Sickle Cell Anemia in ChildrenPhase 3CHEMCHANCT04844099
Dihydroartemisinin-Piperaquine or Sulphadoxine-Pyrimethamine for the Chemoprevention of Malaria in Sickle Cell Anaemia
A Phase 3 study testing Dihydroartemisinin Piperaquine in people with Sickle Cell Anemia in Children and Malaria, run by Liverpool School of Tropical Medicine at 3 sites in 2 countries.
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. Read more about this study
- Who is it for?
- Ages 6 months to 15 years
- Conditions the study is for
- Sickle Cell Anemia in Children, Malaria
- What is being tested?
- Dihydroartemisinin Piperaquine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 723 participants
- Where
- 3 sitesin 2 countries
- Study dates
- 9 Apr 2021to 12 Jul 2023
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 months to 15 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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.
Who cannot join
- 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
Trial locations and contacts
3 sites in 2 countries.
3 sites in 2 countries
Uganda2 sites
Jinja Regional Referral hospital
Jinja
Kitgum General Hospital
Kitgum
About this study
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)
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.
Read the 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.
- Conditions
- Sickle Cell Anemia in Children, Malaria
- Being tested
- Dihydroartemisinin Piperaquine
- Keywords
- dihydroartemisinin-piperaquine, sulphadoxine pyrimethamine, sickle cell, malaria, chemoprevention, prophylaxis
- Medical subject headings
- Malaria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Dihydroartemisinin PiperaquineDrug
Also called D-ARTEPP® (Guilin Pharmaceutical Co. Ltd)
Administered as dihydroartemisinin (20mg) and piperaquine (160 mg)
| Study group | Role | What they receive |
|---|---|---|
| Intervention arm | Experimental | 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 Receives: Drug: Dihydroartemisinin Piperaquine |
| Comparator | Active 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. Receives: Drug: Dihydroartemisinin Piperaquine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 18 months
Secondary outcomes (15)
All cause sick visits
The incidence of all cause sick visits
Measured: 18 months
Incidence of malaria parasitaemia
The incidence of malaria parasitaemia
Measured: 18 months
Malaria specific sick visits
The incidence of malaria-specific sick visits
Measured: 18 months
All-cause and malaria-specific hospitalisation
The incidence of all-cause and malaria-specific hospitalisation
Measured: 18 months
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
Measured: 18 months
Death
The incidence of death.
Measured: 18 months
QTc prolongation
Change in Corrected QT interval (QTc) length and QTc-prolongation on four-monthly ECG recordings.
Measured: 18 months
Serious cardiac adverse events
Incidence of serious cardiac adverse events (e.g., convulsions or syncope within 48 hours after drug intake)
Measured: 18 months
Serious adverse events
Incidence of serious adverse events
Measured: 18 months
Tolerance - vomiting
- Vomiting the study drug within 30 min of administration;
- Incidence of gastrointestinal complaints.
Measured: 18 months
Other gastro-intestinal complaints
Incidence of gastrointestinal complaints.
Measured: 18 months
Level of adherence
Level of adherence to study drugs
Measured: 18 months
Provider costs
Provider costs of delivering the interventions and provider costs of managing malaria in SCA children.
Measured: 18 months
Direct and indirect costs
Direct and indirect costs of patients receiving the interventions and managing cases of malaria.
Measured: 18 months
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.
Measured: 18 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Apr 2021
- Study start9 Apr 2021
- Primary completion30 Jun 2023
- Study completion12 Jul 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (25)Papers the sponsor has linked to this study.
- Other trials for Sickle Cell Anemia in ChildrenStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 723 participants (actual)
Sponsor and investigators
- Lead sponsor
- Liverpool School of Tropical Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- University of Bergen, University of Malawi, Makerere University, Indiana University, Global Health Uganda LTD
- Responsible party
- Sponsor
- Investigators
- Robberstad Bjarne, PhD, Study director, University of Bergen, Norway
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04844099
- Sponsor's protocol ID
- 19-105
- Acronym
- CHEMCHA
- Status last verified
- Sep 2022
- First submitted
- 26 Mar 2021
- Last updated
- 13 Sep 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: At the end of the study, anonymised data will be available to other researchers for further analysis,
Publications
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.
