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.: PACTR202008909968293 Date of Approval: 17/08/2020
Trial Status: Retrospective registration - This trial was registered after enrolment of the first participant
TRIAL DESCRIPTION
Public title MultiMal
Official scientific title Multi-Drug Combination-Therapies to Prevent the Development of Drug Resistance Phase II Controlled Clinical Trial Assessing Candidate Regimens of Multiple-Antimalarial Combinations for the Treatment of Uncomplicated Malaria in Africa
Brief summary describing the background and objectives of the trial Antimalarial drug resistance is one of the most important challenges in the control and elimination of malaria. Artemisinin combination therapy (ACT) as bi-therapy is the standard of care in all malaria endemic countries (World Health Organization, 2018). However, the efficacy of ACTs as bi-therapy declined in the past decade in the Greater Mekong Region of South East Asia (SEA). Subsequently, epidemiological genomic studies confirmed that in fact artemisinin resistance developed much earlier in numerous foci, resulting in resistant parasites. Importantly, drug resistance against the partner drugs evolved simultaneously leading to decreasing cure rates of first line antimalarial treatments in SEA (Amato et al., 2017; 2018; Miotto et al., 2015).One pharmacokinetic consideration, which may explain the failure of all currently employed ACTs to avoid the development of drug resistance, is their pharmacokinetic mismatch. Whereas the artemisinin derivative has a remarkably short half-life of < 3 hours, the partner drugs are characterized by intermediate (lumefantrine) to exceptionally long half-lives (mefloquine, piperaquine with half-lives of more than 4 weeks). This pharmacokinetic mismatch allows for a very short period where the two drugs protect each other and a long period of time when the slowly eliminated partner drug is unprotected from the rapidly eliminated artemisinin derivative in prolonged sub-therapeutic drug levels, and therefore paves the way for the parasite to develop resistance to these drugs if reinfection occurs during the convalescence period. Multi-drug combination therapy is therefore particularly appealing to increase the barriers for resistance if partner drugs with matched half-lives are combined. Primary: To describe the pharmacokinetic properties of each partner drug and their principal active metabolites in the two antimalarial combination treatments artesunate-pyronaridine-atovaquone/proguanil (APAP) and artesunate-fosmidomycin-clindamy.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) MultiMal
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 01/10/2019
Actual trial start date 01/06/2020
Anticipated date of last follow up 03/05/2021
Actual Last follow-up date 31/12/2021
Anticipated target sample size (number of participants) 100
Actual target sample size (number of participants)
Recruitment status Completed
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 Stratified allocation where factors such as age, gender, center, or previous treatment are used in the stratification Sealed opaque envelopes Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Control Group Oral artesunate pyronaridin standard treatment Number of participants scheduled for recruitment: 0 patients in the age-group 18-65y, 10 patients in 11-17y and 10 patients in 6 months - 10y Treatment given: Artesunate-pyronaridine (Pyramax): Once daily oral dosing for three days independent of food: Paediatric dosing regimen: 5 <-8 kg: 1 sachet daily 8 -<15 kg: 2 sachets daily 15-20 kg: 3 sachets daily 1 sachet contains 20 mg artesunate and 60 mg pyronaridine Adult dosing regimen: 20-<24 kg: 1 tablet daily 24-45 kg: 2 tablets daily 45-<65 kg: 3 tablets daily >65 kg: 4 tablets daily 1 tablet contains 60 mg artesunate and 180 mg pyronaridine 3 days Pyronaridine has been developed as a fix dose treatment with artesunate in a 3:1 ratio to treat acute uncomplicated P. falciparum malaria as well as the blood stage P. vivax malaria. In combination, artesunate-pyronaridine is particularly appealing as anti-malarial therapy as it combines the advantages of high efficacy, highly favourable tolerability and safety, low cost, long shelf life, once daily dosing, absence of clinically relevant food effect, and availability of paediatric drug formulations. It has been developed by Medicines for Malaria Venture and has been favourably assessed under §58 by the European Medicine Agency (Sagara et al., 2016; West African Network for Clinical Trials of Antimalarial Drugs (WANECAM), 2018). Artesunate-pyronaridine (Pyramax) constitutes a standard treatment for malaria and will therefore be used as medication in the control group. 20 Active-Treatment of Control Group
