Post-discharge Malaria Chemoprevention(PMC) Study (PMC)

Malaria Chemoprevention With Monthly Treatment With Dihydroartemisinin-piperaquine for the Post-discharge Management of Severe Anaemia in Children Aged Less Than 5 Years in Uganda and Kenya: A Two-arm Randomised Placebo Controlled Trial

This study evaluates the efficacy and safety of 3 months of malaria chemoprevention post-discharge using dihydroartemisinin piperaquine (DHA-P) in children under 5 years of age admitted with severe anemia. One half will receive monthly DHA-P and the other half placebo.

Study Overview

• Status: Completed
• Conditions: Malaria; Severe Anemia
• Intervention / Treatment: Drug: dihydroartemisinin-piperaquine; Drug: dihydroartemisinin-piperaquine placebo

Detailed Description

Children hospitalized with severe anemia in Africa are at high risk of readmission or death within 6 months after discharge. No strategy specifically addresses this post-discharge period. In Malawi, 3 months of post-discharge malaria chemoprevention with monthly 3-day treatment courses of artemether-lumefantrine (AL) in children with severe malarial anemia prevented 31% of deaths and readmissions. This study is a confirmatory efficacy trial in Kenya and Uganda to determine the efficacy and safety of malaria chemoprevention post-discharge. We hypothesize that an additional three months of malaria chemoprevention with monthly 3-day treatment courses with DHA-piperaquine (each providing about 4 weeks of post-treatment prophylaxis) provided during the post-discharge period to children recently admitted with severe anemia is superior to reduce all-cause readmission and mortality rates by 6 months compared with 2 weeks of post-treatment prophylaxis provided by the single course of oral AL when given as part of the standard in-hospital care around the time of discharge.

• Study Type: Interventional
• Enrollment (Actual): 1049
• Phase: Phase 3

Contacts and Locations

Study Locations

• Kenya
  • Kisumu, Kenya
    • Jaramogi Oginga Odinga Teaching and Referral Hospital
  • Homa Bay County
    • Homa Bay, Homa Bay County, Kenya, 40100
      • Homa Bay County Referral Hospital
  • Migori County
    • Migori, Migori County, Kenya, 40400
      • Migori County Referral Hospital
  • Siaya County
    • Siaya, Siaya County, Kenya, 40100
      • Siaya County Referral Hospital
• Uganda
  • Hoima, Uganda
    • Hoima Regional referral Hospital
  • Jinja, Uganda
    • Jinja Regional Referral Hospital
  • Kamuli, Uganda
    • Kamuli Mission Hospital
  • Masaka, Uganda
    • Masaka Regional Referral Hospital
  • Mubende, Uganda
    • Mubende Regional Referral Hospital:

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 5 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Pre-study screening

  1. Haemoglobin <5.0 g/dl or PCV < 15%, or requirement for blood transfusion for other clinical reasons on or during admission to the hospital
  2. Aged less than 59.5 months
  3. Body weight >5 kg
  4. Resident in catchment area Enrolment in study(t=0)
  1. Fulfilled the pre-study screening eligibility criteria
  2. Aged < 59.5 months
  3. Clinically stable, able to take oral medication
  4. Subject completed blood transfusion(s) or became clinically stable without transfusion
  5. Able to feed (for breastfeeding children) or eat (for older children)
  6. Absence of know cardiac problems
  7. Provision of informed consent by parent or guardian Randomisation (t=2 weeks)
  1. Fulfilled enrolment eligibility criteria and was enrolled during recent admission
  2. Aged <60 months
  3. Still clinically stable, able to take to oral medication, able to feed (for breastfeeding children) or eat (for older children) and able to sit unaided (for older children who were already able to do so prior to hospitalisation)

Exclusion Criteria:

• Pre-study screening

  1. Recognised specific other cause of severe anaemia (e.g. trauma, haematological malignancy, known bleeding disorder)
  2. Known sickle cell disease
  3. Anticipated to reach the 5th birthday (60 months of age) within 2 weeks from enrolment (i.e. prior to randomization)
  4. Child will reside for more than 25%of the 6 months study period (i.e. 6 weeks or more) outside of catchment area Enrolment in study (t=0)
  1. Previous enrolment in the present study
  2. Known hypersensitivity to study drug
  3. Sickle cell disease
  4. Use or known need at the time of enrolment for concomitant prohibited medication during the 14 weeks PMC treatment period.
  5. Ongoing or planned participation in another clinical trial involving ongoing or scheduled treatment with prohibited medicinal products or active follow-up during the course of the study (6 months from enrolment)
  6. A known need at the time of enrolment for scheduled surgery during the subsequent course of the study (6 months from enrolment)
  7. Suspected non-compliance with the follow-up schedule
  8. Know heart conditions, or family history of congenital prolongation of the QTc interval.
  9. Taking medicinal products that are known to prolong the QTc interval Randomisation (t=2 weeks)
  1. Used dihydroartemisinin since enrolment
  2. Use or known need at the time of randomisation for concomitant prohibited medication during the 14 weeks PMC treatment period.
  3. Enrolled, or known agreement to enrol into another clinical trial involving ongoing or scheduled treatment with medicinal products during the course of the study (6 months from enrolment)
  4. A known need at the time of randomisation for scheduled surgery during the subsequent course of the study (6 months from enrolment)
  5. Suspected non-compliance with the follow-up schedule
  6. Withdrawal of consent since enrolment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: dihydroartemisinin-piperaquine; dihydroartemisinin-piperaquine (3-day treatment courses, given 2, 6, and 10 weeks after enrollment)	Drug: dihydroartemisinin-piperaquine; Children in both arms will receive standard in-hospital care for severe anaemia (blood transfusion, often combined with quinine or artesunate IV/IM). All children will then receive a 3-day course of AL (whether they initially had malaria or not), which will be started in-hospital as soon as they are able to take oral medication, and will be completed at home after discharge. At 2 weeks after enrolment surviving children will be randomized to receive either a standard 3-day courses of dihydroartemisinin-piperaquine (Eurartesim®, Sigma Tau, Italy) or an identical placebo regimen at 2, 6 and 10 weeks after enrolment.; Other Names: Eurartesim
PLACEBO_COMPARATOR: dihydroartemisinin-piperaquine Placebo; Placebo comparator (matching tablets containing no active ingredients)	Drug: dihydroartemisinin-piperaquine placebo; Children will receive standard in-hospital care for severe anaemia (blood transfusion, often combined with quinine or artesunate IV/IM). All children will then receive a 3-day course of AL (whether they initially had malaria or not), which will be started in-hospital as soon as they are able to take oral medication, and will be completed at home after discharge. At 2 weeks after enrolment surviving children will be randomized to receive either a standard 3-day courses of dihydroartemisinin-piperaquine (Eurartesim®, Sigma Tau, Italy) or an identical placebo regimen at 2, 6 and 10 weeks after enrolment.; Other Names: Eurartesim placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause deaths or all-cause re-admissions by 26 weeks from randomization (composite primary outcome).	Primary outcome	6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Readmission due to severe malaria (defined as any treatment with parenteral quinine or artesunate, or presence of severe anaemia and treatment with oral antimalarials) by 26 weeks from randomization	26 weeks from randomization
All-cause readmission by 26 weeks from randomization	26 weeks from randomization
Readmissions due to severe anaemia (defined as Haemoglobin (Hb) <5g/dL or packed-cell volume (PCV) <15% or requirement for blood transfusion based on other clinical indication)by 26 weeks from randomization	26 weeks from randomization
Readmission due to severe malarial anaemia (severe anaemia plus parenteral or oral antimalarial treatment)by 26 weeks from randomization	26 from randomization
Readmission due to severe anaemia or severe malaria (composite outcome)by 26 weeks from randomization	26 weeks from randomization
All-cause mortality by 26 weeks from randomization	26 weeks from randomization
Clinic visits because of smear of rapid diagnostic test (RDT) confirmed non-severe malaria by 26 weeks from randomization	26 weeks from randomization
Readmission due to severe malaria-specific anaemia (severe anaemia plus parenteral or oral antimalarial treatment and parasite density >5000/microlitre) by 26 weeks from randomization	26 weeks from randomization
Readmission due to severe disease other than severe anaemia and severe malaria by 26 weeks from randomization	26 weeks from randomization
Non-severe all-cause sick-child clinic visits by 26 weeks from randomization	26 weeks from randomization
Non-malaria sick child clinic visits by 26 weeks from randomization	26 weeks from randomization
Malaria infection at 6 month	6 month
Hb at 6 months	6 months
Any anaemia (Hb<11 g/dL), mild anaemia (Hb 8.0-10.99 g/dl) moderate anaemia (Hb 5.0-7.99 g/dL) and severe anaemia (Hb<5 g/dL) at 6 months	6 months
Weight-for-age, height-for-age, and height-for-weight Z-scores, standard deviation (SD) scores of reference population) at 6 months	6 months
Serious adverse events, excluding primary and secondary efficacy outcomes, by 26 weeks from randomization	26 weeks from randomization
Serious adverse events within 7 days after the start of each course of PMC, excluding primary and secondary efficacy outcomes.	26 weeks from randomization
Adverse events by 26 weeks from randomization	26 weeks from randomization
Adverse events within 7 days after start of each course of PMC.	7 days post drug administration
Corrected QT interval (QTc) prolongation measured by electro cardio gram (ECG)4-6 hours after 3rd dose of each course	4-6 hours after 3rd dose of each course
Patients costs of receiving the intervention	26 weeks after randomization
Patients costs related to treatment of the primary disease, readmission or death	26 weeks after randomization
The costs of the health care system of providing the intervention	26 weeks after randomization
The costs of the health system of treating the primary disease and anaemia, as well as treatment of readmissions or costs related to fatalities	26 weeks after randomization

