Clinical trial NCT02671175: Post-discharge Malaria Chemoprevention(PMC) Study
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malaria
Severe Anemia
Lead sponsor: Liverpool School of Tropical Medicine
Sponsor class: OTHER
Collaborators: name: The Research Council of Norway
name: Kenya Medical Research Institute
name: Makerere University
First posted: 2016-02-02
Enrollment: 1049
Sex: ALL
Maximum age (years): 60
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

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.

Eligibility criteria: 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)

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  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)

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  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)

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  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)

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  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

Primary outcomes:
measure: All-cause deaths or all-cause re-admissions by 26 weeks from randomization (composite primary outcome).
timeFrame: 6 months
Secondary outcomes:
measure: 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
timeFrame: 26 weeks from randomization
measure: All-cause readmission by 26 weeks from randomization
timeFrame: 26 weeks from randomization
measure: 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
timeFrame: 26 weeks from randomization
measure: Readmission due to severe malarial anaemia (severe anaemia plus parenteral or oral antimalarial treatment)by 26 weeks from randomization
timeFrame: 26 from randomization
measure: Readmission due to severe anaemia or severe malaria (composite outcome)by 26 weeks from randomization
timeFrame: 26 weeks from randomization
measure: All-cause mortality by 26 weeks from randomization
timeFrame: 26 weeks from randomization
measure: Clinic visits because of smear of rapid diagnostic test (RDT) confirmed non-severe malaria by 26 weeks from randomization
timeFrame: 26 weeks from randomization
measure: 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
timeFrame: 26 weeks from randomization
measure: Readmission due to severe disease other than severe anaemia and severe malaria by 26 weeks from randomization
timeFrame: 26 weeks from randomization
measure: Non-severe all-cause sick-child clinic visits by 26 weeks from randomization
timeFrame: 26 weeks from randomization
measure: Non-malaria sick child clinic visits by 26 weeks from randomization
timeFrame: 26 weeks from randomization
measure: Malaria infection at 6 month
timeFrame: 6 month
measure: Hb at 6 months
timeFrame: 6 months
measure: 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
timeFrame: 6 months
measure: Weight-for-age, height-for-age, and height-for-weight Z-scores, standard deviation (SD) scores of reference population) at 6 months
timeFrame: 6 months
measure: Serious adverse events, excluding primary and secondary efficacy outcomes, by 26 weeks from randomization
timeFrame: 26 weeks from randomization
measure: Serious adverse events within 7 days after the start of each course of PMC, excluding primary and secondary efficacy outcomes.
timeFrame: 26 weeks from randomization
measure: Adverse events by 26 weeks from randomization
timeFrame: 26 weeks from randomization
measure: Adverse events within 7 days after start of each course of PMC.
timeFrame: 7 days post drug administration
measure: Corrected QT interval (QTc) prolongation measured by electro cardio gram (ECG)4-6 hours after 3rd dose of each course
timeFrame: 4-6 hours after 3rd dose of each course
measure: Patients costs of receiving the intervention
timeFrame: 26 weeks after randomization
measure: Patients costs related to treatment of the primary disease, readmission or death
timeFrame: 26 weeks after randomization
measure: The costs of the health care system of providing the intervention
timeFrame: 26 weeks after randomization
measure: The costs of the health system of treating the primary disease and anaemia, as well as treatment of readmissions or costs related to fatalities
timeFrame: 26 weeks after randomization
Other outcomes:
Locations:
city: Homa Bay
country: Kenya
facility: Homa Bay County Referral Hospital
state: Homa Bay County
city: Migori
country: Kenya
facility: Migori County Referral Hospital
state: Migori County
city: Siaya
country: Kenya
facility: Siaya County Referral Hospital
state: Siaya County
city: Kisumu
country: Kenya
facility: Jaramogi Oginga Odinga Teaching and Referral Hospital
city: Hoima
country: Uganda
facility: Hoima Regional Referral Hospital
city: Jinja
country: Uganda
facility: Jinja Regional Referral Hospital
city: Kamuli
country: Uganda
facility: Kamuli Mission Hospital
city: Masaka
country: Uganda
facility: Masaka Regional Referral Hospital
city: Mubende
country: Uganda
facility: Mubende Regional Referral Hospital:
Study officials:
affiliation: Liverpool School of Tropical Medicine
name: Dr Titus K Kwambai, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Kenya Medical Research Institute
name: Dr Simon K Kariuki, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Makerere University
name: Dr Richard IDRO, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Makerere University
name: Dr Robert Opoka, M.Med
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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.