MalariaPhase 3NCT02610400
Evaluation of Reactive Focal Mass Drug Administration (rfMDA) +/- Reactive Focal Vector Control (RAVC) in Namibia
A Phase 3 study testing RACD, RAVC and rfMDA in people with Malaria, run by University of California, San Francisco at 1 site in Namibia.
Trial summary
This is a cluster randomised controlled trial with factorial study design comparing the impact of reactive community-based malaria interventions: 1) presumptive treatment (or rfMDA, reactive focal mass drug administration) versus reactive case detection (RACD), and 2) reactive IRS (indoor residual spraying) versus… Read more about this study
- Who is it for?
- Ages 6 months and olderHealthy volunteers can take part
- Conditions the study is for
- Malaria
- What is being tested?
- RACD, RAVC and rfMDA
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 9,845 participants
- Where
- 1 siteNamibia
- Study dates
- Feb 2016to Dec 2017
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 months and older
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Who may be able to join
- Index Case Investigation Inclusion Criteria:
- Malaria infection (either locally transmitted or imported) detected at a health facility via passive surveillance, and
- Resides in a study Enumeration Area (EA), and
- Provides informed consent
- RACD Intervention Inclusion Criteria:
- Provides informed consent, and
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- Index case resides in study EA, and
- All non-index cases that reside or spent at least one night in the Target Area in the past 4 weeks, and
- Residents of the six houses closest to the index case, and
- If 25 people are not enrolled in the study at the first six houses, plus the index case household, after the second visit then additional houses can be approached on the third visit.
- rfMDA Intervention Inclusion Criteria:
- Provides informed consent, and
- Index case resides in study EA, and
- All non-index cases that reside or spent at least one night in the Target Area in the past 4 weeks, and
- Residents of the six houses closest to the index case, and
- If 25 people are not enrolled in the study at the first six houses, plus the index case household, after the second visit then additional houses can be approached on the third visit.
- Artemether/Lumefantrine (A-L) (combination medication) Inclusion Criteria:
- Consent to take A-L medication
- Does not meet A-L Exclusion Criteria under item #4 below
- Pill count Inclusion Criteria:
- Provides consent, and
- People who receive any number of RACD or rfMDA drug dose(s)
- Reactive Vector Control Inclusion Criteria:
- Informed consent provided by head of household or person in otherwise in charge of household, and
- Index case resides in study EA, and
- Index household and 6 non-index households closest to index household
- Endline Survey, Individual, Inclusion Criteria:
- Provides informed consent, and
- Resides or spent at least 1 night in the EA in the preceding 4 weeks
- Acceptability Assessment: Individual Interviews with study participants, Inclusion Criteria:
- Provides informed consent, and
- Resident of index household or of neighbouring households
- Acceptability Assessment: Individual Interviews with key stakeholders, Inclusion Criteria:
- In leadership position within Zambezi region, and
- Provides informed consent
- Acceptability Assessment: Individual Interview with refusers, Inclusion Criteria:
- Refused to participate in rfMDA, RACD, and/or RAVC, and
- Provides informed consent to take part in the anonymous survey
- Acceptability Assessment: Focus group discussions with study participants, Inclusion Criteria:
- Provides informed consent, and
- Was eligible to be enrolled in the study in participant's Target Area, and
- Either took part in RACD or rfMDA intervention (+/- RAVC), OR refused these interventions
Who cannot join
- Index Case Investigation Exclusion Criteria:
- Malaria infection identified through active case detection
- Refusal to participate
- RACD Intervention Exclusion Criteria:
- Index case does not reside in study EA, or
- Refusal to participate in RACD, or
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- Household received the intervention in the previous 5 weeks, or
- Household > 500 m from the index case, or
- Severe or complicated malaria as assessed by study nurse (this will lead to referral for further evaluation at health facility but not enrolment in study)
- rfMDA Intervention Exclusion Criteria:
- Index case does not reside in study EA, or
- Refusal to participate in rfMDA, or
- Household received the intervention in the previous 5 weeks, or
- Household > 500 m from the index case, or
- Severe or complicated malaria as assessed by study nurse (this will lead to referral for further evaluation at health facility but not enrolment in study)
- Artemether/Lumefantrine (combination medication) Exclusion Criteria:
- Pregnancy in first trimester, or
- Previous regular menstruation, with no menstruation for most recent 4 weeks, or
- Weight < 5 kg*, or
- Severe malaria, or
- Known allergy to A-L, or
- Refusal of the offered A-L
- Note regarding A-L weight exclusion: Because of the pre-set required field at the top of the Eligibility section of this Application, the investigators have indicated a 6 month minimum age limit, primarily to note to the reader that there will be a lower age limit to infants enrolled. Yet during the actual conduct of this trial the investigators will utilize 5 kg weight as the cutoff, rather than using age. A lower weight cutoff of 5 kg is in accordance with A-L's manufacturer (Novartis)'s guidance on supporting pediatric data.
