Clinical trial NCT06070116: Safety and Efficacy of Novel Combination Regimens for Treatment of Onchocerciasis
Official title: Safety and Efficacy of Novel Combination Regimens for Treatment of Onchocerciasis
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE2
Conditions: Onchocercal Subcutaneous Nodule
Onchocerciasis
Onchocerciasis, Ocular
Onchocerca Infection
Tropical Disease
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: National Public Health Institute of Liberia
First posted: 2023-10-06
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: IVM + ALB (IA) - Dose of oral IVM (150 µg/kg) plus ALB (400 mg)

Mox + ALB (MoxA) - Dose of oral Mox (8mg tablets) plus ALB (400mg)

IVM + DEC + ALB (IDA) - Dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)

MOX + DEC + IVM (MoxDA) - Dose of oral Mox (8 mg), DEC (6 mg/kg) and ALB (400 mg)
Primary purpose: TREATMENT

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

Detailed description: The open label, randomized clinical trial studies the safety and efficacy of combination regimens for the treatment of onchocerciasis. Around 300 participants from Bong Mines, Liberia will be randomly assigned to one of four treatment groups after receiving Ivermectin pre-treatment: Ivermectin plus Albendazole (IA0, Ivermectin plus DEC plus Albendazole (IDA), Moxidectin plus albendazole (MoxA), or Moxidectin plus DEC plus Albendazole (MoxDA). Participants will be treated at baseline and 6 months after initial treatment.

Safety will be measured through extensive adverse event monitoring from baseline to 6 months.

Efficacy of the treatment will be measured at 24 months after the initial treatment by the proportion of all adult female worms that are fertile in the Onchocerca nodules and the percentage of participants without microfilaremia at 6, 18, and 24 months after the first treatment.

Eligibility criteria: Inclusion Criteria:

* Adult men and women, 18 years to 75 years old
* Participants must have at least 1 palpable subcutaneous nodule (onchocercoma)
* Participants with mean skin Mf counts ≥ 1 Mf/mg at the time of enrollment (prior to pretreatment)

Exclusion Criteria:

* History of treatment with IVM or Mox less than six months prior to pretreatment with IVM.
* Treatment with IVM or Mox outside of the study after the pre-treatment clearing dose before treatment with one of the four study treatments.
* Pregnant or breastfeeding mothers.
* Severe ocular disease at baseline (assessed just prior to the first study treatment, approximately 6-12 months after IVM pretreatment). Briefly, these conditions include severe uveitis, severe glaucoma, severe keratitis, and/or cataracts that interfere with visualization of the posterior segment of the eye. Details regarding ocular exclusion criteria are provided below. Individuals who are excluded with significant ocular disease will be referred for appropriate All ocular disease exclusion criteria apply to either eye. That is to say, participants will be excluded if any of the ocular exclusion criteria listed below are met for either eye. These exclusions are needed to reduce the risk of study treatments worsening severe pre-existing ocular disease. They also are needed to ensure that study staff will be able to adequately evaluate the posterior segment before and after treatment.

