Triple Artemisinin-based Combination Therapy for Delaying Drug Resistance Development - a Randomized Clinical Trial

Study Overview
=================
Brief Summary
-----------------
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 Polymerase Chain Reaction (PCR)-adjusted adequate clinical and parasitological cure rate on days 28 and 42. 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.

Official Title
-----------------
Can Triple Artemisinin-based Combination Therapy for Treatment of Uncomplicated Plasmodium Falciparum Malaria, Delay Drug Resistance Development of Plasmodium Falciparum in Tanzania: a Randomized Three Arm Clinical Trial

Conditions
-----------------
Uncomplicated Plasmodium Falciparum Malaria

Intervention / Treatment
-----------------
* Drug: Artemether-lumefantrine and Amodiaquine Drug Combination
* Drug: Artemether-lumefantrine then Artesunate amodiaquine
* Drug: Artemether-lumefantrine


Participation Criteria
=================
Eligibility Criteria
-----------------
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 2000-200000/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).

Ages Eligible for Study
-----------------
Minimum Age: 6 Months
Maximum Age: 120 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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).
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Artemether-lumefantrine followed by artesunate amodiaquine<br>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) | Drug: Artemether-lumefantrine then Artesunate amodiaquine<br>* AL will be given twice a day for three days then followed by artesunate amodiaquine once a day for three days<br>* Other names: AL then ASAQ;|
| Experimental: Artemether-lumefantrine with Amodiaquine<br>a standard 3-days dosage of Artemether-Lumefantrine (20/120mg) given together with Amodiaquine hydrocloride(40 base) followed by placebo for another 3 days; | Drug: Artemether-lumefantrine and Amodiaquine Drug Combination<br>* AL and AQ will be given together for three days then followed by placebo for three days<br>* Other names: AL+AQ;|
| Active Comparator: Artemether-Lumefantrine alone<br>a standard 3-days dosage of Artemether-Lumefantrine (20/120mg) followed by placebo for another 3 days | Drug: Artemether-lumefantrine<br>* 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<br>* Other names: AL + Placebo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Crude recurrent parasitemia by day 56 in the respective arms | Laboratory assessment of parasitemia using light microscopy performed at last day of follow up will be the primary outcome assessing the differences in proportion of patients with recurrent parasitemia. | 56th day since enrolment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PCR adjusted cure rates by day 28, 42 and 56. | Assessment of cure rate as determined by parasitemia to distinguish recrudescence and reinfections | Through study completion, an average of 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Artemisinin-based Combination Therapy, Plasmodium falciparum, Uncomplicated malaria