Safety and Efficacy of IDA for Onchocerciasis

Onchocerciasis Clinical Trial

— DOLF IDA/Oncho  

Official title:

Safety and Efficacy of Combination Therapy With Ivermectin, Diethylcarbamazine, and Albendazole (IDA) for Individuals With Onchocerciasis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04188301
• Other study ID #: 201910085
• Status: Completed
• Phase: Phase 2
• Start date: December 6, 2019
• Est. completion date: June 1, 2022

Study information

• Verified date: April 2023
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This DOLF study will investigate the safety and effectiveness of IDA treatment in persons with onchocerciasis when it is administered after pre-treatment with ivermectin to clear or greatly reduce microfilariae from the skin and eyes.

Description:

This study will provide preliminary data on the safety of IDA treatment in persons with onchocerciasis when it is administered after pre-treatment with IVM to clear or greatly reduce microfilariae from the skin and eyes. Widespread use of IDA following IVM pretreatment (I/IDA) has the potential to greatly accelerate elimination of lymphatic filariasis (LF) in African countries that are co-endemic for LF and onchocerciasis. study later. This study will also assess the efficacy of IDA for killing and sterilizing adult filarial worms. An improved macrofilaricidal treatment would be a major advance for the global program to eliminate onchocerciasis. Since the safety and efficacy objectives are both very important, we have included dual primary objectives for the study. Primary objectives: - Safety: To compare rates and types of severe adverse events (grade 3 or higher) that occur within 7 days following 1 day or 3 days of treatment with triple drug treatment ("IDA" = diethylcarbamazine (DEC) with ivermectin (IVM) and albendazole (ALB)) with the comparator regimen of 1 day of treatment with ivermectin and albendazole (IA) in persons with active Onchocerca volvulus infections after pretreatment with ivermectin alone. - Efficacy: To compare the effect of three treatment regimens (1 day of IDA, 3 days of IDA, or IA) for killing or sterilizing adult female O. volvulus worms based on the percentage of all adult female worms in nodules that are alive with embryos in the uterus 18 months after treatment. This is an open label, randomized clinical trial.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 154
• Est. completion date: June 1, 2022
• Est. primary completion date: March 14, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years to 70 Years

Eligibility

Inclusion Criteria:

• Men and women who were previously enrolled in the preceding Part I study (Protocol ID#201804116) and residing in the study area
• Must have at least palpable subcutaneous nodule (onchocercoma)
• Participants with baseline skin Mf counts less than or equal to 3 Mf/mg at the time of enrollment into the Part I study (Protocol ID#201804116)

Exclusion Criteria:

• Pregnant and breastfeeding mothers within 1 month of giving birth
• Severe eye disease at baseline including uveitis, severe glaucoma, severe keratitis, and/or cataracts that interfere with visualization of the posterior segment of the eye as well as the list of ocular diseases as outlined below. All ocular disease exclusion criteria apply to either eye. Bilateral disease is not necessary to exclude a participant. A participant will be excluded if any of the criteria are met for one eye.

1. Any cataract of any type preventing clear visualization of fundus or imaging on Optical Coherence Tomography (OCT).

2. Severe retinal nerve fiber layer thinning in the superior and inferior quadrant analysis on Ocular Coherence Tomography of the optic nerve with a corresponding visual field defect of grade 2 or worse on the same eye.If Ocular Coherence Tomography is not available, the following exclusion criteria will apply: vertical Cup/disc ratio on fundoscopy (not by OCT reading) greater than or equal to 0.80.

3. Intraocular pressure (IOP) greater than or equal to 25 by Goldmann tonometry .12

4. Retinal Detachment or Retinal Break

5. Acute ocular infection (i.e., Viral conjunctivitis, corneal ulcer, endophthalmitis)

6. Optic Atrophy with visual field defect reproducible on confrontation visual field testing..

7. Exam consistent with Herpes Simplex Virus eye infection

8. Homonymous hemianopsia, quadrantanopsia, bitemporal hemianopsia, or central scotoma related to cerebral vascular disease by Automated Visual Field testing and confrontation visual field testing.

