Clinical trial NCT02315690: Evaluation of Reactive Focal Mass Drug Administration for Malaria Elimination in Swaziland
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malaria
Keywords: malaria, Swaziland, reactive case detection, focal mass drug administration
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Ministry of Health, Swaziland
name: Clinton Health Access Initiative, Eswatini
name: University of Texas
First posted: 2014-12-12
Enrollment: 4000
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: Incidence of malaria cases
timeFrame: 2 years
Secondary outcomes:
measure: Seroprevalence
timeFrame: during end line survey after intervention data collection completed
measure: Prevalence
timeFrame: during end line survey after intervention data collection completed
measure: Coverage
timeFrame: 2 years
measure: Adherence
timeFrame: 2 years
measure: Safety related to DHAp
timeFrame: 2 years
measure: Acceptability
timeFrame: 2 years
measure: Cost
timeFrame: 2 years
Other outcomes:
Locations:
city: Mbabane
country: Swaziland
facility: Swaziland Ministry of Health
Study officials:
affiliation: UTSW, UCSF
name: Michelle S Hsiang, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hsiang MS, Hwang J, Kunene S, Drakeley C, Kandula D, Novotny J, Parizo J, Jensen T, Tong M, Kemere J, Dlamini S, Moonen B, Angov E, Dutta S, Ockenhouse C, Dorsey G, Greenhouse B. Surveillance for malaria elimination in Swaziland: a national cross-sectional study using pooled PCR and serology. PLoS One. 2012;7(1):e29550. doi: 10.1371/journal.pone.0029550. Epub 2012 Jan 6.
citation: Sturrock HJ, Novotny JM, Kunene S, Dlamini S, Zulu Z, Cohen JM, Hsiang MS, Greenhouse B, Gosling RD. Reactive case detection for malaria elimination: real-life experience from an ongoing program in Swaziland. PLoS One. 2013 May 20;8(5):e63830. doi: 10.1371/journal.pone.0063830. Print 2013.
citation: Zani B, Gathu M, Donegan S, Olliaro PL, Sinclair D. Dihydroartemisinin-piperaquine for treating uncomplicated Plasmodium falciparum malaria. Cochrane Database Syst Rev. 2014 Jan 20;2014(1):CD010927. doi: 10.1002/14651858.CD010927.
citation: Lwin KM, Phyo AP, Tarning J, Hanpithakpong W, Ashley EA, Lee SJ, Cheah P, Singhasivanon P, White NJ, Lindegardh N, Nosten F. Randomized, double-blind, placebo-controlled trial of monthly versus bimonthly dihydroartemisinin-piperaquine chemoprevention in adults at high risk of malaria. Antimicrob Agents Chemother. 2012 Mar;56(3):1571-7. doi: 10.1128/AAC.05877-11. Epub 2012 Jan 17.
citation: Nankabirwa JI, Wandera B, Amuge P, Kiwanuka N, Dorsey G, Rosenthal PJ, Brooker SJ, Staedke SG, Kamya MR. Impact of intermittent preventive treatment with dihydroartemisinin-piperaquine on malaria in Ugandan schoolchildren: a randomized, placebo-controlled trial. Clin Infect Dis. 2014 May;58(10):1404-12. doi: 10.1093/cid/ciu150. Epub 2014 Mar 12.
citation: Hsiang MS, Hwang J, Tao AR, Liu Y, Bennett A, Shanks GD, Cao J, Kachur SP, Feachem RG, Gosling RD, Gao Q. Mass drug administration for the control and elimination of Plasmodium vivax malaria: an ecological study from Jiangsu province, China. Malar J. 2013 Nov 1;12:383. doi: 10.1186/1475-2875-12-383.
citation: Vilakati S, Mngadi N, Benjamin-Chung J, Dlamini N, Dufour MK, Whittemore B, Bhangu K, Prach LM, Baltzell K, Nhlabathi N, Malambe C, Dlamini B, Helb D, Greenhouse B, Maphalala G, Pindolia D, Kalungero M, Tesfa G, Gosling R, Ntshalintshali N, Kunene S, Hsiang MS. Effectiveness and safety of reactive focal mass drug administration (rfMDA) using dihydroartemisinin-piperaquine to reduce malaria transmission in the very low-endemic setting of Eswatini: a pragmatic cluster randomised controlled trial. BMJ Glob Health. 2021 Jun;6(6):e005021. doi: 10.1136/bmjgh-2021-005021.