Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202302515279954 Date of Approval: 21/02/2023
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title MS201618_0033
Official scientific title Phase IIa Proof of Concept, Multicenter, Randomized, Open-label Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of the Combination M5717 plus Pyronaridine Administered Once Daily for 1 or 2 Days to Adults and Adolescents with Acute Uncomplicated Plasmodium falciparum Malaria
Brief summary describing the background and objectives of the trial Artemisinin-based combination therapies (ACTs) have been the gold standard for acute uncomplicated P. falciparum malaria, but the increasing reports of emergent resistant strains to artemisinin-related compound therapies makes it necessary to look for new therapeutic tools. In this context, the current study intends to explore in a Proof of Concept the safety, preliminary efficacy, and pharmacokinetics (PK) of M5717 (free base) in combination with pyronaridine (tetraphosphate). An ACT containing combination pyronaridine-artesunate (Pyramax) will be used as internal control, mainly for safety purposes.
Type of trial RCT
Acronym (If the trial has an acronym then please provide)
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied Malaria
Purpose of the trial Treatment: Drugs
Anticipated trial start date 20/02/2023
Actual trial start date 29/03/2023
Anticipated date of last follow up 23/06/2023
Actual Last follow-up date 08/05/2024
Anticipated target sample size (number of participants) 137
Actual target sample size (number of participants) 38
Recruitment status Stopped early/ terminated
Publication URL
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Simple randomization using a randomization table created by a computer software program Allocation was determined by the holder of the sequence who is situated off site Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group M5717 and Pyronaridine tetraphosphate M5717 and Pyronaridine tetraphosphate will be given in combination M5717 Part A: 330 mg once daily (single oral dose) for adults only Part B (Cohort B0, B1 and B2): 500 mg once daily oral dose for adolescents equal to or more than 24 kg but less than 45 kg; Part B (Cohort B0, B1 and B2): 660 mg once daily oral dose for adults and adolescents equal to or more than 45 kg Pyronaridine tetraphosphate Part A: 360 mg once daily (single oral dose) for adults Part B (Cohort B0, B1 and B2): 2-4 tablets (360mg to 720 mg) once daily oral dose for adults and adolescents with a minimum weight of 24 kg, based on weight categories. Part A - 1 day Part B - 1 day (Cohort B0 or B1) or two days (Cohort B2) M5717: Sprinkle capsules for oral dosage, 30mg and 100 mg Pyronaridine tetraphosphate tablets 180 mg 112
Control Group Pyramax Part B Cohort 3: 2-4 Tablets once daily oral dose for adults and adolescents weighing equal to or more than 24 kg, The dosage is based on weight categories in line with the registered prescribing information. Part B Cohort B3: 3 Days Pyramax 180 mg/60 mg film-coated tablets 25 Active-Treatment of Control Group
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
1. Are ≥ 12 and ≤ 55 years of age (≥ 18 and ≤ 55 years of age for Part A) at the time of signing the informed consent. 2. Microscopic confirmation of acute uncomplicated P. falciparum using Giemsa-stained thick and thin film. 3. P. falciparum parasitemia of 1,000 to 50,000 asexual parasites/µL of blood in Part A and P. falciparum parasitemia of > 1,000 to ≤ 150,000 asexual parasites/µL of blood in Part B. 4. Axillary temperature ≥ 37.5ºC or tympanic temperature ≥ 38.0ºC (use as per COVID-19 protocols at the site [only at Screening]), or history of fever during the previous 24 hours (at least documented verbally). 