9. Acute Angle Closure Glaucoma

10. Gonioscopy grade 0 (slit) limiting ability to safely dilate patient

11. Severe Tremor, blepharospasm, or other voluntary or involuntary motor condition that prevents ability to examine patient with slit lamp, OCT, gonioscopy, IOP measurement, fundus photography, and Frequency doubling technology perimetry.

12. Cognitive impairment sufficient to prevent ability to understand and perform Visual Acuity Test with Tumbling E chart, confrontation visual field, slit lamp exam, or any other ocular exam component.

13. Optic nerve edema

14. Active retinopathy or retinitis not attributable to onchocercal disease

15. History of uveitis not associated with onchocercal disease

16. Any pre-existing chorioretinal scar or retinal degeneration and other significant retinal pathologies (foveomacular schisis, dystrophies, arterial macroaneurysms etc) involving the macula.

17. Severe ocular pain, that patient rates as 9 or 10 out of 10 pain.

18. Best corrected or pinhole visual acuity worse than 6/60 (20/200)

19. Age related macular degeneration (AMD)

• Significant comorbidities such as renal insufficiency, liver failure, or any other acute or chronic illness identified by study clinicians and investigators that interferes with the participant's ability to go to school or work or perform routine household chores.
• Prior allergic / hypersensitivity reactions or intolerance to IVM, ALB, or DEC.
• Treatment with IVM outside of the study after the pre-treatment clearing dose provided in the Part I study.
• >5 motile Mf in the anterior chamber in either eye at the time of enrollment (after pre-treatment with IVM).
• Any Mf identified in the posterior segment of the eye at the time of enrollment (six months after pre-treatment with IVM).
• Any other condition identified by study clinicians or investigators that may preclude participation in the study.

Related Conditions & MeSH terms

• Onchocerciasis

Intervention

Drug:
• IVM w/ ALB
Participants will be given a single dose of oral IVM (150 µg/kg) plus ALB (400 mg) (IVM/ALB)
• Single dose of IDA
Participants will be given a single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
• Three daily doses of IDA
Participants will be given one daily dose for 3 days of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)

Locations

Country	Name	City	State
Ghana	University of Health and Allied Sciences	Hohoe

Sponsors (3)

Lead Sponsor	Collaborator
Washington University School of Medicine	Case Western Reserve University, University of Health and Allied Sciences

Country where clinical trial is conducted

Ghana, 

References & Publications (41)

Awadzi K, Gilles HM. Diethylcarbamazine in the treatment of patients with onchocerciasis. Br J Clin Pharmacol. 1992 Oct;34(4):281-8. doi: 10.1111/j.1365-2125.1992.tb05632.x. No abstract available. — View Citation

Awadzi K, Opoku NO, Attah SK, Lazdins-Helds J, Kuesel AC. A randomized, single-ascending-dose, ivermectin-controlled, double-blind study of moxidectin in Onchocerca volvulus infection. PLoS Negl Trop Dis. 2014 Jun 26;8(6):e2953. doi: 10.1371/journal.pntd.0002953. eCollection 2014 Jun. — View Citation

Banla M, Tchalim S, Karabou PK, Gantin RG, Agba AI, Kere-Banla A, Helling-Giese G, Heuschkel C, Schulz-Key H, Soboslay PT. Sustainable control of onchocerciasis: ocular pathology in onchocerciasis patients treated annually with ivermectin for 23 years: a cohort study. PLoS One. 2014 Jun 2;9(6):e98411. doi: 10.1371/journal.pone.0098411. eCollection 2014. — View Citation

Basanez MG, Pion SD, Boakes E, Filipe JA, Churcher TS, Boussinesq M. Effect of single-dose ivermectin on Onchocerca volvulus: a systematic review and meta-analysis. Lancet Infect Dis. 2008 May;8(5):310-22. doi: 10.1016/S1473-3099(08)70099-9. — View Citation