- Pill count Exclusion Criteria:
- Refusal to participate in pill count, or
- Individuals who did not receive any drug doses through RACD or rfMDA
- Reactive Vector Control Exclusion Criteria:
- Refusal by head of household to participate in RAVC, or
- Already received RAVC during current transmission season, or
- Household is > 500 m from index case household (note: refusal to participate in RACD or rfMDA is not an exclusion criterion for RAVC)
- Endline Survey, Individual, Exclusion Criteria:
- Refusal to participate in Endline Survey (note: lack of participation in rfMDA or RACD is not an exclusion criterion)
- Acceptability Assessment: Individual Interviews with study participants, Exclusion Criteria:
- Refusal to participate in Acceptability Assessment, or
- Speaks language not understood or able to be translated, or
- Key stakeholder [see below]
- Age < 15 years
- Acceptability Assessment: Individual Interviews with key stakeholders, Exclusion Criteria:
- Refusal to participate in Acceptability Assessment, or
- Speaks language not understood or able to be translated, or
- Not in leadership position
- Acceptability Assessment: Individual Interview with refusers, Exclusion Criteria:
- Refusal to participate in Acceptability Assessment, or
- Speaks language not understood or able to be translated, or
- Age < 15 years
- Acceptability Assessment: Focus group discussions with study participants, Exclusion Criteria:
- Refusal to participate in Acceptability Assessment, or
- Speaks language not understood or able to be translated, or
- Key stakeholder or in another leadership position, or
- Age < 15 years
Trial locations and contacts
1 site in 1 country.
Namibia1 site
University of Namibia Multidisciplinary Research Centre
Windhoek
About this study
Official title: Targeted Parasite Elimination in the Human and Mosquito to Reduce Malaria Transmission: A Cluster Randomised Controlled Factorial Design Trial of Reactive Focal Drug Administration (rfMDA) Versus Reactive Case Detection (RACD), With and Without Reactive Vector Control (RAVC), From the Low Endemic Setting of Namibia
This is a cluster randomised controlled trial with factorial study design comparing the impact of reactive community-based malaria interventions: 1) presumptive treatment (or rfMDA, reactive focal mass drug administration) versus reactive case detection (RACD), and 2) reactive IRS (indoor residual spraying) versus control on the incidence of malaria in Namibia.
Read the detailed description
In recent years, many countries, including Namibia, have experienced reductions in malaria transmission in association with the scale-up of effective interventions and are now moving towards malaria elimination. In malaria control, the goal is to reduce the clinical burden of malaria. In malaria elimination, the aim is to interrupt transmission, and it becomes necessary to address not only symptomatic malaria, but also asymptomatic infections that contribute to transmission. Since malaria transmission is highly geographically heterogeneous, elimination activities should target hot spots, or areas where the risk of future infection is highest. Hence, in the transition from control to elimination, enhanced surveillance and response is necessary to target hot spots with interventions to interrupt transmission.
Reactive case detection (RACD), active surveillance in communities around passively detected cases, is a recommended elimination strategy to identify secondary cases and hot spots. However, RACD can be labour-, time-, and cost- intensive, and misses people who are absent during screening or refuse to have their blood drawn. Furthermore, both microscopy and rapid diagnostic tests (RDTs) utilized in RACD have shortcomings, for instance, the suboptimal sensitivity of RDTs for low parasite density and non-falciparum infections. Polymerase chain reaction (PCR) offers markedly improved sensitivity over RDTs but requires hours of processing time, sophisticated technical skills, and expensive equipment. Given these limitations, presumptive treatment may be a more feasible and effective strategy to reduce and interrupt transmission.
