Onchocerciasis
Conditions
Keywords
ophthalmology
Brief 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.
Detailed 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.
Interventions
DRUGIVM w/ ALB
Participants will be given a single dose of oral IVM (150 µg/kg) plus ALB (400 mg) (IVM/ALB)
DRUGSingle dose of IDA
Participants will be given a single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
DRUGThree 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)
Sponsors
Case Western Reserve University
University of Health and Allied Sciences
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
While this is an open label study and there is no placebo treatment group, all efforts will be made to ensure that that medical/technical staff assessing skin Mf, adverse events (AEs) and ophthalmological findings will be unaware of initial baseline skin and ocular Mf findings and treatment arm as best as possible.
Intervention model description
Participants will be split into two strata - those without ocular Mf detected six months after ivermectin pretreatment in the Part I preceding study AND without ocular Mf detected at baseline in the part II study will be in stratum 1. Those participants with ocular Mf detected 6 months after ivermectin pretreatment in the preceding study OR with ocular Mf detected at the baseline exam for this study will be in stratum 2. Stratum 1 will be enrolled first, followed by stratum 2. Members of each stratum will be evenly randomized into one of three treatment arms: 1. IVM + ALB - Single dose of oral IVM (150 µg/kg) plus ALB (400 mg) (IVM/ALB) 2. IDA x 1 dose - Single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg) 3. IDA x 3 doses -Once daily for 3 days oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Eligibility
Sex/Gender
ALL
Age
16 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rates of Severe Adverse Events (SAEs) Across Study Arms | Within 7 days following end of treatment | 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. |
| Percentage of Worms Killed Across Study Arms | 18 months following treatment. | 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. |
| Percentage of Worms Sterilized Across Study Arms | 18 months following treatment. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effectiveness of Clearing Microfilariae From Skin by Skin Snips | Baseline, 3 months, 12 months, & 18 months following treatment. | 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. |
| Rates of SAEs by Treatment Group in Those With Intraocular Microfilariae Just Prior to Treatment With IDA | within 7 days following end of treatment | 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. |
| Effectiveness for Preventing Reappearance of Microfilariae in the Skin by Skin Snips | Baseline, 12 months, and 18 months following treatment | 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. |
| Rates of Ocular Adverse Events (Any Grade) by Treatment Group | within 3 months of treatment with IDA | Rates of ocular adverse events of any grade within 3 months will be compared by treatment group. |
| Effectiveness of Killing Adult Female Worms | 18 months following treatment | 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. |
Countries
Ghana
Participant flow
Recruitment details
Participants recruited in the Nkwanta North District in the Volta Region in Ghana through open community meetings.
Participants by arm
| Arm | Count |
|---|---|
| IVM + ALB Single dose of oral IVM (150 µg/kg) plus ALB (400 mg)
IVM w/ ALB: Participants will be given a single dose of oral IVM (150 µg/kg) plus ALB (400 mg) (IVM/ALB) | 52 |
| IDA x 1 Dose Single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
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) | 51 |
| IDA x 3 Doses Once daily for 3 days 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) | 51 |
| Total | 154 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Month 12 | Death | 1 | 1 | 0 |
| Month 12 | Lost to Follow-up | 0 | 0 | 2 |
| Month 18 | Lost to Follow-up | 6 | 0 | 0 |
| Month 3 | Lost to Follow-up | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | IVM + ALB | IDA x 1 Dose | IDA x 3 Doses | Total |
|---|---|---|---|---|
| Age, Continuous | 40.3 years STANDARD_DEVIATION 12.18 | 38.52 years STANDARD_DEVIATION 14.08 | 37.65 years STANDARD_DEVIATION 2.16 | 37.65 years STANDARD_DEVIATION 13.32 |
| Ocular Microfilarae positive Negative for ocular microfilarae | 50 Participants | 49 Participants | 51 Participants | 150 Participants |
| Ocular Microfilarae positive Positive for ocular microfilarae | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Race and Ethnicity Not Collected | — | — | — | 0 Participants |
| Region of Enrollment Ghana | 52 participants | 51 participants | 51 participants | 154 participants |
| Sex: Female, Male Female | 21 Participants | 18 Participants | 11 Participants | 50 Participants |
| Sex: Female, Male Male | 31 Participants | 33 Participants | 40 Participants | 104 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 52 | 1 / 51 | 0 / 51 |
| other Total, other adverse events | 11 / 52 | 15 / 51 | 11 / 51 |
| serious Total, serious adverse events | 0 / 52 | 0 / 51 | 0 / 51 |
Outcome results
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.