Bird AC, Anderson J, Fuglsang H. Morphology of posterior segment lesions of the eye in patients with onchocerciasis. Br J Ophthalmol. 1976 Jan;60(1):2-20. doi: 10.1136/bjo.60.1.2. — View Citation

Bird AC, el-Sheikh H, Anderson J, Fuglsang H. Changes in visual function and in the posterior segment of the eye during treatment of onchocerciasis with diethylcarbamazine citrate. Br J Ophthalmol. 1980 Mar;64(3):191-200. doi: 10.1136/bjo.64.3.191. — View Citation

Braun G, McKechnie NM, Connor V, Gilbert CE, Engelbrecht F, Whitworth JA, Taylor DW. Immunological crossreactivity between a cloned antigen of Onchocerca volvulus and a component of the retinal pigment epithelium. J Exp Med. 1991 Jul 1;174(1):169-77. doi: 10.1084/jem.174.1.169. — View Citation

Chandrashekar R, Curtis KC, Weil GJ. Molecular characterization of a parasite antigen in sera from onchocerciasis patients that is immunologically cross-reactive with human keratin. J Infect Dis. 1995 Jun;171(6):1586-92. doi: 10.1093/infdis/171.6.1586. — View Citation

Chandrashekar R, Ogunrinade AF, Alvarez RM, Kale OO, Weil GJ. Circulating immune complex-associated parasite antigens in human onchocerciasis. J Infect Dis. 1990 Nov;162(5):1159-64. doi: 10.1093/infdis/162.5.1159. — View Citation

Dadzie KY, Bird AC, Awadzi K, Schulz-Key H, Gilles HM, Aziz MA. Ocular findings in a double-blind study of ivermectin versus diethylcarbamazine versus placebo in the treatment of onchocerciasis. Br J Ophthalmol. 1987 Feb;71(2):78-85. doi: 10.1136/bjo.71.2.78. — View Citation

Diawara L, Traore MO, Badji A, Bissan Y, Doumbia K, Goita SF, Konate L, Mounkoro K, Sarr MD, Seck AF, Toe L, Touree S, Remme JH. Feasibility of onchocerciasis elimination with ivermectin treatment in endemic foci in Africa: first evidence from studies in Mali and Senegal. PLoS Negl Trop Dis. 2009 Jul 21;3(7):e497. doi: 10.1371/journal.pntd.0000497. — View Citation

Donner A, Koval JJ. A multivariate analysis of family data. Am J Epidemiol. 1981 Jul;114(1):149-54. doi: 10.1093/oxfordjournals.aje.a113162. — View Citation

Duke BO. Human onchocerciasis--an overview of the disease. Acta Leiden. 1990;59(1-2):9-24. — View Citation

Eisenbarth A, Achukwi MD, Renz A. Ongoing Transmission of Onchocerca volvulus after 25 Years of Annual Ivermectin Mass Treatments in the Vina du Nord River Valley, in North Cameroon. PLoS Negl Trop Dis. 2016 Feb 29;10(2):e0004392. doi: 10.1371/journal.pntd.0004392. eCollection 2016 Feb. — View Citation

Evans DS, Unnasch TR, Richards FO. Onchocerciasis and lymphatic filariasis elimination in Africa: it's about time. Lancet. 2015 May 30;385(9983):2151-2. doi: 10.1016/S0140-6736(15)61022-4. No abstract available. — View Citation

Fischer P, Kipp W, Bamuhiga J, Binta-Kahwa J, Kiefer A, Buttner DW. Parasitological and clinical characterization of Simulium neavei-transmitted onchocerciasis in western Uganda. Trop Med Parasitol. 1993 Dec;44(4):311-21. — View Citation

Fischer PU, King CL, Jacobson JA, Weil GJ. Potential Value of Triple Drug Therapy with Ivermectin, Diethylcarbamazine, and Albendazole (IDA) to Accelerate Elimination of Lymphatic Filariasis and Onchocerciasis in Africa. PLoS Negl Trop Dis. 2017 Jan 5;11(1):e0005163. doi: 10.1371/journal.pntd.0005163. eCollection 2017 Jan. No abstract available. — View Citation

