A Randomized, Double-Blind, Placebo-controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of MMV371 Long-Acting Injection in Healthy Adults and Adolescents in Rwanda
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 80
- 试验地点
- 1
- 主要终点
- Incidence of adverse events over the 24-week study period
研究概览
简要总结
This Phase 1b study will assess the safety, tolerability and pharmacokinetics (PK, this measures the levels of study drug in the body) of a single injection of MMV371 in healthy adult and adolescent participants in Rwanda. MMV371 has been designed as a long acting injection (LAI). Protective efficacy (PE) will be assessed as an exploratory endpoint. Protective efficacy measures if participants are protected from becoming ill with malaria whilst the MMV371 is still present in their body. The study will enroll approximately 80 healthy male and female participants, aged 12 to 50 years. Before starting the study participants will be given a standard approved course of artemether lumifantrine (AL) to clear any malaria infection they have. Once the AL course has been completed the study drug will be given by injection in the muscle of the upper arm, the side of the thigh, or the hip. Three out of four participants will receive MMV371 and 1 in four participants will receive placebo. Placebo is a dummy medicine. All participants have an equal chance of being assigned to receive the injection in the upper arm, outer thigh or hip. Neither the participants nor the researchers treating the participants will know who received MMV371 or placebo until after the study is completed.
Key study features include:
- Study duration for each participant: up to 7 months
- MMV371 or placebo given: a single intramuscular (IM) injection
- Visit schedule: Participants will remain in-clinic on Days -1-2 (2 overnight stays), followed by 15 follow-up visits: Day 4, then weekly for 1 month, and subsequently every 2 weeks until the End-of-Study (EoS) visit at Week 24.
These frequent visits are necessary to monitor safety, the levels of MMV371 in the body, and to perform malaria detection testing until EoS (Week 24).
详细描述
The study design is aligned with the objectives of this Phase 1b trial, which are to evaluate the safety, tolerability and PK of a single IM administration of MMV371 in adults and adolescents.
To meet these objectives, the study uses a randomized, placebo controlled, parallel group design, which is a well-established and widely accepted approach for early clinical evaluation of investigational medicinal products targeted for malaria chemoprevention in compliance with Good Clinical Practice (GCP). The rationale for the key design elements of this study is outlined below.
Parallel arms followed by an optional fourth arm: The initial parallel design with Arm 1-3 allows for the efficient evaluation of multiple dose levels previously tested in healthy participants (446 and 669 mg) and for comparison of three muscle injection sites two of which (ventrogluteal region and vastus lateralis) have not been evaluated in the MMV371 UK FIH study. The option to introduce an additional arm (Arm 4) after interim review of the data by the SDRT will potentially allow for the evaluation of a higher dose level (up to 1338 mg) based on emerging data from the 3 initial parallel arms. This adaptive approach with assessment of preliminary efficacy will support optimal dose selection for subsequent studies.
Randomization: to minimize the risk of bias in the assignment of participants to treatment groups and to increase the likelihood that known and unknown participant attributes (e.g., demographic and baseline characteristics) are evenly balanced across treatment groups, and to enhance the validity of comparisons across dose groups.
Placebo control: The use of a placebo control is scientifically and ethically justified, as no chemoprevention tool is recommended by current guidelines for the proposed age group (12-50 yo). The inclusion of a placebo arm will help to establish the frequency and magnitude of changes in safety endpoints that may occur in the target population in the absence of active IMP. Placebo in this Phase1b study will also enable the characterization of the true infection rate at the selected study site and support analysis of the protective efficacy of the active agent.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 12 Years 至 50 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. For adolescents, written assent and parental/legal authorized representative (LAR) consent must be obtained, in accordance with local regulations.
- •Able to provide proof of identity to the satisfaction of the Investigator or delegate completing the enrolment process
- •Able and willing to communicate effectively and comply with all study procedures for the duration of the study (including IM injections, safety assessments, blood sampling, malaria monitoring, follow-up visits)
- •Living within local jurisdiction of trial site(s) and available for the duration of the trial Demographics and Contraception
- •Male or female participants aged 12 to 50 years inclusive at the time of signing informed consent/assent.
- •WOCBP must be non-pregnant and non-lactating, confirmed by a negative highly sensitive serum pregnancy test at screening and a negative urine pregnancy test at admission, prior to IMP administration. WOCBP must agree to use, at minimum, acceptable contraception methods, as defined by the Clinical Trials Coordination Group (CTCG) guidance, from 21 days prior to study Day 1 through the End-of Study visit (Week 24) (Clinical Trials Coordination Group (CTCG), 2024).
