Dihydroartemisinin-Piperaquine or Sulphadoxine-Pyrimethamine for the Chemoprevention of Malaria in Sickle Cell Anaemia (CHEMCHA)

September 12, 2023 updated by: Liverpool School of Tropical Medicine

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)

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

723

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Malawi
      • Blantyre, Malawi
        • Queen Elizabeth Hospital
  • Uganda
      • Jinja, Uganda
        • Jinja Regional Referral Hospital
      • Kitgum, Uganda
        • Kitgum General Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

6 months to 15 years (Child)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Intervention arm
The intervention will be oral dihydroartemisinin (20mg) and piperaquine (160 mg) and administered once weekly at approximate doses of dihydroartemisinin 2.5mg/kg/day and piperaquine 20mg/kg/day based on participants' weight categories
Drug: Dihydroartemisinin Piperaquine
Administered as dihydroartemisinin (20mg) and piperaquine (160 mg)
Other Names:
  • D-ARTEPP® (Guilin Pharmaceutical Co. Ltd)
Active Comparator: Comparator
The active control will be Sulphadoxine-Pyrimethamine (SP), the current standard of care for malaria chemoprevention for SCA in Uganda and Malawi. This will also be provided by Guilin Pharmaceutical Co. Ltd as their generic World Health Organization-approved sulphadoxine-pyrimethamine 500/25mg tablets. It will be administered as monthly single-day courses of SP at approximate doses of S=25mg/kg and P=1.25mg/kg.
Drug: Dihydroartemisinin Piperaquine
Administered as dihydroartemisinin (20mg) and piperaquine (160 mg)
Other Names:
  • D-ARTEPP® (Guilin Pharmaceutical Co. Ltd)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of clinical malaria
Time Frame: 18 months
An episode of malaria will be defined as a history of fever in the preceding 48hrs or documented axillary temperature ≥37.5 degrees centigrade plus microscopy confirmed Plasmodium falciparum malaria
18 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
All cause sick visits
Time Frame: 18 months
The incidence of all cause sick visits
18 months
Incidence of malaria parasitaemia
Time Frame: 18 months
The incidence of malaria parasitaemia
18 months
Malaria specific sick visits
Time Frame: 18 months
The incidence of malaria-specific sick visits
18 months
All-cause and malaria-specific hospitalisation
Time Frame: 18 months
The incidence of all-cause and malaria-specific hospitalisation
18 months
Sickle Cell Anaemia-related vaso-occlusive events
Time Frame: 18 months
The incidence of SCA-related vaso-occlusive events (including severe pain events and dactylitis); acute chest syndrome, stroke and need for blood transfusion
18 months
Death
Time Frame: 18 months
The incidence of death.
18 months
QTc prolongation
Time Frame: 18 months
Change in Corrected QT interval (QTc) length and QTc-prolongation on four-monthly ECG recordings.
18 months
Serious cardiac adverse events
Time Frame: 18 months
Incidence of serious cardiac adverse events (e.g., convulsions or syncope within 48 hours after drug intake)
18 months
Serious adverse events
Time Frame: 18 months
Incidence of serious adverse events
18 months
Tolerance - vomiting
Time Frame: 18 months
  1. Vomiting the study drug within 30 min of administration;
  2. Incidence of gastrointestinal complaints.
18 months
Other gastro-intestinal complaints
Time Frame: 18 months
Incidence of gastrointestinal complaints.
18 months
Level of adherence
Time Frame: 18 months
Level of adherence to study drugs
18 months
Provider costs
Time Frame: 18 months
Provider costs of delivering the interventions and provider costs of managing malaria in SCA children.
18 months
Direct and indirect costs
Time Frame: 18 months
Direct and indirect costs of patients receiving the interventions and managing cases of malaria.
18 months
Incremental cost-effectiveness
Time Frame: 18 months
Incremental cost-effectiveness of replacing current standards of care (SP) with DP or DP+SP from the perspectives of the health care provider and the society.
18 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Liverpool School of Tropical Medicine

Collaborators

University of Bergen
Indiana University
Makerere University
University of Malawi
Global Health Uganda LTD

Investigators

  • Study Director: Robberstad Bjarne, PhD, University of Bergen, Norway

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 9, 2021

Primary Completion (Actual)

June 30, 2023

Study Completion (Actual)

July 12, 2023

Study Registration Dates

First Submitted

March 26, 2021

First Submitted That Met QC Criteria

April 8, 2021

First Posted (Actual)

April 14, 2021

Study Record Updates

Last Update Posted (Actual)

September 13, 2023

Last Update Submitted That Met QC Criteria

September 12, 2023

Last Verified

September 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 19-105

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

At the end of the study, anonymised data will be available to other researchers for further analysis,

IPD Sharing Time Frame

Beginning of 2025

IPD Sharing Access Criteria

  1. Ethical approval has been obtained.
  2. The terms of the original patient consent are not violated.
  3. The agreement on its use is according to prevailing laws on intellectual property rights.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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