Fuglsang H, Anderson J. Further observations on the relationship between ocular onchocerciasis and the head nodule, and on the possible benefit of nodulectomy. Br J Ophthalmol. 1978 Jul;62(7):445-9. doi: 10.1136/bjo.62.7.445. — View Citation

Greene BM, Gbakima AA, Albiez EJ, Taylor HR. Humoral and cellular immune responses to Onchocerca volvulus infection in humans. Rev Infect Dis. 1985 Nov-Dec;7(6):789-95. doi: 10.1093/clinids/7.6.789. — View Citation

Greene BM, Taylor HR, Brown EJ, Humphrey RL, Lawley TJ. Ocular and systemic complications of diethylcarbamazine therapy for onchocerciasis: association with circulating immune complexes. J Infect Dis. 1983 May;147(5):890-7. doi: 10.1093/infdis/147.5.890. — View Citation

Greene BM, Taylor HR, Cupp EW, Murphy RP, White AT, Aziz MA, Schulz-Key H, D'Anna SA, Newland HS, Goldschmidt LP, et al. Comparison of ivermectin and diethylcarbamazine in the treatment of onchocerciasis. N Engl J Med. 1985 Jul 18;313(3):133-8. doi: 10.1056/NEJM198507183130301. — View Citation

Herricks JR, Hotez PJ, Wanga V, Coffeng LE, Haagsma JA, Basanez MG, Buckle G, Budke CM, Carabin H, Fevre EM, Furst T, Halasa YA, King CH, Murdoch ME, Ramaiah KD, Shepard DS, Stolk WA, Undurraga EA, Stanaway JD, Naghavi M, Murray CJL. The global burden of disease study 2013: What does it mean for the NTDs? PLoS Negl Trop Dis. 2017 Aug 3;11(8):e0005424. doi: 10.1371/journal.pntd.0005424. eCollection 2017 Aug. No abstract available. — View Citation

Johnson TP, Tyagi R, Lee PR, Lee MH, Johnson KR, Kowalak J, Elkahloun A, Medynets M, Hategan A, Kubofcik J, Sejvar J, Ratto J, Bunga S, Makumbi I, Aceng JR, Nutman TB, Dowell SF, Nath A. Nodding syndrome may be an autoimmune reaction to the parasitic worm Onchocerca volvulus. Sci Transl Med. 2017 Feb 15;9(377):eaaf6953. doi: 10.1126/scitranslmed.aaf6953. — View Citation

Jolodar A, Fischer P, Buttner DW, Miller DJ, Schmetz C, Brattig NW. Onchocerca volvulus: expression and immunolocalization of a nematode cathepsin D-like lysosomal aspartic protease. Exp Parasitol. 2004 Jul-Aug;107(3-4):145-56. doi: 10.1016/j.exppara.2004.06.006. — View Citation

Katabarwa MN, Eyamba A, Nwane P, Enyong P, Kamgno J, Kuete T, Yaya S, Aboutou R, Mukenge L, Kafando C, Siaka C, Mkpouwoueiko S, Ngangue D, Biholong BD, Andze GO. Fifteen years of annual mass treatment of onchocerciasis with ivermectin have not interrupted transmission in the west region of cameroon. J Parasitol Res. 2013;2013:420928. doi: 10.1155/2013/420928. Epub 2013 Apr 17. — View Citation

Kawabata M, Izui S, Anan S, Kondo S, Fukumoto S, Flores GZ, Kobayakawa T. Circulating immune complexes and their possible relevance to other immunological parameters in Guatemalan onchocerciasis. Int Arch Allergy Appl Immunol. 1983;72(2):128-33. doi: 10.1159/000234854. — View Citation

Opoku NO, Bakajika DK, Kanza EM, Howard H, Mambandu GL, Nyathirombo A, Nigo MM, Kasonia K, Masembe SL, Mumbere M, Kataliko K, Larbelee JP, Kpawor M, Bolay KM, Bolay F, Asare S, Attah SK, Olipoh G, Vaillant M, Halleux CM, Kuesel AC. Single dose moxidectin versus ivermectin for Onchocerca volvulus infection in Ghana, Liberia, and the Democratic Republic of the Congo: a randomised, controlled, double-blind phase 3 trial. Lancet. 2018 Oct 6;392(10154):1207-1216. doi: 10.1016/S0140-6736(17)32844-1. Epub 2018 Jan 18. Erratum In: Lancet. 2018 Oct 6;392(10154):1196. — View Citation

Rodriguez-Perez MA, Fernandez-Santos NA, Orozco-Algarra ME, Rodriguez-Atanacio JA, Dominguez-Vazquez A, Rodriguez-Morales KB, Real-Najarro O, Prado-Velasco FG, Cupp EW, Richards FO Jr, Hassan HK, Gonzalez-Roldan JF, Kuri-Morales PA, Unnasch TR. Elimination of Onchocerciasis from Mexico. PLoS Negl Trop Dis. 2015 Jul 10;9(7):e0003922. doi: 10.1371/journal.pntd.0003922. eCollection 2015. — View Citation

Rutterford C, Copas A, Eldridge S. Methods for sample size determination in cluster randomized trials. Int J Epidemiol. 2015 Jun;44(3):1051-67. doi: 10.1093/ije/dyv113. Epub 2015 Jul 13. — View Citation

Semba RD, Donnelly JJ, Young E, Green WR, Scott AL, Taylor HR. Experimental ocular onchocerciasis in cynomolgus monkeys. IV. Chorioretinitis elicited by Onchocerca volvulus microfilariae. Invest Ophthalmol Vis Sci. 1991 Apr;32(5):1499-507. — View Citation

Semba RD, Murphy RP, Newland HS, Awadzi K, Greene BM, Taylor HR. Longitudinal study of lesions of the posterior segment in onchocerciasis. Ophthalmology. 1990 Oct;97(10):1334-41. doi: 10.1016/s0161-6420(90)32413-2. — View Citation

Taylor HR, George T. Microfilaria in the cornea in onchocerciasis. Trans R Soc Trop Med Hyg. 1987;81(1):148. doi: 10.1016/0035-9203(87)90308-7. No abstract available. — View Citation

Taylor HR, Murphy RP, Newland HS, White AT, D'Anna SA, Keyvan-Larijani E, Aziz MA, Cupp EW, Greene BM. Treatment of onchocerciasis. The ocular effects of ivermectin and diethylcarbamazine. Arch Ophthalmol. 1986 Jun;104(6):863-70. doi: 10.1001/archopht.1986.01050180097039. — View Citation

Taylor HR, Semba RD, Newland HS, Keyvan-Larijani E, White A, Dukuly Z, Greene BM. Ivermectin treatment of patients with severe ocular onchocerciasis. Am J Trop Med Hyg. 1989 May;40(5):494-500. doi: 10.4269/ajtmh.1989.40.494. — View Citation

Taylor HR. Ivermectin treatment of ocular onchocerciasis. Acta Leiden. 1990;59(1-2):201-6. — View Citation

Taylor HR. Onchocerciasis. Int Ophthalmol. 1990 May;14(3):189-94. doi: 10.1007/BF00158317. — View Citation

Taylor MJ, Awadzi K, Basanez MG, Biritwum N, Boakye D, Boatin B, Bockarie M, Churcher TS, Debrah A, Edwards G, Hoerauf A, Mand S, Matthews G, Osei-Atweneboana M, Prichard RK, Wanji S, Adjei O. Onchocerciasis Control: Vision for the Future from a Ghanian perspective. Parasit Vectors. 2009 Jan 21;2(1):7. doi: 10.1186/1756-3305-2-7. — View Citation