- •Post-menopausal participants must have menopause confirmed at screening, defined as a follicle-stimulating hormone (FSH) level ≥ 25.8 mIU/mL Baseline Characteristics
- •Healthy volunteers, as determined by:
- •physical examination Vital signs 12 lead ECG absence of malaria symptoms at baseline (note: a positive blood smear without malaria symptoms at baseline is not exclusionary) Hematology, biochemistry or urinalysis results at screening or at the admission visit (Day -1) that are within the standard clinically acceptable laboratory ranges defined for this study (See section 10.7 Appendix 7)
- •For adults (18-50 years): Body Weight ≥45 kg at screening
- •For adolescents (12-17 years): body weight ≥35 kg at screening Participant-reported outcomes (PROs)
- •Able to understand and complete participant-reported outcome assessments (e.g., injection-site reaction diary and injection acceptability assessments), either independently or with assistance, in a language and format approved by the Ethics Committee.
排除标准
- •Medical Conditions
- •Positive malaria blood smear microscopy at the Admission visit (Day -1).
- •Acute febrile illness within 96 hours prior to enrolment or within 96h prior to Day
- •Serious adverse reaction or clinically significant hypersensitivity to drugs or formulation excipients used in the study: artemether-lumefantrine (Coartem® or generic formulations) and atovaquone (Wellvone®/Mepron® and/or Malarone® or their generics).
- •Any history of severe allergic reaction with generalized urticaria, angioedema, or anaphylaxis prior to enrolment that, in the opinion of the Investigator, has a reasonable risk of recurrence during the trial.
- •Any current uncontrolled medical or psychiatric condition, or substance abuse problems that, in the opinion of the Investigator, would make it unlikely for the participant to comply with the protocol, may interfere with study assessments, or could jeopardize the safety of the participant.
- •Evidence of clinically significant neurologic, cardiac, gastro-intestinal, dermatologic, pulmonary, hepatic, endocrine, rheumatologic, autoimmune, haematological, oncologic, or renal disease, as determined by medical history, physical examination, and/or laboratory evaluations, including urinalysis.
- •History of a bleeding disorder diagnosed by a physician (e.g., factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or a history of significant bruising with blood draws.
- •Known or documented sickle cell disease by history. Note: known sickle cell trait is not exclusionary.
- •Presence of sinus node dysfunction; clinically significant PR interval prolongation (>220 msec); intermittent second- or third-degree atrioventricular block; complete bundle branch block; sustained cardiac arrhythmias including, but not limited to, atrial fibrillation or supraventricular tachycardia; any symptomatic arrhythmia except isolated extrasystoles; abnormal T wave morphology that may interfere with QT/QTc assessment; or QTcF >450 msec (adults and adolescents).
- •Physical Examination
- •Participants who do not have adequate venous access for multiple venipunctures or cannulation, as assessed by the Investigator or delegate at screening.
- •Participants with tattoos, scars or other clinically significant dermatological lesions or conditions overlying the deltoid, gluteal, or vastus lateralis region that, in the opinion of the Investigator, may interfere with injection site assessments.
- •Diagnostic Assessments
- •Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab). or human immunodeficiency virus (HIV) 1 and 2 antibody results.
- •Prior Study Participation
- •Participants who have received any IMP in a clinical research study within the 90 days prior to Day 1, or within fewer than 5 elimination half-lives prior to Day 1 (whichever is longer). Note: Past, current, or planned participation in non-interventional (observational) studies is not exclusionary.
- •Participants who are currently enrolled in another interventional clinical trial within 90 days prior to Day 1, or who intend to participate in another interventional clinical trial during their participation in this study.
- •Donation of blood or plasma, or loss of more than 400 mL of blood, within 90 days prior to Day
- •Prior and Concomitant Medication or Vaccine
- •Use of antimalarial chemoprevention or treatment, and/or antibiotics with known antimalarial activity (see Section 10.6 Appendix 6), within 6 weeks or fewer than 5 elimination half-lives prior to Screening (whichever is longer).
- •Current or recent (within 30 days prior to Day 1) use of rifampin/rifampicin, rifabutin, tetracycline, or indinavir due to potential drug-drug interaction risk with atovaquone.