Reactive focal mass drug administration (rfMDA), a form of presumptive treatment, has been used successfully in China to overcome some of the weaknesses of RACD. rfMDA targets remaining reservoirs of infection in low endemic settings by treating everyone at high risk (subjects residing around an index case), rather than rely on RDT results, which have been shown to miss infections. In a low transmission setting such as Namibia, only a small proportion of the populations is at high risk of infection, therefore, only a small number of people need to be targeted (perhaps 20-50 people). Additional indoor residual spraying (IRS) targeted to homes in high risk locations can also be implemented.
rfMDA is a promising strategy, but evidence does not yet exist to prove its efficacy in Africa. Questions remain about where to target rfMDA, what drugs to use, and whether drugs should be used alone or in combination with additional vector control. For rfMDA to be most successful, it is necessary to kill parasites in the human as well as the vector population of the target area. However, one challenge of pre-transmission season IRS is that it is difficult to predict where future infections will occur. A reactive approach, in conjunction with the pre-transmission approach, will ensure coverage of effective vector control in the highest risk areas. Further, if there is unknown resistance to the insecticide used during pre-transmission season, the subsequent reactive use of a different, and presumably effective insecticide, will provide better protection.
In this study the investigators will utilise a cluster randomized controlled study design to evaluate rfMDA in response to a passively identified index case and compare it to RACD. The investigators will study each intervention (rfMDA, RACD) both with and without additional focal insecticide spraying.
56 enumeration areas (EAs) within catchment areas of 11 study health facilities will be randomized to one of four intervention arms:
- RACD only
- RACD with RAVC
- rfMDA only
- rfMDA with RAVC
A rapid reporting surveillance system will capture confirmed, passively identified cases at all study health facilities, and those cases will trigger an intervention by the study team if located in one of the study EAs.
- Conditions
- Malaria
- Being tested
- RACD, RAVC, rfMDA
- Medical subject headings
- Malaria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RACDCombination product
Also called Reactive Case Detection
Active malaria surveillance using rapid diagnostic test in households around passively-detected index case. RDT-positive subjects are treated per national policy, under which combination medication artemether-lumefantrine is first-line, using dosing (mg artemether / mg lumefantrine):
(i) 5-14kg patient: 20/120mg twice (8 hr apart) on day 1, 20/120mg twice (12 hr apart) on each of days 2 and 3 then stop (ii) 15-24kg patient: 40/240mg twice (8 hrs apart) on day 1, 40/240mg twice (12 hrs apart) on each of days 2 and 3 then stop (iii) 25-34kg patient: 60/360mg twice (8 hrs apart) on day 1, 60/360mg twice (12 hrs apart) on each of days 2 and 3 then stop (iv) > 34kg patient: 80/480mg twice (8 hrs apart) on day 1, 80/480mg twice (12 hrs apart) on each of days 2 and 3, then stop
RAVCCombination product
Also called Reactive Vector Control
Focal, targeted indoor spraying with long-lasting insecticide pirimiphos-methyl or Actellic 300 CS, a World Health Organization (WHO)-approved organophosphate. Safety measures: (i) seeking advance permission to spray; (ii) temporarily removing items (utensils, water, food, pets) from the building during spray; (iii) covering all unremovable items; (iv) asking inhabitants to temporarily relocate outdoors during spray; (v) advising children remain outdoors until floors washed; and (vi) avoiding of spraying of any rooms that contain inhabitants, animals, or incorrectly removed/covered items. Actellic will be applied according to National Vector-borne Disease Control Program (NVDCP) indoor residual spraying (IRS) guidelines, using a Hudson X-pert sprayer (Hudson Manufacturing Co., Chicago, USA) at 40 mL/m-sq.
rfMDACombination product
Also called Reactive focal mass drug administration
Presumptive treatment, using the medication A-L, of the inhabitants of households surrounding a passively-detected index case, without incorporating a diagnostic test step. The investigators will administer A-L with dosing as follows (mg artemether / mg lumefantrine):
(i) 5-14kg patient: 20/120mg twice (8 hours apart) on day 1, 20/120mg twice (12 hours apart) on each of days 2 and 3, then stop (ii) 15-24kg patient: 40/240mg twice (8 hours apart) on day 1, 40/240mg twice (12 hours apart) on each of days 2 and 3, then stop (iii) 25-34kg patient: 60/360mg twice (8 hours apart) on day 1, 60/360mg twice (12 hours apart) on each of days 2 and 3, then stop (iv) > 34kg patient: 80/480mg twice (8 hours apart) on day 1, 80/480mg twice (12 hours apart) on each of days 2 and 3, then stop
| Study group | Role | What they receive |
|---|---|---|
| RACD without RAVC | Experimental | In this arm, subjects will receive RACD without the addition of RAVC. Receives: Combination Product: RACD |
| RACD+RAVC | Experimental | In this arm, subjects will receive both:
(i) reactive case detection (RACD) and (ii) additional reactive vector control (RAVC) Receives: Combination Product: RACD; Combination Product: RAVC |
| rfMDA without RAVC | Experimental | In this arm, subjects will receive reactive focal mass drug administration (rfMDA) without the addition of RAVC. Receives: Combination Product: RAVC; Combination Product: rfMDA |
| rfMDA+RAVC | Experimental | In this arm, subjects will receive both:
(i) reactive focal mass drug administration (rfMDA) and (ii) RAVC. Receives: Combination Product: rfMDA |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence
Incidence of confirmed, passively identified malaria cases
Measured: Up to 12 months
Secondary outcomes (8)
All-age infection prevalence
The investigators will determine all-age infection prevalence using loop-mediated isothermal amplification (LAMP) during the cross-sectional household survey. This survey will be administered to a sample of residents of all intervention Enumeration Areas in the Study Area at study conclusion.