  1. Any cataract that prevents clear visualization of fundus or imaging by OCT.
  2. Severe retinal nerve fiber layer thinning of the optic nerve in the superior and inferior quadrant analysis by OCT with a corresponding visual field defect in the superior and inferior hemifield, and/or visual field loss within 5 degrees of fixation in at least one hemifield. Note: If OCT is not available, the following exclusion criteria will apply: vertical cup/disc ratio by fundoscopy greater than or equal to 0.80 with a corresponding visual field defect in the superior and inferior hemifield, and/or visual field loss within 5 degrees of fixation in at least one hemifield.
  3. Intraocular pressure (IOP) greater than or equal to 25 by Goldmann tonometry.
  4. Retinal detachment or retinal break.
  5. Acute ocular infection (i.e., viral conjunctivitis, corneal ulcer, endophthalmitis).
  6. Optic atrophy with a reproducible visual field defect detected by confrontation visual field testing.
  7. Exam consistent with Herpes simplex virus eye infection.
  8. Homonymous hemianopsia, quadrantopsia, 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 participant.
  11. Severe tremor, blepharospasm, or other voluntary or involuntary motor condition that limits careful slit lamp examinations, OCT, gonioscopy, IOP measurement, fundus photography, and automated perimetry.
  12. Cognitive impairment that limits participant's ability to understand and perform a Visual Acuity Test with a 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. A history of uveitis not associated with onchocerciasis.
  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 the participant rates as 9 or 10 out of 10.
  18. Best corrected or pinhole visual acuity worse than 6/60 (20/200).
  19. Age-related macular degeneration (AMD).
  20. \>5 motile Mf in the anterior chamber in either eye at the time of secondary screening (6 months after pre-treatment with IVM).\*
  21. The presence of one or more Mf in the posterior segment of the eye (detected by any opthalmological test performed) at the time of treatment (at least six months after pre-treatment with IVM). \*Note regarding exclusion criteria t and u: The cut-off of 5 Mf in either anterior chamber was suggested by external reviewers of our proposal to the Gates Foundation. These were experts in onchocerciasis selected by the Foundation. The reviews were anonymous, so we do not know their names. They also suggested that we exclude persons with any Mf in the posterior segment of the eye, and we have added that exclusion criterion to the protocol.
* Significant comorbidities such as renal insufficiency (creatinine \> 2 times the upper limit of normal), liver disease (jaundice or either AST or ALT greater than 2.5 times the upper limit of normal), 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 or hypersensitivity reactions or intolerance to IVM, Mox, ALB, or DEC.
* Evidence of severe or systemic comorbidities (aside from features of onchocerciasis), as judged by a study physician. Persons with baseline medical conditions that correspond to adverse event severity scores of grade 3 or higher will also be excluded.
* Evidence of urinary tract infection as indicated by 3+ nitrites by dipstick (individuals with 1+ or 2+ nitrites will not be excluded) or underlying chronic kidney disease as indicated by 3+ protein or 3+ blood by dipstick. Persons with urinary tract infections can be enrolled after their infections are treated and cured.
* Hgb \<7 gm/dL; any such individuals will be referred to a local health center for evaluation and treatment).

Primary outcomes:
measure: Rates and types of severe or serious adverse events within 6 months following Ivermectin treatments
timeFrame: Baseline to 6 months
measure: Rates and types of severe or serious adverse events within 6 months following Moxidectin treatments
timeFrame: Baseline to 6 months
measure: Proportion of all adult female worms that are fertile 24 months after first treatment
timeFrame: 24 months
Secondary outcomes:
measure: Rates of adverse events grade 3 or higher by Ivermectin treatment group, that occur within 7 days of treatment
timeFrame: Baseline to 7 days after first treatment.
measure: Rates of adverse events grade 3 or higher by Moxidectin treatment group, that occur within 7 days of treatment
timeFrame: Baseline to 7 days after first treatment.
measure: Rates of adverse events grade 3 or higher in participants with ocular MF in Ivermectin treatment groups.
timeFrame: Baseline to 7 days after first treatment.
measure: Rates of adverse events grade 3 or higher in participants with ocular MF in Moxidectin treatment groups.
timeFrame: Baseline to 7 days after first treatment.
measure: Rates of ocular adverse events (any grade) by Ivermectin treatment group
timeFrame: Baseline to 7 days after first treatment.
measure: Rates of ocular adverse events (any grade) by Moxidectin treatment groups
timeFrame: Baseline to 7 days after first treatment.
measure: Percentage of adult female worms in nodules that are alive
timeFrame: 24 Months
measure: Percentage of nodules with microfilaria in tissue
timeFrame: 24 Months
measure: Percentage of nodules that do not contain living adult worms
timeFrame: 24 Months
measure: Percentage of participants without microfiladermia after the first study treatment.
timeFrame: 6, 18, and 24 Months
measure: Percentage of participants with recurrence of microfilariae in the skin across treatment groups
timeFrame: 18 and 24 Months
measure: Microfilariae density in the skin across treatment groups
timeFrame: 6, 8, and 24 Months
measure: Percentage of nodules with fully or partially calcified worms
timeFrame: 24 Months
Other outcomes:
Locations:
city: Bong Town
country: Liberia
facility: Bong County Hospital
state: Bong County
Study officials:
affiliation: Washington University School of Medicine
name: Peter Fischer, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Public Health Institute of Liberia
name: Patrick Kpanyen, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Washington University School of Medicine
name: Gary Weil, MD
role: PRINCIPAL_INVESTIGATOR
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