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Evaluation of Reactive Focal Mass Drug Administration for Malaria Elimination in Swaziland (fMDA)

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ClinicalTrials.gov Identifier: NCT02315690
Recruitment Status : Completed
First Posted : December 12, 2014
Last Update Posted : September 5, 2021
Sponsor:
Collaborators:
Ministry of Health, Swaziland
Clinton Health Access Initiative, Eswatini
University of Texas
Information provided by (Responsible Party):
University of California, San Francisco

Tracking Information
First Submitted Date  ICMJE December 8, 2014
First Posted Date  ICMJE December 12, 2014
Last Update Posted Date September 5, 2021
Actual Study Start Date  ICMJE September 2015
Actual Primary Completion Date July 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 9, 2014)
Incidence of malaria cases [ Time Frame: 2 years ]
Cumulative incidence of malaria cases by locality
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 2, 2017)
  • Seroprevalence [ Time Frame: during end line survey after intervention data collection completed ]
    Prevalence of antibody response to markers of recent malaria exposure in target areas
  • Prevalence [ Time Frame: during end line survey after intervention data collection completed ]
    Prevalence of infection by loop mediated isothermal amplification (LAMP) in target areas
  • Coverage [ Time Frame: 2 years ]
    Proportion of persons residing within approximately 200 m of the index case who consented to participate in the study and who completed the initial procedures for their study arm (finger prick for RDT (rapid diagnostic test) in the RACD arm, initial dose of DHAp in the fMDA arm)
  • Adherence [ Time Frame: 2 years ]
    Proportion of persons who completed 3 days of therapy among all individuals initiated on fMDA as assessed by pill count in the first intervention per study locality
  • Safety related to DHAp [ Time Frame: 2 years ]
    Number of participants experiencing serious adverse events (SAEs) deemed possibly, probably, or definitely related to DHAp
  • Acceptability [ Time Frame: 2 years ]
    Qualitative assessment among individuals residing in target areas and with surveillance agents.
  • Cost [ Time Frame: 2 years ]
    Cost per index case-level intervention, cost per case averted, collected in 10 RACD and 10 fMDA events.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 9, 2014)
  • Seroprevalence [ Time Frame: in final year of the study ]
    Prevalence of antibody response to markers of recent malaria exposure in Target Areas
  • Prevalence [ Time Frame: in final year of the study ]
    Prevalence of infection by LAMP (loop mediated isothermal amplification) and gametocytemia QT-NASBA in Target Areas
  • Proportion of imported incident cases [ Time Frame: 2 years ]
    Cumulative proportion of incident cases that a imported by locality
  • Time to first post-intervention incident local case [ Time Frame: 2 years ]
    Time from an intervention in a Target Area until the subsequent incident local case in the study period in the Target Area
  • Transmission potential measured by microsatellite genotyping [ Time Frame: 2 years ]
    Relatedness of infections (detect through passive surveillance and the April-May cross sectional survey) as measured by microsatellite genotyping, with analyses at the levels of the Target Area and locality (cluster)
  • Coverage [ Time Frame: 2 years ]
    Proportion of persons residing within approximately 200 m of the index case who consented to participate in the study and who completed the initial procedures for their study arm (finger prick for RDT (rapid diagnostic test) in the RACD arm, initial dose of DP in the TPE arm)
  • Adherence [ Time Frame: 2 years ]
    Proportion of persons who completed 3 days of therapy among all individuals initiated on TPE as assessed by pill count in the first intervention per study locality
  • Prevalence of SAEs (serious adverse events) related to DP [ Time Frame: 2 years ]
    Proportion of subjects experiencing SAEs deemed possibly, probably, or definitely related to DP, out of the total number of subjects enrolled
  • Acceptability [ Time Frame: 2 years ]
    Qualitative assessment among individuals residing in Target Areas and Key Stakeholders.
  • Cost [ Time Frame: 2 years ]
    Cost per index case-level intervention, cost per case averted, collected at every 10th RACD or TPE event
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Evaluation of Reactive Focal Mass Drug Administration for Malaria Elimination in Swaziland
Official Title  ICMJE Evaluating the Effectiveness and Feasibility of Reactive Focal Mass Drug Administration vs. Reactive Case Detection as a Community Level Intervention in Response to a Passively Identified Index Malaria Case in Swaziland
Brief Summary This is a cluster randomised controlled trial comparing the impact of two community based malaria interventions: reactive case detection (RACD) vs reactive targeted presumptive treatment (focal mass drug administration, fMDA) on the incidence of malaria in Swaziland.
Detailed Description

Title Evaluating the effectiveness and feasibility of reactive focal mass drug administration (fMDA) vs. reactive case detection (RACD) as a community level intervention in response to a passively identified index malaria case in Swaziland

Study design Cluster randomised controlled trial

Aims

Primary aim: To compare the impact of fMDA versus RACD on malaria incidence.