PubMed 15466925Eridani S. Sickle cell protection from malaria. Hematol Rep. 2011 Oct 19;3(3):e24. doi: 10.4081/hr.2011.e24. Epub 2011 Nov 4.
PubMed 23285410McAuley 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.
PubMed 20530796Sinclair 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.
PubMed 19588433Cisse 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.
PubMed 19784374Lwin 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.
PubMed 22252804Kwambai 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.
PubMed 30400934Mytton 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.
PubMed 17827358Keating 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.
PubMed 22515619Gutman 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.
PubMed 27865890O'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.
PubMed 16033653Nakibuuka 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.
PubMed 19852829Jiang 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.
PubMed 30914041Staedke 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.
PubMed 15117308McCollum 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.
PubMed 17283199
Study at a glance
From the registry record, last updated by the sponsor on 13 Sep 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT04844099
- Acronym / sponsor ID
- CHEMCHA / 19-105
- Conditions
- Sickle Cell Anemia in Children, Malaria
- Keywords
- dihydroartemisinin-piperaquine, sulphadoxine pyrimethamine, sickle cell, malaria, chemoprevention, prophylaxis
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 723 participants (actual)
- Lead sponsor
- Liverpool School of Tropical MedicineUniversity, hospital or other
- Collaborators
- University of Bergen, University of Malawi, Makerere University, Indiana University, Global Health Uganda LTD
- Study start
- 9 Apr 2021 (actual)
- Primary completion
- 30 Jun 2023 (actual)
- Study completion
- 12 Jul 2023 (actual)
- First posted
- 14 Apr 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- 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
| Arm | Type | Receives |
|---|---|---|
| Intervention arm | Experimental | Drug: Dihydroartemisinin PiperaquineThe 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 |
| Comparator | Active comparator | Drug: Dihydroartemisinin PiperaquineThe 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. |
Who may qualify
- Ages
- 6 months to 15 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (6 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Dihydroartemisinin PiperaquineAlso: D-ARTEPP® (Guilin Pharmaceutical Co. Ltd)Administered as dihydroartemisinin (20mg) and piperaquine (160 mg) | Drug | Comparator, Intervention arm |
Primary outcome
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
15 secondary outcomes
All cause sick visits
Time frame: 18 months
Incidence of malaria parasitaemia
Time frame: 18 months
Malaria specific sick visits
Time frame: 18 months
All-cause and malaria-specific hospitalisation
Time frame: 18 months
Sickle Cell Anaemia-related vaso-occlusive events
Time frame: 18 months
Death
Time frame: 18 months
QTc prolongation
Time frame: 18 months
Serious cardiac adverse events
Time frame: 18 months
Serious adverse events
Time frame: 18 months
Tolerance - vomiting
Time frame: 18 months
Other gastro-intestinal complaints
Time frame: 18 months
Level of adherence
Time frame: 18 months
Provider costs
Time frame: 18 months
Direct and indirect costs
Time frame: 18 months
Incremental cost-effectiveness
Time frame: 18 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Sep 2023.
- Background: PubMed 15466925Weatherall 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.
- Background: PubMed 23285410Eridani S. Sickle cell protection from malaria. Hematol Rep. 2011 Oct 19;3(3):e24. doi: 10.4081/hr.2011.e24. Epub 2011 Nov 4.
- Background: PubMed 20530796McAuley 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.
- Background: PubMed 19588433Sinclair 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.
- Background: PubMed 19784374Cisse 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.
- Background: PubMed 22252804Lwin 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.
- Background: PubMed 30400934Kwambai 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.
- Background: PubMed 17827358Mytton 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.
- Background: PubMed 22515619Keating 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.
- Background: PubMed 27865890Gutman 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.
- Background: PubMed 16033653O'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.
- Background: PubMed 19852829Nakibuuka 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.
- Individual participant dataSharing planned: Yes. At the end of the study, anonymised data will be available to other researchers for further analysis,
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Robberstad Bjarne, PhD study director
University of Bergen, Norway
3 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Dihydroartemisinin Piperaquine in people with Sickle Cell Anemia in Children and Malaria, run by Liverpool School of Tropical Medicine at 3 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Uganda, Malawi. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of clinical malaria (time frame: 18 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04844099, which also lists 25 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Sep 2023.