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.: PACTR202311879488648 Date of Approval: 28/11/2023
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Ethiopia In-vivo Drug Efficacy Study 2023
Official scientific title Therapeutic efficacy of Artemether-Lumefantrine for the treatment of uncomplicated Plasmodium falciparum
Brief summary describing the background and objectives of the trial Monitoring antimalarial drug efficacy is important for the early detection of resistance, which in turn enables timely action to prevent its spread and limit its impact on global health. Artemisinin resistance is characterized by delayed parasite clearance following treatment with artemisinin derivatives. In therapeutic efficacy studies (TES), delayed parasite clearance is defined by either a parasite clearance half-life (PC½) of ≥5 hours or persistent parasitemia by microscopy on day 3 after treatment. Artemisinin resistance P.falciparum parasites have been reported in Southeast Asia, and recently detected in Africa. The slow-clearing phenotype is associated with nonsynonymous mutations in the propeller region of the P. falciparum kelch13 (K13) gene. The mutations such as F446I, Y493H, R539T, I543T, P553L, R561H, P574L, C580Y, A675V in the Greater Mekong Sub-region (GMS) and R561H or P574L in Rwanda have been validated as markers of artemisinin partial resistance. In addition, R622I has been reported as a marker of artemisinin resistance in Ethiopia, Eritrea, and other neighboring countries. Therefore, the aim of this study is to assess the therapeutic efficacy of Artemether-Lumefantrine (the front-line treatment since 2004) for uncomplicated P. falciparum infections in Ethiopia. The study also aims to identify genetic determinants of artemisinin resistance in Ethiopia.
Type of trial Non-Randomised
Acronym (If the trial has an acronym then please provide) TES2023
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 13/10/2023
Actual trial start date 27/11/2023
Anticipated date of last follow up 01/05/2024
Actual Last follow-up date 13/05/2024
Anticipated target sample size (number of participants) 440
Actual target sample size (number of participants) 436
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
Single Group Non-randomised Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group Artemetherlumefantrine Fixed-dose tablets containing 20 mg of artemether plus 120 mg of lumefantrine twice daily For three days Artemether-lumefantrine (Coartem; Novartis) is the first-line antimalarial drug used to treat falciparum malaria in Ethiopia. 440
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
1. Able to give informed consent, assent and/or parental/guardian permission 2. Age ≥ 6 months 3. Weight ≥ 5.0 kg 4. Hemoglobin ≥ 7 g/dl 5. Axillary temperature ≥ 37.5º C or history of fever during the previous 24 hours 6. Ability to swallow oral medication 7. Slide-confirmed P. falciparum mono-infection with parasite density ≥ 1000 parasites per µL. 1. General danger signs or symptoms of severe malaria 2. Mixed Plasmodium infection 3. Anemia defined as hemoglobin < 7 g/dl 4. Presence of febrile conditions caused by diseases other than malaria 5. Serious or chronic medical condition 6. Pregnant or breastfeeding 7. Refusal to take pregnancy test for women of childbearing age ( 12–49 years) 8. History of hypersensitivity to study or rescue medication in this study 9. Taking regular medication which may interfere with antimalarial pharmacokinetics or efficacy 10. Children weighing less than 5 kilograms 11. Severe malnutrition in children aged between 6-59 months as defined by the presence of symmetrical edema involving at least the feet or a mid-upper arm circumference < 115 mm 80 and over: 80+ Year,Adolescent: 13 Year-18 Year,Adult: 19 Year-44 Year,Aged: 65+ Year(s),Child: 6 Year-12 Year,Infant: 13 Month(s)-24 Month(s),Middle Aged: 45 Year(s)-64 Year(s),Preschool Child: 2 Year-5 Year 6 Month(s) 85 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 20/10/2023 AHRI ALERT Ethics Review Committee
Ethics Committee Address
Street address City Postal code Country
Jimma 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 13/10/2023 National Research Ethics Review Committee
Ethics Committee Address
Street address City Postal code Country
Addis Ababa Addis Ababa 23976 Ethiopia
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Adequate clinical and parasitological response Day 28
