Effectiveness of Mass Drug Administration for Reducing Seasonal Malaria Transmission in Zanzibar (MaDrAZ)

Effectiveness of Mass Drug Administration (MDA) for Reducing Seasonal Malaria Transmission Towards Its Elimination in Hotspot Areas in Zanzibar - a Cluster-randomised Controlled Trial

The overall aim of this study is to determine the effectiveness of two rounds of mass drug administration (MDA) with dihydroartemisinin-piperaquine (DHAp) + single low dose (SLD) primaquine for reducing seasonal malaria transmission in Shehias considered hotspots on Unguja Island, Zanzibar.

Study Overview

• Status: Completed
• Conditions: Malaria; Plasmodium Infections
• Intervention / Treatment: Drug: MDA with DHAp and SLD Primaquine

Detailed Description

Study design: This is a cluster-randomised controlled study with two arms: an intervention arm with two rounds of MDA with dihydroartemisinin-piperaquine (DHAp) + single low dose (SLD) primaquine, and a control arm with no MDA.

Study site and study population: The study will be conducted in 16 hotspot Shehias (8 Shehias randomly allocated to each arm), in three districts (West, Central and South districts) in Unguja Island, Zanzibar. Hotspot Shehias [Shehia being the smallest administrative structure in Zanzibar] are defined as Shehias with an annual malaria incidence of >0.8%, calculated as the number of confirmed malaria infections notified at health facilities and during active case detection in 2015 / Shehia projected population for 2015. The study population will include all consenting residents of the selected Shehias, reaching approximately 24000 people.

Study implementation: Two rounds of MDA with DHAp (D-ARTEPP, Guilin Pharmaceutical (Shanghai) Co., Ltd., China) and SLD (0.25mg/kg) primaquine (Primaquine, Remedica Ltd.,Cyprus ) will be conducted approximately four weeks apart in the intervention Shehias, at the anticipated lowest point of malaria transmission prior to the onset of malaria transmission associated with the main rains in April-June 2016. The first drug dose including DHAp and SLD primaquine will be given under supervision whenever possible; the other two doses of the standard once daily DHAp regimen will be taken unsupervised at home. Labelled packets containing all three doses will be left with the head of household with clear instructions for individuals not present at the time of the household visit.

Study objectives: The primary objective of the study is to determine the effectiveness of two rounds of MDA with DHAp + SLD primaquine for reducing seasonal malaria transmission in Shehias considered hotspots on Unguja Island, Zanzibar. The secondary objectives of the study include determining MDA coverage, compliance, and safety after one and two rounds of DHAp + SLD primaquine.

• Study Type: Interventional
• Enrollment (Actual): 22500
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Tanzania
  • Urban District, Zanzibar
    • Mwanakwerekwe, Urban District, Zanzibar, Tanzania
      • Zanzibar Malaria Elimination Programme

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Permanent or temporary resident of study Shehias (i.e., persons who stayed in the selected household the night before the interview)
• Provision of informed consent (refusal must be recorded)
• Age >6 months

Exclusion Criteria:

• Women pregnant in first trimester (assessed by a specific set of questions designed to exclude pregnancy)
• Severe disease that requires immediate referral to health facility or hospital
• Concurrent antimalarial treatment at time of MDA or during the last 14 days
• Inability to take oral medication

Additional exclusion criteria for treatment with SLD Primaquine:

• Pregnancy (all trimesters, assessed by a specific set of questions designed to exclude pregnancy)
• Women breast feeding infants aged < 6months

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MDA with DHAp and SLD Primaquine; MDA will be conducted at two time points with an approximate four-week interval. All consenting and eligible community members will be administered age-appropriate treatment dose of dihydroartemisinin-piperaquine (D-ARTEPP, Guilin Pharmaceutical (Shanghai) Co., Ltd., China) and single low dose (0.25mg/kg) primaquine (Primaquine, Remedica Ltd., Cyprus) in house-to-house campaigns.	Drug: MDA with DHAp and SLD Primaquine; Other Names: Mass drug administration with DHAp and SLD Primaquine; MDA with Dihydroartemisinin-Piperaquine and SLD Primaquine; MDA with D-ARTEPP and single low dose Primaquine
No Intervention: Control; The control arm (no MDA) will have the standard care offered by the Ministry of Health and Social welfare which applies to both arms. This includes passive case detection of individuals seeking treatment at local health facilities, and universal coverage of long lasting insecticide treated bed nets and indoor residual spraying in the study areas.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative notified malaria incidence in the MDA and control Shehias	Cumulative notified malaria incidence determined as the number of confirmed malaria cases notified at health facilities (monitored through the malaria case notification system during the period of six months) over the Shehia population size determined by population enumeration at the time of the intervention.	6 months after second round of MDA

