Lymphatic Filariasis (LF) in Ivory Coast

Lymphatic Filariasis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02974049
• Other study ID #: 08-14-13
• Status: Completed
• Phase: N/A
• Start date: January 2015
• Est. completion date: September 25, 2018

Study information

• Verified date: April 2019
• Source: University Hospitals Cleveland Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 189
• Est. completion date: September 25, 2018
• Est. primary completion date: September 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Filariasis
• Lymphatic Filariasis

Intervention

Drug:
• Albendazole
Subjects in Arms 1, 2, and 4 will receive 400mg of Albendazole Subjects in Arm 3 will receive 800mg of Albendazole
• Ivermectin
Subjects in Arms 1 and 4 will receive 200mg/kg body weight
• Diethylcarbamazine
Participants in Arm 4 will receive 6mg/kg of Diethylcarbamazine per body weight

Locations

Country	Name	City	State
Côte D'Ivoire	Cote d'Ivoire	Abidjan

Sponsors (2)

Lead Sponsor	Collaborator
University Hospitals Cleveland Medical Center	Washington University School of Medicine

Country where clinical trial is conducted

Côte D'Ivoire, 

References & Publications (22)

Awadzi K, Edwards G, Duke BO, Opoku NO, Attah SK, Addy ET, Ardrey AE, Quartey BT. The co-administration of ivermectin and albendazole--safety, pharmacokinetics and efficacy against Onchocerca volvulus. Ann Trop Med Parasitol. 2003 Mar;97(2):165-78. — View Citation

Awadzi K, Edwards G, Opoku NO, Ardrey AE, Favager S, Addy ET, Attah SK, Yamuah LK, Quartey BT. The safety, tolerability and pharmacokinetics of levamisole alone, levamisole plus ivermectin, and levamisole plus albendazole, and their efficacy against Onchocerca volvulus. Ann Trop Med Parasitol. 2004 Sep;98(6):595-614. — View Citation

Bockarie MJ, Tavul L, Ibam I, Kastens W, Hazlett F, Tisch DJ, Alpers MP, Kazura JW. Efficacy of single-dose diethylcarbamazine compared with diethylcarbamazine combined with albendazole against Wuchereria bancrofti infection in Papua New Guinea. Am J Trop Med Hyg. 2007 Jan;76(1):62-6. — View Citation

Boussinesq M, Kamgno J, Pion SD, Gardon J. What are the mechanisms associated with post-ivermectin serious adverse events? Trends Parasitol. 2006 Jun;22(6):244-6. Epub 2006 Apr 24. — View Citation

Chu, B. K., P. J. Hooper, M. H. Bradley, D. A. McFarland and E. A. Ottesen

Geary TG, Mackenzie CD. Progress and challenges in the discovery of macrofilaricidal drugs. Expert Rev Anti Infect Ther. 2011 Aug;9(8):681-95. doi: 10.1586/eri.11.76. Review. — View Citation

Geary TG. Ivermectin 20 years on: maturation of a wonder drug. Trends Parasitol. 2005 Nov;21(11):530-2. Epub 2005 Aug 26. Review. — View Citation

Hoerauf A, Pfarr K, Mand S, Debrah AY, Specht S. Filariasis in Africa--treatment challenges and prospects. Clin Microbiol Infect. 2011 Jul;17(7):977-85. doi: 10.1111/j.1469-0691.2011.03586.x. Review. — View Citation

Hooper PJ, Bradley MH, Biswas G, Ottesen EA. The Global Programme to Eliminate Lymphatic Filariasis: health impact during its first 8 years (2000-2007). Ann Trop Med Parasitol. 2009 Oct;103 Suppl 1:S17-21. doi: 10.1179/000349809X12502035776513. — View Citation

Horton J. Albendazole: a broad spectrum anthelminthic for treatment of individuals and populations. Curr Opin Infect Dis. 2002 Dec;15(6):599-608. Review. — View Citation

