Clinical trial NCT03178643: Enhancing Preventive Therapy of Malaria In Children With Sickle Cell Anemia in East Africa (EPiTOMISE)
Official title: Enhancing Preventive Therapy of Malaria In Children With Sickle Cell Anemia in East Africa (EPiTOMISE)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Malaria,Falciparum
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2017-06-07
Enrollment: 246
Sex: ALL
Minimum age (years): 1
Maximum age (years): 10
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This is a randomized, three-arm, open-label, clinical trial of malaria chemoprevention in children with sickle-cell anemia (SCA) at a single site in Homa Bay, Kenya. The study will enroll 246 children under 10 years of age, randomize participants 1:1:1 to one of three malaria chemoprevention regimens, and follow participants monthly for 12 months in order to record clinical episodes of malaria or SCA-related morbidity. Analyses will compare the efficacy of each regimen to prevent malaria and SCA morbidity.

Detailed description: Purpose of the study:

Primary Objective: To compare the efficacy of daily proguanil with monthly sulfadoxine/pyrimethanine-amodiaquine (SP-AQ) and with monthly dihydroartemisinin-piperaquine (DP) on the incidence of falciparum malaria in children with SCA.

Secondary Objective: To compare the efficacy of these malaria chemoprevention strategies on the incidence of major complications of SCA.

Background \& significance

Over 240,000 children with sickle cell anemia (SCA) are born in Africa annually. This number will increase to over 350,000 annual births of children with SCA by the year 2050. Without sophisticated medical care, SCA patients in African settings die at young ages: in a Western Kenya cohort of newborns, 25% of SCA children died before their 3rd birthday. Caring effectively for these children will be a major challenge for developing medical and public health systems in Africa including Kenya, and modeling studies suggest that the adequate provision of effective preventive care can substantially reduce the mortality of these children. Preventive care for SCA children must be evidence-based and tailored to the unique epidemiology of comorbidities in African settings.

Children under 5 years of age in sub-Saharan Africa also suffer the majority of the annual 350 million infections and 500,000 deaths globally. Reducing this burden is a global public health priority, particularly in areas of high transmission like Western Kenya. In the absence of an effective vaccine, global malaria control requires effective treatments and a suite of preventive measures that act upon the parasite, environment, and host. Among these preventive strategies is the administration of prophylactic antimalarials to high risk groups, including pregnant women, infants, and children exposed to seasonal malaria transmission. In these high-risk groups malaria morbidity is substantially reduced by routine periodic intake of effective antimalarials.

Children with SCA are at high risk of life-threatening malaria. In East Africa children with SCA admitted to the hospital with malaria parasites were more likely to die than those without parasites. Malaria is also a precipitant of sickle-cell pain crises, by unclear mechanisms. It remains unclear how SCA influences the overall risk of malaria, because most studies have been hospital based and therefore unsuited to capture mild episodes. The twin observations that malaria is more severe in SCA children and precipitates painful crises in these children indicate that the prevention of P. falciparum infections is critical to prolong the survival of SCA children in malaria-endemic areas.

Design \& procedures - This is a randomized, three-arm, open-label, clinical trial of malaria chemoprevention in children with sickle-cell anemia (SCA) at a single site in Homa Bay, Kenya. The study will enroll 246 children under 10 years of age, randomize participants 1:1:1 to one of three malaria chemoprevention regimens, and follow participants monthly for 12 months in order to record clinical episodes of malaria or SCA-related morbidity. Analyses will compare the efficacy of each regimen to prevent malaria and SCA morbidity.

Eligibility criteria: Inclusion Criteria:

* Age greater than 12 months and less than 10 years at enrollment;
* Current attendance at or willingness to attend the study SCA clinic at HBCH;
* Residence in either Homa Bay County or the Rongo or Awendo sub-counties of Migori County;
* Confirmed hemoglobin genotype of HbSS by electrophoresis, HPLC, or PCR;
* No immediate, apparent, or reported plans to relocate residence from Homa Bay County or the Rongo or Awendo sub-counties of Migori County in the next 2 years;
* Ability to take oral medication and be willing to adhere to the medication regimen or caregiver willingness to give the medical regimen as prescribed;
* Ability and willingness of parent or legally authorized representative (LAR) to give informed consent;
* Assent of child in those \> 7 years.

Exclusion Criteria:

* Taking routine antimalarial prophylaxis for another indication (including co-trimoxazole for HIV infection);
* Temperature of ≥ 37.5C at screening or history of objective or subjective fever in the preceding 24 hours during screening;
* Known allergy or sensitivity to sulfadoxine, pyrimethamine, amodiaquine, proguanil, dihydroartemisinin, piperaquine, artemether, lumefantrine, pencillin (if under 5 years old), or derivatives of these compounds;
* Known chronic medical condition other than SCA (i.e. malignancy, HIV) requiring frequent medical attention;
* Currently participating in another clinical research study, or having participated in one in the prior 30 days;
* Living in the same household as a previously-enrolled study participant;
* Chronic use of medications known to prolong the QT interval in children (see Appendix J);
* Fridericia's corrected QT interval (QTcF) interval \> 450msec.

Primary outcomes:
measure: Incidence of Clinical Malaria Per Patient Year
timeFrame: 12 months
Secondary outcomes:
measure: Number of Participants With Severe Anemia
timeFrame: 12 months
measure: Number of Participants With Severe Malaria
timeFrame: 12 months
measure: Number of Participants With Hospitalization for Malaria
timeFrame: 12 months
measure: Number of Participants With Light Microscopy (LM)-Positive Malaria
timeFrame: 12 months
measure: Number of Participants With Unconfirmed Malaria
timeFrame: 12 months
measure: Number of Participants With Fatal Malaria
timeFrame: 12 months
measure: Number of Participants With Asymptomatic Parasitization
timeFrame: 12 months
measure: Number of Participants With Painful Events
timeFrame: 12 months
measure: Number of Participants With Dactylitis
timeFrame: 12 months
measure: Number of Participants With Transfusions
timeFrame: 12 months
measure: Number of Participants With Acute Chest Syndrome
timeFrame: 12 months
measure: Number of Participants With All-cause Hospitalization
timeFrame: 12 months
measure: All-cause Deaths
timeFrame: 12 months
measure: Molecular Markers of Malaria Parasite Drug Resistance
timeFrame: 12 months
Other outcomes:
Locations:
city: Homa Bay Town
country: Kenya
facility: Homa Bay County Referral Hospital
state: Homa Bay County
Study officials:
References:
citation: Taylor SM, Korwa S, Wu A, Green CL, Freedman B, Clapp S, Kirui JK, O'Meara WP, Njuguna FM. Monthly sulfadoxine/pyrimethamine-amodiaquine or dihydroartemisinin-piperaquine as malaria chemoprevention in young Kenyan children with sickle cell anemia: A randomized controlled trial. PLoS Med. 2022 Oct 10;19(10):e1004104. doi: 10.1371/journal.pmed.1004104. eCollection 2022 Oct.