Experimental Group Oral artesunate pyronaridine atovaquone proguanil Number of participants scheduled for recruitment: 10 patients in agegroup 18-65y, 10 patients in 11-17y and 20 patients in 6 months - 10y Treatment given: Oral artesunate pyronaridine atovaquone proguanil once daily oral dosing for three days with food/milk: Dose for "atovaquone proguanil": 5-8 kg: Atovaquone/proguanil 125 mg/50 mg 9-10 kg: Atovaquone/proguanil 187.5 mg/75 mg 11-20 kg: Atovaquone/proguanil 250 mg/100 mg 21-30 kg: Atovaquone/proguanil 500 mg/200 mg 31-40 kg: Atovaquone/proguanil 750 mg/300 mg >40 kg: Atovaquone/proguanil 1000 mg/400 mg Dose for "artesunate pyronaridine": Paediatric dosing regimen: 5 <-8 kg: 1 sachet daily 8 -<15 kg: 2 sachets daily 15-20 kg: 3 sachets daily 1 sachet contains 20 mg artesunate and 60 mg pyronaridine Adult dosing regimen: 20-<24 kg: 1 tablet daily 24-45 kg: 2 tablets daily 45-<65 kg: 3 tablets daily >65 kg: 4 tablets daily 1 tablet contains 60 mg artesunate and 180 mg pyronaridine 3 days The combination of rapidly eliminated drugs artesunate and proguanil (half-life < 1 day) with the intermediate half-life of pyronaridine (~7-10 days) and atovaquone (~3 days) lead to a faster drug elimination than the conventional partner drugs mefloquine or piperaquine and therefore shorter exposure of sub-therapeutic drug levels in regions of high malaria transmission. In addition, the combination of artesunate – which eliminates young stage gametocytes, with atovaquone-proguanil, which has been demonstrated to exert a delayed effect on the sexual development of Plasmodium spp., will most likely lead to an enhanced anti-transmission property of this drug combination. This is considered a crucial feature to avoid the selection of drug resistance in high transmission settings. Importantly this drug combination allows for once daily dosing, which is considered a significant advantage for patient adherence compared to twice daily dosing regimens. 40
Experimental Group Oral artesunate fosmidomycin clindamycin Number of participants scheduled for recruitment: 10 patients in age group 18-65y, 10 patients in 11-17y and 20 patients in 6 months - 10y Artesunate: 2 mg/kg twice daily oral dosing for 3 days independent of food as calculated closest to the capsule strength Fosmidomycin: 30 mg/kg twice daily oral dosing for 3 days independent of food as calculated closest to the capsule strength Clindamycin hydrochloride: 10 mg/kg twice daily oral dosing for 3 days independent of food as calculated closest to the capsule strength (150 mg, 300 mg, 600 mg) 3 days The combination of artesunate-fosmidomycin-clindamycin is anticipated to exert high efficacy based on the known antimalarial properties of these drugs in combination therapy. Whereas fosmidomycin selectively inhibits the non-mevalonate pathway of isoprenoid synthesis, clindamycin is known to act directly on the apicoplast of Plasmodium parasites and artemisinins exert again a different mode of action. The combination of three independently acting antimalarials therefore is anticipated to increase the barrier for the development of de novo drug resistance. All drugs have a favourable tolerability profile. 40
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
- Male or female patient age >6 months <66 years - Body weight >5 kg <90 kg - Presence of mono-infection of P. falciparum with Fever, as defined by axillary temperature ≥ 37.5°C or oral/rectal/tympanic temperature ≥ 38°C, or history of fever in the previous 24 hours and Microscopically confirmed parasite infection, in range 1,000 to 100,000 asexual parasites /μL of blood. - Written informed consent provided by the adult patient, or parent or legally acceptable representative (LAR) of the minor patient or by an impartial witness (if the patient or patient’s LAR is illiterate), stating that the information has been read and/or is understood, and by the medically qualified Investigator. Children will be asked to provide assent where appropriate. The age from which this will be sought will be defined by local legislation. - Presence of severe malaria (according to WHO definition – WHO 2013) - Anti-malarial treatment in the last 6 weeks. - Known history