 60 mg M5717
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.
干预措施: M5717 60 mg (Drug)
Late liver stage: 200 mg M5717
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.
干预措施: PfSPZ Challenge (Biological)
Late liver stage: 100 mg M5717
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.
干预措施: PfSPZ Challenge (Biological)
Late liver stage: 100 mg M5717
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.
干预措施: M5717 100 mg (Drug)
Late liver stage: 200 mg M5717
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.
干预措施: M5717 200 mg (Drug)
结局指标
主要结局
Early Liver Stage: Time to First Positive Parasitemia Based on Quantitative Polymerase Chain Reaction (qPCR)
时间窗: Early Liver Stage: From Day 1 up to Day 28
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: Number of Participants Over Time With Positive Parasitemia
时间窗: Early Liver Stage: From Day 1 up to Day 28
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: Number of Participants With Documented Blood Stage Parasite Growth
时间窗: Early Liver Stage: From Day 1 up to Day 28
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: Number of Participants Over Time With Positive Parasitemia
时间窗: Late Liver Stage: From Day 5 up to Day 32
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: Time to First Positive Parasitemia Based on Quantitative Polymerase Chain Reaction (qPCR)
时间窗: Late Liver Stage: From Day 5 up to Day 32
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: Number of Participants With Documented Blood Stage Parasite Growth
时间窗: Late Liver Stage: From Day 5 up to Day 32
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: Clinical Symptoms of Malaria Assessed Using Malaria Clinical Score
时间窗: 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
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: Clinical Symptoms of Malaria Assessed Using Malaria Clinical Score
时间窗: 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
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.
Dose Exposure Response Relationship of M5717 Assessed by Logistic Regression Model
时间窗: From Day 5 up to Day 32
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.
次要结局
- Apparent Terminal Half-life (t1/2) of M5717(Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose)
- Elimination Rate Constant (Lambda z) of M5717(Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose)
- Apparent Total Body Clearance From Blood (CL/f) of M5717(Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose)
- 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)
- 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)
- Blood Concentration at 168 Hours (C168) of M5717(At 168 hours post-dose)
- 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)
- Area Under the Blood Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M5717(Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose)
- Area Under the Blood Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-tlast) of M5717(Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 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, 0.5, 1, 2, 3, 6, 12 and 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, 0.5, 1, 2, 3, 6, 12, 24, 120 and 168 hours post-dose)
- Maximum Observed Blood Concentration (Cmax) of M5717(Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose)
- Blood Concentration at 24 Hours (C24) of M5717(At 24 hours post-dose)
- Time to Reach Maximum Blood Concentration (Tmax) of M5717(Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose)
- Apparent Volume of Distribution (Vz/F) During the Terminal Phase of M5717(Pre-dose, 0.5, 1, 2, 3, 6, 12, 24, 120, 168, 192, 600, and 768 hours post-dose)