Time frame: 18 months following treatment.
Population: The analysis was conducted on worms from participants who had nodulectomies conducted at 18 months. Not all participants who completed the study had nodulectomies conducted.
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| IVM + ALB | Percentage of Worms Killed Across Study Arms | 127 Female worms in nodules |
| IDA x 1 Dose | Percentage of Worms Killed Across Study Arms | 142 Female worms in nodules |
| IDA x 3 Doses | Percentage of Worms Killed Across Study Arms | 159 Female worms in nodules |
Comparison: IA vs IDA for living female O. volvulus worms in nodules after treatment.p-value: 0.19295% CI: [0.84, 2.38]Regression, Logistic
Comparison: IA vs IDA3 for living female O. volvulus worms in nodules after treatment.p-value: 0.10795% CI: [0.92, 2.29]Regression, Logistic
p-value: 0.06895% CI: [0.97, 2.15]Regression, Logistic
Comparison: IDA vs IDA3 for living female O. volvulus worms in nodules after treatment.p-value: 0.91895% CI: [0.59, 1.79]Regression, Logistic
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.
Time frame: 18 months following treatment.
Population: The analysis was conducted on worms from participants who had nodulectomies conducted at 18 months. Not all participants who completed the study had nodulectomies conducted. Female worms were excluded who had collapsed uteri that could not be evaluated for fertility.
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| IVM + ALB | Percentage of Worms Sterilized Across Study Arms | 41 Female worms with intact uterus |
| IDA x 1 Dose | Percentage of Worms Sterilized Across Study Arms | 40 Female worms with intact uterus |
| IDA x 3 Doses | Percentage of Worms Sterilized Across Study Arms | 34 Female worms with intact uterus |
Comparison: IA vs IDA in fertile female O. volvulus worms in nodules after treatment.p-value: 0.13495% CI: [0.85, 3.21]Regression, Logistic
Comparison: IA vs IDA3 for fertile female O. volvulus worms in nodules after treatment.p-value: 0.02395% CI: [1.12, 4.44]Regression, Logistic
Comparison: IDA1 vs IDA3 for fertile female O. volvulus worms in nodules after treatment.p-value: 0.4395% CI: [0.64, 2.85]Regression, Logistic
Comparison: IA vs IDA treatment groups for fertile female O. volvulus worms in nodules after treatment.p-value: 0.02395% CI: [1.09, 3.34]Regression, Logistic
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.
Time frame: Within 7 days following end of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IVM + ALB | Rates of Severe Adverse Events (SAEs) Across Study Arms | 0 Participants |
| IDA x 1 Dose | Rates of Severe Adverse Events (SAEs) Across Study Arms | 0 Participants |
| IDA x 3 Doses | Rates of Severe Adverse Events (SAEs) Across Study Arms | 0 Participants |
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.
Time frame: Baseline, 12 months, and 18 months following treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IVM + ALB | Effectiveness for Preventing Reappearance of Microfilariae in the Skin by Skin Snips | Month 12 | 23 Count of microfilarae+ participants |
| IVM + ALB | Effectiveness for Preventing Reappearance of Microfilariae in the Skin by Skin Snips | Baseline | 7 Count of microfilarae+ participants |
| IVM + ALB | Effectiveness for Preventing Reappearance of Microfilariae in the Skin by Skin Snips | Month 18 | 20 Count of microfilarae+ participants |
| IDA x 1 Dose | Effectiveness for Preventing Reappearance of Microfilariae in the Skin by Skin Snips | Month 12 | 21 Count of microfilarae+ participants |
| IDA x 1 Dose | Effectiveness for Preventing Reappearance of Microfilariae in the Skin by Skin Snips | Baseline | 6 Count of microfilarae+ participants |
| IDA x 1 Dose | Effectiveness for Preventing Reappearance of Microfilariae in the Skin by Skin Snips | Month 18 | 15 Count of microfilarae+ participants |
| IDA x 3 Doses | Effectiveness for Preventing Reappearance of Microfilariae in the Skin by Skin Snips | Baseline | 0 Count of microfilarae+ participants |
| IDA x 3 Doses | Effectiveness for Preventing Reappearance of Microfilariae in the Skin by Skin Snips | Month 18 | 17 Count of microfilarae+ participants |
| IDA x 3 Doses | Effectiveness for Preventing Reappearance of Microfilariae in the Skin by Skin Snips | Month 12 | 21 Count of microfilarae+ participants |
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.