5. Have a body weight ≥ 24 kg. 6. “All sexes allowed” The Investigator confirms that each participant agrees to use appropriate contraception and barriers, if applicable. The contraception (in line with local regulations), barrier, and pregnancy testing requirements are below. Male study participants: Agree to the following during the study intervention period and for ≥ 120 days after the last dose of study intervention: a. Refrain from donating fresh unwashed semen PLUS, either: b. Abstain from intercourse with a WOCBP. OR c. Use a male condom: When having sexual intercourse with a WOCBP, who is not currently pregnant, and instruct her to use a highly effective contraceptive method with a failure rate of <1% per year, as described in protocol Appendix 3. Female study participants: - Is not breastfeeding. - Is not pregnant (i.e., has a negative serum pregnancy test, as required by local regulations, within 24 hours before the first dose of study intervention). - Is not a WOCBP. - If a WOCBP, uses a highly effective contraceptive method (i.e., with a failure rate of <1% per year), preferably with low user dependency, as described in protocol Appendix 3. 7. Capable of giving signed informed consent, as per protocol Appendix 2, which includes compliance with the requirements and restrictions listed in the ICF and protocol 1. Mixed Plasmodium infections as per thin film microscopy results. 2. Signs and symptoms of severe malaria according to WHO 2021 criteria (WHO 2021). 3. Known liver abnormalities, liver cirrhosis (compensated or decompensated), known active or history of hepatitis B or C (testing not required), underlying hepatic injury or known severe liver disease, known gallbladder or bile duct disease, acute or chronic pancreatitis, or severe malnutrition. 4. Known history or evidence of clinically significant disorders such as, cardiovascular, respiratory (including active tuberculosis), hepatic, renal, gastrointestinal, immunological (including known HIV-AIDS), neurological (including auditory), endocrine, infectious, malignancy, psychiatric, history of convulsions, or other abnormality (including head trauma). 5. Previous treatment with pyronaridine as part of a combination therapy during the last 3 months. 6. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days or until the expected PD effect has returned to Baseline, whichever is longer. 7. Prior antimalarial therapy or antibiotics with antimalarial activity within a minimum of their 5 plasma half-lives (or within 4 weeks of Screening if half-life is unknown). 8. Patients taking medications prohibited by the protocol. 9. Previous participation in any malaria vaccine study or received malaria vaccine in any other circumstance during the last 3 months. 10. Participation in any clinical study within 3 months or 5 half lives prior to Screening or during participation in this study. 11-19 Diagnostic assessments including serum creatinine levels, AST and/or ALT, TB, QTc interval, electrolyte balance, moderate to severe anaemia, severe malnutrition, severe vomiting. See Protocol for details on exclusion criteria 11-19. 20. Known history of hypersensitivity, allergic or adverse reactions to pyronaridine, M5717, and/or artesunate. 21 Known history or current substance abuse. Adolescent: 13 Year-18 Year,Adult: 19 Year-44 Year,Middle Aged: 45 Year(s)-64 Year(s) 12 Year(s) 55 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 30/09/2022 CERMEL Comite d Ethique Institutionnel
Ethics Committee Address
Street address City Postal code Country
Centre de Recherches Medicale de Lambarene, Fondation Internationale de l Hopital Albert Schweitzer Lambarene 242 Gabon
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 27/02/2023 VDREC Vector Control Division Research and Ethics Committee
Ethics Committee Address
Street address City Postal code Country
15 Bombo Road Kampala 10101 Uganda
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 16/03/2023 UNCST Uganda National Council for Science and Technology
Ethics Committee Address
Street address City Postal code Country
Plot 6 Kimera Road Kampala 10101 Uganda
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 18/01/2023 Comite d Ethique pour la researche en sante
Ethics Committee Address
Street address City Postal code Country
Building Lamizana, 09BP 7009 Ouagadougou 09 0000 Burkina Faso
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 19/10/2023 Comite Nacional de Bioetica Para a Saude
Ethics Committee Address
Street address City Postal code Country
Ministeril de Saude - 2o andar Dto, Av Eduardo Mondlane - Salvador Allende Maputo 264 Mozambique
