TIPTOP Sulfadoxine-pyrimethamine (SP) Drug Resistance Study (TIPTOP-DRS)

Monitoring of Markers of Sulfadoxine-pyrimethamine (SP) Resistance in the Implementation Countries of TIPTOP Project

The main objective of this study is to monitor SP resistance via molecular markers in the context of the TIPTOP project implementation of community distributed SP for women during pregnancy.

The specific objective is to detect trends over time in the proportion of symptomatic children with a positive rapid diagnostic test (RDT) residing in the areas where C-IPTp is implemented who carry parasites with dhfr/dhps mutations compared to those in control areas with no community SP distribution.

Study Overview

• Status: Completed
• Conditions: Malaria in Pregnancy
• Intervention / Treatment: Other: Community distribution of Sulfadoxine-pyrimethamine (SP)

Detailed Description

The TIPTOP (Transforming Intermittent Preventive Treatment for Optimal Pregnancy) project will explore an alternative innovative approach to antenatal care (ANC) facilities or clinic for the delivery of IPTp-SP. It will sustain and scale up a community-based delivery system to be implemented in addition to the traditional ANC clinic-based delivery system with the aim of expanding coverage of IPTp-SP. The innovative approach, called community IPTp (C-IPTp-SP), will be implemented in four sub-Saharan African countries: Nigeria, Democratic Republic of Congo (DRC), Madagascar and Mozambique. TIPTOP will use community health workers (CHWs) as a delivery channel to increase coverage of IPTp-SP to a minimum of 50% in project areas to prevent malaria in pregnancy (MiP). It is expected that this will lead to a substantial increase in the consumption of SP, not supervised by professional health workers. To address the concern that this may lead to an increase in the accumulation of mutations in dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) that could lead to an increase of the parasite resistance to SP, TIPTOP will monitor the prevalence of molecular markers of SP resistance in the population at three times during the project: at baseline, midline - following approximately 18 months of implementation - and endline - after 3 years of implementation. Providing evidence on the effects on SP resistance of C-IPTp is important for decision-making as to whether C-IPTp can be recommended as an additional channel for IPTp delivery or if the use of an alternative drug for IPTp should be considered. Moreover, it is expected that the SP resistance monitoring will also help to mitigate the risk of perceiving SP as a failed drug negatively affecting demand for quality-assured (QA) SP for IPTp (risk management). C-IPTp will be implemented in each country initially in a "test" area (Phase I) and later expanded to two additional areas (Table 1). All areas have been selected purposefully. Trends of SP resistance will be monitored in the initial "test" area, with C-IPTp, and in a neighbouring area with similar epidemiologic characteristics but with no C-IPTp (control area). A health facility-based, cross-sectional survey will be conducted before project implementation (baseline), after 18 months of intervention (midline) and after three years of intervention (endline) to measure the prevalence of molecular markers associated with resistance to SP in symptomatic children under five years of age with a positive RDT attending selected health facilities in the intervention and control areas. Monitoring the prevalence of alleles associated with resistance to drugs is, by standard protocol, done by collecting samples from symptomatic children with evidence of infection. The rationale for this is that any over- or misuse of drug in any sub-population, including pregnant women, may select parasites strains resistant to SP and that those strains are then transferred by mosquitos to the general population and most easily detected in children.

During the surveys, blood samples will be collected onto filter papers (dried blood spots). The surveys will be undertaken in the intervention area (the initial area of implementation of C-IPTp) and one control area (with no C-IPTp) in each country (Figure 1). C-IPTp-SP delivery in the area of initial implementation will start immediately after baseline surveys and sample collection. The sample collection will be performed in four selected first level of care health facilities in the intervention area and four health facilities in the control area.

• Study Type: Observational
• Enrollment (Actual): 7200

Contacts and Locations

Study Locations

• Congo, The Democratic Republic of the
  • Kwango
    • Kenge, Kwango, Congo, The Democratic Republic of the
      • Kenge District, Community Setting
• Madagascar
  • Fianarantsoa
    • Mananjary, Fianarantsoa, Madagascar
      • Mananjary District, Community Setting
• Mozambique
  • Sofala
    • Nhamatanda, Sofala, Mozambique
      • Nhamatanda District, Community Setting
• Nigeria
  • Ebonyi
    • Ohaukwu, Ebonyi, Nigeria
      • Ohaukwu District, Community Setting

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

Study population will be children under five years of age attending the selected health facilities in the intervention and control areas.

Description

Inclusion Criteria:

• • Children under five years of age.

  • Being resident in the project area at the time of the survey.
  • Clinical signs and symptoms suggestive of malaria infection: fever (axillary temperature ≥37.5ºC) or history of fever in the preceding 24 hours.

Exclusion Criteria:

• Not willing to provide informed consent
• Signs or symptoms of severe malaria

Study Plan

How is the study designed?

Design Details

• Observational Models: Ecologic or Community
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Intervention; Children tested will live within an area targeted for community IPTp distribution for pregnant women.	Other: Community distribution of Sulfadoxine-pyrimethamine (SP); Community health workers will distribute SP to pregnant women, targeting at least three times during pregnancy.; Other Names: C-IPTp-SP
Control; Children tested will live within an area NOT targeted for C-IPTp, but will live in an area nearby.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change in prevalence of molecular markers associated with SP resistance at 36 months	change in prevalence of molecular markers associated with SP resistance (codons 108, 51 and 59 in dhfr and 437, 540 and 581 in dhps) in blood samples collected from symptomatic children under five years with a positive RDT attending the selected health facilities at 36 months (baseline to endline)	baseline to endline (approximately 36 months later)
change in prevalence of molecular markers associated with SP resistance at 18 months	change in prevalence of molecular markers associated with SP resistance (codons 108, 51 and 59 in dhfr and 437, 540 and 581 in dhps) in blood samples collected from symptomatic children under five years with a positive RDT attending the selected health facilities. from baseline to midline (18 months)	baseline to midline (approximately 18 months later)

Collaborators and Investigators

• Sponsor: Jhpiego
• Collaborators: Barcelona Institute for Global Health
• Investigators: Study Director: Elaine Roman, MA, Jhpiego

Study record dates

Study Major Dates

• Study Start (Actual): March 5, 2018
• Primary Completion (Actual): November 30, 2021
• Study Completion (Actual): November 30, 2021

Study Registration Dates

• First Submitted: June 24, 2019
• First Submitted That Met QC Criteria: June 25, 2019
• First Posted (Actual): June 26, 2019

Study Record Updates

• Last Update Posted (Actual): June 15, 2023
• Last Update Submitted That Met QC Criteria: June 13, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: drug resistance; Sulfadoxine-pyrimethamine
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Folic Acid Antagonists; Anti-Infective Agents, Urinary; Pyrimethamine; Sulfadoxine; Fanasil, pyrimethamine drug combination
• Other Study ID Numbers: TIPTOP_DRS_2019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: At this time there is no plan to share the individual-level data with other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No