Secondary Outcome 1. Document genetic polymorphisms implicated in antimalarial drug resistance 2. Distinguish reinfections and recrudescent infections 3. Compare the transmissibility of P. falciparum parasites with delayed and rapid parasite clearance and markers of drug resistance 4. Identify genetic changes related to signs of delayed parasite clearance or resistance 5. Determine fever, parasite and antigen clearance rates as measured by microscopy adjusted by 18S-based quantitative PCR 6. Assess hematological responses 7. Assess pfhrp2/3 gene deletion among P. falciparum-infected patients On days 0, 1, 2, 3, 7, 14, 21, and 28
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Maksegnit Health Center Maksegnit Maksegnit Ethiopia
Abobo Catholic Health Center Abobo Abobo Ethiopia
Mizan Health Center Mizan Teferi Mizan Teferi Ethiopia
Asaita Hospital Asaita Asaita Ethiopia
Assosa Health Center Assosa Assosa 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 USAID 1300 Pennsylvania Avenue NW Washington DC 20523 United States of America Funding Agency
COLLABORATORS
Name Street address City Postal code Country
Jimee Hwang Atlanta, GA 30329 Atlanta United States of America
Samuel Girma Entoto Addis Ababa Ethiopia
Hiwot Teka Entoto Addis Ababa Ethiopia
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Fitsum Tadesse fitsum.girma@ahri.gov.et +251912627540 Jima road, ALERT compound
City Postal code Country Position/Affiliation
Addis Ababa 1005 Ethiopia Malaria unit head
Role Name Email Phone Street address
Public Enquiries Gudissa Assefa gudissa.assefa@moh.gov.et +25192049927 Addis Ababa
City Postal code Country Position/Affiliation
Addis Ababa Ethiopia Malaria and Other Vector Borne Disease Prevention and Control Desk Lead
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 Malaria Unit Head
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes De-identified individual clinical trial participant-level data including demographic data, and clinical and parasitological evaluation data will be shared to the Ethiopian Ministry of Health, policymakers, collaborating institutions and researchers for further analyses and decision-making. The dataset will be shared via the publication URL: https://ahri.gov.et/. Clinical Study Report,Informed Consent Form,Statistical Analysis Plan,Study Protocol After the End of the study Key findings and supplementary data will be accessed via publications and workshops.
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
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Trial description 23/11/2023 To give more background information. Monitoring antimalarial drug efficacy and resistance is important for the early detection of resistance, which in turn enables timely action to prevent its spread and limit its impact on global health. The aim of this study is to assess the therapeutic efficacy of Artemether-Lumefantrine for uncomplicated P. falciparum infections in Ethiopia Monitoring antimalarial drug efficacy is important for the early detection of resistance, which in turn enables timely action to prevent its spread and limit its impact on global health. Artemisinin resistance is characterized by delayed parasite clearance following treatment with artemisinin derivatives. In therapeutic efficacy studies (TES), delayed parasite clearance is defined by either a parasite clearance half-life (PC½) of ≥5 hours or persistent parasitemia by microscopy on day 3 after treatment. Artemisinin resistance P.falciparum parasites have been reported in Southeast Asia, and recently detected in Africa. The slow-clearing phenotype is associated with nonsynonymous mutations in the propeller region of the P. falciparum kelch13 (K13) gene. The mutations such as F446I, Y493H, R539T, I543T, P553L, R561H, P574L, C580Y, A675V in the Greater Mekong Sub-region (GMS) and R561H or P574L in Rwanda have been validated as markers of artemisinin partial resistance. In addition, R622I has been reported as a marker of artemisinin resistance in Ethiopia, Eritrea, and other neighboring countries. Therefore, the aim of this study is to assess the therapeutic efficacy of Artemether-Lumefantrine (the front-line treatment since 2004) for uncomplicated P. falciparum infections in Ethiopia. The study also aims to identify genetic determinants of artemisinin resistance in Ethiopia.
