Potrójna terapia skojarzona oparta na artemizyninie w celu opóźnienia rozwoju lekooporności — randomizowane badanie kliniczne (3ACT)
Potrójna terapia skojarzona oparta na artemizyninie w leczeniu niepowikłanej malarii Plasmodium falciparum, opóźnienie rozwoju lekooporności Plasmodium falciparum w Tanzanii: randomizowane trzyramienne badanie kliniczne
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.
Przegląd badań
Status
Typ studiów
Zapisy (Rzeczywisty)
Faza
- Faza 2
- Faza 3
Kontakty i lokalizacje
Lokalizacje studiów
-
-
Dar esSalaam
-
Bagamoyo, Dar esSalaam, Tanzania, 255
- Kibindu
-
-
Yombo
-
Bagamoyo, Yombo, Tanzania, +255
- Yombo Dispensary
-
-
Kryteria uczestnictwa
Kryteria kwalifikacji
Wiek uprawniający do nauki
Akceptuje zdrowych ochotników
Płeć kwalifikująca się do nauki
Opis
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).
Plan studiów
Jak projektuje się badanie?
Szczegóły projektu
- Główny cel: Leczenie
- Przydział: Randomizowane
- Model interwencyjny: Przydział równoległy
- Maskowanie: Podwójnie
Broń i interwencje
Grupa uczestników / Arm |
Interwencja / Leczenie |
|---|---|
|
Eksperymentalny: 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
Inne nazwy:
|
|
Eksperymentalny: 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
Inne nazwy:
|
|
Aktywny komparator: 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
Inne nazwy:
|
Co mierzy badanie?
Podstawowe miary wyniku
Miara wyniku |
Opis środka |
Ramy czasowe |
|---|---|---|
|
Crude recurrent parasitemia by day 42 in the respective arms
Ramy czasowe: 42nd day since enrollment
|
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
|
Miary wyników drugorzędnych
Miara wyniku |
Opis środka |
Ramy czasowe |
|---|---|---|
|
PCR adjusted cure rates by day 28, 42 and 56.
Ramy czasowe: Through study completion, an average of 1 year
|
Assessment of cure rate as determined by parasitemia to distinguish recrudescence and reinfections |
Through study completion, an average of 1 year
|
|
Crude recurrent parasitemia by day 28 and 56 in the respective arms
Ramy czasowe: Day 28 and day 56 since enrollment
|
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
|
Inne miary wyników
Miara wyniku |
Opis środka |
Ramy czasowe |
|---|---|---|
|
Median time to recurrent parasitemia by microscopy
Ramy czasowe: 56 days since enrolment
|
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
|
|
PCR determined parasite clearance times
Ramy czasowe: Baseline to day 3
|
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
|
|
Maximum plasma concentrations (Cmax) of the intervention drugs.
Ramy czasowe: Baseline and Day 7
|
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
|
|
Change in hemoglobin level (g/dl)
Ramy czasowe: Baseline and day 7
|
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
|
|
Proportion of Microscopy determined gametocyte carriage
Ramy czasowe: Baseline and day 3
|
Assessment of how many patients in each treatment arm harbour gametocytes |
Baseline and day 3
|
|
Prevalence of genetic markers of drug resistance.
Ramy czasowe: Through study completion, an average of 1 year
|
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
|
Współpracownicy i badacze
Śledczy
- Główny śledczy: Billy E Ngasala, PhD, Muhimbili University of Health and Allied Sciences
- Główny śledczy: Andreas Mårtensson, PhD, Muhimbili University of Health and Allied Sciences
Publikacje i pomocne linki
Publikacje ogólne
- 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.
Daty zapisu na studia
Główne daty studiów
Rozpoczęcie studiów (Rzeczywisty)
Zakończenie podstawowe (Rzeczywisty)
Ukończenie studiów (Rzeczywisty)
Daty rejestracji na studia
Pierwszy przesłany
Pierwszy przesłany, który spełnia kryteria kontroli jakości
Pierwszy wysłany (Rzeczywisty)
Aktualizacje rekordów badań
Ostatnia wysłana aktualizacja (Rzeczywisty)
Ostatnia przesłana aktualizacja, która spełniała kryteria kontroli jakości
Ostatnia weryfikacja
Więcej informacji
Terminy związane z tym badaniem
Słowa kluczowe
Dodatkowe istotne warunki MeSH
- Choroby przenoszone przez wektory
- Choroby przenoszone przez komary
- Infekcje
- Infekcje pierwotniakowe
- Choroby pasożytnicze
- Malaria
- Malaria, Falciparum
- Organiczne chemikalia
- Przygotowania farmaceutyczne
- Węglowodory
- Węglowodory, cykliczne
- Terpeny
- Policykliczne aromatyczne węglowodory
- Węglowodory, aromatyczne
- Związki policykliczne
- Chemikalia nieorganiczne
- Kombinacje narkotyków
- Reaktywne formy tlenu
- Wolne rodniki
- Artemether
- Artemisiniiny
- Lumefantryna
- Fluorens
- Sesquiterpenes
- Artemeter, kombinacja leków Lumefantryna
Inne numery identyfikacyjne badania
- 3ACT-2023
Informacje o lekach i urządzeniach, dokumenty badawcze
Bada produkt leczniczy regulowany przez amerykańską FDA
Bada produkt urządzenia regulowany przez amerykańską FDA
produkt wyprodukowany i wyeksportowany z USA
Te informacje zostały pobrane bezpośrednio ze strony internetowej clinicaltrials.gov bez żadnych zmian. Jeśli chcesz zmienić, usunąć lub zaktualizować dane swojego badania, skontaktuj się z register@clinicaltrials.gov. Gdy tylko zmiana zostanie wprowadzona na stronie clinicaltrials.gov, zostanie ona automatycznie zaktualizowana również na naszej stronie internetowej .