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.: PACTR202110520435408 Date of Approval: 13/10/2021
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Ethiopia P. vivax and P. falciparum in-vivo Effectiveness Study 2021-22
Official scientific title Therapeutic Effectiveness of Artemether-Lumefantrine or Artesunate-Pyronaridine Plus Single Dose Primaquine for the Treatment of Uncomplicated Plasmodium falciparum and Chloroquine or Artesunate-Pyronaridine Plus 14 Days Primaquine for Uncomplicated Plasmodium vivax.
Brief summary describing the background and objectives of the trial A prospective longitudinal treatment efficacy study at selected health centers in Amhara and Southern Nations and Nationalities administrative regions in Ethiopia will be conducted to assess the safety and therapeutic effectiveness of Artemether-Lumefantrine (AL) or Artesunate-Pyronaridine (AP/ Pyramax) plus single-dose Primaquine (PQ) for uncomplicated Plasmodium falciparum and Chloroquine (CQ) or Artesunate-Pyronaridine plus 14 days Primaquine for uncomplicated Plasmodium vivax infections. The study aims to recruit 402 adult patients (>18 years) who fulfill the recruitment criteria and give written informed consent.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) TES2021
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 18/10/2021
Actual trial start date
Anticipated date of last follow up 31/01/2022
Actual Last follow-up date
Anticipated target sample size (number of participants) 402
Actual target sample size (number of participants)
Recruitment status Recruiting
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 Sealed opaque envelopes Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group AP and PQ arm for P. vivax Standard dosing. AP is given once daily for three consecutive days. Each Pyramax tablet contains 60 mg Artesunate, and 180 mg Pyronaridine tetraphosphate, and each Pyramax granule sachet contains 20 mg Artesunate and 60 mg Pyronaridine tetraphosphate. Dosing is done based on weight. PQ (7.5 mg base tablet) is given as 0.25mg/kg daily for 14 days 14 days Artesunate-pyronaridine (AP; Pyramax®), a fixed-dose ACT, is the first ACT to be specifically indicated for the treatment of both blood-stage Pf and Pv following multicenter clinical studies in Africa and Asia and is a WHO-recommended first-line therapy for the treatment of uncomplicated malaria in adults and children weighing 5 kg and above in all malaria-endemic areas. Primaquine (PQ) is an 8 aminoquinoline that is highly active against the liver and sexual stages of malaria parasites. It is used for transmission-blocking in Pf malaria patients and protection from infection relapse in the case of Pv malaria patients. 113
Experimental Group AP and PQ arm for Pf Artesunate-Pyronaridine (Pyramax) is administered once daily for three consecutive days. Each Pyramax tablet contains 60 mg Artesunate, and 180 mg Pyronaridine tetraphosphate, and each Pyramax granule sachet contains 20 mg Artesunate and 60 mg Pyronaridine tetraphosphate. 7.5 mg base PQ tablet is given as 0.25mg/kg daily on the day of infection detection (day 0) 3 days Artesunate-pyronaridine (Pyramax®) is the first ACT to be specifically indicated for the treatment of both blood-stage Pf and Pv following multicenter clinical studies in Africa and Asia and is a WHO-recommended first-line therapy for the treatment of uncomplicated malaria in adults and children weighing 5 kg and above in all malaria-endemic areas. Primaquine, an 8-aminoquinoline, is the only licensed antimalarial that is used extensively as a single-dose gametocytocidal drug in P. falciparum malaria. Potent gametocytocidal drugs such as PQ could help deter the spread of antimalarial drug resistance. Resistant or partially resistant parasites may increase their investment in gametocytes; as such gametocyte density and mosquito infectivity can serve as an early warning of deteriorating drug effectiveness. 88
Control Group CQ and PQ arm for Pv Standard dosing: CQ, a total of 25mg base per kg over 3 days (10 mg base/kg on Days 1 and 2, and 5 mg base/kg on Day 3). PQ (7.5 mg base tablet) is given as 0.25mg/kg daily for 14 days 14 days CQ is the recommended 1st line treatment of vivax malaria in Ethiopia and has a long elimination half-life of 108-291 hours (4-12 days). Primaquine (PQ) is the only currently licensed antimalarial that prevents Plasmodium vivax (Pv) relapses. 113 Active-Treatment of Control Group
