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Effectiveness and Safety of Intermittent Preventive Treatment for Malaria Using Either Dihydroartemisinin-piperaquine or Artesunate-amodiaquine in Reducing Malaria Related Morbidities and Improving Cognitive Ability in School-aged Children in Tanzania (InSMART-school)

Primary Purpose

Malaria,Falciparum, Anemia

Status
Unknown status
Phase
Phase 3
Locations
Tanzania
Study Type
Interventional
Intervention
Dihydroartemisinin-piperaquine
Artesunate-amodiaquine
Sponsored by
National Institute for Medical Research, Tanzania
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Malaria,Falciparum focused on measuring Malaria, school children, randomized controlled trial, safety, effectiveness, Dihydroartemisinin-piperaquine, cognitive, Artesunate-amodiaquine, malaria serology, drug resistance

Eligibility Criteria

5 Years - 15 Years (Child)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Includes parental/guardian informed consent
  • Assent by primary school children aged 11 years and above.
  • Aged 5-15 years.
  • Currently, lives within the pre-defined catchment area of Muheza District.
  • Will remain within the same area throughout the study period (preferably class five and below).

Exclusion Criteria:

  • Students at class 6 and 7
  • Currently enrolled in another study or participated in another investigational drug study within the last 30 days.
  • Known to have heart disease or a known cardiac ailment.
  • Reports known hypersensitivity to the study drugs.
  • Not willing to undergo all study procedures including physical examination and to provide blood samples as per this study protocol.
  • Having clinical features of severe anaemia
  • Febrile due to non-malaria illness at the time of recruitment.
  • Has apparent severe infection or any condition that requires hospitalization
  • Illness or conditions like hematologic, cardiac, renal, hepatic diseases which in the judgement of the investigator would place the subject at undue risk or interfere with the results of the study, including known G6PD deficiency and SS sickle cell.
  • Body weight < 14 k

Sites / Locations

  • National Institute for Medical Research

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

No Intervention

Arm Label

DP

ASAQ

Control

Arm Description

Dihydroartemisinin-piperaquine (DP), antimalarial drug to be given every 4 months 3 rounds for the first year. A second non-interventional year will assess possible rebound effects.

Artesunate-amodiaquine (ASAQ), antimalarial drugs to be given every 4 months 3 rounds for the first year. A second non-interventional year will assess possible rebound effects.

No intervention drugs will be given, but normal routine standard of care will be provided.

Outcomes

Primary Outcome Measures

Change from baseline in mean haemoglobin concentration at months 12 and 20 of follow-up
Will measure change from baseline haemoglobin concentration at month 12 (intervention period) and at month 20 (post intervention period to assess rebound effect) [Note: a trend of change at each visit will also be assessed with respect to malaria seasonality]
Clinical malaria incidence from month 0 till months 12 and 20 of follow up
number of symptomatic malaria episodes during and after intervention period

Secondary Outcome Measures

Prevalence of asymptomatic malaria infections at month 0, 12 and 20 of follow up
to be measured from microscopic detection of malaria parasite on blood slides
Prevalence of PCR confirmed sub-microscopic parasitaemia at months 0,12 and 20 of follow up
Polymerase chain reaction (PCR) confirmed from random subset of finger prick dry blood spots samples
Prevalence of soil transmitted helminths and schistosomiasis
A stool sample will be used to determine prevalence (defined as adult or eggs) of STH and S. mansoni infection determined by duplicate Kato-Katz thick smears technique. Urine samples will be visually examined for the presence of blood (macrohaematuria) followed by laboratory examination for schistosomiasis infection (S.haematobium)
Prevalence of schistosomiasis
Urine samples will be visually examined for the presence of blood (macrohaematuria) followed by laboratory examination for schistosomiasis infection (S.haematobium) for confirmation.
Prevalence of validated common P. falciparum polymorphisms known to be associated with drug sensitivity at baseline, at months 12 and 20
from random subset of finger prick dry blood spots samples
Proportion of children seropositive for Plasmodium falciparum AMA-1 and MSP-119 at baseline, at month 12 and 20
from random subset of finger prick dry blood spots samples, Antibody responses to P. falciparum blood-stages antigens, apical membrane antigen (AMA-1) and merozoite surface protein (MSP-119) will be determined.
Change in serum antibody responses to Plasmodium falciparum AMA-1 and MSP-119 at baseline, at month 12 and 20
From random subset of finger prick dry blood spots samples to be eluted for ELISA
Percentages of school children with malnutrition through WHO's BMI z-score
weight in kilograms and height in meters will be combined to report BMI in kg/m^2
Relative risk (RR), for all adverse events categorised to severity at month 12 and 20
Adverse events will be detected throughout the study, Each intervention arm will be compared to control arm to determine risk of an adverse event among the two arms. Also events in two intervention arms will be compared to each other to assess risk in the two intervention arms.