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Part A Primary Objective - To evaluate the safety and tolerability of the M5717-pyronaridine combination in adult participants with acute uncomplicated malaria due to P. falciparum. Primary Endpoint - Incidence, severity, and seriousness of study intervention-related TEAEs, as per CTCAE v 5.0 Additional endpoints related to safety and tolerability up to Day 29 (± 2 days): laboratory assessments, ECGs, and vital signs. Treatment start up to Day 29 plus or minus 2 days
Secondary Outcome Part A Secondary Objective - To characterize the PK of M5717 and pyronaridine in adult participants with acute uncomplicated malaria due to P. falciparum. Secondary Endpoint: • PK profiles for M5717 and pyronaridine • PK parameters of M5717 and pyronaridine such as AUC 0-tlast, AUC 0-∞, AUC 0-24, Cmax, t½, tmax, CL/F, VZ/F, when data permits Throughout study when data permits
Secondary Outcome Part A Secondary Objective - To describe the clinical efficacy of the M5717-pyronaridine combination in adult participants with acute uncomplicated malaria due to P. falciparum Secondary Endpoint – Early treatment failure (ETF) defined as meeting any of the following: • Danger signs or severe malaria 1, 2, or 3 days after treatment, in the presence of parasitemia • Parasitemia 2 days after treatment higher than on day of treatment, irrespective of axillary temperature • Parasitemia 3 days after treatment with axillary temperature ≥ 37.5°C • Parasitemia 3 days after treatment ≥ 25% of count on day of treatment Day 1 to Day 3 after treatment
Secondary Outcome Part A Secondary Objective - To describe the clinical efficacy of the M5717-pyronaridine combination in adult participants with acute uncomplicated malaria due to P. falciparum Secondary Endpoint: Late Clinical Failure (LCF) defined as: • Danger signs or severe malaria in the presence of parasitemia on any day between 4 and 28 days after treatment (i.e., between Days 5 and 29) in participants who did not previously meet any of the criteria of ETF • Presence of parasitemia on any day between 4 and 28 days after treatment with axillary temperature ≥ 37.5°C in participants who did not previously meet any of the criteria of ETF Day 4 to Day 28 after treatment - between Day 5 and Day 29
Secondary Outcome Part A Secondary Objective - To describe the clinical efficacy of the M5717-pyronaridine combination in adult participants with acute uncomplicated malaria due to P. falciparum Secondary Endpoint: Late parasitological failure (LPF) defined as: • Presence of parasitemia on any day between 7 and 28 days after treatment (i.e., between Days 8 and 29) with axillary temperature < 37.5°C in participants who did not previously meet any of the criteria of ETF or LCF Between 7 and 28 days after treatment - i.e., between Days 8 and 29
Secondary Outcome Part A Secondary Objective - To describe the clinical efficacy of the M5717-pyronaridine combination in adult participants with acute uncomplicated malaria due to P. falciparum Secondary Endpoint: • Crude (polymerase chain reaction/PCR-uncorrected) ACPR 14, 28, and 42 days after treatment defined as absence of parasitemia (thick smear/microscopy), irrespective of axillary temperature, in participants who did not previously meet any of the criteria of ETF, LCF, or LPF 14, 28, and 42 Days after treatment
Secondary Outcome Part A Secondary Objective - To describe the clinical efficacy of the M5717-pyronaridine combination in adult participants with acute uncomplicated malaria due to P. falciparum Secondary Endpoint: • PCR-adjusted ACPR 14, 28, and 42 days after treatment defined as absence of parasitemia (thick smear/microscopy, after adjustment for parasitemia due to new infections as determined by genotyping using PCR techniques), irrespective of axillary temperature, in participants who did not previously meet any of the criteria of ETF, LCF, or LPF 14, 28, and 42 Days after treatment
Secondary Outcome Part A Secondary Objective - To describe the clinical efficacy of the M5717-pyronaridine combination in adult participants with acute uncomplicated malaria due to P. falciparum Secondary Endpoint: • Crude (PCR-uncorrected) efficacy 8 days after treatment, defined as absence of parasitemia (thick smear/microscopy) in participants who did not previously meet any of the criteria of ETF or LCF 8 Days after treatment
Secondary Outcome Part A Secondary Objective - To describe the clinical efficacy of the M5717-pyronaridine combination in adult participants with acute uncomplicated malaria due to P. falciparum Secondary Endpoint: • PCR-adjusted efficacy 8 days after treatment as defined as absence of parasitemia (thick smear/microscopy, after adjustment for parasitemia due to new infections as determined by genotyping using PCR techniques) in participants who did not previously meet any of the criteria of ETF or LCF 8 Days after treatment
Secondary Outcome Part A Secondary Objective - To describe the clinical efficacy of the M5717-pyronaridine combination in adult participants with acute uncomplicated malaria due to P. falciparum Secondary Endpoint: • PRR defined as decrease in viable parasites over 48 hours, corresponding to 1 asexual parasite life cycle Over 48 hours
Secondary Outcome Part A Secondary Objective - To describe the clinical efficacy of the M5717-pyronaridine combination in adult participants with acute uncomplicated malaria due to P. falciparum Secondary Endpoint: • Fever clearance time defined as the time from first dosing to the first measurement of an axillary temperature < 37.5°C for 2 consecutive temperature readings plus confirmed normal temperature 24 h after the first normal body temperature reading. 2 Consecutive temperature readings plus confirmed normal temperature 24 h after the first normal body temperature reading
Secondary Outcome Part A Secondary Objective - To describe the clinical efficacy of the M5717-pyronaridine combination in adult participants with acute uncomplicated malaria due to P. falciparum Secondary Endpoint: • Parasite clearance time defined as time from dosing to the first negative (no parasites) film (microscopy) Time from dosing to the first negative/no parasites film,- microscopy
Secondary Outcome Part A Secondary Objective - To describe the clinical efficacy of the M5717-pyronaridine combination in adult participants with acute uncomplicated malaria due to P. falciparum Secondary Endpoint: • Time to recrudescence, defined as the time from primary cure to the re-emergence of the same parasite strain that originated the primary infection Time from primary cure to the re-emergence of the same parasite strain that originated the primary infection
Secondary Outcome Part A Secondary Objective - To describe the clinical efficacy of the M5717-pyronaridine combination in adult participants with acute uncomplicated malaria due to P. falciparum Secondary Endpoint: • Time to re-infection, defined as the time from primary cure to the re-emergence of a different parasite strain that originated the primary infection Time from primary cure to the re-emergence of a different parasite strain that originated the primary infection
Secondary Outcome Part A Secondary Objective - To describe the clinical efficacy of the M5717-pyronaridine combination in adult participants with acute uncomplicated malaria due to P. falciparum Secondary Endpoint: • Time to re-emergence, defined as the time from primary cure to having recrudescence or re-infection (the first one that occurs) Time from primary cure to having recrudescence or re-infection - the first one that occurs
Primary Outcome Part B Primary Objective - To describe clinical efficacy of the M5717-pyronaridine combination and of Pyramax in adult and adolescent participants with acute uncomplicated malaria due to P. falciparum • Endpoint - PCR-adjusted ACPR 28 days after first treatment (i.e., on Day 29) defined as absence of parasitemia (thick smear/microscopy, after adjustment for parasitemia due to new infections as determined by genotyping using PCR techniques), irrespective of axillary temperature, in participants who did not previously meet any of the criteria of ETF, LCF, or LPF Day 29
