약물 내성 발달 지연을 위한 삼중 아르테미시닌 기반 병용 요법 - 무작위 임상 시험 (3ACT)
복잡하지 않은 열대열열 말라리아 치료를 위한 삼중 아르테미시닌 기반 병용 요법, 탄자니아 열열열열열체의 약물 내성 개발 지연: 무작위 3군 임상 시험
Background: Artemisinin resistance has emerged in parts of Southeast Asia, and there are reports in Africa of reduced susceptibility of Plasmodium falciparum parasites against artemisinin-based combination therapy (ACT). No new drugs are available in the pipeline to replace ACTs in case they fail.
This study aims to assess whether a sequential administration of triple ACTs with different partner-drugs can improve the efficacy of ACT for treatment of uncomplicated malaria.
Methods: A health facility-based, three-arm partially blinded randomized clinical trial will be conducted to assess efficacy and safety of a sequential administration of artemether-lumefantrine followed immediately by artesunate-amodiaquine (AL+ASAQ) or artemether-lumefantrine with by amodiaquine (AL+AQ) compared to artemether-lumefantrine plus placebo (AL+PBO). Eligible children aged 6 - 120 months and with microscopy confirmed uncomplicated P. falciparum malaria will be enrolled, administered with trial medicines and followed-up at 0 (just prior to first drug intake) and 8 hours on day 0, 12 hourly on days 1, 2, 3, 4, 5, followed by once daily on days 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 28, 35, 42 and 56 for clinical and laboratory evaluations. Clinical evaluation will involve assessment of signs and symptoms related to the disease and or trial medicine during follow-up. Laboratory evaluation will include microscopic determination of presence of malaria parasites and species, hemoglobin level, molecular analysis for markers of drug resistance and to differentiate recrudescence from new infection. The primary outcome will be crude recurrent parasitemia by day 42 in the respective arms.
Expected outcomes: The findings will give an insight on whether 3 ACTs are more efficacious than the use of first-line regimen alone, and are tolerable for treatment of uncomplicated falciparum malaria.
연구 개요
상태
연구 유형
등록 (실제)
단계
- 2 단계
- 3단계
연락처 및 위치
연구 장소
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Dar esSalaam
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Bagamoyo, Dar esSalaam, 탄자니아, 255
- Kibindu
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Yombo
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Bagamoyo, Yombo, 탄자니아, +255
- Yombo Dispensary
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참여기준
자격 기준
공부할 수 있는 나이
건강한 자원 봉사자를 받아들입니다
연구 대상 성별
설명
Patients presenting at the health facility with suspected acute uncomplicated malaria will be screened for eligibility.
Inclusion Criteria:
- Age from 6 - 120 months
- Weight ≥ 5 kg
- Body temperature ≥37.5°C or history of fever in the last 24 hours
- Microscopy confirmed P. falciparum mono-infection
- Parasitemia level of 1000-200000/μL
- Ability to swallow oral medication
- Ability and willingness to abide by the study protocol and the stipulated follow-up visits
- A written proxy informed consent from a parent/guardian
Exclusion Criteria:
- Children aged below 6 months will not be included in the study because ACTs are contraindicated in this group.
- Evidence of severe malaria or danger signs
- Known allergy to trial medicines
- Reported antimalarial intake ≤2 weeks
- Haemoglobin <5 g/dL
- Blood transfusion within last 90 days
- Febrile condition other than malaria
- Known underlying chronic or severe disease (including severe malnutrition).
공부 계획
연구는 어떻게 설계됩니까?
