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

  • STATUS
    Recruiting
  • End date
    Jun 18, 2024
  • participants needed
    548
  • sponsor
    Liverpool School of Tropical Medicine
Updated on 18 August 2021

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.

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.

Details
Condition Malaria Vaccines, Malaria, Sickle Cell Anemia in Children
Treatment dihydroartemisinin piperaquine
Clinical Study IdentifierNCT04844099
SponsorLiverpool School of Tropical Medicine
Last Modified on18 August 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

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

Exclusion Criteria

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

How to participate?

Step 1 Connect with a study center
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar

Primary Contact

site

0/250

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider

Loading...

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

user name

Added by • 

 • 

Private

Reply by • Private
Loading...

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.
Loading...

No annotations made yet

Add a private note
  • abc Select a piece of text from the left.
  • Add notes visible only to you.
  • Send it to people through a passcode protected link.
Add a private note