Secondary Outcome Part B Secondary Objective - To describe the clinical and parasitological efficacy of the M5717-pyronaridine combination and of Pyramax in adult and adolescent participants with acute uncomplicated malaria due to P. falciparum • ETF • LCF • LPF • Crude (PCR-uncorrected) ACPR 14, 28 and 42 days after treatment • PCR-adjusted ACPR 14 and 42 days after treatment • Crude (PCR-uncorrected) efficacy 8 days after treatment • PCR-adjusted efficacy 8 days after treatment • PRR • Fever clearance time • Parasite clearance time • Time to recrudescence • Time to re-infection • Time to re-emergence Day 1-29, and 42 Days after treatment, as with to timepoints in Part A
Secondary Outcome Part B Secondary Objective - To evaluate the safety and tolerability of the M5717-pyronaridine combination in adult and adolescent participants with acute uncomplicated malaria due to P. falciparum Endpoints • Incidence, severity, and seriousness of study intervention related TEAEs, as per CTCAE v 5.0 • Additional endpoints related to safety and tolerability up to Day 2 (± 2 days): laboratory assessments, ECGs, and vital signs. Day 1 - 29
Secondary Outcome Part B Secondary Objective - To characterize the PK of M5717 and pyronaridine in adult and adolescent participants with acute uncomplicated malaria due to P. falciparum in Cohorts B0, B1 and B2. Endpoints • PK profiles for M5717 and pyronaridine in Cohorts B0, B1 and B2. • PK parameters of M5717 and pyronaridine such as AUC0-tlast, AUC0 ∞, AUC0-24, Cmax, t½, tmax, CL/F, VZ/F, when data permits Throughout study when data permits
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Groupe de Recherche Action en Sante GRAS 06 BP 10248 Ouagadougou BP 10248 Burkina Faso
Institut de Recherche en Science de la Sante Unite de Recherche Clinique de Nanoro IRSS URCN Campus URCN, BP 18 Nanoro BP 18 Burkina Faso
Centre de Recherches Medicales de Lambarene CERMEL CERMEL BP 242 Lambarene BP 242 Gabon
Centro de Investigacao em Saude de Manhica Fundacao Manhica CISM FM CISM FM Rua 12, vila da Manhica Bairo Cambeve Maputo district CP1929 Mozambique
Infectious Diseases Research Collaboration IDRC IDRC Clinic, Station road, Tororo Hospital Tororo 3306 Uganda
FUNDING SOURCES
Name of source Street address City Postal code Country
PAMAfrica Grant with funding from EDCTP EDCTP Europe Anna van Saksenlaan 51 2593 HW The Hague 2593 HW Netherlands
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Merck Healthcare KGaA Frankfurter Str. 250 Darmstadt 64293 Germany Commercial Sector/Industry
COLLABORATORS
Name Street address City Postal code Country
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Ghyslain Mombo Ngoma ghyslain.mombongoma@cermel.org +24177989191 Centre de Recherches Medicales de Lambarene CERMEL Albert Schweitzer Hospital
City Postal code Country Position/Affiliation
Lambarene BP242 Gabon Coordinating Investigator
Role Name Email Phone Street address
Public Enquiries Henk Badenhorst henk.badenhorst@external.merckgroup.com +27112311900 ICON Global Strategic Solutions, Building 29 2nd Floor Woodlands Office Park, Woodlands Drive, Woodmead
City Postal code Country Position/Affiliation
Johannesburg 0001 South Africa Senior Clinical Research Manager at ICON performing services on behalf of Merck Healthcare KGaA
Role Name Email Phone Street address
Scientific Enquiries Birgitta Leopoldt birgitta.leopold@merckgroup.com +4915114540511 Frankfurter Str. 250
City Postal code Country Position/Affiliation
Darmstadt 64293 Germany RA Strategic Project Leader
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes The sponsor is committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on the website https://bit.ly/IPD21 Analytic Code,Clinical Study Report,Statistical Analysis Plan,Study Protocol Within six months after the approval of a new product or a new indication for an approved product in both the United States and the European Union Qualified scientific and medical researchers can request the data. Such requests must be submitted in writing to the company's portal and will be internally reviewed regarding criteria for researchers' qualification and legitimacy of the research proposal.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
https://bit.ly/IPD21 No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information