Full Information

First Posted
August 14, 2018
Last Updated
August 31, 2021
Sponsor
National Institute for Medical Research, Tanzania
Collaborators
Universiteit Antwerpen
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1. Study Identification

Unique Protocol Identification Number
NCT03640403
Brief Title
Effectiveness and Safety of Intermittent Preventive Treatment for Malaria Using Either Dihydroartemisinin-piperaquine or Artesunate-amodiaquine in Reducing Malaria Related Morbidities and Improving Cognitive Ability in School-aged Children in Tanzania
Acronym
InSMART-school
Official Title
Effectiveness and Safety of Intermittent Preventive Treatment for Malaria Using Either Dihydroartemisinin-piperaquine or Artesunate-amodiaquine in Reducing Malaria Related Morbidities and Improving Cognitive Ability in School-aged Children in Tanzania: A Controlled Randomised Trial
Study Type
Interventional

2. Study Status

Record Verification Date
September 2020
Overall Recruitment Status
Unknown status
Study Start Date
March 26, 2019 (Actual)
Primary Completion Date
December 31, 2020 (Actual)
Study Completion Date
December 31, 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
National Institute for Medical Research, Tanzania
Collaborators
Universiteit Antwerpen

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Background: In high-transmission settings, up to 70% of school-aged children harbour malaria parasites which is mostly asymptomatic, thus, from an epidemiological point of view, they contribute significantly as reservoir to onward malaria transmission to others. In endemic areas, malaria accounts for around 50% of the mortality, 13-50% of all school absenteeism, and causes anaemia in approximately 85 million school-aged children of sub Saharan Africa that also impairs the cognitive development of children. Intermittent preventive treatment (IPT) of pregnant women as well as seasonal malaria chemoprevention in children under the age of five have been implemented in several sub-Saharan countries and have proven to be very effective. However, none of these IPT strategies is targeting school children. A clinical trial is being conducted to expand the IPT by testing effectiveness and safety of two antimalarial drugs Dihydroartemisinin-piperaquine (DP) and Artesunate-amodiaquine (ASAQ) in preventing malaria related morbidity in school aged children (IPTsc) living in high endemic areas. Methods: A randomized, open label, controlled trial will enrol 1602 school children aged 5-15 years, who will receive either DP or ASAQ or control (no drug ), using a "balanced block design" with the "standard of care" arm as reference. The interventional treatments are given every 4 months 3 rounds for the first year. A second non-interventional year will assess possible rebound effects. All study-arms receive bed nets, early diagnosis and care for malaria, and praziquantel and albendazole as mass treatment for helminthiasis. The primary endpoint are change from baseline in mean haemoglobin concentration at months 12 and 20 of follow-up and clinical malaria incidence from month 0 till months 12 and 20 of follow up. Adverse events will be monitored throughout the study. Mixed design methods will be used to assess the acceptability, cost-effectiveness and feasibility of this IPTsc as part of a more comprehensive school children health package. Discussion: The national school health programme (NSHP), Tanzania, combines schistosomiasis and soil transmitted helminthes (STH) control package under national schistosomiasis and STH control programme (NSSCP). Malaria intervention using IPTsc strategy may be integrated in NSHP with the same platform as NSSCP, however, there is limited systematic evidence to assess the operational feasibility of this approach. School aged children are a reachable target population in any endemic malaria setting. The suggested strategy will provide effective protection against malaria, hasten either the elimination process and/or diminish the reservoir and burden.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malaria,Falciparum, Anemia
Keywords
Malaria, school children, randomized controlled trial, safety, effectiveness, Dihydroartemisinin-piperaquine, cognitive, Artesunate-amodiaquine, malaria serology, drug resistance