- •Use of chronic (≥14 days) oral or IV corticosteroids (excluding topical or nasal) at immunosuppressive doses (i.e., prednisone >10 mg/day) or other immunosuppressive drugs within 30 days prior to Day
- •Receipt of a live attenuated vaccine within 4 weeks or an inactivated vaccine within 2 weeks prior to Day
- •Receipt or planned receipt during the study of any doses of a malaria vaccine (investigational or registered, such as RTS, S/AS01 or R21/Matrix-M) or monoclonal antibodies (mAb) directed against Plasmodium falciparum.
- •Receipt of immunoglobulins and/or blood products within the past 6 months. Lifestyle Characteristics
- •History or medical, occupational, or family problems related to alcohol or illicit drug use within the past 12 months that, in the opinion of the Investigator, may interfere with study participation, compliance, or participant safety.
- •Other Exclusion Criteria
- •Participants who are, or are immediate family members of, study site staff or Sponsor employees involved in the conduct of the study.
- •Any other condition or circumstance that, in the opinion of the Investigator, would make the participant unsuitable for the study or could compromise participant safety or data integrity.
研究组 & 干预措施
Placebo (2 mL) IM in the deltoid
Participants will receive a single 2mL IM injection in the deltoid. Participants will be randomized at a 1:1:1 ratio to the three parallel arms, each corresponding to a specific dose and injection site, and within each arm will receive MMV371 or placebo in a 3:1 ratio.
干预措施: Placebo for MMV371 (Drug)
Placebo (3 mL) IM in the ventrogluteal region
Participants will receive a single 3mL IM injection in the ventrogluteal region. Participants will be randomized at a 1:1:1 ratio to the three parallel arms, each corresponding to a specific dose and injection site, and within each arm will receive MMV371 or placebo in a 3:1 ratio.
干预措施: Placebo for MMV371 (Drug)
Placebo (3 mL) IM in the vastus lateralis
Participants will receive a single 3mL IM injection in the vastus lateralis. Participants will be randomized at a 1:1:1 ratio to the three parallel arms, each corresponding to a specific dose and injection site, and within each arm will receive MMV371 or placebo in a 3:1 ratio.
干预措施: Placebo for MMV371 (Drug)
Optional arm placebo dose and location TBD
If Arm 4 is initiated after SDRT recommendation, participants will be randomized via the IRT system to receive MMV371 or placebo in a 3:1 ratio (MMV371:placebo). The highest dose proposed for Arm 4 will not exceed 1338 mg (6mL given into two separate injections of 3 mL each in the ventrogluteal region or vastus lateralis).
干预措施: Placebo for MMV371 (Drug)
MMV371 446 mg (2 mL) IM in the deltoid
Participants will receive a single 2mL IM injection in the deltoid. Participants will be randomized at a 1:1:1 ratio to the three parallel arms, each corresponding to a specific dose and injection site, and within each arm will receive MMV371 or placebo in a 3:1 ratio.
干预措施: MMV371 (Drug)
MMV371 669 mg (3 mL) IM in the ventrogluteal region
Participants will receive a single 3mL IM injection in the ventrogluteal region. Participants will be randomized at a 1:1:1 ratio to the three parallel arms, each corresponding to a specific dose and injection site, and within each arm will receive MMV371 or placebo in a 3:1 ratio.
干预措施: MMV371 (Drug)
MMV371 669 (3 mL) IM in the vastus lateralis
Participants will receive a single 3mL IM injection in the vastus lateralis. Participants will be randomized at a 1:1:1 ratio to the three parallel arms, each corresponding to a specific dose and injection site, and within each arm will receive MMV371 or placebo in a 3:1 ratio.
干预措施: MMV371 (Drug)
Optional arm MMV371 dose and location TBD
If Arm 4 is initiated after SDRT recommendation, participants will be randomized via the IRT system to receive MMV371 or placebo in a 3:1 ratio (MMV371:placebo). The highest dose proposed for Arm 4 will not exceed 1338 mg (6mL given into two separate injections of 3 mL each in the ventrogluteal region or vastus lateralis).
干预措施: MMV371 (Drug)
结局指标
主要结局
Incidence of adverse events over the 24-week study period
时间窗: From signature of informed consent until 30 days after End of Study Visit Day 169 (Week 24)
The number of AEs, will be presented
Incidence of grade 2 or greater injection site reactions (ISRs) over the 24-week study period
时间窗: From MMV371 admin on day 1 to EOS visit, day 169 (wk 24)
The number of ISRs will be presented
Incidence of clinically significant laboratory, vital signs and ECG abnormalities over the 24-week study period
时间窗: From informed consent to 30 days post EoS visit wk24 day169
Count of events will be presented
次要结局
未报告次要终点