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PCR determined community prevalence of Plasmodium infections in the MDA and control Shehias	PCR determined community prevalence of Plasmodium infections determined by cross-sectional screening in every other household in the study area at the time of the first round of MDA, and at six months after the second round of MDA.	Baseline and 3 months after second round of MDA

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Population coverage of the MDA intervention at each round	MDA coverage determined as the number of administered DHAp and SLD primaquine doses during the first and second round of MDA, over over the Shehia population size determined by population enumeration at the time of the intervention.	Through completion of first and second round of MDA, i.e. 15 days and 48 days after initiation of MDA, respectively.
Proportion of population receiving two rounds of MDA	The proportion of the population having received zero, one or two rounds of MDA. Refusal and reason for refusal to participate will be recorded.	Through completion of the second round of MDA, i.e. 48 days after initiation of MDA.
Population compliance to the MDA intervention at each round	MDA compliance, i.e. the proportion of the population that have taken one, two or all three doses of DHAp + SLD primaquine, will be evaluated in a subset of the population by post-MDA surveys conducted seven days after the initiation of each MDA round. The post MDA surveys will include both a questionnaire and finger prick blood sampling for measuring piperaquine blood concentrations.	7 days after both first and second round of MDA
Occurence of adverse events after MDA with DHAp and SLD primaquine	A brief questionnaire will be conducted in a subset of the population during post-MDA surveys conducted seven days after the initiation of each MDA round. The questionnaire will include specific questions regarding adverse events such as vomiting, nausea, gastrointestinal upset, rash and fatigue. Severe adverse events, especially symptoms of haemolysis, will be captured at health facilities where haemoglobin and dark urine (representing haemolysis) will be measured and reported using the pharmacovigilance forms and the Primaquine Roll Out Monitoring Pharmacovigilance Tool (PROMPT) developed by the Global Health Group at University of California San Francisco.	14 days after both first and second round of MDA
Cumulative notified malaria incidence in the MDA and control Shehias during the following high transmission season.	Cumulative notified malaria incidence during the following high transmission season, monitored through the malaria case notification system, to assess the long-term effectivness of MDA.	15 months after second round of MDA

Collaborators and Investigators

• Sponsor: Ulrika Morris
• Collaborators: Uppsala University; University of California, San Francisco; RTI International; Mahidol Oxford Tropical Medicine Research Unit; Zanzibar Malaria Elimination Programme; The President's Malaria Initiative
• Investigators: Principal Investigator: Anders Björkman, MD, PhD, Karolinska Institutet; Principal Investigator: Abdullah S Ali, Programme Manager, Zanzibar Malaria Elimination Programme

Publications and helpful links

General Publications

• Shah MP, Hwang J, Choi L, Lindblade KA, Kachur SP, Desai M. Mass drug administration for malaria. Cochrane Database Syst Rev. 2021 Sep 29;9(9):CD008846. doi: 10.1002/14651858.CD008846.pub3.
• Morris U, Msellem MI, Mkali H, Islam A, Aydin-Schmidt B, Jovel I, Shija SJ, Khamis M, Ali SM, Hodzic L, Magnusson E, Poirot E, Bennett A, Sachs MC, Tarning J, Martensson A, Ali AS, Bjorkman A. A cluster randomised controlled trial of two rounds of mass drug administration in Zanzibar, a malaria pre-elimination setting-high coverage and safety, but no significant impact on transmission. BMC Med. 2018 Dec 10;16(1):215. doi: 10.1186/s12916-018-1202-8.

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2016
• Primary Completion (Actual): December 31, 2016
• Study Completion (Actual): September 30, 2017

Study Registration Dates

• First Submitted: March 17, 2016
• First Submitted That Met QC Criteria: March 22, 2016
• First Posted (Estimate): March 29, 2016

Study Record Updates

• Last Update Posted (Actual): October 5, 2017
• Last Update Submitted That Met QC Criteria: October 3, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Malaria; Zanzibar; Plasmodium; Mass drug administration; Malaria elimination; Dihydroartemisinin-Piperaquine; Single low dose Primaquine
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Primaquine; Piperaquine; Artenimol
• Other Study ID Numbers: MaDrAZ-001; ZAMREC/0001/January/2016 (Other Identifier: Zanzibar Medical Research Ethical Committee)