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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT04844099
Other study ID # 19-105
Secondary ID
Status Completed
Phase Phase 3
First received
Last updated
Start date April 9, 2021
Est. completion date July 12, 2023

Study information

Verified date September 2022
Source Liverpool School of Tropical Medicine
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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-ARTEPPĀ® (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.


Recruitment information / eligibility

Status Completed
Enrollment 723
Est. completion date July 12, 2023
Est. primary completion date June 30, 2023
Accepts healthy volunteers No
Gender All
Age group 6 Months to 15 Years
Eligibility 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 Design


Intervention

Drug:
Dihydroartemisinin Piperaquine
Administered as dihydroartemisinin (20mg) and piperaquine (160 mg)

Locations

Country Name City State
Malawi Queen Elizabeth Hospital Blantyre
Uganda Jinja Regional Referral hospital Jinja
Uganda Kitgum General Hospital Kitgum

Sponsors (6)

Lead Sponsor Collaborator
Liverpool School of Tropical Medicine Global Health Uganda LTD, Indiana University, Makerere University, University of Bergen, University of Malawi

Countries where clinical trial is conducted

Malawi,  Uganda, 

References & Publications (23)

Bigira V, Kapisi J, Clark TD, Kinara S, Mwangwa F, Muhindo MK, Osterbauer B, Aweeka FT, Huang L, Achan J, Havlir DV, Rosenthal PJ, Kamya MR, Dorsey G. Protective efficacy and safety of three antimalarial regimens for the prevention of malaria in young Ugandan children: a randomized controlled trial. PLoS Med. 2014 Aug 5;11(8):e1001689. doi: 10.1371/journal.pmed.1001689. eCollection 2014 Aug. — View Citation

Chandramohan D, Owusu-Agyei S, Carneiro I, Awine T, Amponsa-Achiano K, Mensah N, Jaffar S, Baiden R, Hodgson A, Binka F, Greenwood B. Cluster randomised trial of intermittent preventive treatment for malaria in infants in area of high, seasonal transmission in Ghana. BMJ. 2005 Oct 1;331(7519):727-33. doi: 10.1136/bmj.331.7519.727. — View Citation

Cisse B, Cairns M, Faye E, NDiaye O, Faye B, Cames C, Cheng Y, NDiaye M, Lo AC, Simondon K, Trape JF, Faye O, NDiaye JL, Gaye O, Greenwood B, Milligan P. Randomized trial of piperaquine with sulfadoxine-pyrimethamine or dihydroartemisinin for malaria intermittent preventive treatment in children. PLoS One. 2009 Sep 28;4(9):e7164. doi: 10.1371/journal.pone.0007164. — View Citation

Eke FU, Anochie I. Effects of pyrimethamine versus proguanil in malarial chemoprophylaxis in children with sickle cell disease: a randomized, placebo-controlled, open-label study. Curr Ther Res Clin Exp. 2003 Sep;64(8):616-25. doi: 10.1016/j.curtheres.2003.09.003. — View Citation

Eridani S. Sickle cell protection from malaria. Hematol Rep. 2011 Oct 19;3(3):e24. doi: 10.4081/hr.2011.e24. Epub 2011 Nov 4. — View Citation

Gutman J, Kovacs S, Dorsey G, Stergachis A, Ter Kuile FO. Safety, tolerability, and efficacy of repeated doses of dihydroartemisinin-piperaquine for prevention and treatment of malaria: a systematic review and meta-analysis. Lancet Infect Dis. 2017 Feb;17(2):184-193. doi: 10.1016/S1473-3099(16)30378-4. Epub 2016 Nov 17. — View Citation

Jiang T, Chen J, Fu H, Wu K, Yao Y, Eyi JUM, Matesa RA, Obono MMO, Du W, Tan H, Lin M, Li J. High prevalence of Pfdhfr-Pfdhps quadruple mutations associated with sulfadoxine-pyrimethamine resistance in Plasmodium falciparum isolates from Bioko Island, Equatorial Guinea. Malar J. 2019 Mar 26;18(1):101. doi: 10.1186/s12936-019-2734-x. — View Citation

Kamya MR, Kapisi J, Bigira V, Clark TD, Kinara S, Mwangwa F, Muhindo MK, Kakuru A, Aweeka FT, Huang L, Jagannathan P, Achan J, Havlir DV, Rosenthal PJ, Dorsey G. Efficacy and safety of three regimens for the prevention of malaria in young HIV-exposed Ugandan children: a randomized controlled trial. AIDS. 2014 Nov 28;28(18):2701-9. doi: 10.1097/QAD.0000000000000497. — View Citation

Keating GM. Dihydroartemisinin/Piperaquine: a review of its use in the treatment of uncomplicated Plasmodium falciparum malaria. Drugs. 2012 May 7;72(7):937-61. doi: 10.2165/11203910-000000000-00000. — View Citation

Kwambai TK, Dhabangi A, Idro R, Opoka R, Kariuki S, Samuels AM, Desai M, van Hensbroek MB, John CC, Robberstad B, Wang D, Phiri K, Ter Kuile FO. Malaria chemoprevention with monthly dihydroartemisinin-piperaquine for the post-discharge management of severe anaemia in children aged less than 5 years in Uganda and Kenya: study protocol for a multi-centre, two-arm, randomised, placebo-controlled, superiority trial. Trials. 2018 Nov 6;19(1):610. doi: 10.1186/s13063-018-2972-1. — View Citation

Lwin KM, Phyo AP, Tarning J, Hanpithakpong W, Ashley EA, Lee SJ, Cheah P, Singhasivanon P, White NJ, Lindegardh N, Nosten F. Randomized, double-blind, placebo-controlled trial of monthly versus bimonthly dihydroartemisinin-piperaquine chemoprevention in adults at high risk of malaria. Antimicrob Agents Chemother. 2012 Mar;56(3):1571-7. doi: 10.1128/AAC.05877-11. Epub 2012 Jan 17. — View Citation