Secondary aims

Effectiveness:

  1. To compare the impact of fMDA versus RACD on seroprevalence.
  2. To compare the impact of fMDA versus RACD on prevalence of infection.

Feasibility:

  1. To evaluate the safety of fMDA.
  2. To measure the adherence of DHAp using a modified DOT regimen.
  3. To determine the feasibility of reaching 80% coverage for fMDA.
  4. To compare the acceptability of fMDA.
  5. To compare the costs and cost-effectiveness of fMDA versus RACD.

Study site Eastern endemic region of Swaziland, a very low endemic malaria elimination setting. A total of 287 health facilities and their catchment areas are located in this area.

Time frame September 2015 - August 2017

Cluster or unit of randomisation At-risk localities will be randomized to either fMDA or RACD using a block stratified randomization based on risk rank and population

Target area Individuals residing within 200 m (fMDA arm) or 500 m (RACD arm) of an index case detected in passive surveillance, individuals residing immediately beyond 200 m in the fMDA arm will be included if a minimum of 30 individuals are not enrolled within 200 m.

Intervention All individuals residing in study localities will receive vector control preventative measures as per program. In the fMDA arm, all individuals in the target area will receive dihydroartemisinin-piperaquine (DHAp) once daily for 3 days with the first dose taken no later than 5 weeks from the index case presentation (goal within one week). Individuals in RACD target areas will be tested by RDT and taken to the nearest health facility for treatment as per program operating procedures.

Evaluation methods The primary outcome measure of incidence will be obtained through routine surveillance data.

Secondary outcomes of effectiveness will be measured at study conclusion by collecting a dried blood spot (DBS) from all residents in target areas in both arms. Prevalence of infection will be measured by loop-mediated isothermal amplification (LAMP) and seroprevalence measured by quantifying markers of recent malaria exposure.

Secondary outcomes of feasibility will be measured as follows:

  1. Safety: number of serious adverse events deemed possibly, probably, or definitely related to DHAp.
  2. Adherence: proportion of individuals who completed three days of therapy among all individuals initiated on DHAp in the fMDA arm, assessed by pill count.
  3. Coverage: proportion of individuals residing within 200m (fMDA localities) or 500m (RACD localities) of an index case who consented to participate and who completed the initial procedures for their study arm (initial dose of DHAp in the fMDA arm or finger prick for RDT in the RACD arm).
  4. Acceptability: proportion of eligible individuals refusing to take part in the study and a qualitative assessment of a subset of individuals in the fMDA arm.
  5. Cost: cost per index case-level intervention and cost per case averted.

Sample size The sample size is based on the number of study localities that experienced at least one incident case of malaria in the previous season. Within 77 randomized localities, we expect that 63 localities will have an incident case of malaria and receive an intervention. For the primary objective, we hypothesize that mFDA will be more effective than RACD. At the current sample size, the study is powered to detect a difference in cumulative incidence if incidence in the fMDA arm is reduced 50% compared to the RACD arm. Incidence will be measured at the locality level and among the at-risk population, or all individuals in an enumeration area (EA) where at least one case was identified (expected to be approximately 55,928 individuals among a total study population of 211,189, or a harmonic mean of 656 per locality (41,328 effective population)). Secondary outcomes of seroprevalence and prevalence will be measured on individuals residing in target areas (total N=5,400) with a harmonic mean of 60 persons receiving intervention per locality (3,780 effective population).

Primary outcome Incidence of malaria cases

Secondary outcomes

  1. Seroprevalence by ELISA
  2. Prevalence of infection
  3. Coverage of the intervention: proportion of the target population that receives a finger prick in the RACD arm and receives an initial dose of DHAp in the TPE arm (intention to treat analysis).
  4. Adherence to DHAp in TPE arm.
  5. Safety of DHAp
  6. Acceptance
  7. Cost per intervention episode, per case averted
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Malaria
Intervention  ICMJE
  • Drug: dihydroartemisinin-piperaquine (DHAp)
    In the fMDA arm, all individuals in the target area will receive dihydroartemisinin-piperaquine (DHAp) once daily for 3 days with the first dose taken no later than 5 weeks from the index case presentation (goal within one week).
    Other Name: Eurartesim
  • Procedure: reactive case detection
    Individuals in RACD target areas will be tested by RDT and if positive will be taken to the nearest health facility for treatment as per program operating procedures.
    Other Name: screen and treat; test and treat
Study Arms  ICMJE
  • Active Comparator: Reactive case detection (RACD)
    Individuals in RACD Target Areas will be tested by RDT (rapid diagnostic test) and if positive, taken to the nearest health facility for treatment with artemether-lumefantrine per national policy.
    Intervention: Procedure: reactive case detection
  • Experimental: Reactive focal mass drug administration (fMDA)
    In the fMDA arm, all individuals in the Target Area will receive dihydroartemisinin-piperaquine (DHAp) once daily for 3 days with the first dose taken no later than 5 weeks from the index case presentation (goal within one week).
    Intervention: Drug: dihydroartemisinin-piperaquine (DHAp)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 26, 2017)
4000
Original Estimated Enrollment  ICMJE
 (submitted: December 9, 2014)
6000
Actual Study Completion Date  ICMJE July 2017
Actual Primary Completion Date July 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