or evidence of clinically significant disorders such as, cardiovascular, respiratory (including active tuberculosis), hepatic, renal, gastrointestinal, immunological (including active HIV-AIDS), neurological (including auditory), endocrine, infectious, malignancy, psychiatric, history of convulsions or other abnormality (including head trauma). - Mixed Plasmodium infection - Severe vomiting, defined as more than three times in the 24 hours prior to enrolment in the study or inability to tolerate oral treatment, or severe diarrhoea defined as 3 or more watery stools per day - Severe malnutrition (defined for subjects aged ten years or less as the weight-for- height being below -3 standard deviation or less than 70% of median of the NCHS/WHO normalised reference values, and for subjects aged greater than ten years, a body mass index (BMI) of less than 16 (WFP Manual, Chapter 1)). - Known history of hypersensitivity, allergic or adverse reactions to any of the study drugs - Known active Hepatitis A IgM (HAV-IgM), Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV Ab). - Haemoglobin level below 8 g/dL. - Serum creatinine levels ≥2 x ULN - Female patients of child bearing potential must be neither pregnant (as demonstrated by a negative pregnancy test) nor lactating, and must be willing to take measures not to become pregnant during the study period and safety follow-up period. - Have received an investigational drug within the past 4 weeks. - Previous participation in any malaria vaccine study or received malaria vaccine in any other circumstance. - Refusal to participate and to provide written or witnessed informed consent or assent. Adolescent: 13 Year-18 Year,Adult: 19 Year-44 Year,Aged: 65+ Year(s),Child: 6 Year-12 Year,Infant: 0 Month-23 Month,Infant: 1 Month-23 Month,Middle Aged: 45 Year(s)-64 Year(s),Preschool Child: 2 Year-5 Year 6 Month(s) 66 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 22/06/2020 School of Medicine Sciences
Ethics Committee Address
Street address City Postal code Country
College of Health Science Ghana 00000 Ghana
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 05/12/2019 Scientific Review Committee
Ethics Committee Address
Street address City Postal code Country
BP 242 Lambarene Gabon 00000 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 24/03/2020 Ethik Kommission der Aerztekammer Hamburg
Ethics Committee Address
Street address City Postal code Country
Weidestrasse 122 b Hamburg 22083 Germany
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome To describe the pharmacokinetic properties of each partner drug and their principal active metabolites in the two antimalarial combination treatments artesunate-pyronaridine-atovaquone/proguanil (APAP) and artesunate-fosmidomycin-clindamycin (AFC), respectively in patients with uncomplicated malaria. Screen, 0, 15m, 30m, 45m, 90m, 3h, 5h, 8h, 24h, 48h, 7d, 14d, 21d, 28d, 35d, 42d
Secondary Outcome • To determine the PCR corrected adequate clinical and parasitological response on Day 42 in per protocol population • To determine the PCR corrected cure rate on day 28 in per protocol population • To determine the PCR uncorrected cure rates on days 28 and 42 in intention to treat population • To determine the safety and tolerability of combination therapies in intention to treat population • To determine the parasite clearance dynamics of combination therapies • To determine the proportion of patients with sexual stage parasitaemia during follow up 28d, 42d and total follow-up
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
St. Francis Xavier Hospital 120 Mankessim - Kumasi Rd Assin Fosu 00000 Ghana
CERMEL B.P. 242 Gabon 00000 Gabon
FUNDING SOURCES
Name of source Street address City Postal code Country
Deutsches Zentrum fuer Infektionsforschung Inhoffenstrasse 7 Braunschweig 38124 Germany
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Bernhard Nocht Institute for Tropical Medicine Bernhard Nocht Strasse 74 Hamburg 20359 Germany Individual
COLLABORATORS
Name Street address City Postal code Country
Universitaet Hamburg Mittelweg 177 Hamburg 20148 Germany
CERMEL B.P. 242 Gabon 00000 Gabon
St. Francis Xavier Hospital 120 Mankessim - Kumasi Rd Assin Fosu 00000 Ghana
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Michael Ramharter ramharter@bnitm.de 00494042818511 Bernhard Nocht Strasse 74
City Postal code Country Position/Affiliation
Hamburg 20359 Germany Head of Clinical Research Group
Role Name Email Phone Street address