디자인 세부사항
- 주 목적: 치료
- 할당: 무작위
- 중재 모델: 병렬 할당
- 마스킹: 더블
무기와 개입
참가자 그룹 / 팔 |
개입 / 치료 |
|---|---|
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실험적: Artemether-lumefantrine followed by artesunate amodiaquine
a standard 3-days dosage, twice a day course of Artemether-Lumefantrine (20/120mg) immediately followed by a standard 3-days, once a day course of Artesunate-Amodiaquine (40base) |
AL will be given twice a day for three days then followed by artesunate amodiaquine once a day for three days
다른 이름들:
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실험적: Artemether-lumefantrine with Amodiaquine
a standard 3-days dosage of Artemether-Lumefantrine (20/120mg) given together with Amodiaquine hydrocloride(40 base) followed by placebo for another 3 days; |
AL and AQ will be given together for three days then followed by placebo for three days
다른 이름들:
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활성 비교기: Artemether-Lumefantrine alone
a standard 3-days dosage of Artemether-Lumefantrine (20/120mg) followed by placebo for another 3 days |
This will be the comparator arm as standard treatment, where only AL will be given twice a day for three days then placebo for three days
다른 이름들:
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연구는 무엇을 측정합니까?
주요 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
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Crude recurrent parasitemia by day 42 in the respective arms
기간: 42nd day since enrollment
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Laboratory assessment of parasitemia using light microscopy performed at 42nd day of follow up will be the primary outcome assessing the differences in proportion of patients with recurrent parasitemia. |
42nd day since enrollment
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2차 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
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PCR adjusted cure rates by day 28, 42 and 56.
기간: Through study completion, an average of 1 year
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Assessment of cure rate as determined by parasitemia to distinguish recrudescence and reinfections |
Through study completion, an average of 1 year
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Crude recurrent parasitemia by day 28 and 56 in the respective arms
기간: Day 28 and day 56 since enrollment
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Laboratory assessment of parasitemia using light microscopy performed at day 28 and the last day (56th) of follow up will be the primary outcome assessing the differences in proportion of patients with recurrent parasitemia. |
Day 28 and day 56 since enrollment
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기타 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
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Median time to recurrent parasitemia by microscopy
기간: 56 days since enrolment
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This outcome compares across the three arms how long it takes until patients return with parasitemia. It will provide information on the post treatment prophylaxis of each arm. |
56 days since enrolment
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PCR determined parasite clearance times
기간: Baseline to day 3
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PCR determined parasite clearance times are determined by using PCR to measure the amount of parasite DNA in the patient's blood at various time points after treatment. The parasite clearance time is then calculated as the time it takes for the amount of parasite DNA to fall below a certain threshold level, indicating that the parasite has been cleared from the patient's blood. |
Baseline to day 3
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Maximum plasma concentrations (Cmax) of the intervention drugs.
기간: Baseline and Day 7
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The Pharmacokinetics profiles of artesunate/dihydroartemisinin, lumefantrine/desbutyl-lumefantrine and amodiaquine/desethyl-amodiaquine will be assessed, focusing on Plasma concentrations to determine Cmax. |
Baseline and Day 7
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Change in hemoglobin level (g/dl)
기간: Baseline and day 7
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Haemoglobin concentration will be measured at baseline day 0 on day 7 to determine whether patients are anemic or not. . Anemia will be categorized as mild (Hb < 11 g/dL), moderate (< 7 g/dL) or severe (Hb < 5 g/dL). |
Baseline and day 7
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Proportion of Microscopy determined gametocyte carriage
기간: Baseline and day 3
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Assessment of how many patients in each treatment arm harbour gametocytes |
Baseline and day 3
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Prevalence of genetic markers of drug resistance.
기간: Through study completion, an average of 1 year
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Selection of genetic markers of drug resistance among recurrent parasitemia during follow-up and during the early treatment phase. The markers will include P. falciparum chloroquine resistance transporter gene (Pfcrt), and P. falciparum multidrug resistance gene 1 (Pfmdr1) for lumefantrine and amodiaquine; P. falciparum multidrug resistance proteins, the sarco/endoplasmic reticulum Ca2+-ATPase orthologue of P. falciparum (pfatp6), and P. falciparum kelch propeller gene 13 (PfKelch13) for artemisinin; and plasmepsin 2 and 3 for piperaquine. |
Through study completion, an average of 1 year
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공동 작업자 및 조사자
수사관
- 수석 연구원: Billy E Ngasala, PhD, Muhimbili University of Health and Allied Sciences
- 수석 연구원: Andreas Mårtensson, PhD, Muhimbili University of Health and Allied Sciences
간행물 및 유용한 링크
일반 간행물
- Holmstrom O, Linder N, Ngasala B, Martensson A, Linder E, Lundin M, Moilanen H, Suutala A, Diwan V, Lundin J. Point-of-care mobile digital microscopy and deep learning for the detection of soil-transmitted helminths and Schistosoma haematobium. Glob Health Action. 2017 Jun;10(sup3):1337325. doi: 10.1080/16549716.2017.1337325.
- Smit MR, Ochomo EO, Aljayyoussi G, Kwambai TK, Abong'o BO, Chen T, Bousema T, Slater HC, Waterhouse D, Bayoh NM, Gimnig JE, Samuels AM, Desai MR, Phillips-Howard PA, Kariuki SK, Wang D, Ward SA, Ter Kuile FO. Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2018 Jun;18(6):615-626. doi: 10.1016/S1473-3099(18)30163-4. Epub 2018 Mar 27.
- Leang R, Taylor WR, Bouth DM, Song L, Tarning J, Char MC, Kim S, Witkowski B, Duru V, Domergue A, Khim N, Ringwald P, Menard D. Evidence of Plasmodium falciparum Malaria Multidrug Resistance to Artemisinin and Piperaquine in Western Cambodia: Dihydroartemisinin-Piperaquine Open-Label Multicenter Clinical Assessment. Antimicrob Agents Chemother. 2015 Aug;59(8):4719-26. doi: 10.1128/AAC.00835-15. Epub 2015 May 26.
- Mwaiswelo R, Ngasala B, Gil JP, Malmberg M, Jovel I, Xu W, Premji Z, Mmbando BP, Bjorkman A, Martensson A. Sustained High Cure Rate of Artemether-Lumefantrine against Uncomplicated Plasmodium falciparum Malaria after 8 Years of Its Wide-Scale Use in Bagamoyo District, Tanzania. Am J Trop Med Hyg. 2017 Aug;97(2):526-532. doi: 10.4269/ajtmh.16-0780.
- Mwaiswelo R, Ngasala B, Jovel I, Xu W, Larsson E, Malmberg M, Gil JP, Premji Z, Mmbando BP, Martensson A. Prevalence of and Risk Factors Associated with Polymerase Chain Reaction-Determined Plasmodium falciparum Positivity on Day 3 after Initiation of Artemether-Lumefantrine Treatment for Uncomplicated Malaria in Bagamoyo District, Tanzania. Am J Trop Med Hyg. 2019 May;100(5):1179-1186. doi: 10.4269/ajtmh.18-0729.
- Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ, Ringwald P, Silamut K, Imwong M, Chotivanich K, Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day NP, Lindegardh N, Socheat D, White NJ. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009 Jul 30;361(5):455-67. doi: 10.1056/NEJMoa0808859.
연구 기록 날짜
연구 주요 날짜
연구 시작 (실제)
기본 완료 (실제)
연구 완료 (실제)
연구 등록 날짜
최초 제출
QC 기준을 충족하는 최초 제출
처음 게시됨 (실제)
연구 기록 업데이트
마지막 업데이트 게시됨 (실제)
QC 기준을 충족하는 마지막 업데이트 제출
마지막으로 확인됨
추가 정보
이 연구와 관련된 용어
추가 관련 MeSH 약관
기타 연구 ID 번호
- 3ACT-2023
약물 및 장치 정보, 연구 문서
미국 FDA 규제 의약품 연구
미국 FDA 규제 기기 제품 연구
미국에서 제조되어 미국에서 수출되는 제품
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