Time frame: Baseline, 3 months, 12 months, & 18 months following treatment.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| IVM + ALB | Effectiveness of Clearing Microfilariae From Skin by Skin Snips | Baseline | 3.1 Count of Skin Microfilaria |
| IVM + ALB | Effectiveness of Clearing Microfilariae From Skin by Skin Snips | Month 3 | 1.9 Count of Skin Microfilaria |
| IVM + ALB | Effectiveness of Clearing Microfilariae From Skin by Skin Snips | Month 12 | 4.9 Count of Skin Microfilaria |
| IVM + ALB | Effectiveness of Clearing Microfilariae From Skin by Skin Snips | Month 18 | 7.0 Count of Skin Microfilaria |
| IDA x 1 Dose | Effectiveness of Clearing Microfilariae From Skin by Skin Snips | Month 18 | 9.0 Count of Skin Microfilaria |
| IDA x 1 Dose | Effectiveness of Clearing Microfilariae From Skin by Skin Snips | Baseline | 1.7 Count of Skin Microfilaria |
| IDA x 1 Dose | Effectiveness of Clearing Microfilariae From Skin by Skin Snips | Month 12 | 2.5 Count of Skin Microfilaria |
| IDA x 1 Dose | Effectiveness of Clearing Microfilariae From Skin by Skin Snips | Month 3 | 3 Count of Skin Microfilaria |
| IDA x 3 Doses | Effectiveness of Clearing Microfilariae From Skin by Skin Snips | Month 18 | 8.6 Count of Skin Microfilaria |
| IDA x 3 Doses | Effectiveness of Clearing Microfilariae From Skin by Skin Snips | Month 3 | 2.1 Count of Skin Microfilaria |
| IDA x 3 Doses | Effectiveness of Clearing Microfilariae From Skin by Skin Snips | Month 12 | 4.7 Count of Skin Microfilaria |
| IDA x 3 Doses | Effectiveness of Clearing Microfilariae From Skin by Skin Snips | Baseline | NA Count of Skin Microfilaria |
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.
Time frame: 18 months following treatment
Population: Analysis conducted on participants who had nodulectomies conducted at 18 months. Not all participants who completed the study had nodulectomies conducted.
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| IVM + ALB | Effectiveness of Killing Adult Female Worms | 127 Female worms in nodule |
| IDA x 1 Dose | Effectiveness of Killing Adult Female Worms | 142 Female worms in nodule |
| IDA x 3 Doses | Effectiveness of Killing Adult Female Worms | 159 Female worms in nodule |
Comparison: IA vs IDA for living female O. volvulus worms in nodules after treatment.p-value: 0.19295% CI: [0.84, 2.38]Regression, Logistic
Comparison: IA vs IDA3 for living female O. volvulus worms in nodules after treatment.p-value: 0.10795% CI: [0.92, 2.29]Regression, Logistic
Comparison: IA vs IDA groups for living female O. volvulus worms in nodules after treatment.p-value: 0.06895% CI: [0.97, 2.15]Regression, Logistic
Comparison: IDA vs IDA3 for living female O. volvulus worms in nodules after treatment.p-value: 0.91895% CI: [0.59, 1.79]Regression, Logistic
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.
Time frame: within 3 months of treatment with IDA
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IVM + ALB | Rates of Ocular Adverse Events (Any Grade) by Treatment Group | 4 Participants |
| IDA x 1 Dose | Rates of Ocular Adverse Events (Any Grade) by Treatment Group | 4 Participants |
| IDA x 3 Doses | Rates of Ocular Adverse Events (Any Grade) by Treatment Group | 3 Participants |
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.
Time frame: within 7 days following end of treatment
Population: For the Arm IDA x 3 doses, no participants had intraocular microfilariae present at baseline.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IVM + ALB | Rates of SAEs by Treatment Group in Those With Intraocular Microfilariae Just Prior to Treatment With IDA | 0 Participants |
| IDA x 1 Dose | Rates of SAEs by Treatment Group in Those With Intraocular Microfilariae Just Prior to Treatment With IDA | 0 Participants |
| IDA x 3 Doses | Rates of SAEs by Treatment Group in Those With Intraocular Microfilariae Just Prior to Treatment With IDA | 0 Participants |