Scientific Enquiries Johannes Mischlinger mischlinger@bnitm.de 04042818480 Bernhard Nocht Strasse 74
City Postal code Country Position/Affiliation
Hamburg 20359 Germany Doctor of Medicine Epidemiologist
Role Name Email Phone Street address
Public Enquiries Johannes Mischlinger mischlinger@bnitm.de 04042818480 Bernhard Nocht Strasse 74
City Postal code Country Position/Affiliation
Hamburg 20359 Germany Doctor of Medicine Epidemiologist
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices). Individual participant data may be used for meta-analysis. Study Protocol Beginning 9 months and ending 36 months following article publications. Data might be shared with investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose. Proposals may be submitted up to 36 months following article publication. After 36 months the data will be available in our Institute's data warehouse but without investigator support other than deposited metadata.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
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
Section Name Field Name Date Reason Old Value Updated Value
Eligibility Age group 14/04/2020 age categories added Preschool Child: 2 Year-5 Year, Child: 6 Year-12 Year, Adolescent: 13 Year-18 Year, Adult: 19 Year-44 Year, Middle Aged: 45 Year(s)-64 Year(s) Infant: 1 Month-23 Month, Infant: 0 Month-23 Month, Preschool Child: 2 Year-5 Year, Child: 6 Year-12 Year, Adolescent: 13 Year-18 Year, Adult: 19 Year-44 Year, Middle Aged: 45 Year(s)-64 Year(s), Aged: 65+ Year(s)
Section Name Field Name Date Reason Old Value Updated Value
Ethics Ethics List 15/07/2020 Ethical Approval letter FALSE, School of Medicine Sciences, College of Health Science, Ghana, 00000, Ghana, 01 Jun 2020, , 233322063248, chrpe.knust.kath@gmail.com, FALSE, School of Medicine Sciences, College of Health Science, Ghana, 00000, Ghana, 01 Jun 2020, , 233322063248, chrpe.knust.kath@gmail.com, 9740_9008_4737.pdf
Section Name Field Name Date Reason Old Value Updated Value
Ethics Ethics List 10/08/2020 PDF had not yet been attached. Now, the PDF with the positive opinion of the scientific review committee is attached. FALSE, Scientific Review Committee, BP 242 Lambarene, Gabon, 00000, Gabon, 01 Jun 2020, , 24107989191, admin@cermel.org, TRUE, Scientific Review Committee, BP 242 Lambarene, Gabon, 00000, Gabon, 01 Jun 2020, 05 Dec 2019, 24107989191, admin@cermel.org, 9740_9010_4737.pdf
Section Name Field Name Date Reason Old Value Updated Value
Ethics Ethics List 10/08/2020 Date became recently available. FALSE, School of Medicine Sciences, College of Health Science, Ghana, 00000, Ghana, 01 Jun 2020, , 233322063248, chrpe.knust.kath@gmail.com, 9740_9008_4737.pdf TRUE, School of Medicine Sciences, College of Health Science, Ghana, 00000, Ghana, 01 Jun 2020, 22 Jun 2020, 233322063248, chrpe.knust.kath@gmail.com, 9740_9008_4737.pdf
Section Name Field Name Date Reason Old Value Updated Value
Reporting Plan to share IPD 14/08/2020 A IPD sharing statement is now compulsory since 01/JAN/2020. Therefore, we added these data. Undecided Yes
Section Name Field Name Date Reason Old Value Updated Value
Reporting IPD description 14/08/2020 A IPD sharing statement is now compulsory since 01/JAN/2020. Therefore, we added these data. Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices). Individual participant data may be used for meta-analysis.
Section Name Field Name Date Reason Old Value Updated Value
Reporting IPD-Sharing time frame 14/08/2020 A IPD sharing statement is now compulsory since 01/JAN/2020. Therefore, we added these data. Beginning 9 months and ending 36 months following article publications.
Section Name Field Name Date Reason Old Value Updated Value
Reporting Key access criteria 14/08/2020 A IPD sharing statement is now compulsory since 01/JAN/2020. Therefore, we added these data. Data might be shared with investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose. Proposals may be submitted up to 36 months following article publication. After 36 months the data will be available in our Institute's data warehouse but without investigator support other than deposited metadata.
Section Name Field Name Date Reason Old Value Updated Value
Reporting Study protocol document 14/08/2020 A IPD sharing statement is now compulsory since 01/JAN/2020. Therefore, we added these data. Study Protocol
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Recruitment status 09/11/2021 Recruitment and follow-up are completed. Not yet recruiting Completed