Measured: Up to 12 months
All-age seroprevalence
The investigators will determine all-age seroprevalence using ELISA during the cross-sectional household survey. This survey will be administered to a sample of residents of all intervention EAs in the Study Area at study conclusion.
Measured: Up to 12 months
Feasibility of attaining coverage
The investigators will compare coverage of each intervention package and determine the feasibility of reaching 80% coverage for each intervention package. For RACD intervention, this equates to the proportion of the population living in the Target Area that receives a finger prick to test for malaria. For TPE intervention, coverage equates to the proportion that receive an initial dose of antimalarial drug (intention to treat analysis). For RAVC intervention, coverage is defined as the proportion of houses in the Target Area that receive reactive Indoor Residual Spraying (IRS).
Measured: Up to 12 months
Safety: Serious adverse events (SAEs)
The investigators will compare the count of serious adverse events (SAEs) relative to the total number of participants receiving an Intervention, across interventions.
Measured: Up to 12 months
Acceptability
Using focus group discussions (FGDs), the investigators will ask two questions: "Was this intervention acceptable to [participant]?" and "Would [participant] participate in this intervention again if given the opportunity?". The investigators will compare the % of "yes" responses to each of these questions, in the TPE versus the RACD arms.
Measured: Up to 12 months
Refusal rates
Refusal rates for each intervention
Measured: Up to 12 months
Cost of intervention
The investigators will collect detailed expenditure data on costs of delivery of the TPE and RACD interventions. Calculations will include costs for all consumables, as well as staff time, which will be prospectively collected every 10th TPE or RACD event. The investigators will compare TPE versus RACD in terms of cost per intervention event as well as cost per population intervened upon.
Measured: Up to 12 months
Medication adherence
The investigators will measure medication adherence in both TPE and RACD by scheduled pill counts in a random subset of subjects receiving each of those interventions.
Measured: Up to 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Nov 2015 (estimated)
- Study startFeb 2016
- Primary completionDec 2017
- Study completionDec 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (13)Papers the sponsor has linked to this study.
- Other trials for MalariaStudies of the same condition, open and under way.
- More trials run by University of California, San FranciscoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- None (open label)
- Enrolment
- 9,845 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, San Francisco
- Sponsor type
- University, hospital or other
- Collaborators
- University of Texas, London School of Hygiene and Tropical Medicine, University of Southampton, The Novartis Foundation, Clinton Health Access Initiative, Nigeria
- Responsible party
- Sponsor
- Investigators
- Michelle Hsiang, MD, Principal investigator, University of California, San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02610400
- Sponsor's protocol ID
- OPP1089413_Namibia_rfMDA
- Status last verified
- Jul 2020
- First submitted
- 18 Sep 2015
- Last updated
- 17 Jul 2020
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided
Publications
Bousema T, Griffin JT, Sauerwein RW, Smith DL, Churcher TS, Takken W, Ghani A, Drakeley C, Gosling R. Hitting hotspots: spatial targeting of malaria for control and elimination. PLoS Med. 2012 Jan;9(1):e1001165. doi: 10.1371/journal.pmed.1001165. Epub 2012 Jan 31.
PubMed 22303287Moonen B, Cohen JM, Snow RW, Slutsker L, Drakeley C, Smith DL, Abeyasinghe RR, Rodriguez MH, Maharaj R, Tanner M, Targett G. Operational strategies to achieve and maintain malaria elimination. Lancet. 2010 Nov 6;376(9752):1592-603. doi: 10.1016/S0140-6736(10)61269-X. Epub 2010 Oct 28.