Horton J. The development of albendazole for lymphatic filariasis. Ann Trop Med Parasitol. 2009 Oct;103 Suppl 1:S33-40. doi: 10.1179/000349809X12502035776595. Review. — View Citation

Hotez PJ, Savioli L, Fenwick A. Neglected tropical diseases of the Middle East and North Africa: review of their prevalence, distribution, and opportunities for control. PLoS Negl Trop Dis. 2012;6(2):e1475. doi: 10.1371/journal.pntd.0001475. Epub 2012 Feb 28. Review. — View Citation

Kitzman D, Wei SY, Fleckenstein L. Liquid chromatographic assay of ivermectin in human plasma for application to clinical pharmacokinetic studies. J Pharm Biomed Anal. 2006 Mar 3;40(4):1013-20. Epub 2005 Oct 19. — View Citation

Mand S, Debrah A, Batsa L, Adjei O, Hoerauf A. Reliable and frequent detection of adult Wuchereria bancrofti in Ghanaian women by ultrasonography. Trop Med Int Health. 2004 Oct;9(10):1111-4. — View Citation

McGarry HF, Plant LD, Taylor MJ. Diethylcarbamazine activity against Brugia malayi microfilariae is dependent on inducible nitric-oxide synthase and the cyclooxygenase pathway. Filaria J. 2005 Jun 2;4:4. — View Citation

Moreno Y, Nabhan JF, Solomon J, Mackenzie CD, Geary TG. Ivermectin disrupts the function of the excretory-secretory apparatus in microfilariae of Brugia malayi. Proc Natl Acad Sci U S A. 2010 Nov 16;107(46):20120-5. doi: 10.1073/pnas.1011983107. Epub 2010 Nov 1. — View Citation

Ottesen EA, Duke BO, Karam M, Behbehani K. Strategies and tools for the control/elimination of lymphatic filariasis. Bull World Health Organ. 1997;75(6):491-503. Review. — View Citation

Ottesen EA, Hooper PJ, Bradley M, Biswas G. The global programme to eliminate lymphatic filariasis: health impact after 8 years. PLoS Negl Trop Dis. 2008 Oct 8;2(10):e317. doi: 10.1371/journal.pntd.0000317. — View Citation

Ottesen EA. Lymphatic filariasis: Treatment, control and elimination. Adv Parasitol. 2006;61:395-441. Review. — View Citation

Teruel M, Dercole J, Catalano R. Evaluation of potential embryo toxicity of albendazole sulphoxide in CF1 mice. Biocell. 2011 Apr;35(1):29-33. — View Citation

Weil GJ, Curtis KC, Fakoli L, Fischer K, Gankpala L, Lammie PJ, Majewski AC, Pelletreau S, Won KY, Bolay FK, Fischer PU. Laboratory and field evaluation of a new rapid test for detecting Wuchereria bancrofti antigen in human blood. Am J Trop Med Hyg. 2013 Jul;89(1):11-15. doi: 10.4269/ajtmh.13-0089. Epub 2013 May 20. — View Citation

Zouré HG, Wanji S, Noma M, Amazigo UV, Diggle PJ, Tekle AH, Remme JH. The geographic distribution of Loa loa in Africa: results of large-scale implementation of the Rapid Assessment Procedure for Loiasis (RAPLOA). PLoS Negl Trop Dis. 2011 Jun;5(6):e1210. doi: 10.1371/journal.pntd.0001210. Epub 2011 Jun 28. — View Citation

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Total clearance of Microfilariae	The percentage of participants with total clearance of Microfilariae	36 months
Secondary	Total clearance of MF at 24 months	Percentage of subjects with total clearance of MF at 24 months	24 months
Secondary	Percent MF reduction	Percent MF reduction at 24 and 36 months compared to baseline level	24 and 36 months
Secondary	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
Secondary	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
Secondary	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
Secondary	Diversity of parasites	Diversity of parasites before and after treatment using genetic markers	0 and 36 months
Secondary	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