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Actual trial start date 27/03/2024 One week elapsed for provision of training to field team. 20 Nov 2023 27 Nov 2023
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Anticipated date of last follow up 27/03/2024 Due to decrease in malaria case flow. 29 Feb 2024 01 May 2024
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Completion date 14/05/2025 Low participant enrollment due to low case detection rate 13 May 2024
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Target no of participants 27/03/2024 One study site excluded due to security issue. 528 440
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Final no of participants 14/05/2025 Temporary cessation of P. falciparum infections 436
Section Name Field Name Date Reason Old Value Updated Value
Trial Information Recruitment status 14/05/2025 Recruitment completed Recruiting Completed
Section Name Field Name Date Reason Old Value Updated Value
Eligibility Inclusion criteria 13/12/2023 Recruitment parasite density adjusted based on transmission. 1. Able to give informed consent, assent and/or parental/guardian permission 2. Age ≥ 6 months 3. Weight ≥ 5.0 kg 4. Hemoglobin ≥ 7 g/dl 5. Axillary temperature ≥ 37.5º C or history of fever during the previous 24 hours 6. Ability to swallow oral medication 7. Slide-confirmed P. falciparum mono-infection at any level of parasitemia 1. Able to give informed consent, assent and/or parental/guardian permission 2. Age ≥ 6 months 3. Weight ≥ 5.0 kg 4. Hemoglobin ≥ 7 g/dl 5. Axillary temperature ≥ 37.5º C or history of fever during the previous 24 hours 6. Ability to swallow oral medication 7. Slide-confirmed P. falciparum mono-infection with parasite density ≥ 500 parasites per µL.
Section Name Field Name Date Reason Old Value Updated Value
Eligibility Inclusion criteria 27/03/2024 Modified based on transmission intensity. 1. Able to give informed consent, assent and/or parental/guardian permission 2. Age ≥ 6 months 3. Weight ≥ 5.0 kg 4. Hemoglobin ≥ 7 g/dl 5. Axillary temperature ≥ 37.5º C or history of fever during the previous 24 hours 6. Ability to swallow oral medication 7. Slide-confirmed P. falciparum mono-infection with parasite density ≥ 500 parasites per µL. 1. Able to give informed consent, assent and/or parental/guardian permission 2. Age ≥ 6 months 3. Weight ≥ 5.0 kg 4. Hemoglobin ≥ 7 g/dl 5. Axillary temperature ≥ 37.5º C or history of fever during the previous 24 hours 6. Ability to swallow oral medication 7. Slide-confirmed P. falciparum mono-infection with parasite density ≥ 1000 parasites per µL.