PubMed 21035841Carter R, Mendis KN, Roberts D. Spatial targeting of interventions against malaria. Bull World Health Organ. 2000;78(12):1401-11. Epub 2003 Nov 17.
PubMed 11196487Hsiang 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.
PubMed 22238621Sturrock 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.
PubMed 23700437Hsiang 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.
PubMed 24175930Oxborough RM, Kitau J, Jones R, Feston E, Matowo J, Mosha FW, Rowland MW. Long-lasting control of Anopheles arabiensis by a single spray application of micro-encapsulated pirimiphos-methyl (Actellic(R) 300 CS). Malar J. 2014 Jan 29;13:37. doi: 10.1186/1475-2875-13-37.
PubMed 24476070White NJ. Intermittent presumptive treatment for malaria. PLoS Med. 2005 Jan;2(1):e3. doi: 10.1371/journal.pmed.0020003.
PubMed 15696210Katrak S, Gasasira A, Arinaitwe E, Kakuru A, Wanzira H, Bigira V, Sandison TG, Homsy J, Tappero JW, Kamya MR, Dorsey G. Safety and tolerability of artemether-lumefantrine versus dihydroartemisinin-piperaquine for malaria in young HIV-infected and uninfected children. Malar J. 2009 Nov 30;8:272. doi: 10.1186/1475-2875-8-272.
PubMed 19948038Banek K, Lalani M, Staedke SG, Chandramohan D. Adherence to artemisinin-based combination therapy for the treatment of malaria: a systematic review of the evidence. Malar J. 2014 Jan 6;13:7. doi: 10.1186/1475-2875-13-7.
PubMed 24386988Ntuku H, Smith-Gueye C, Scott V, Njau J, Whittemore B, Zelman B, Tambo M, Prach LM, Wu L, Schrubbe L, Kang Dufour MS, Mwilima A, Uusiku P, Sturrock H, Bennett A, Smith J, Kleinschmidt I, Mumbengegwi D, Gosling R, Hsiang M. Cost and cost effectiveness of reactive case detection (RACD), reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) to reduce malaria in the low endemic setting of Namibia: an analysis alongside a 2x2 factorial design cluster randomised controlled trial. BMJ Open. 2022 Jun 23;12(6):e049050. doi: 10.1136/bmjopen-2021-049050.
PubMed 35738650Hsiang MS, Ntuku H, Roberts KW, Dufour MK, Whittemore B, Tambo M, McCreesh P, Medzihradsky OF, Prach LM, Siloka G, Siame N, Gueye CS, Schrubbe L, Wu L, Scott V, Tessema S, Greenhouse B, Erlank E, Koekemoer LL, Sturrock HJW, Mwilima A, Katokele S, Uusiku P, Bennett A, Smith JL, Kleinschmidt I, Mumbengegwi D, Gosling R. Effectiveness of reactive focal mass drug administration and reactive focal vector control to reduce malaria transmission in the low malaria-endemic setting of Namibia: a cluster-randomised controlled, open-label, two-by-two factorial design trial. Lancet. 2020 Apr 25;395(10233):1361-1373. doi: 10.1016/S0140-6736(20)30470-0.
PubMed 32334702Medzihradsky OF, Kleinschmidt I, Mumbengegwi D, Roberts KW, McCreesh P, Dufour MK, Uusiku P, Katokele S, Bennett A, Smith J, Sturrock H, Prach LM, Ntuku H, Tambo M, Didier B, Greenhouse B, Gani Z, Aerts A, Gosling R, Hsiang MS. Study protocol for a cluster randomised controlled factorial design trial to assess the effectiveness and feasibility of reactive focal mass drug administration and vector control to reduce malaria transmission in the low endemic setting of Namibia. BMJ Open. 2018 Jan 27;8(1):e019294. doi: 10.1136/bmjopen-2017-019294.