Control Group AL and PQ arm for Pf Artemether-lumefantrine (Coartem) administered twice daily for three days as tablets containing 20 mg of artemether plus 120 mg of lumefantrine in a fixed-dose combination at a dosage. Primaquine: 7.5 mg base tablet. Medication is given as 0.25mg/kg on the day of infection detection *day 0). 3 days AL is currently the first-line anti-malarial recommended by the Ethiopian FMOH for the treatment of uncomplicated falciparum malaria. It has a short half-life of 0.86-5.16 hours, while lumefantrine has a long elimination half-life of 32.7-275 hours. Primaquine, an 8-aminoquinoline, is the only licensed antimalarial that is used extensively as a single-dose gametocytocidal drug in P. falciparum malaria. Potent gametocytocidal drugs such as PQ could help deter the spread of antimalarial drug resistance. Resistant or partially resistant parasites may increase their investment in gametocytes; as such gametocyte density and mosquito infectivity can serve as an early warning of deteriorating drug effectiveness. 88 Active-Treatment of Control Group
Experimental Group AP and delayed PQ for Pv AP is given once daily for three consecutive days. Each Pyramax tablet contains 60 mg Artesunate, and 180 mg Pyronaridine tetraphosphate, and each Pyramax granule sachet contains 20 mg Artesunate and 60 mg Pyronaridine tetraphosphate. Dosing is done based on weight. PQ (7.5 mg base tablet) is given as 0.25mg/kg daily for 14 days starting from day 3 after the start of the administration of AP. Treatment of AP during 3 days (d1, 2, 3); PQ during 14 days (d4-17). Follow-up of patients continues over 42 days. 17 days Artesunate-pyronaridine (Pyramax®), a fixed-dose ACT, is the first ACT to be specifically indicated for the treatment of both blood-stage Pf and Pv following multicenter clinical studies in Africa and Asia and is a WHO-recommended first-line therapy for the treatment of uncomplicated malaria in adults and children weighing 5 kg and above in all malaria-endemic areas. Primaquine is an 8 aminoquinoline that is highly active against the liver and sexual stages of malaria parasites. It is used for transmission-blocking in Pf malaria patients and protection from infection relapse in the case of Pv malaria patients. In order to assess the gametocytocidal effect of AP, PQ will be administered to the patients 3 days after the start of the administration of AP. 25
Control Group CQ and delayed PQ CQ is administered as a total of 25mg base per kg over 3 days (10 mg base/kg on Days 1 and 2, and 5 mg base/kg on Day 3). Dosing is done based on weight. PQ (7.5 mg base tablet) is given as 0.25mg/kg daily for 14 days starting from day 3 after the start of the administration of CQ. Treatment of CQ during 3 days (d1, 2, 3); PQ during 14 days (d4-17). Follow-up of patients continues over 42 days. 17 days CQ is the recommended 1st line treatment of vivax malaria in Ethiopia and has a long elimination half-life of 108-291 hours (4-12 days). Primaquine (PQ) is the only currently licensed antimalarial that prevents Plasmodium vivax (Pv) relapses. To evaluate the gametocytocidal effect of CQ, administration of PQ will begin on day 3 and continues for 14 days as per the standard treatment schedule and dosage. 25 Active-Treatment of Control Group
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
• Those living within 20 km of the catchment of the health facility with a traceable address or phone contact number • Volunteer to give their address or phone number and willing to not travel for the duration of the study • Volunteer to comply with the study protocol, visit schedule, or get traced in case defaulted • Age ≥ 18 years • Slide-confirmed infection with Pf, with parasitemia of 500-100,000 asexual forms/μl or slide confirmed infection with Pv with > 250 asexual forms/μl • For the gametocyte clearance and mosquito feeding endpoints, patients with microscopy-detected gametocytes prior to treatment will be eligible to be enrolled • Axillary temperature ≥ 37.5º C or history of fever during the previous 24 or 48 hours for Pf and Pv infection, respectively • Ability to swallow oral medication • General danger signs or symptoms of severe malaria • Mixed Plasmodium infection • Severe anemia, defined as hemoglobin (Hb) < 7 g/dl • Presence of febrile conditions caused by diseases other than malaria (e.g. measles, acute lower respiratory tract infection, COVID-19, severe diarrhea with dehydration) • Serious or chronic medical condition (e.g. cardiac, renal, hepatic diseases, sickle cell disease, HIV/AIDS) • Positive pregnancy test or breastfeeding • Refusal to take a pregnancy test for women of child-bearing age (defined as 18–49 years old or menstruating) • History of hypersensitivity to study or rescue medication in this study • Taking regular medication which may interfere with antimalarial pharmacokinetics or efficacy 80 and over: 80+ Year,Adolescent: 13 Year-18 Year,Adult: 19 Year-44 Year,Aged: 65+ Year(s),Middle Aged: 45 Year(s)-64 Year(s) 18 Year(s) 80 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 04/02/2021 National Research Ethics Review Committee
Ethics Committee Address
Street address City Postal code Country
Addis Ababa Addis Ababa 23976 Ethiopia
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 23/08/2021 Ethiopian Food and Drug Authority
Ethics Committee Address
Street address City Postal code Country
Addis Ababa Addis Ababa 5681 Ethiopia