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 23/11/2023 To correct for total sample size into 528. Experimental Group, Artemetherlumefantrine, Fixed-dose tablets containing 20 mg of artemether plus 120 mg of lumefantrine twice daily , For three days, Artemether-lumefantrine (Coartem; Novartis) is the first-line antimalarial drug used to treat falciparum malaria in Ethiopia. , 88, Experimental Group, Artemetherlumefantrine, Fixed-dose tablets containing 20 mg of artemether plus 120 mg of lumefantrine twice daily , For three days, Artemether-lumefantrine (Coartem; Novartis) is the first-line antimalarial drug used to treat falciparum malaria in Ethiopia. , 528,
Section Name Field Name Date Reason Old Value Updated Value
Intervention Intervention List 27/03/2024 One study site excluded due to security issue. Experimental Group, Artemetherlumefantrine, Fixed-dose tablets containing 20 mg of artemether plus 120 mg of lumefantrine twice daily , For three days, Artemether-lumefantrine (Coartem; Novartis) is the first-line antimalarial drug used to treat falciparum malaria in Ethiopia. , 528, Experimental Group, Artemetherlumefantrine, Fixed-dose tablets containing 20 mg of artemether plus 120 mg of lumefantrine twice daily , For three days, Artemether-lumefantrine (Coartem; Novartis) is the first-line antimalarial drug used to treat falciparum malaria in Ethiopia. , 440,
Section Name Field Name Date Reason Old Value Updated Value
Outcome OutCome List 27/03/2024 Facilities such as Tri-gas incubator and culture media components were not accessed during the study period due to delay in procurement and shipment processes. Secondary Outcome, 1. Document genetic polymorphisms implicated in antimalarial drug resistance 2. Distinguish reinfections and recrudescent infections 3. Determine the survival time of Ethiopian parasite isolates in ring-stage assay 4. Compare the transmissibility of P. falciparum parasites with delayed and rapid parasite clearance and markers of drug resistance 5. Identify genetic changes related to signs of delayed parasite clearance or resistance 6. Determine fever, parasite, cytokine, antigen, and antibody clearance rates as measured by microscopy adjusted by 18S-based quantitative PCR 7. Assess hematological responses 8. Assess pfhrp2/3 gene deletion among P. falciparum-infected patients , On days 0, 1, 2, 3, 7, 14, 21, and 28 Secondary Outcome, 1. Document genetic polymorphisms implicated in antimalarial drug resistance 2. Distinguish reinfections and recrudescent infections 3. Compare the transmissibility of P. falciparum parasites with delayed and rapid parasite clearance and markers of drug resistance 4. Identify genetic changes related to signs of delayed parasite clearance or resistance 5. Determine fever, parasite and antigen clearance rates as measured by microscopy adjusted by 18S-based quantitative PCR 6. Assess hematological responses 7. Assess pfhrp2/3 gene deletion among P. falciparum-infected patients , On days 0, 1, 2, 3, 7, 14, 21, and 28
Section Name Field Name Date Reason Old Value Updated Value
Recruitment Centre RecruitmentCentre List 27/03/2024 Mizan Health Center was re-selected due to higher case load Aman Hospital, Mizan Aman, Mizan Aman, , Ethiopia Mizan Health Center, Mizan Teferi, Mizan Teferi, , Ethiopia
Section Name Field Name Date Reason Old Value Updated Value
Recruitment Centre RecruitmentCentre List 27/03/2024 Excluded due to instability in the area, and feeding assay is conducted in Maksegnit. Metehara Health Center, Metehara, Metehara, , Ethiopia
Section Name Field Name Date Reason Old Value Updated Value
Sponsors Sponsors List 27/03/2024 The sponsor is USAID Centers for Disease Control and Prevention , Atlanta, GA 30329, Atlanta, , United States of America, Primary Sponsor, Funding Agency, USAID, 1300 Pennsylvania Avenue NW, Washington, DC 20523, United States of America, Primary Sponsor, Funding Agency,
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 27/03/2024 He is one of a collaborators Samuel Girma, Entoto , Addis Ababa, , Ethiopia
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 27/03/2024 He becomes a collaborator Samuel Girma, Entoto, Addis Ababa, , Ethiopia
Section Name Field Name Date Reason Old Value Updated Value
Collaborators Collaborators List 27/03/2024 She becomes a collaborator Hiwot Teka, Entoto, Addis Ababa, , Ethiopia
Section Name Field Name Date Reason Old Value Updated Value
Reporting IPD description 23/11/2023 To correct IPD description. 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. De-identified individual clinical trial participant-level data including demographic data, and clinical and parasitological evaluation data will be shared to the Ethiopian Ministry of Health, policymakers, collaborating institutions and researchers for further analyses and decision-making. The dataset will be shared via the publication URL: https://ahri.gov.et/.
Section Name Field Name Date Reason Old Value Updated Value
Reporting Key access criteria 23/11/2023 To modify key data access criteria. 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. Key findings and supplementary data will be accessed via publications and workshops.