PubMed 29374672
Study at a glance
From the registry record, last updated by the sponsor on 17 Jul 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Targeted Parasite Elimination in the Human and Mosquito to Reduce Malaria Transmission: A Cluster Randomised Controlled Factorial Design Trial of Reactive Focal Drug Administration (rfMDA) Versus Reactive Case Detection (RACD), With and Without Reactive Vector Control (RAVC), From the Low Endemic Setting of Namibia
- ClinicalTrials.gov ID
- NCT02610400
- Acronym / sponsor ID
- OPP1089413_Namibia_rfMDA
- Conditions
- Malaria
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 9,845 participants (actual)
- Lead sponsor
- University of California, San FranciscoUniversity, hospital or other
- Collaborators
- University of Texas, London School of Hygiene and Tropical Medicine, University of Southampton, The Novartis Foundation, Clinton Health Access Initiative, Nigeria
- Study start
- Feb 2016
- Primary completion
- Dec 2017 (actual)
- Study completion
- Dec 2017 (actual)
- First posted
- 20 Nov 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a cluster randomised controlled trial with factorial study design comparing the impact of reactive community-based malaria interventions: 1) presumptive treatment (or rfMDA, reactive focal mass drug administration) versus reactive case detection (RACD), and 2) reactive IRS (indoor residual spraying) versus control on the incidence of malaria in Namibia.
Detailed description
In recent years, many countries, including Namibia, have experienced reductions in malaria transmission in association with the scale-up of effective interventions and are now moving towards malaria elimination. In malaria control, the goal is to reduce the clinical burden of malaria. In malaria elimination, the aim is to interrupt transmission, and it becomes necessary to address not only symptomatic malaria, but also asymptomatic infections that contribute to transmission. Since malaria transmission is highly geographically heterogeneous, elimination activities should target hot spots, or areas where the risk of future infection is highest. Hence, in the transition from control to elimination, enhanced surveillance and response is necessary to target hot spots with interventions to interrupt transmission.
Reactive case detection (RACD), active surveillance in communities around passively detected cases, is a recommended elimination strategy to identify secondary cases and hot spots. However, RACD can be labour-, time-, and cost- intensive, and misses people who are absent during screening or refuse to have their blood drawn. Furthermore, both microscopy and rapid diagnostic tests (RDTs) utilized in RACD have shortcomings, for instance, the suboptimal sensitivity of RDTs for low parasite density and non-falciparum infections. Polymerase chain reaction (PCR) offers markedly improved sensitivity over RDTs but requires hours of processing time, sophisticated technical skills, and expensive equipment. Given these limitations, presumptive treatment may be a more feasible and effective strategy to reduce and interrupt transmission.
Reactive focal mass drug administration (rfMDA), a form of presumptive treatment, has been used successfully in China to overcome some of the weaknesses of RACD. rfMDA targets remaining reservoirs of infection in low endemic settings by treating everyone at high risk (subjects residing around an index case), rather than rely on RDT results, which have been shown to miss infections. In a low transmission setting such as Namibia, only a small proportion of the populations is at high risk of infection, therefore, only a small number of people need to be targeted (perhaps 20-50 people). Additional indoor residual spraying (IRS) targeted to homes in high risk locations can also be implemented.
rfMDA is a promising strategy, but evidence does not yet exist to prove its efficacy in Africa. Questions remain about where to target rfMDA, what drugs to use, and whether drugs should be used alone or in combination with additional vector control. For rfMDA to be most successful, it is necessary to kill parasites in the human as well as the vector population of the target area. However, one challenge of pre-transmission season IRS is that it is difficult to predict where future infections will occur. A reactive approach, in conjunction with the pre-transmission approach, will ensure coverage of effective vector control in the highest risk areas. Further, if there is unknown resistance to the insecticide used during pre-transmission season, the subsequent reactive use of a different, and presumably effective insecticide, will provide better protection.
In this study the investigators will utilise a cluster randomized controlled study design to evaluate rfMDA in response to a passively identified index case and compare it to RACD. The investigators will study each intervention (rfMDA, RACD) both with and without additional focal insecticide spraying.
56 enumeration areas (EAs) within catchment areas of 11 study health facilities will be randomized to one of four intervention arms:
- RACD only
- RACD with RAVC
- rfMDA only
- rfMDA with RAVC
A rapid reporting surveillance system will capture confirmed, passively identified cases at all study health facilities, and those cases will trigger an intervention by the study team if located in one of the study EAs.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| RACD without RAVC | Experimental | Combination Product: RACDIn this arm, subjects will receive RACD without the addition of RAVC. |
| RACD+RAVC | Experimental | Combination Product: RACD, Combination Product: RAVCIn this arm, subjects will receive both: (i) reactive case detection (RACD) and (ii) additional reactive vector control (RAVC) |
| rfMDA without RAVC | Experimental | Combination Product: RAVC, Combination Product: rfMDAIn this arm, subjects will receive reactive focal mass drug administration (rfMDA) without the addition of RAVC. |
| rfMDA+RAVC | Experimental | Combination Product: rfMDAIn this arm, subjects will receive both: (i) reactive focal mass drug administration (rfMDA) and (ii) RAVC. |
Who may qualify
- Ages
- 6 months and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (42 listed)
- Index Case Investigation Inclusion Criteria:
- RACD Intervention Inclusion Criteria:
- rfMDA Intervention Inclusion Criteria:
- Artemether/Lumefantrine (A-L) (combination medication) Inclusion Criteria:
- Pill count Inclusion Criteria:
Key exclusion criteria (50 listed)
- Index Case Investigation Exclusion Criteria:
- RACD Intervention Exclusion Criteria:
- rfMDA Intervention Exclusion Criteria:
- Artemether/Lumefantrine (combination medication) Exclusion Criteria:
- Pill count Exclusion Criteria:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RACDAlso: Reactive Case DetectionActive malaria surveillance using rapid diagnostic test in households around passively-detected index case. RDT-positive subjects are treated per national policy, under which combination medication artemether-lumefantrine is first-line, using dosing (mg artemether / mg lumefantrine): (i) 5-14kg patient: 20/120mg twice (8 hr apart) on day 1, 20/120mg twice (12 hr apart) on each of days 2 and 3 then stop (ii) 15-24kg patient: 40/240mg twice (8 hrs apart) on day 1, 40/240mg twice (12 hrs apart) on each of days 2 and 3 then stop (iii) 25-34kg patient: 60/360mg twice (8 hrs apart) on day 1, 60/360mg twice (12 hrs apart) on each of days 2 and 3 then stop (iv) > 34kg patient: 80/480mg twice (8 hrs apart) on day 1, 80/480mg twice (12 hrs apart) on each of days 2 and 3, then stop | Combination product | RACD without RAVC, RACD+RAVC |
| RAVCAlso: Reactive Vector ControlFocal, targeted indoor spraying with long-lasting insecticide pirimiphos-methyl or Actellic 300 CS, a World Health Organization (WHO)-approved organophosphate. Safety measures: (i) seeking advance permission to spray; (ii) temporarily removing items (utensils, water, food, pets) from the building during spray; (iii) covering all unremovable items; (iv) asking inhabitants to temporarily relocate outdoors during spray; (v) advising children remain outdoors until floors washed; and (vi) avoiding of spraying of any rooms that contain inhabitants, animals, or incorrectly removed/covered items. Actellic will be applied according to National Vector-borne Disease Control Program (NVDCP) indoor residual spraying (IRS) guidelines, using a Hudson X-pert sprayer (Hudson Manufacturing Co., Chicago, USA) at 40 mL/m-sq. | Combination product | RACD+RAVC, rfMDA without RAVC |
| rfMDAAlso: Reactive focal mass drug administrationPresumptive treatment, using the medication A-L, of the inhabitants of households surrounding a passively-detected index case, without incorporating a diagnostic test step. The investigators will administer A-L with dosing as follows (mg artemether / mg lumefantrine): (i) 5-14kg patient: 20/120mg twice (8 hours apart) on day 1, 20/120mg twice (12 hours apart) on each of days 2 and 3, then stop (ii) 15-24kg patient: 40/240mg twice (8 hours apart) on day 1, 40/240mg twice (12 hours apart) on each of days 2 and 3, then stop (iii) 25-34kg patient: 60/360mg twice (8 hours apart) on day 1, 60/360mg twice (12 hours apart) on each of days 2 and 3, then stop (iv) > 34kg patient: 80/480mg twice (8 hours apart) on day 1, 80/480mg twice (12 hours apart) on each of days 2 and 3, then stop | Combination product | rfMDA without RAVC, rfMDA+RAVC |
Primary outcome
Incidence
Time frame: Up to 12 months
Incidence of confirmed, passively identified malaria cases
8 secondary outcomes
All-age infection prevalence
Time frame: Up to 12 months
All-age seroprevalence
Time frame: Up to 12 months
Feasibility of attaining coverage
Time frame: Up to 12 months
Safety: Serious adverse events (SAEs)
Time frame: Up to 12 months
Acceptability
Time frame: Up to 12 months
Refusal rates
Time frame: Up to 12 months
Cost of intervention
Time frame: Up to 12 months
Medication adherence
Time frame: Up to 12 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Jul 2020.
