Optimization of Seasonal Malaria Chemoprevention (SMC) Delivery (SMC)

Optimal Delivery of Seasonal Malaria Chemoprevention and Its Effects on the Acquisition of Malaria Immunity

Based in part on the pivotal studies conducted in Mali, SMC was approved by WHO as a policy for malaria control in countries with seasonal malaria transmission such as Mali in March 2012. The goals are to identify the most effective method to deliver SMC, and to obtain more information on the long term impact of SMC on malaria immunity. Our specific aims are 1) to determine the optimal mode (fixed-point (FPD) vs door-to-door delivery (DDD); directly observed treatment (DOT) vs non-DOT (NDOT)) and frequency (3 vs 4 doses per season) of SMC delivery; 2) to compare quantitative measures of immunity in children who do and do not receive SMC. A cluster-randomized design will be sued. The target population will be children aged 3-59 months old in Ouelessebougou district, Mali. In Year 1, villages in four sub-districts will be randomized into four groups (FPD+DOT; FPD+NDOT; DDD+DOT; DDD+NDOT). The optimal mode of delivery will be selected based on the SMC coverage during the first year, and will then be implemented in villages of two additional sub-districts. Villages in these two newly selected sub-districts will be randomized in two groups. Children in the first group will received three rounds of SMC and those in the second group will receive four rounds of SMC to determine the optimal frequency of SMC based on the incidence rate of clinical malaria as measured by passive surveillance. In Year 3, children in the selected sub-districts will received SMC by the optimal delivery system determined in Years 1 -2. A survey will be conducted collect data on mortality and hospital admission and compare these outcomes in areas where SMC was implemented and areas where SMC was not implemented.

Study Overview

• Status: Unknown
• Conditions: Anemia; Malaria
• Intervention / Treatment: Other: FPD+NDOT; Other: FPD+DOT; Other: DDD+NDOT; Other: DDD+DOT

Detailed Description

Based in part on the pivotal studies conducted in Mali, SMC was approved by WHO as a policy for malaria control in countries with seasonal malaria transmission such as Mali in March 2012. The strategy is a highly cost-effective approach to reduce childhood mortality in these areas. Despite the huge benefit of the SMC on malaria infection and disease, the optimal approach to deliver SMC remains to be determined and there is no data on the long term effect of this strategy on the development of immunity to malaria. While fixed-point delivery (FPD) combined with non directly observed treatment (NDOT) by community health workers is attractive for the SMC implementation, it is need to be evaluated and compared to other mode of delivery. The objectives are to identify the most effective method to deliver SMC, and to obtain information on the long term impact of SMC on malaria immunity. Specifically, i) to determine the optimal mode (fixed-point (FPD) vs door-to-door delivery (DDD); directly observed treatment (DOT) vs. non-DOT (NDOT)) and frequency (3 vs. 4 doses per season) of SMC delivery; ii) to compare quantitative measures of immunity in children who do and do not receive SMC over a three year period.

The design is a cluster-randomized trial over three years. The target population is children aged 3-59 months old living in Ouelessebougou district, Mali. In Year 1, villages in four sub-districts will be randomized into four groups (FPD+DOT; FPD+NDOT; DDD+DOT; DDD+NDOT). The optimal mode of delivery will be selected based on the SMC coverage during the first year, and will then be implemented in villages of two additional sub-districts. Villages in these two newly selected sub-districts will be randomized in two groups. Children in the first group will received three rounds of SMC and those in the second group will receive four rounds of SMC to determine the optimal frequency of SMC based on the incidence rate of clinical malaria as measured by passive surveillance. Children in the four sub-districts selected in Year 1 will continue to receive three rounds of SMC in Year 2 using the optimal mode of delivery. In Year 3, children in the randomly selected sub-districts will received SMC by the optimal delivery system determined in Years 1 -2. Immune responses will be measured and compared between the children receiving SMC to a cohort of children not receiving SMC, to assess the impact of SMC on key antimalarial antibody responses over the three year period using cross-sectional surveys at the beginning and the end of the transmission season.

In Year 3, 4 and 5 surveys will be conducted to collect data on mortality and hospital admissions and compare these outcomes in areas where SMC was implemented and areas where SMC was not implemented.

• Study Type: Interventional
• Enrollment (Anticipated): 10000
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Mali
  • Bamako, Mali
    • Recruiting
    • Malaria Research and Training Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 4 years (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Age >= 3 months & < 60 months

Exclusion Criteria:

• severe, chronic illness
• known allergy to one of the study drugs (SP or AQ)
• known HIV positive subjects using Cotrimoxazole.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: FPD+NDOT; Fixed-point delivery (FPD) combined with non directly observed treatment (NDOT)	Other: FPD+NDOT; Other Names: fixed-point delivery + non directly observed treatment
Other: FPD+DOT; Fixed-point delivery (FPD) combined with directly observed treatment (DOT)	Other: FPD+DOT; Other Names: fixed-point delivery + directly observed treatment
Other: DDD+NDOT; door-to-door delivery (DDD) combined with non directly observed treatment (NDOT)	Other: DDD+NDOT; Door to door delivery + non directly observed treatment
Other: DDD+DOT; door-to-door delivery (DDD) combined with directly observed treatment (NDOT)	Other: DDD+DOT; Door to door delivery + directly observed treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Coverage of SMC	SMC coverage will be defined as proportion of the children who have received the three treatments doses at each of the three rounds of SMC.	1-5 weeks after last round of SMC in Year1
Incidence of clinical malaria in Year 2	Clinical malaria defined as signs and symptoms suggestive of malaria with positive RDT and/or positive blood smear.	up to 4 weeks after the last round of SMC
Mortality rate	death	1, 2, 3, 4 years of the intervention
Hospital admission	Hospitalization	1, 2, 3, 4 years of the intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
malaria parasitemia	Parasite prevalence defined as the proportion of children with a positive malaria blood smear and parasite density	one week before the first round of SMC and 4-6 weeks after the last round of SMC
moderate anemia	Prevalence of moderate anemia defined as hemoglobin concentration < 8 g/dL measured by hemoglobin analyzer	one week before the first round of SMC and 4-6 weeks after the last round of SMC
immune response to malaria parasite	Cellular and humoral antimalarial immune responses to malaria parasites	one week before the first round of SMC and 4-6 weeks after the last round of SMC
molecular markers of resistance to SP + AQ	Frequency of mutations at codons 51, 59, and 108 of the dhfr gene, 437 and 540 of the dhps gene, codon 76 in the P. falciparum chloroquine transporter gene (pfcrt), and codon 86 of the P. falciparum multidrug resistance gene one (pfmdr1).	one week before the first round of SMC and 4-6 weeks after the last round of SMC
nutritional status	Prevalence of wasting stunting and underweight as defined by WHO Global database on Child Growth and Malnutrition	one week before the first round of SMC and 4-6 weeks after the last round of SMC
Clinical malaria in Year 1	Clinical malaria defined as signs and symptoms suggestive of malaria with positive RDT and/or positive blood smear.	up to 4 weeks after the last round of SMC

Collaborators and Investigators

• Sponsor: University of Bamako

Publications and helpful links

General Publications

• Issiaka D, Barry A, Traore T, Diarra B, Cook D, Keita M, Sagara I, Duffy P, Fried M, Dicko A. Impact of seasonal malaria chemoprevention on hospital admissions and mortality in children under 5 years of age in Ouelessebougou, Mali. Malar J. 2020 Mar 3;19(1):103. doi: 10.1186/s12936-020-03175-y.
• Barry A, Issiaka D, Traore T, Mahamar A, Diarra B, Sagara I, Kone D, Doumbo OK, Duffy P, Fried M, Dicko A. Optimal mode for delivery of seasonal malaria chemoprevention in Ouelessebougou, Mali: A cluster randomized trial. PLoS One. 2018 Mar 5;13(3):e0193296. doi: 10.1371/journal.pone.0193296. eCollection 2018.

Study record dates

Study Major Dates

• Study Start: August 1, 2014
• Primary Completion (Anticipated): December 1, 2018
• Study Completion (Anticipated): December 1, 2018

Study Registration Dates

• First Submitted: December 29, 2015
• First Submitted That Met QC Criteria: December 31, 2015
• First Posted (Estimate): January 5, 2016

Study Record Updates

• Last Update Posted (Actual): May 2, 2018
• Last Update Submitted That Met QC Criteria: April 30, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: malaria; immunity; resistance; sulfadoxine-pyrimethamine; seasonal malaria chemoprevention; amodiaquine; delivery method
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria
• Other Study ID Numbers: 2014-61