RACD Inclusion Criteria:

  • Index case resides in study locality
  • All non-index cases that reside or spent at least one night in the Target Area in the past 5 weeks
  • Non-index case resides within 200 meters of index case unless study team was not able to recruit 30 individuals by 3rd visit, in which case non-index case individuals may reside up to 500 meters from index case
  • Provide informed consent

RACD Exclusion Criteria:

  • Refusal to participate
  • Target Area overlaps with prior RACD Target Area from within the past 5 weeks

fMDA Inclusion Criteria:

  • Index case resides in study locality
  • All non-index cases that reside or have spent at least one night in the Target Area in the past 5 weeks
  • Non-index case resides within 200 meters of index case unless study team was not able to recruit 30 individuals by 3rd visit, in which case non-index case individuals may reside up to 500 meters from index case
  • Provide informed consent

fMDA Exclusion Criteria:

  • Refusal to participate
  • Temperature > 38.0⁰C, report of fever in the past 48 hours, or other illness (will be referred to the nearest health facility for further evaluation)
  • fMDA Target Area overlaps with prior Target Area within the past 8 weeks
  • For fMDA specifically (though still eligible for follow-up blood survey):

    • Pregnancy, breastfeeding, and women who have had menarche but no menses in the past 4 weeks
    • Children less than 6 months of age or <5 kg
    • Known allergy or history of adverse reaction to DP (still eligible for f/u blood surveys)
    • Already taken 2 courses of DP in the past year or taken 1 course within the past 2 months
    • Moderate or severe renal or hepatic insufficiency
    • Currently with severe malaria
    • Family history of sudden death or of congenital prolongation of the QTc (correct QT interval) interval.
    • Known congenital prolongation of the QTc-interval or any clinical condition known to prolong the QTc interval.
    • History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia. Any predisposing cardiac conditions for arrhythmia such as severe hypertension, left ventricular hypertrophy (including hypertrophic cardiomyopathy) or congestive cardiac failure accompanied by reduced left ventricle ejection fraction.
    • Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia or hypomagnesaemia (including vomiting in child)
    • Taking medicinal products that are known to prolong the QTc interval. See note for list of drugs.
    • Recent treatment with medicinal products known to prolong the QTc interval that may still be circulating at the time that Eurartesim is commenced (e.g. mefloquine, halofantrine, lumefantrine, chloroquine, quinine and other antimalarial agents) taking into account their elimination half-life

NOTE: Medicinal products that are known to prolong the QTc interval include:

  • Antiarrhythmics (e.g. amiodarone, disopyramide, dofetilide, ibutilide, procainamide, quinidine, hydroquinidine, sotalol).
  • Neuroleptics (e.g. phenothiazines, sertindole, sultopride, chlorpromazine, haloperidol, mesoridazine, pimozide, or thioridazine), antidepressive agents.
  • Certain antimicrobial agents, including agents of the following classes: - macrolides (e.g. erythromycin, clarithromycin), - fluoroquinolones (e.g. moxifloxacin, sparfloxacin), - imidazole and triazole antifungal agents, - and also pentamidine and saquinavir.
  • Certain non-sedating antihistamines (e.g. terfenadine, astemizole, mizolastine).
  • Cisapride, droperidol, domperidone, bepridil, diphemanil, probucol, levomethadyl, methadone, vinca alkaloids, arsenic trioxide
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Swaziland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02315690
Other Study ID Numbers  ICMJE Swaziland fMDA
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of California, San Francisco
Study Sponsor  ICMJE University of California, San Francisco
Collaborators  ICMJE
  • Ministry of Health, Swaziland
  • Clinton Health Access Initiative, Eswatini
  • University of Texas
Investigators  ICMJE
Principal Investigator: Michelle S Hsiang, MD UTSW, UCSF
PRS Account University of California, San Francisco
Verification Date August 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP