Lymphatic Filariasis (LF) in Ivory Coast

Study Overview
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Brief Summary
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The recommended treatment for elimination of LF in sub-Saharan Africa is annual mass drug administration (MDA) with single dose Albendazole (ALB) plus Ivermectin (IVM) given for at least 5-7 years. However, in areas where LF is co-endemic with a related filarial parasite, Loa loa, co-infection with L. loa represents a serious barrier to LF elimination because IVM used in LF MDA can result in severe reactions and even death in individuals with high microfilaria (mf) levels of L. loa. Screening for heavy L. loa infection is problematic. To overcome this problem, monotherapy with ALB is possible, since this drug has little or no effect on circulating mf and thus would not cause adverse effects in people with heavy L. loa infections. Moreover ALB has been shown to have embryostatic or embryocidal effects in female adult worms resulting in decreased mf levels with time as natural attrition of circulating mf occurs. Thus this open-label, randomized clinical trial will examine treatment with ALB monotherapy administered twice per year over a period of 3 years with the primary endpoint being the proportion of individuals with total clearance of mf at 36 months and Alere antigen test negativity (a more sensitive circulating antigen test of filarial infection). Two of the treatment arms will include ALB at two different doses, 400mg or 800mg (fixed dose twice yearly) as compared to standard treatment of ALB (400 mg) plus IVM (150-200 µg/kg) administered annually. Observations from an ongoing clinical trial in Papua New Guinea suggest that a single dose of triple therapy with ALB + IVM + DEC may be highly effective in sterilizing adult female worms. Therefore to confirm and expand these important preliminary observations in a different population, a fourth arm will be included in the current clinical trial in which subjects will receive all three drugs. The clinical trial will be performed in a region of Cote d'Ivoire where onchocerciasis and loiasis are not endemic.

Detailed Description
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Lymphatic filariasis (LF) is a deforming and disabling infectious disease that causes elephantiasis and genital deformity (especially hydroceles). The infection affects some 120 million people in 81 countries in tropical and subtropical regions with well over 1 billion people at risk of acquiring the disease. LF is caused by Wuchereria bancrofti and Brugia spp. (B. malayi and B. timori), nematode parasites that are transmitted by mosquitoes. The World Health Organization (WHO) developed a plan for LF elimination that is based on using novel approaches to rapidly map endemic areas and 4 to 6 annual rounds of MDA with antifilarial medication. A recent summary from WHO reported that more than 4 billion doses of MDA were distributed between 2000 and 2012. Thus, the Global Program to Eliminate Lymphatic Filariasis (GPELF) is the largest infectious disease intervention program attempted to date based on MDA (Ottesen, Hooper et al. 2008). MDA has worked better in some areas than others. There are a number of challenges faced by GPELF. These include (among others) inability to conduct MDA programs in areas of Africa where L. loa is coendemic because of the unacceptable risk of Serious Adverse Events (SAE's) with IVM in persons with heavy L. loa infections (Hoerauf, Pfarr et al. 2011), the limited macrofilaricidal activity of current MDA regimens (especially ALB + IVM) that necessitate repeated annual rounds of MDA (Geary and Mackenzie , Hoerauf, Pfarr et al. 2011), and the difficulty of achieving high compliance rates for MDA over a period of years (Hoerauf, Pfarr et al. 2011). It is clear that new (or reformulated) drugs and/or dosing schedules for LF MDA have the potential to greatly improve the number of countries that will successfully eliminate LF by the WHO target date of 2020. This is especially important for areas of Central and West Africa where MDA has not been implemented because of the possible co-infection with L. loa and logistical and financial challenges to delivering annual doses of IVM + ALB MDA to millions of individuals over multiple years.

Official Title
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Alternative Chemotherapies for Lymphatic Filariasis (LF) Treatment and Elimination in Africa [Cote d'Ivoire]

Conditions
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Lymphatic Filariasis

Intervention / Treatment
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* Drug: Albendazole
* Drug: Ivermectin
* Drug: Diethylcarbamazine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women and men 18-70 years ≥50 MF/mL based on Nuclepore filtration Willing to give informed consent Exclusion Criteria: Prior treatment for LF within last 5 years Pregnancy (perform pregnancy test) Hemoglobin <7 g/dL Permanent disability, serious medical illness that prevents or impedes study participation and/or comprehension AST/ALT and creatinine >1.5 upper limit of normal Proteinuria or hematuria >3+ Skin snip positivity for O. volvulus MF

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard Treatment<br>Albendazole 400 mg + Ivermectin 200 µg/kg body weight administered annually (at 0, 12 and 24 months) | Drug: Albendazole<br>* Subjects in Arms 1, 2, and 4 will receive 400mg of Albendazole Subjects in Arm 3 will receive 800mg of Albendazole<br>* Other names: ALB;Drug: Ivermectin<br>* Subjects in Arms 1 and 4 will receive 200mg/kg body weight<br>* Other names: IVM;|
| Experimental: ALB 400 mg x2 per year<br>Albendazole 400 mg given at 0, 6, 12, 18, 24 and 30 months | Drug: Albendazole<br>* Subjects in Arms 1, 2, and 4 will receive 400mg of Albendazole Subjects in Arm 3 will receive 800mg of Albendazole<br>* Other names: ALB;|
| Experimental: ALB 800 mg x2 per year<br>Albendazole 800 mg given at 0, 6, 12, 18, 24 and 30 months | Drug: Albendazole<br>* Subjects in Arms 1, 2, and 4 will receive 400mg of Albendazole Subjects in Arm 3 will receive 800mg of Albendazole<br>* Other names: ALB;|
| Experimental: ALB 400mg + IVM 200mcg/kg + DEC 6mg/kg<br>Albendazole 400 mg plus Ivermectin 200 µg/kg body weight plus Diethylcarbamazine 6 mg/kg body weight given one time only | Drug: Albendazole<br>* Subjects in Arms 1, 2, and 4 will receive 400mg of Albendazole Subjects in Arm 3 will receive 800mg of Albendazole<br>* Other names: ALB;Drug: Ivermectin<br>* Subjects in Arms 1 and 4 will receive 200mg/kg body weight<br>* Other names: IVM;Drug: Diethylcarbamazine<br>* Participants in Arm 4 will receive 6mg/kg of Diethylcarbamazine per body weight<br>* Other names: DEC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total clearance of Microfilariae | The percentage of participants with total clearance of Microfilariae | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total clearance of MF at 24 months | Percentage of subjects with total clearance of MF at 24 months | 24 months | 
| Percent MF reduction | Percent MF reduction at 24 and 36 months compared to baseline level | 24 and 36 months | 
| Reduction in W. bancrofti antigen level | Percent reduction in W. bancrofti antigen level measured by Og4C3 assay at 12, 24 and 36 months compared to baseline level | 12, 24 and 36 months | 
| Alere Filariasis Test Strip negative | Percentage of subjects that become Alere Filariasis Test Strip negative at 12, 24 and 36 months | 12, 24 and 36 months | 
| reduction in viable worm nests | Percent reduction in viable worm nests relative to baseline (time 0) based on follow up scrotal ultrasound examination performed at 12, 24 and 36 months | 12, 24, and 36 months | 
| Diversity of parasites | Diversity of parasites before and after treatment using genetic markers | 0 and 36 months | 
| type and level of parasite-specific host immune response | Relation of type and level of parasite-specific host immune response with the initial and sustained clearance of parasites | 0 and 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ivermectin, Albendazole, Diethylcarbamazine