Collaborators and Investigators

• Sponsor: Liverpool School of Tropical Medicine
• Collaborators: The Research Council of Norway; Makerere University; Kenya Medical Research Institute
• Investigators: Principal Investigator: Dr Titus K Kwambai, MSc, Liverpool School of Tropical Medicine; Principal Investigator: Dr Simon K Kariuki, PhD, Kenya Medical Research Institute; Principal Investigator: Dr Richard IDRO, PhD, Makerere University; Principal Investigator: Dr Robert Opoka, M.Med, Makerere University

Publications and helpful links

General Publications

• Kwambai TK, Dhabangi A, Idro R, Opoka R, Watson V, Kariuki S, Kuya NA, Onyango ED, Otieno K, Samuels AM, Desai MR, Boele van Hensbroek M, Wang D, John CC, Robberstad B, Phiri KS, Ter Kuile FO. Malaria Chemoprevention in the Postdischarge Management of Severe Anemia. N Engl J Med. 2020 Dec 3;383(23):2242-2254. doi: 10.1056/NEJMoa2002820.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 20, 2016
• Primary Completion (ACTUAL): October 24, 2018
• Study Completion (ACTUAL): December 12, 2018

Study Registration Dates

• First Submitted: January 28, 2016
• First Submitted That Met QC Criteria: January 28, 2016
• First Posted (ESTIMATE): February 2, 2016

Study Record Updates

• Last Update Posted (ACTUAL): June 4, 2020
• Last Update Submitted That Met QC Criteria: June 2, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Hematologic Diseases; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Anemia; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Piperaquine; Artenimol; Artemisinins
• Other Study ID Numbers: 14.034; 2965 (OTHER: Kenya Medical Research Institute); 2015-125 (OTHER: Uganda REC); 2014/1911 (OTHER: Norway REC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All individual-participant data collected during this trial will be stored in a public data repository after de-identification. Data and documents, including the study protocol, and the statistical analysis plan, will be made available and access to data provided when a proposal has been approved by the investigators, after consideration of overlap between the proposal and any ongoing efforts. Data will be available beginning at three months after publication of this Article.
• IPD Sharing Time Frame: 3 months after publication of this Article
• IPD Sharing Access Criteria: Proposals should be directed to feiko.terkuile@lstmed.ac.uk and Bjarne.Robberstad@uib.no; to gain access, data requesters will need to sign a data access agreement, and the de-identified database will be transferred electronically
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF