Clinical trial NCT04844099: Dihydroartemisinin-Piperaquine or Sulphadoxine-Pyrimethamine for the Chemoprevention of Malaria in Sickle Cell Anaemia
Official title: Dihydroartemisinin-Piperaquine or Sulphadoxine-Pyrimethamine for the Chemoprevention of Malaria in Children With Sickle Cell Anaemia in Eastern and Southern Africa: a Double Blind Randomised Trial (CHEMCHA)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Sickle Cell Anemia in Children
Malaria
Keywords: dihydroartemisinin-piperaquine
sulphadoxine pyrimethamine
sickle cell
malaria
chemoprevention
prophylaxis
Lead sponsor: Liverpool School of Tropical Medicine
Sponsor class: OTHER
Collaborators: name: University of Bergen
name: University of Malawi
name: Makerere University
name: Indiana University
name: Global Health Uganda LTD
First posted: 2021-04-14
Enrollment: 723
Sex: ALL
Minimum age (years): 6
Maximum age (years): 15
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This will be a randomized, double-blind, parallel-group superiority trial of weekly single-day courses of DP for an average of 18 months compared to monthly single-day courses of SP in SCA patients. The study will be conducted in Uganda and Malawi, using randomisation stratified by bodyweight and study centre. Participants will be randomized using an allocation of 1:1 to DP or SP. Patients on DP will also receive an SP placebo, and those on SP will in addition, receive a DP placebo
Primary purpose: PREVENTION

Brief summary: Sickle Cell Anaemia (SCA) is an inherited disease that makes the body produce red blood cells with abnormal sickle-shaped cells. The sickle-shaped cells are rigid, not flexible and break up easily resulting in anaemia. The abnormal cells also stick to the vessel walls, causing a blockage that slows or stops the flow of blood. When this happens, oxygen cannot reach nearby tissues. The lack of oxygen can cause attacks of sudden, severe pain, called pain crises, stroke or damage to important organs such as the spleen. All of these can lead to death. These attacks can occur without warning and are often started and made worse by infections such as malaria. Therefore, in many countries in Africa where malaria is common, children with SCA are given malaria medicines to prevent the infection. However, many of the medicines do not work effectively, are too difficult to take or they have side effects, resulting in poor adherence.

The aim of this study is to find safe, acceptable and effective medicines for malaria prevention in children with SCA in eastern and southern Africa. The investigators propose to conduct a study to find out whether giving weekly doses of dihydroartemisinin-piperaquine, also called DP, is safe, more effective, acceptable and cost-effective than the current strategy of monthly sulphadoxine-pyrimethamine (SP) to prevent malaria in children with sickle cell anaemia. Overall, 548 children aged 6 months to 15 years will be chosen randomly to receive either weekly DP or monthly SP for about 18 months. To test if the study medicine is effective, the study will compare the case burden of malaria. The investigators will also monitor every child for any type of illness, blood transfusions and other complications of sickle cell anaemia and admissions to the hospital. In addition, the study will evaluate the impact of DP on the development of resistance by malaria parasites. The study will also include nested safety studies on the effect of DP on the heart. All study participants will receive all the other usual care and treatments, including patient education on home care, and daily penicillin if younger than 5 years. If proven safe and efficacious, chemoprophylaxis with DP may decrease the incidence of malaria in children with SCA, prevent ill-health and deaths, and improve wellbeing.

Detailed description: Background and rationale:

An estimated 300,000 babies are born with Sickle Cell Anaemia (SCA) annually. Affected children have chronic ill health and many suffer a premature death. Ill health is commonly precipitated by febrile illnesses including malaria. Antimalarial chemoprophylaxis is an important strategy, but current regimes are either sub-optimally effective (e.g., monthly sulphadoxine-pyrimethamine, SP) or difficult to adhere to (e.g., daily proguanil). The investigators propose dihydroartemisinin-piperaquine (DP) as the agent with the most potential to be used across Africa.

Objectives:

Our objective is to determine the efficacy, safety, uptake, and cost-effectiveness of malaria chemoprevention with weekly single day courses of DP vs monthly single day courses of SP in children with SCA in eastern and southern Africa.

Hypothesis:

The hypothesis is that weekly single day courses of DP, is safe and more efficacious, compared to monthly single day courses of SP, for the malaria chemoprevention in children with SCA in eastern and southern Africa.

Design:

This will a randomised, double-blind controlled parallel-group superiority trial of weekly single day courses of DP for an average of 18 months compared to monthly single-day courses of SP in SCA patients. The study will be conducted in Uganda and Malawi. Participants will be randomised to DP or SP (1:1), stratified by bodyweight and study centre. The study will also assess the acceptability and uptake of the two interventions, the safety and pharmacokinetics of weekly DP, the development of resistance to DP and cost-effectiveness. At the end of the study, this information will be used to inform regional health policy.

Sites:

Participants will be recruited from Jinja Regional Referral hospital and Kitgum General hospital in Uganda and Queen Elizabeth (Blantyre) hospital in Malawi.

Interventions:

The intervention will be oral DP administered weekly for an average of 18 months based on weight categories. DP will be provided as tablets of D-ARTEPP® (Guilin Pharmaceutical Co. Ltd) and administered as dihydroartemisinin (20mg) and piperaquine (160 mg) at approximate doses of dihydroartemisinin 2.5mg/kg/day and piperaquine 20mg/kg/day. The active control will be the current standard of care for chemoprevention in Uganda and Malawi - monthly single-dose SP (S=25mg/kg). The same manufacturer will provide SP as the generic SP (in 500/25mg scored tablets).

Other care:

In addition to the above-mentioned malaria regimens, the participants will receive the standard of care for Sickle Cell Anaemia (including parental education on care, treatment for both the acute and chronic complications of Sickle Cell Anaemia, and daily penicillin prophylaxis if \<5 years).

Sample size:

With the minimum incidence rate of clinical malaria in SCA patients receiving monthly SP estimated at 0.2 events per year, and an effect size of 50% if DP is used, at a power of 0.9 and 0.05 level of significance, followed up for 18 months and allowing for 20% losses to follow up, and one interim analysis, the investigators will need 548 participants (274 in either arm) followed up for an average 18 months or until 824 person-years.

Follow up:

Participants will be followed for up for an average of 18 months or until 412 person-years of observation is achieved in each group (a combined total of 824 person-years of observation). This will be achieved by following between 548 and 824 participants for an average of 12 to 18 months each.

Outcome measures:

The primary efficacy outcome measures will be the incidence of clinical malaria. Secondary efficacy outcomes will include the incidence of malaria parasitaemia, all-cause sick-child clinic visits, SCA-related vaso-occlusive events (including severe pain events and dactylitis), acute chest syndrome, stroke, hospitalisations, blood-transfusions, and death.

Secondary safety outcome measures: QTc-prolongation on ECG recordings and incidence of serious cardiac adverse events (e.g., convulsions or syncope within 48 hours after drug intake). Tolerance: % vomiting drug within 30 minutes of administration. Others are cost-effectiveness, development of resistance to piperaquine, feasibility, acceptability, and uptake.

Data Analysis: Primary analysis will be by intention to treat. Incidence rates will be calculated, and rate ratios estimated using Poisson regression, with treatment (as randomised) as the predictor variable and the stratification factors site and weight-band as covariates.

Eligibility criteria: Inclusion criteria

1. Children ages 6 months - 15 years
2. Has a laboratory diagnosis of Sickle Cell Anaemia (HbSS) on haemoglobin electrophoresis, High-Performance Liquid Chromatography or Iso-electric focusing;
3. Weighs ≥5kg;
4. The parent has provided written consent.

Exclusion Criteria:

1. Known chronic disease e.g. congenital heart disease;
2. Known red cell disorder e.g. thalassaemia, glucose-6-phosphate dehydrogenase deficiency;
3. Known allergy to DP or SP;
4. Receiving daily cotrimoxazole prophylaxis;
5. Unlikely to comply with the follow-up schedule;
6. Participating in another trial

Primary outcomes:
measure: Incidence of clinical malaria
timeFrame: 18 months
Secondary outcomes:
measure: All cause sick visits
timeFrame: 18 months
measure: Incidence of malaria parasitaemia
timeFrame: 18 months
measure: Malaria specific sick visits
timeFrame: 18 months
measure: All-cause and malaria-specific hospitalisation
timeFrame: 18 months
measure: Sickle Cell Anaemia-related vaso-occlusive events
timeFrame: 18 months
measure: Death
timeFrame: 18 months
measure: QTc prolongation
timeFrame: 18 months
measure: Serious cardiac adverse events
timeFrame: 18 months
measure: Serious adverse events
timeFrame: 18 months
measure: Tolerance - vomiting
timeFrame: 18 months
measure: Other gastro-intestinal complaints
timeFrame: 18 months
measure: Level of adherence
timeFrame: 18 months
measure: Provider costs
timeFrame: 18 months
measure: Direct and indirect costs
timeFrame: 18 months
measure: Incremental cost-effectiveness
timeFrame: 18 months
Other outcomes:
Locations:
city: Blantyre
country: Malawi
facility: Queen Elizabeth Hospital
city: Jinja
country: Uganda
facility: Jinja Regional Referral hospital
city: Kitgum
country: Uganda
facility: Kitgum General Hospital
Study officials:
affiliation: University of Bergen, Norway
name: Robberstad Bjarne, PhD
role: STUDY_DIRECTOR
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