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 13/07/2021 AHRI ALERT Ethical Review Committee
Ethics Committee Address
Street address City Postal code Country
Jima road, ALERT compound Addis Ababa 1005 Ethiopia
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 20/08/2020 Human Research Protection Office Institutional Review Boards
Ethics Committee Address
Street address City Postal code Country
154 Haven Avenue New York 4310 United States of America
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Day 28 rate of adequate clinical and parasitological response (ACPR) of AL-PQ for Pf and CQ-PQ for PV. The absence of parasitemia by day 28 without previously meeting any of the criteria for Early Treatment Failure, Late Clinical Failure, and Late Parasitological Failure. The PCR-adjusted and unadjusted proportion of treatment failures will be determined together with the frequency of severe malaria, anemia, and hospitalizations by the treatment arm. After Day 28 of recruitment
Primary Outcome Day 28 rate of ACPR of AP-PQ for Pf and for PV. The absence of parasitemia by day 28 without previously meeting any of the criteria for Early Treatment Failure, Late Clinical Failure, and Late Parasitological Failure. The PCR-adjusted and unadjusted proportion of treatment failures will be determined together with the frequency of severe malaria, anemia, and hospitalizations by the treatment arm. After Day 28 of recruitment
Secondary Outcome Document genetic polymorphisms implicated in antimalarial drug resistance. We will deploy length polymorphism genotyping techniques and/or targeted amplicon sequencing to monitor known/novel drug resistance markers. Molecular studies including polymorphisms and copy number variations of pfcrt, pfmdr1, PfK13, pvcrt-o, pvmdr1, pvdhfr, pvdhps and plasmepsin associated with altered drug sensitivity (including those not currently known or characterized) will be performed for surveillance purposes and will have no impact on the clinical management of study patients. At enrolment and, if applicable, day of recurrent parasitemia
Secondary Outcome To assess gametocytocidal effect of single dose PQ for Pf in the 2 Pf arms. Gametocyte carriage/clearance rates are determined as the proportion of patients with gametocytes on days 0, 1, 2, 3, 7, and 14. Gametocyte concentration will be quantified by microscopy and stage specific reverse transcriptase qPCR (RT-qPCR) will be performed from the RNAprotect samples. Blood samples in RNAprotect buffer will be used for the extraction of RNA. RNA-based stage-specific assays include gametocyte sex specific and asexual stage specific markers. Pre-treatment and all days up to day 14 after the start of treatment/study
Secondary Outcome Evaluate the effect of CQ and AP on short-term clearance of Pv gametocytes. Short-term clearance of gametocytes, day 3, will be determined by microscopy and stage-specific transcript-based RT-qPCR. At enrolment and 72h post initiation of treatment
Secondary Outcome Within-person change in infectivity to mosquitoes, comparing infectivity pre-treatment with infectivity post-initiation of treatment. Infectivity is assessed as a percentage of infected mosquitoes and the infection burden in these mosquitoes. The proportion of infectious individuals will be determined as the proportion of patients who infect at least one mosquito on days 0, 1, 2, and 3. The proportion of infected mosquitoes is determined as the proportion of infected mosquitoes (as the proportion of total dissected mosquitoes) on days 0, 1, 2, and 3 expressed as an absolute proportion on each of these days and as percentage reduction on days 1, 2, and 3 compared to pre-treatment (day 0). Infection burden in mosquitoes is determined as the density of oocysts in mosquitoes on days 0, 1, 2, and 3 expressed as absolute density on each of these days and as percentage reduction on days 1, 2, and 3 compared to pre-treatment (day 0). Pre-treatment, 24h, 48h and 72h post initiation of treatment
Primary Outcome Day 42 rate of ACPR of AP-PQ for PV. The absence of parasitemia by day 42 without previously meeting any of the criteria for Early Treatment Failure, Late Clinical Failure, and Late Parasitological Failure. The PCR-adjusted and unadjusted proportion of treatment failures will be determined together with the frequency of severe malaria, anemia, and hospitalizations by the treatment arm. Day 42 after first detection of infection and initiation of treatment
Primary Outcome Safety and tolerability of combination treatment Day 42 after first detection of infection and initiation of treatment
Secondary Outcome To assess gametocytocidal effect of PQ for Pv in the 2 Pv arms with a standard administration of PQ. Gametocyte carriage/clearance rates are determined as the proportion of patients with gametocytes on days 0, 1, 2, 3, 7, and 14. Pre-treatment and all days up to day 14 after the start of treatment/study