- Background: PubMed 22303287Bousema T, Griffin JT, Sauerwein RW, Smith DL, Churcher TS, Takken W, Ghani A, Drakeley C, Gosling R. Hitting hotspots: spatial targeting of malaria for control and elimination. PLoS Med. 2012 Jan;9(1):e1001165. doi: 10.1371/journal.pmed.1001165. Epub 2012 Jan 31.
- Background: PubMed 21035841Moonen B, Cohen JM, Snow RW, Slutsker L, Drakeley C, Smith DL, Abeyasinghe RR, Rodriguez MH, Maharaj R, Tanner M, Targett G. Operational strategies to achieve and maintain malaria elimination. Lancet. 2010 Nov 6;376(9752):1592-603. doi: 10.1016/S0140-6736(10)61269-X. Epub 2010 Oct 28.
- Background: PubMed 11196487Carter R, Mendis KN, Roberts D. Spatial targeting of interventions against malaria. Bull World Health Organ. 2000;78(12):1401-11. Epub 2003 Nov 17.
- Background: PubMed 22238621Hsiang 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.
- Background: PubMed 23700437Sturrock 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.
- Background: PubMed 24175930Hsiang 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.
- Background: PubMed 24476070Oxborough RM, Kitau J, Jones R, Feston E, Matowo J, Mosha FW, Rowland MW. Long-lasting control of Anopheles arabiensis by a single spray application of micro-encapsulated pirimiphos-methyl (Actellic(R) 300 CS). Malar J. 2014 Jan 29;13:37. doi: 10.1186/1475-2875-13-37.
- Background: PubMed 15696210White NJ. Intermittent presumptive treatment for malaria. PLoS Med. 2005 Jan;2(1):e3. doi: 10.1371/journal.pmed.0020003.
- Background: PubMed 19948038Katrak S, Gasasira A, Arinaitwe E, Kakuru A, Wanzira H, Bigira V, Sandison TG, Homsy J, Tappero JW, Kamya MR, Dorsey G. Safety and tolerability of artemether-lumefantrine versus dihydroartemisinin-piperaquine for malaria in young HIV-infected and uninfected children. Malar J. 2009 Nov 30;8:272. doi: 10.1186/1475-2875-8-272.
- Background: PubMed 24386988Banek K, Lalani M, Staedke SG, Chandramohan D. Adherence to artemisinin-based combination therapy for the treatment of malaria: a systematic review of the evidence. Malar J. 2014 Jan 6;13:7. doi: 10.1186/1475-2875-13-7.
- Derived from this study: PubMed 35738650Ntuku H, Smith-Gueye C, Scott V, Njau J, Whittemore B, Zelman B, Tambo M, Prach LM, Wu L, Schrubbe L, Kang Dufour MS, Mwilima A, Uusiku P, Sturrock H, Bennett A, Smith J, Kleinschmidt I, Mumbengegwi D, Gosling R, Hsiang M. Cost and cost effectiveness of reactive case detection (RACD), reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) to reduce malaria in the low endemic setting of Namibia: an analysis alongside a 2x2 factorial design cluster randomised controlled trial. BMJ Open. 2022 Jun 23;12(6):e049050. doi: 10.1136/bmjopen-2021-049050.
- Derived from this study: PubMed 32334702Hsiang MS, Ntuku H, Roberts KW, Dufour MK, Whittemore B, Tambo M, McCreesh P, Medzihradsky OF, Prach LM, Siloka G, Siame N, Gueye CS, Schrubbe L, Wu L, Scott V, Tessema S, Greenhouse B, Erlank E, Koekemoer LL, Sturrock HJW, Mwilima A, Katokele S, Uusiku P, Bennett A, Smith JL, Kleinschmidt I, Mumbengegwi D, Gosling R. Effectiveness of reactive focal mass drug administration and reactive focal vector control to reduce malaria transmission in the low malaria-endemic setting of Namibia: a cluster-randomised controlled, open-label, two-by-two factorial design trial. Lancet. 2020 Apr 25;395(10233):1361-1373. doi: 10.1016/S0140-6736(20)30470-0.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michelle Hsiang, MD principal investigator
University of California, San Francisco
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing RACD, RAVC and rfMDA in people with Malaria, run by University of California, San Francisco at 1 site in Namibia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 42 inclusion and 50 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Jul 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Namibia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence (time frame: Up to 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02610400, which also lists 13 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jul 2020.