Clinical trial NCT02899936: Death to Onchocerciasis and Lymphatic Filariasis (DOLF) Triple Drug Therapy for Lymphatic Filariasis
Official title: Community Based Safety Study of 2-drug (Diethylcarbamazine and Albendazole) Versus 3-drug (Ivermectin, Diethylcarbamazine and Albendazole) Therapy for Lymphatic Filariasis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Lymphatic Filariasis
Keywords: Mass drug administration
Safety Data
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: Case Western Reserve University
name: Indian Council of Medical Research
First posted: 2016-09-14
Enrollment: 23789
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The DOLF Triple Drug Therapy for Lymphatic Filariasis study will determine the frequency, type and severity of adverse events following triple-drug therapy (IVM+DEC+ALB, IDA) compared to the standard two-drug treatment (DEC+ALB, DA) in infected and uninfected individuals in a community in 5 different countries. The objective is to acquire safety, efficacy, and acceptability data to assess the safety and acceptability of the IDA drug combination.

Detailed description: In 2000, the World Health Organization (WHO) launched the Global Programme to Eliminate Lymphatic Filariasis (GPELF) to eliminate lymphatic filariasis as a public health problem by 2020. To interrupt transmission, WHO recommends therapy using combinations of two medicines delivered to entire at-risk populations through a strategy known as mass drug administration. Ivermectin (IVM) and albendazole (ALB) are administered in areas where onchocerciasis is co-endemic; diethylcarbamazine (DEC) and albendazole (ALB) are administered in areas where onchocerciasis is not co-endemic.

Results of a pilot study in Papua New Guinea suggest that triple drug therapy (ivermectin, diethylcarbamazine and albendazole) is superior to the currently recommended two-drug regimen (DEC+ALB, DA). A single dose of the triple therapy (IVM+DEC+ALB, IDA) rapidly achieved complete clearance of Wuchereria bancrofti microfilariae from the blood of 12 individuals for at least one year post-treatment. All six individuals tested at 24 months were still amicrofilaremic, suggesting that the triple therapy might permanently sterilizes adult filarial worms. Many people treated in these studies experienced transient systemic adverse events commonly associated with diethylcarbamazine or ivermectin treatment of filariasis. Adverse events were more frequent after the triple therapy than after the usual combination of two drugs. However, no serious adverse events were observed. The dramatic reduction and sustained decrease of microfilaria along with the safety profile seen in the Papua New Guinea studies suggest that the triple drug therapy may be a useful tool to achieve the goal of eliminating lymphatic filariasis as a public health problem by 2020.

Although the study cited above has clearly demonstrated the superiority of the triple therapy for clearing W. bancrofti microfilaria from the blood, more safety and efficacy data are needed before triple therapy can be rolled out on a large scale as a mass drug administration regimen in lymphatic filariasis endemic countries. WHO recommends a best practice called "cohort event monitoring" for demonstrating safety of new drug regimens for public health program use. Establishing safety through such methodology requires pre and post treatment assessment from at least 10,000 people treated with the triple therapy across multiple settings.

It is therefore proposed to conduct a cohort event monitoring study to acquire safety data. Efficacy and acceptability components will also be included in the study. Similar studies will be conducted simultaneously in Haiti, India, Indonesia, Papua New Guinea and Sri Lanka to reach the 10,000 people necessary to assess the safety of this new drug combination.

This will be an open label, two-armed study. The two arms are (1) mass drug administration (MDA) with the currently used combination of two-drug regimen (DA) and (2) MDA with triple drug therapy (IDA).

Eligibility criteria: In India:

Inclusion Criteria:

1. Age ≥ 5 years, male or female for IDA arm and age \> 2 years for DA arm.
2. Able to provide informed consent to participate in the trial (forms to be attached)
3. No evidence of severe or systemic co-morbidities except for features of filarial disease

Exclusion Criteria:

1. Age \< 5 years (ivermectin is contraindicated in children below 5 years of age) for IDA arm and age \< 2 years for DA arm
2. Pregnant women (DEC, ivermectin and albendazole are contraindicated in pregnancy)
3. Severe chronic illness (for example, chronic renal failure, inability to care for oneself with activities of daily living)
4. History of previous allergy to MDA drugs

For rest of countries:

Inclusion Criteria:

1. Age ≥ 5 years, for IDA and DA arms (males and females).
2. Able to provide informed consent or give parental consent for minors to participate in the trial
3. No evidence of severe or systemic co-morbidities except for features of filarial disease

Exclusion Criteria:

1. Age \< 5 years (ivermectin is not approved for use in children less than 5 years of age)
2. Unable to provide informed consent or give parental consent for minors to participate in the trial
3. Pregnant women (DEC, ivermectin and albendazole are not known to be safe for use during pregnancy)
4. Severe chronic illness (chronic renal insufficiency, severe chronic liver disease, or any illness that is severe enough to interfere with activities of daily living)
5. History of previous allergy to MDA drugs

Primary outcomes:
measure: Number of participants with treatment-related adverse events as assessed by modified CTCAE v4.0 scale
timeFrame: within 7 days of drug administration
Secondary outcomes:
measure: Number of participants with clearance of microfilaremia (MF) as measured with microfilaremia night blood smear testing (finger prick - 60ul)
timeFrame: baseline (pre-treatment), within 7 days of drug administration and follow up at 12 months
measure: Number of participants Filarial Test Strip (FTS) and/or MF positive as tested with FTS and night blood smears with treatment-related adverse events as assessed by modified CTCAE v4.0 scale
timeFrame: baseline (pre-treatment), within 7 days of drug administration and follow up at 12 months
measure: Community acceptance will be measured using on a survey using likert scale questions based on perception of efficacy, intent to participate and relevance of the treatment.
timeFrame: 6-8 months
measure: Prevalence of STH (hookworm, ascaris, trichuris and strongyloides) as measured by Kato-katz or PCR at baseline and 12 months after treatment
timeFrame: Stool collected at baseline (pre-treatment), 4 weeks (individual response), and 12 months (community prevalence).
Other outcomes:
Locations:
city: Port-au-Prince
country: Haiti
facility: Ministere de la Sante Publique et de la Population
city: Puducherry
country: India
facility: Vector Control Research Centre
city: Jakarta
country: Indonesia
facility: Universitas Indonesia
city: Madang
country: Papua New Guinea
facility: Papua New Guinea Institute for Medical Research
Study officials:
affiliation: Washington University School of Medicine
name: Gary Weil, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Case Western Reserve University
name: Christopher King, MD PHD
role: PRINCIPAL_INVESTIGATOR
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