Secondary Outcome To assess gametocytocidal effect of PQ for Pv in the 2 Pv arms with delayed, 3 days, administration of PQ. Gametocyte carriage/clearance rates are determined as the proportion of patients with gametocytes on days 0, 1, 2, 3, 7, and 14. Pre-treatment and all days up to day 14 after the start of treatment/study
Primary Outcome Day 42 rate of ACPR of AP-PQ for Pf. The absence of parasitemia by day 42 without previously meeting any of the criteria for Early Treatment Failure, Late Clinical Failure, and Late Parasitological Failure. The PCR-adjusted and unadjusted proportion of treatment failures will be determined together with the frequency of severe malaria, anemia, and hospitalizations by the treatment arm. Day 42 after first detection of infection or start of treatment
Secondary Outcome Distinguish reinfections and recrudescent infections. Distinguishing between reinfections and recrudescent infections may be undertaken using neutral microsatellites, msp1/msp2/glurp, or targeted amplicon sequencing. At enrolment and, if applicable, day of recurrent parasitemia
Secondary Outcome Determine fever, parasite, cytokine, antigen, and antibody clearance rates in each treatment group as measured by microscopy adjusted by 18S based quantitative PCR. The host response by production of both cytokines and antibodies has been shown to correlate with malaria disease severity and clearance of parasites from the host. Data for cytokine and antibody detection will be gathered through the bead-based multiplex platform analysis of DBS as described previously. At the end of the study, day 42 since start of treatment
Secondary Outcome Assess hematological responses. Hemoglobin concentrations will be measured using a portable spectrophotometer on days 0, 14, 28, and 42. Additionally, hemoglobin will be measured for patients on radical cure primaquine on days 3 and 7. At the end of the study, day 42 since start of treatment
Secondary Outcome Assess day 42 ACPR rate for AL-PQ and CQ-PQ At the end of the study, day 42 since the start of treatment
Secondary Outcome Assess hrp2/3 gene deletion among enrolled Pf patient. Gene deletions (such as hrp2 and hrp3) and protein levels (such as HRP2, aldolase, and LDH) associated with the detection of infection with RDTs may also be explored. At enrolment and, if applicable, day of recurrent parasitemia
Secondary Outcome To assess gametocytocidal effect of CQ and AP for Pv on day 3 in the 2 arms with delayed administration of PQ. This effect will be compared with the arms with immediate treatment with PQ to determine whether PQ accelerates gametocyte clearance compared to CQ alone and AP alone.. Pre-treatment, 24h, 48h and 72h post initiation of treatment
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Maksegnit Health center Maksegnit Gonder Zuriya Ethiopia
Enfranz Health center Enfranz Gonder Zuriya Ethiopia
FUNDING SOURCES
Name of source Street address City Postal code Country
U.S. Presidents Malaria Initiative Entoto Street Addis Ababa 1014 Ethiopia
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor ICAP at Columbia University Beyene Aba sebsis street Addis Ababa Ethiopia University
COLLABORATORS
Name Street address City Postal code Country
Teun Bousema Geert Grooteplein Zuid 26-28 Nijmegen 6525 GA Netherlands
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Fitsum Tadesse fitsum.girma@ahri.gov.et +251912627540 Jimma Road, ALERT compound
City Postal code Country Position/Affiliation
Addis Ababa 1005 Ethiopia Armauer Hansen Research Institute
Role Name Email Phone Street address
Public Enquiries Bereket Alemayehu bh2267@cumc.columbia.edu +251988143843 Addis Ababa
City Postal code Country Position/Affiliation
Addis Ababa 1000 Ethiopia ICAP at Columbia University
Role Name Email Phone Street address
Scientific Enquiries Fitsum Tadesse fitsum.girma@ahri.gov.et +251912627540 Jimma Road, ALERT compound
City Postal code Country Position/Affiliation
Addis Ababa 1005 Ethiopia Armauer Hansen Research Institute
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes The Ethiopian MoH regularly disseminates key findings to the general public. This occurs through press releases and by including media reporters in data dissemination workshops with local leaders at the conclusion of each major activity, or sooner as important findings become available. Furthermore, the data will be shared with the international community and researchers through publication on internationally recognized peer-reviewed journals and presentations at international meetings in the form of oral or poster presentations. Clinical Study Report,Informed Consent Form,Statistical Analysis Plan,Study Protocol After the End of the study The data will be shared with the Ministry of Health and other stakeholders. It will also be shared with the international community and researchers through publication in internationally recognized peer-reviewed journals.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
https://ahri.gov.et/ 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