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
A randomized, controlled, open label study assessing the effectiveness and safety of 2 antimalarial drugs for IPTsc, namely DP and ASAQ by a 3-arm trial using a "balanced block design" with the "standard of care" arm as reference.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
1555 (Actual)

8. Arms, Groups, and Interventions

Arm Title
DP
Arm Type
Experimental
Arm Description
Dihydroartemisinin-piperaquine (DP), antimalarial drug to be given every 4 months 3 rounds for the first year. A second non-interventional year will assess possible rebound effects.
Arm Title
ASAQ
Arm Type
Active Comparator
Arm Description
Artesunate-amodiaquine (ASAQ), antimalarial drugs to be given every 4 months 3 rounds for the first year. A second non-interventional year will assess possible rebound effects.
Arm Title
Control
Arm Type
No Intervention
Arm Description
No intervention drugs will be given, but normal routine standard of care will be provided.
Intervention Type
Drug
Intervention Name(s)
Dihydroartemisinin-piperaquine
Intervention Description
Dihydroartemisinin-piperaquine (DP). One of the Artemisinin combination therapy(ACTs), indicated for treatment of uncomplicated malaria. It will to be given every 4 months 3 rounds for a year.
Intervention Type
Drug
Intervention Name(s)
Artesunate-amodiaquine
Intervention Description
Artesunate-amodiaquine (ASAQ). One of the Artemisinin combination therapy(ACTs), indicated for treatment of uncomplicated malaria. It will to be given every 4 months 3 rounds for a year.
Primary Outcome Measure Information:
Title
Change from baseline in mean haemoglobin concentration at months 12 and 20 of follow-up
Description
Will measure change from baseline haemoglobin concentration at month 12 (intervention period) and at month 20 (post intervention period to assess rebound effect) [Note: a trend of change at each visit will also be assessed with respect to malaria seasonality]
Time Frame
at months 0, 12 and 20
Title
Clinical malaria incidence from month 0 till months 12 and 20 of follow up
Description
number of symptomatic malaria episodes during and after intervention period
Time Frame
at months 0, 12 and 20
Secondary Outcome Measure Information:
Title
Prevalence of asymptomatic malaria infections at month 0, 12 and 20 of follow up
Description
to be measured from microscopic detection of malaria parasite on blood slides
Time Frame
from month 0 till month12 and 20
Title
Prevalence of PCR confirmed sub-microscopic parasitaemia at months 0,12 and 20 of follow up
Description
Polymerase chain reaction (PCR) confirmed from random subset of finger prick dry blood spots samples
Time Frame
at months 0, 12 and 20
Title
Prevalence of soil transmitted helminths and schistosomiasis
Description
A stool sample will be used to determine prevalence (defined as adult or eggs) of STH and S. mansoni infection determined by duplicate Kato-Katz thick smears technique. Urine samples will be visually examined for the presence of blood (macrohaematuria) followed by laboratory examination for schistosomiasis infection (S.haematobium)
Time Frame
at baseline, at month 12 and month 20.
Title
Prevalence of schistosomiasis
Description
Urine samples will be visually examined for the presence of blood (macrohaematuria) followed by laboratory examination for schistosomiasis infection (S.haematobium) for confirmation.
Time Frame
at baseline, at month 12 and month 20.
Title
Prevalence of validated common P. falciparum polymorphisms known to be associated with drug sensitivity at baseline, at months 12 and 20
Description
from random subset of finger prick dry blood spots samples
Time Frame
at baseline, at month 12 and 20.
Title
Proportion of children seropositive for Plasmodium falciparum AMA-1 and MSP-119 at baseline, at month 12 and 20
Description
from random subset of finger prick dry blood spots samples, Antibody responses to P. falciparum blood-stages antigens, apical membrane antigen (AMA-1) and merozoite surface protein (MSP-119) will be determined.
Time Frame
at baseline, at month 12 and 20.
Title
Change in serum antibody responses to Plasmodium falciparum AMA-1 and MSP-119 at baseline, at month 12 and 20
Description
From random subset of finger prick dry blood spots samples to be eluted for ELISA
Time Frame
at baseline, at month 12 and 20.
Title
Percentages of school children with malnutrition through WHO's BMI z-score
Description
weight in kilograms and height in meters will be combined to report BMI in kg/m^2
Time Frame
at month 0, 12, and 20
Title
Relative risk (RR), for all adverse events categorised to severity at month 12 and 20
Description
Adverse events will be detected throughout the study, Each intervention arm will be compared to control arm to determine risk of an adverse event among the two arms. Also events in two intervention arms will be compared to each other to assess risk in the two intervention arms.
