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
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
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:
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).
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.
Placebo recipients will be pooled to distinguish IMP-related effects from background rates of AEs, ISR, and document naturally occurring malaria infections in this study population.
Blinded treatment will be used to reduce potential bias during data collection and evaluation of clinical endpoints.
Background antimalarial curative treatment: all participants will receive standard-of-care background antimalarial treatment with AL prior to IMP administration to clear any pre-existing asymptomatic malaria infection (standard AL regimen as per label recommendation and in line with local malaria treatment guidelines). This ensures a valid assessment of protective efficacy of MMV371 and prevents participants with asymptomatic baseline infection from being placed at increased risk of clinical malaria before ATV is expected to reach efficacious plasma concentrations.
Selection of IM injection sites: MMV371 is being developed as a LAI. The final product will combine two drugs and may require injection volumes that may exceed what can be safely or practically administered into the deltoid muscle (i.e. 2 mL for an adult or adolescent). MMV371 administration in the deltoid, ventrogluteal region, and vastus lateralis muscles will allow to assess PK and IM tolerability across different injection sites, guide the selection of the most appropriate site for future LAI development, and support dosing strategies that may require volumes greater than 2 mL. Larger muscles are commonly used for licensed LAI products and are expected to improve local tolerability for depot injections.
Study population: this study will include healthy adults and adolescents residing in a moderate malaria transmission area in Rwanda to evaluate safety, tolerability, PK, and PE (exploratory) of MMV371 in the target population.
Inclusion of adolescents is justified by the anticipated future use of MMV371 across all age groups in malaria endemic settings and is supported by planned safety monitoring and age-appropriate consent/assent procedures. There is no expected difference in drug metabolism in adolescents compared to adults. Furthermore, and based on prior experience with other LAI drugs, overall PK for a given dose of MMV371 after IM administration is not expected to differ between adults and adolescents with a BW ≥ 35kg (US Prescribing Information Cabenuva®, 2025).
Inclusion of both sexes, including WOCBP, allows characterization of safety, tolerability and PK across the intended user population, in line with GCP principles of equitable access to innovative medicine.
Study duration: The total study duration for the participant will be up to 7 months: approximately 1 month for screening and enrolment and 6 months for the follow-up period. Based on the known PK profile of ATV after IM administration of MMV371 from the FIH study, a 24-week post-dose period is considered sufficient to assess the PK and PE of the LAI agent.
Inpatient Period: participants will remain as inpatients from Day -1 through the morning of Day 2 (two nights at the clinic) to allow close safety and tolerability monitoring during a phase where allergic reaction may occur, scheduled PK sampling, and to ensure compliance with study procedures and instructions.
Single center: to minimize inter-site variability, ensure procedural consistency, and standardized assessments across all participants. This approach is particularly appropriate for an early-phase study.
Primary endpoint: safety and tolerability, including incidence of TEAEs, serious adverse events (SAEs), and Injection Site Reactions (ISRs), is clinically relevant for a Phase 1b of an LAI drug candidate. Establishing an acceptable safety and tolerability profile constitutes a clinically meaningful outcome, enabling progression to later phase studies focused on sustained malaria prevention.
Ethical considerations:
The study design incorporates measures to minimize participant risk, including antimalarial curative treatment with AL prior to IMP administration, close clinical monitoring, predefined pausing and stopping rules, and safety oversight by SDRT. Placebo arm helps characterize background safety events within the study population, supporting appropriate interpretation of safety findings.
The anticipated benefits of generating data directly relevant to malaria endemic populations justify the proposed design and are consistent with ethical principles outlined in ICH GCP and the Declaration of Helsinki.
Collection of demographic characteristics, including age, sex, and race, is justified to support interpretation of PK variability and to explore potential pharmacogenomic or drug resistance markers that may influence the efficacy and safety of MMV371 in the study population.
Justification for Dose:
Overall, the doses of MMV371 to be evaluated in this study are selected based on:
This approach ensures that participants are not exposed to ATV levels beyond those established in malaria prophylaxis with oral ATV-PG (Malarone®) , providing confidence in systemic safety for the target population.
MMV371 will be administered in this study at doses of 446 mg and 669mg (Arm 1-3) and possibly up to a maximum of 1338 mg (Arm 4). The intended dose range 446-1338mg is expected to achieve plasma concentrations at or above the target protective concentration to optimize protective efficacy against malaria infection.
Justification for ATV exposure:
MMV371 is a prodrug of atovaquone (ATV). In the study MMV_MMV371_23_01_FIH, MMV371 concentrations in whole blood were consistently below the limit of quantification, indicating rapid in vivo hydrolysis to ATV and the absence of clinically relevant systemic exposure to MMV371 in participants.
Several clinical studies have demonstrated prolonged protection from malaria infection following the curative 3-day dosing regimen of Malarone® in endemic countries (Polhemus et al., 2008; Shanks et al., 1999) or following daily administration of lower doses to healthy participants prior to malaria inoculation with a sporozoite challenge (Deye et al., 2012). Data from these studies have shown that the minimal protective plasma concentration of ATV needed to achieve effective chemoprophylaxis in humans is approximately 50 to 100 ng/mL in plasma (~25 to 50 ng/mL in whole blood), which is approximately 50 to 100-fold below the mean steady-state concentration in prophylaxis trials with daily administration of oral ATV-PGL (once-daily dose of 250 mg ATV/100 mg PGL).
The safety and tolerability of orally administered ATV have been well-established, with clinical data spanning over 3 decades. Clinical trials conducted with oral ATV as a monotherapy for the prevention and treatment of Pneumocystis jiroveci pneumonia and for malaria prophylaxis (in combination with PGL), have shown a good safety and tolerability profile when ATV is administered once daily. In malaria prophylaxis trials with Malarone®, the observed steady state plasma concentration of ATV was approximately 5,100 ng/mL (Thapar et al., 2002). In pneumonia clinical trials conducted with ATV monotherapy (Wellvone®/Mepron®), the observed steady state plasma concentration of ATV was 14,300 ng/mL (Hughes et al., 1991). The ATV-equivalent IM doses proposed for Arms 1-3 in this study (669/600 mg and 446/400 mg MMV371/equivalent ATV) are approximately 2.5- to 3.75-fold lower than the recommended single oral dose of Wellvone®/Mepron® (1500 mg ATV once daily). In the FIH study, MMV371 was administered IM in the deltoid muscle and demonstrated an acceptable safety, tolerability and PK profile. Based on MMV371 FIH data, the proposed 669 mg dose to be evaluated in Arms 2 and 3 is expected to achieve plasma concentrations above the protective concentration for efficacy, while maintaining maximum plasma concentrations (Cmax) approximately 50-fold below those observed following standard oral administration of Malarone® for malaria prophylaxis (mean ATV steady-state plasma concentrations = 5,100 ng/mL).
Similarly, assuming dose-proportionality following IM administration of MMV371, the maximum dose of 1338 mg (corresponding to 1200 mg ATV) proposed for this study (optional Arm 4) is expected to be associated with plasma ATV concentrations which would be at least 25-fold lower than those observed following oral administration of 250 mg ATV once daily in combination with 100 mg PGL (Malarone®) in a multiple-dosing regimen for malaria prophylaxis. The maximum ATV-equivalent IM dose proposed for this study (1200 mg ATV) is approximately 1.25-fold lower than the recommended single oral dose of Wellvone®/Mepron® (1500 mg ATV once daily).
Larger muscles, specifically the ventrogluteal region and vastus lateralis, were not evaluated in the MMV371 FIH study. However, these muscles are routinely used for licensed LAI medicines for infectious diseases or antipsychotics and are recognized to better accommodate larger injection volumes with improved local tolerability (US Prescribing Information Cabenuva® , 2025; US Prescribing Information Invega® , 2025).
Rationale for doses evaluated in Arms 1 to 3:
MMV371 doses of 446 mg (2 mL, single injection) and 669 mg (3 mL, administered as two 1.5 mL injections in the right and left deltoid) - equivalent to 400 mg and 600 mg ATV, respectively - were previously evaluated in the study MMV_MMV371_23_01_FIH conducted in healthy adults, primarily of Caucasian ethnicity. These doses demonstrated acceptable safety, tolerability, and PK profiles, supporting further clinical evaluation. In the highest dose group (669 mg, two injections of 1.5mL), 2 of 24 participants experienced transient and reversible delayed Grade 3 ISR of swelling or nodule after IM deltoid administration. Administration in larger muscles such as the ventrogluteal region or vastus lateralis could potentially reduce this incidence of swelling/nodule ISRs.
Evaluating the 446 mg (2 mL) deltoid dose in Arm 1 provides a scientific and clinical bridge between the initial FIH study conducted in European Caucasian participants. Conducting this Phase1b study in the African population will allow further evaluation of the risk/benefit of MMV371 along with preliminary PE.
LAI volumes up to 5 mL have been tested in large muscles and volumes of 3 mL are routinely used for marketed products (Jogiraju et al., 2025). Evaluating 669 mg (3 mL) dose as a single IM injection in Arms 1-3 into larger muscles (ventrogluteal region or vastus lateralis) will further document MMV371 safety/tolerability following administration in alternate injection sites suitable for larger volume IM injection.
Rationale for optional Arm 4:
The SDRT will review interim safety/tolerability and PK data from Arms 1-3 to evaluate whether a final group of healthy participants should be recruited in the study (Arm 4). If such a decision is taken, the proposed dose for Arm 4 will be expected to be associated with acceptable safety/tolerability and yield ATV plasma exposure above the minimum target protective concentration (50 ng/mL) for at least 3 months.
To achieve this goal and while the 669 mg dose might be recommended for additional evaluation, the optional Arm 4 may also be used to evaluate a higher dose of MMV371, which will not exceed 1338 mg, administered as two separate 3 mL injections into the ventrogluteal region or the vastus lateralis. The MMV371 maximum dose of 1338 mg has not been evaluated in the MMV371 UK FIH study, however, the expected maximal plasma concentrations of ATV (assuming dose proportionality) after IM administration are projected to remain at least 25-fold below the mean steady-state levels observed with daily oral Malarone® prophylaxis (5,100 ng/mL).
End-of-Study Definition:
The end of the study is defined as the date of the last visit of the last participant, after completion of all protocol-specified assessments for that visit and when any outstanding study-related findings, adverse events, or injection-site reactions identified at that visit have been appropriately documented and followed-up by the Investigator, in accordance with the protocol.
Study Population:
The study population will consist of healthy male and female adults and adolescents, aged 12 to 50 years, residing in a moderate malaria transmission area in Rwanda. Participants may include individuals with asymptomatic malaria infection at inclusion, which will be cleared prior to investigational product administration by systematic oral malaria treatment with AL, regardless of parasitemia detection. The proposed population is representative of the intended target population for MMV371 as a LAI for malaria prevention. Because this intervention is intended for populations at risk of malaria in endemic areas, efforts will be made to ensure balanced gender and adult/adolescent representation.
Inclusion Criteria:
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.
Exclusion Criteria:
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 1.
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 1.
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 1.
Receipt of a live attenuated vaccine within 4 weeks or an inactivated vaccine within 2 weeks prior to Day 1.
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.
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