Repeat Ivermectin Mass Drug Administrations for Control of Malaria: a Pilot Safety and Efficacy Study (RIMDAMAL)

• ClinicalTrials.gov Identifier: NCT02509481
• Recruitment Status: Completed
• First Posted: July 28, 2015
• Results First Posted: January 4, 2019
• Last Update Posted: January 4, 2019
• Sponsor: Colorado State University
• Collaborators: Institut de Recherche en Sciences de la Sante, Burkina Faso; Centre Muraz; Ministère de la Santé du Burkina Faso
• Information provided by (Responsible Party): Colorado State University

Tracking Information

• First Submitted Date: July 23, 2015
• First Posted Date: July 28, 2015
• Results First Submitted Date: July 6, 2018
• Results First Posted Date: January 4, 2019
• Last Update Posted Date: January 4, 2019
• Study Start Date: June 2015
• Actual Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 2, 2019)

Incidence of Clinical Malaria Episodes [ Time Frame: Approximately 18 weeks, from the start of the first MDA to 3 weeks following the last MDA in the Experimental arm ]

Cumulative incidence of malaria episodes in a cohort of village children ≤ 5 years of age (as assessed by active case surveillance in study villages - malaria episode defined as ≥38.0°C fever or history of fever in the last 24 hours + positive rapid diagnostic test for Plasmodium falciparum). Incidence is reported as malaria episodes per child over the course of the trial, a higher incidence is a worse outcome.

Original Primary Outcome Measures (submitted: July 24, 2015)

Incidence of clinical malaria episodes [ Time Frame: Approximately 18 weeks, from the start of the first MDA to 3 weeks following the last MDA in the Experimental arm ]

Cumulative incidence of malaria episodes in children ≤ 5 years of age (as assessed by active case surveillance in study villages - malaria episode defined as ≥38.0°C fever or history of fever in the last 24 hours + positive rapid diagnostic test for Plasmodium falciparum).

Current Secondary Outcome Measures (submitted: January 2, 2019)

• Adverse Events [ Time Frame: Approximately 18 weeks, from the start of the first MDA to 3 weeks following the last MDA in the Experimental arm ]
  The number of adverse events. Adverse events data were collected via passive case detection from total population.
• Entomological Indicator of Parasite Transmission [ Time Frame: Approximately 20 weeks, from before the start of the first MDA to 4 weeks following the last MDA in the Experimental arm ]
  Change in human IgG reactivity (optical density; ∆OD) to an Anopheles salivary gland antigen (peptide gSG6-P1) over the trial period. A score of 0 indicates no change in seroreactivity from from immediately before to immediately after the trial, suggesting consistent mosquito biting throughout the trial. A positive score indicates increasing seroreactivity and thus increasing mosquito biting on participants from immediately before to immediately after the trial. A negative score indicates decreasing seroreactivity and thus decreasing mosquito biting on participants from immediately before to immediately after the trial.
• Molecular Force of P. Falciparum Infection [ Time Frame: Approximately 18 weeks, from the start of the first MDA to 3 weeks following the last MDA in the Experimental arm ]
  Examination of new P. falciparum clones acquired from the beginning to the end of the intervention (molecular force of infection; mFOI) per child. Molecular genotyping used capillary blood taken at the time of diagnosis of each positive malaria episode and consisted of nPCR of the msp2 gene. We calculated the multiplicity of infection (MOI) per malaria episode, and then calculated the molecular force of infection (mFOI) associated with malaria episodes per child (over course of the trial)
• Number of 6-10 Year Old Participants With Soil Transmitted Helminths (STH) [ Time Frame: Approximately 20 weeks, from before the start of the first MDA to 4 weeks following the last MDA in the Experimental arm ]
  Prevalence of soil transmitted helminth infections in children between 6-10 years old from the beginning to the end of the intervention
• Entomological Inoculation Rate [ Time Frame: 6 sampling periods over 18 weeks, starting in week 2 following the first MDA, and sampling every 3 weeks thereafter until week 17 of the treatment phase. ]
  The entomological inoculation rate (EIR per week per person) is the measure of the human biting rate per person per week, multiplied by the sporozoite rate (in biting mosquitoes) per week, an estimated from sampling mosquitoes from 8 households located in the center of each study village. The EIR was calculated for each of the 6 sampling weeks of the treatment phase.

Original Secondary Outcome Measures (submitted: July 24, 2015)

• Force of Plasmodium falciparum infection [ Time Frame: Approximately 20 weeks, from before the start of the first MDA to 4 weeks following the last MDA in the Experimental arm ]
  Examination of new P. falciparum infections acquired from the beginning to the end of the intervention (molecular force of infection)
• Soil transmitted helminths [ Time Frame: Approximately 20 weeks, from before the start of the first MDA to 4 weeks following the last MDA in the Experimental arm ]
  Examination of prevalence and intensity of soil transmitted helminth infections in children between 6-10 years old from the beginning to the end of the intervention
• Entomological indicators of parasite transmission [ Time Frame: Approximately 20 weeks, from before the start of the first MDA to 3 weeks following the last MDA in the Experimental arm ]
  Indoor-resting blood fed and host-seeking Anopheles mosquitoes from houses in the center of each village will be identified and counted, and subset samples will be tested for parity, Plasmodium sporozoites, and infections with Wuchereria bancrofti.
• Adverse events [ Time Frame: Approximately 18 weeks, from the start of the first MDA to 3 weeks following the last MDA in the Experimental arm ]
  The number, frequency and type (classified by seriousness, causality and expectedness) of adverse events. Adverse events data are collected via passive case detection.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Repeat Ivermectin Mass Drug Administrations for Control of Malaria: a Pilot Safety and Efficacy Study
• Official Title: Repeat Ivermectin Mass Drug Administrations for Control of Malaria: a Pilot Safety and Efficacy Study
• Brief Summary: The purpose of this study is to determine whether repeated ivermectin mass drug administrations to Burkinabé villagers, performed in three week intervals over the rainy-season, is well-tolerated and safe, and also effective in reducing local malaria transmission and thus clinical malaria episodes in treated village children.

Detailed Description

Primary Objective: To determine the efficacy of repeated ivermectin mass drug administrations (IVM MDA) (150 µg/kg), given to the population of eligible patients in enrolled villages, for reducing the cumulative incidence of uncomplicated malaria episodes in enrolled village children (≤ 5 years of age) over the course of the treatment.

Hypothesis: Repeated IVM MDA starting at the beginning of the rainy season will be well tolerated and safe, and will reduce clinical malaria episodes in children by significantly reducing malaria transmission among treated villages.

Overview Study Design: Single-blind (outcomes assessor); parallel assignment with 2 arms; cluster-randomized control trial to determine the effect of repeated IVM MDA on malaria transmission and clinical malaria episodes. The unit of randomization will be the village (cluster). 8 villages total will be enrolled in two arms. The active comparator arm (4 villages) will receive a single standard MDA (IVM; 150-200 µg/kg + albendazole; 400 mg) soon after the start of the rainy season, while the experimental arm (4 villages) will receive the standard MDA on the same date, plus 5 more IVM MDA at 3 week intervals thereafter. The primary endpoint will be the cumulative incidence of clinical malaria episodes in children ≤5 year of age within each village.

Sites: This study will be conducted in villages along the main east-west and north-south road corridors in the Sud-Ouest administrative region of Burkina Faso.

Study Population: Indigenous Burkinabé from various ethnic groups (Dagara, Bobo, Lobi, Mossi, etc.). The entire eligible population of each enrolled village will receive the MDAs, following the standard inclusion/exclusion criteria of MDA for control of microfilaremia caused by Wuchereria bancrofti (lymphatic filariasis; LF). Clinical incidence of malaria will be assessed only in children living in enrolled villages who are ≤ 5 years of age, most of whom will not have received any treatment due to the standard MDA exclusion criteria of children < 90 cm.

Study Interventions: 2 arms: 1) Active comparator arm - single standard MDA with IVM (150 µg/kg) + albendazole (ALB;400 mg) soon after the beginning of the rainy season; 2) Experimental arm, single standard MDA with IVM (150 µg/kg) + ALB (400 mg) plus 5 more MDA with IVM alone (150 µg/kg) at 3 week intervals thereafter. Community health workers and trained by local health authority of the Sud-Ouest region will perform the first MDA in both arms with logistical assistance from the study investigators. Repeated MDAs will only occur in the experimental-arm villages, and be performed by the study investigators.

Follow-up Procedures: Trained nurses will visit each study village each week over the course of the study to investigate and record any adverse events or severe adverse events communicated by the study population. They will also perform active case surveillance each week on enrolled village children for clinical malaria episodes, defined as ≥38.0°C fever or history of fever in the last 24 hours + positive rapid diagnostic test for Plasmodium falciparum. Secondary measures will be collected by the nurses.

Sample Size: Assuming an 80% cumulative incidence of malaria episodes in the control arm and an intracluster correlation coefficient of 0.02, 4 clusters are needed per arm and 69 children enrolled per cluster to detect a conservative 40% reduction in incidence in the treatment arm with 80% power and a statistical confidence of 95%.

Safety Outcomes:

• Adverse events (seriousness, causality, expectedness)

Secondary Outcomes:

• Incidence of new P. falciparum infections acquired (molecular force-of-infection)
• Prevalence and intensity (eggs/larvae per gram of feces) of soil transmitted helminth infections in a subset of treated patients between 6-10 years of age.
• Indoor-resting Anopheles mosquito capture rate
• Outdoor-host seeking Anopheles mosquito capture rate
• Adult mosquito age structure (parity rate) in captured mosquitoes
• Plasmodium sporozoite rate/entomological inoculation rate in captured mosquitoes
• Rate of Wuchereria bancrofti in captured mosquitoes

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Outcomes Assessor); Primary Purpose: Treatment

Condition

• Malaria
• Lymphatic Filariasis

Intervention

• Drug: Ivermectin
  Other Name: Mectizan
• Drug: Albendazole

Study Arms

• Active Comparator: Single MDA
  Single mass drug administration of ivermectin (150 µg/kg) + albendazole (400 mg) performed after the start of the rainy season as part of public health efforts to eliminate lymphatic filariasis.
  Interventions:

  • Drug: Ivermectin
  • Drug: Albendazole
• Experimental: Repeated MDA
  Same at Active Comparator, but then followed by five more mass drug administrations of ivermectin only (150 µg/kg) every three weeks thereafter.
  Interventions:

  • Drug: Ivermectin
  • Drug: Albendazole

• Publications *: Foy BD, Alout H, Seaman JA, Rao S, Magalhaes T, Wade M, Parikh S, Soma DD, Sagna AB, Fournet F, Slater HC, Bougma R, Drabo F, Diabate A, Coulidiaty AGV, Rouamba N, Dabire RK. Efficacy and risk of harms of repeat ivermectin mass drug administrations for control of malaria (RIMDAMAL): a cluster-randomised trial. Lancet. 2019 Apr 13;393(10180):1517-1526. doi: 10.1016/S0140-6736(18)32321-3. Epub 2019 Mar 14.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 22, 2016): 2712
• Original Estimated Enrollment (submitted: July 24, 2015): 2700
• Actual Study Completion Date: December 2015
• Actual Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Residence in the study site
• Able to understand the information and willing to give consent and assent (parent or guardian consent if study participant age is < 18 years)

Exclusion Criteria:

• Residence outside of in the study site
• Height ≤ 90 cm
• Permanent disability, serious medical illness that prevents or impedes study participation and/or comprehension
• Pregnancy
• Breast feeding if infant is within 1 week of birth
• Known allergy to the study drugs

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Burkina Faso, United States

Administrative Information

• NCT Number: NCT02509481
• Other Study ID Numbers: 5375011; OPP1116536 ( Other Grant/Funding Number: The Bill and Melinda Gates Foundation )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Colorado State University
• Original Responsible Party: Same as current
• Current Study Sponsor: Colorado State University
• Original Study Sponsor: Same as current

Collaborators

• Institut de Recherche en Sciences de la Sante, Burkina Faso
• Centre Muraz
• Ministère de la Santé du Burkina Faso

Investigators

• Principal Investigator: Brian D. Foy, PhD; Colorado State University
• Principal Investigator: Roch K Dabire, PhD; Institute de Recherche en Sciences de la Santé

• PRS Account: Colorado State University
• Verification Date: January 2019