Time Frame
at month 12 and 20
Other Pre-specified Outcome Measures:
Title
number of days missed school attendance pre and post intervention period
Description
number of days absent from school pre and post intervention period
Time Frame
at baseline, at month 12 and 20
Title
Change in educational performance
Description
measured by annual change in average score of educational performance pre and post intervention period [to be provided by respective class teachers]
Time Frame
at baseline, at month 12 and 20
Title
change in sustained attention on cognition evaluated using two code transmission tasks using TEA-Ch
Description
sub group of 20 students selected at random in each class will be involved, sustained attention will be evaluated using two code transmission tasks, adapted from the Test of Everyday Attention for Children (TEA-Ch)
Time Frame
evaluated at baseline, at month 12 and 20.
Title
change in psychomotor functions tested by 20mShuttle Run Test pre and post intervention
Description
sub group of 20 students selected at random in each class will be involved.Physical fitness will also be assessed using the 20 meter Shuttle Run Test (20mSRT). During this test children run continuously between two lines apart turning when signalled to do so by recorded beeps and a "shuttle" is defined as a run between one line to another. The 20mSRT has 20 levels.
Time Frame
evaluated at baseline, at month 12 and 20.
Title
Proportion of participants accepting IPTsc, using and completing dose of given study drugs.
Description
This will be useful on future pragmatic implementation
Time Frame
at baseline, month 4, and 8
Title
Comparison of cost effectiveness of intervention between groups.
Description
Evaluated by assessing the implementation cost (setup, salaries, transport, price scenarios, etc), the study impact as well as possible synergies with other school health intervention programs. In addition,cost per child treated per year, the cost per anaemia case averted and cost per case P. falciparum parasitaemia averted as a result of the intervention, will also be evaluated to determine cost effectiveness of the program.
Time Frame
at month 12.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
5 Years
Maximum Age & Unit of Time
15 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Includes parental/guardian informed consent Assent by primary school children aged 11 years and above. Aged 5-15 years. Currently, lives within the pre-defined catchment area of Muheza District. Will remain within the same area throughout the study period (preferably class five and below). Exclusion Criteria: Students at class 6 and 7 Currently enrolled in another study or participated in another investigational drug study within the last 30 days. Known to have heart disease or a known cardiac ailment. Reports known hypersensitivity to the study drugs. Not willing to undergo all study procedures including physical examination and to provide blood samples as per this study protocol. Having clinical features of severe anaemia Febrile due to non-malaria illness at the time of recruitment. Has apparent severe infection or any condition that requires hospitalization Illness or conditions like hematologic, cardiac, renal, hepatic diseases which in the judgement of the investigator would place the subject at undue risk or interfere with the results of the study, including known G6PD deficiency and SS sickle cell. Body weight < 14 k
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John PA Lusingu, MD, PhD
Organizational Affiliation
National Institute for Medical Research, Tanzania
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jean-pierre Van geertruyden, MD, PhD
Organizational Affiliation
Global health institute, University of Antwerp, Belgium.
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institute for Medical Research
City
Tanga
ZIP/Postal Code
255
Country
Tanzania

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
32382685
Citation
Makenga G, Baraka V, Francis F, Nakato S, Gesase S, Mtove G, Madebe R, Kyaruzi E, Minja DTR, Lusingu JPA, Van Geertruyden JP. Effectiveness and safety of intermittent preventive treatment for malaria using either dihydroartemisinin-piperaquine or artesunate-amodiaquine in reducing malaria related morbidities and improving cognitive ability in school-aged children in Tanzania: A study protocol for a controlled randomised trial. Contemp Clin Trials Commun. 2020 Feb 20;17:100546. doi: 10.1016/j.conctc.2020.100546. eCollection 2020 Mar.
Results Reference
derived

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Effectiveness and Safety of Intermittent Preventive Treatment for Malaria Using Either Dihydroartemisinin-piperaquine or Artesunate-amodiaquine in Reducing Malaria Related Morbidities and Improving Cognitive Ability in School-aged Children in Tanzania

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