Thomsen EK, Sanuku N, Baea M, Satofan S, Maki E, Lombore B, Schmidt MS, Siba PM, Weil GJ, Kazura JW, Fleckenstein LL, King CL. Efficacy, Safety, and Pharmacokinetics of Coadministered Diethylcarbamazine, Albendazole, and Ivermectin for Treatment of Bancroftian Filariasis. Clin Infect Dis. 2016 Feb 1;62(3):334-341. doi: 10.1093/cid/civ882. Epub 2015 Oct 20. — View Citation

Wojtkowski M, Bajraszewski T, Gorczynska I, Targowski P, Kowalczyk A, Wasilewski W, Radzewicz C. Ophthalmic imaging by spectral optical coherence tomography. Am J Ophthalmol. 2004 Sep;138(3):412-9. doi: 10.1016/j.ajo.2004.04.049. — View Citation

Zarroug IM, Hashim K, ElMubark WA, Shumo ZA, Salih KA, ElNojomi NA, Awad HA, Aziz N, Katabarwa M, Hassan HK, Unnasch TR, Mackenzie CD, Richards F, Higazi TB. The First Confirmed Elimination of an Onchocerciasis Focus in Africa: Abu Hamed, Sudan. Am J Trop Med Hyg. 2016 Nov 2;95(5):1037-1040. doi: 10.4269/ajtmh.16-0274. Epub 2016 Jun 27. — View Citation

Zimmerman PA, Dadzie KY, De Sole G, Remme J, Alley ES, Unnasch TR. Onchocerca volvulus DNA probe classification correlates with epidemiologic patterns of blindness. J Infect Dis. 1992 May;165(5):964-8. doi: 10.1093/infdis/165.5.964. — View Citation

* Note: There are 41 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rates of Severe Adverse Events (SAEs) Across Study Arms	Rates of severe adverse events (grade 3 or higher) following 1-day or 3-day triple drug treatment will be compared against those of the comparator regimen of 1 day of IVM/ALB.	Within 7 days following end of treatment
Primary	Percentage of Worms Killed Across Study Arms	The effect of three treatment regimens for killing adult female O. volvulus worms will be compared based on the percentage of all adult female worms in nodules that are alive with embryos in the uterus 18 months after treatment.	18 months following treatment.
Primary	Percentage of Worms Sterilized Across Study Arms	The effect of three treatment regimens for sterilizing adult female O. volvulus worms will be compared based on the percentage of all adult female worms that are fertile in the nodules 18 months after treatment.	18 months following treatment.
Secondary	Rates of SAEs by Treatment Group in Those With Intraocular Microfilariae Just Prior to Treatment With IDA	Rates of adverse events grade 3 or higher that occur within 7 days of treatment in the subset of participants who have intraocular microfilariae just prior to treatment with IDA will be compared by treatment group.	within 7 days following end of treatment
Secondary	Rates of Ocular Adverse Events (Any Grade) by Treatment Group	Rates of ocular adverse events of any grade within 3 months will be compared by treatment group.	within 3 months of treatment with IDA
Secondary	Effectiveness of Killing Adult Female Worms	The effectiveness of three treatment regimens for killing adult female O. volvulus worms based on the percentage of all adult female worms in nodules that are alive 18 months after treatment.	18 months following treatment
Secondary	Effectiveness of Clearing Microfilariae From Skin by Skin Snips	The effectiveness of three treatment regimens for complete clearance of microfilariae from the skin as determined by skin snips at 3, 12, and 18 months after treatment with IDA will be compared by treatment arm.	Baseline, 3 months, 12 months, & 18 months following treatment.
Secondary	Effectiveness for Preventing Reappearance of Microfilariae in the Skin by Skin Snips	The effectiveness of three treatment regimens for preventing reappearance of microfilariae in the skin as determined by skin snips at 12 and 18 months after treatment will be compared by treatment arm. Measured by the presence of microfilariae in skin snips.	Baseline, 12 months, and 18 months following treatment