Lynch C, Pearce R, Pota H, Cox J, Abeku TA, Rwakimari J, Naidoo I, Tibenderana J, Roper C. Emergence of a dhfr mutation conferring high-level drug resistance in Plasmodium falciparum populations from southwest Uganda. J Infect Dis. 2008 Jun 1;197(11):1598-604. doi: 10.1086/587845. — View Citation

Matthews JI, Molitor JT, Hunt KK Jr. Pyrimethamine-induced leukopenia and thrombocytopenia in a patient with malaria and tropical sprue: case report. Mil Med. 1973 May;138(5):280-3. No abstract available. — View Citation

McAuley CF, Webb C, Makani J, Macharia A, Uyoga S, Opi DH, Ndila C, Ngatia A, Scott JA, Marsh K, Williams TN. High mortality from Plasmodium falciparum malaria in children living with sickle cell anemia on the coast of Kenya. Blood. 2010 Sep 9;116(10):1663-8. doi: 10.1182/blood-2010-01-265249. Epub 2010 Jun 8. — View Citation

McCollum AM, Mueller K, Villegas L, Udhayakumar V, Escalante AA. Common origin and fixation of Plasmodium falciparum dhfr and dhps mutations associated with sulfadoxine-pyrimethamine resistance in a low-transmission area in South America. Antimicrob Agents Chemother. 2007 Jun;51(6):2085-91. doi: 10.1128/AAC.01228-06. Epub 2007 Feb 5. — View Citation

Mytton OT, Ashley EA, Peto L, Price RN, La Y, Hae R, Singhasivanon P, White NJ, Nosten F. Electrocardiographic safety evaluation of dihydroartemisinin piperaquine in the treatment of uncomplicated falciparum malaria. Am J Trop Med Hyg. 2007 Sep;77(3):447-50. — View Citation

Nakibuuka V, Ndeezi G, Nakiboneka D, Ndugwa CM, Tumwine JK. Presumptive treatment with sulphadoxine-pyrimethamine versus weekly chloroquine for malaria prophylaxis in children with sickle cell anaemia in Uganda: a randomized controlled trial. Malar J. 2009 Oct 24;8:237. doi: 10.1186/1475-2875-8-237. — View Citation

O'Meara WP, Breman JG, McKenzie FE. The promise and potential challenges of intermittent preventive treatment for malaria in infants (IPTi). Malar J. 2005 Jul 20;4:33. doi: 10.1186/1475-2875-4-33. — View Citation

Oniyangi O, Omari AA. Malaria chemoprophylaxis in sickle cell disease. Cochrane Database Syst Rev. 2006 Oct 18;2006(4):CD003489. doi: 10.1002/14651858.CD003489.pub2. — View Citation

Pearson RD, Hewlett EL. Use of pyrimethamine-sulfadoxine (Fansidar) in prophylaxis against chloroquine-resistant Plasmodium falciparum and Pneumocystis carinii. Ann Intern Med. 1987 May;106(5):714-8. doi: 10.7326/0003-4819-106-5-714. — View Citation

Sinclair D, Zani B, Donegan S, Olliaro P, Garner P. Artemisinin-based combination therapy for treating uncomplicated malaria. Cochrane Database Syst Rev. 2009 Jul 8;2009(3):CD007483. doi: 10.1002/14651858.CD007483.pub2. — View Citation

Staedke SG, Sendagire H, Lamola S, Kamya MR, Dorsey G, Rosenthal PJ. Relationship between age, molecular markers, and response to sulphadoxine-pyrimethamine treatment in Kampala, Uganda. Trop Med Int Health. 2004 May;9(5):624-9. doi: 10.1111/j.1365-3156.2004.01239.x. — View Citation

Weatherall D, Hofman K, Rodgers G, Ruffin J, Hrynkow S. A case for developing North-South partnerships for research in sickle cell disease. Blood. 2005 Feb 1;105(3):921-3. doi: 10.1182/blood-2004-06-2404. Epub 2004 Oct 5. — View Citation

* Note: There are 23 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Primary Incidence of clinical malaria 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 All cause sick visits The incidence of all cause sick visits 18 months
Secondary Incidence of malaria parasitaemia The incidence of malaria parasitaemia 18 months
Secondary Malaria specific sick visits The incidence of malaria-specific sick visits 18 months
Secondary All-cause and malaria-specific hospitalisation The incidence of all-cause and malaria-specific hospitalisation 18 months
Secondary Sickle Cell Anaemia-related vaso-occlusive events 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
Secondary Death The incidence of death. 18 months
Secondary QTc prolongation Change in Corrected QT interval (QTc) length and QTc-prolongation on four-monthly ECG recordings. 18 months
Secondary Serious cardiac adverse events Incidence of serious cardiac adverse events (e.g., convulsions or syncope within 48 hours after drug intake) 18 months
Secondary Serious adverse events Incidence of serious adverse events 18 months
Secondary Tolerance - vomiting Vomiting the study drug within 30 min of administration;
Incidence of gastrointestinal complaints.
18 months
Secondary Other gastro-intestinal complaints Incidence of gastrointestinal complaints. 18 months
Secondary Level of adherence Level of adherence to study drugs 18 months
Secondary Provider costs Provider costs of delivering the interventions and provider costs of managing malaria in SCA children. 18 months
Secondary Direct and indirect costs Direct and indirect costs of patients receiving the interventions and managing cases of malaria. 18 months
Secondary Incremental cost-effectiveness 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
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