Efficacy, Safety, and PK of Ascending Dosages of Moxidectin Versus Ivermectin Against Strongyloides Stercoralis

Study Overview
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Brief Summary
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This study is a phase 2, blinded and randomized clinical trial. The phase 2a trial is single blinded and conducted in Lao, while the phase 2b trial is double-blinded and conducted in Lao and Cambodia. The study aims at providing evidence on effective doses and safety of moxidectin in adults against infection with S. stercoralis in Laos (trial 2a) and efficacy and safety of moxidectin compared to ivermectin in adults against infection with S. stercoralis in Laos and Cambodia (trial 2b). The efficacy of the treatment will be assessed by collecting three stool samples once pre-treatment and once 21 days post-treatment. The stool samples will be analyzed by a quantitative Baermann assay.

Detailed Description
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This is a phase 2a single-blinded and a phase 2b double-blinded randomized clinical trial, which aims to determine efficacy and safety of (2a) seven ascending oral moxidectin dosages in 210 adults infected with S. stercoralis, namely placebo, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg in Lao and (2b) the recommended dose moxidectin (i.e. the most promising dosage identified in trial A; between 2-12 mg) in comparison to the standard treatment dose of ivermectin (200 µg/kg) in 245 adults infected with S. stercoralis in Lao and Cambodia. Embedded in the trial is a pharmacokinetic/-dynamic study with the goal to measure moxidectin disposition in adults and to determine population pharmacokinetic (PK) parameters of the optimal dose of moxidectin in the treatment of S. stercoralis. The primary objective is to determine the dose-response of moxidectin based on cure rates (CR) against S. stercoralis and to quantify the efficacy of the recommended dose to the standard treatment (ivermectin) in adults. The secondary objectives of the trial are: Evaluation of the safety and tolerability of the dose-dependent treatment regimes, evaluation of the safety and tolerability of moxidectin compared to ivermectin, comparison of the larvae reduction rate (LRR) of the different treatment regimens against S. stercoralis (trial 2a,b), determination of an exposure- (including Cmax, area under curve (AUC) and tmax) -response correlation of moxidectin in adults, comparison of the exposure-response of moxidectin using venous and capillary blood, evaluation of the cure rate of the different moxidectin treatment regimens against co-infection and the determination of the population PK parameters of the optimal dose of moxidectin in the treatment of S. stercoralis. After obtaining informed consent from each individual, the medical history of the participants will be assessed with a standardized questionnaire, in addition to a clinical examination carried out by the study physician before treatment. Enrollment will be based on collection and analysis by a quantitative Baermann method (in duplicates) of three stool samples. Randomization of participants into the different treatment arms will be stratified according to intensity of infection. The adults will also be interviewed before treatment, 3 and 24 hours as well as 21 days after treatment about the occurrence of adverse events (AE). The efficacy of the treatment will be determined 21 days post-treatment by collecting another three stool samples. All stool samples will be examined with duplicate Baermann assays recorded quantitatively. Co-infection with T. trichiura, A. lumbricoides and hookworm infection will be identified using duplicate Kato-Katz thick smears on stool samples. A subsample of adults will further be sampled using finger pricking for micro sampling at 0, 2, 4, 8, 24, and 72 hours, 7 and 21 days post treatment to evaluate pharmacokinetic parameters (trial phase 2a) and at defined time windows, that are based on the PK model earned from trial 2a (trial phase 2b). For validation of the analytical method the subsample of one study arm (8 mg, trial phase 2a) will undergo venous blood sampling in addition to finger pricking. An available case analysis (full analysis set according to the intention to treat principle) will be performed, including all subjects with primary end point data. Supplementary, a per-protocol analysis will be conducted. CRs will be calculated as the percentage of larvae-positive subjects at baseline who become larvae-negative after treatment. Larvae per gram (LPG) stool sample will be assessed by calculating the mean of the larvae counts from the three duplicate Baermann assays and divided by the mean weighted amount of these stool samples. The LRR will be calculated following: (LRR = (1-(mean at follow-up/mean at baseline))*100) Geometric and arithmetic mean larvae counts will be calculated for the different treatment arms before and after treatment to assess the corresponding LRRs. Bootstrap resampling method with 2,000 replicates will be used to calculate 95% confidence intervals (CIs) for LRRs. Emax models using the dose finding package of the statistical software environment R will be implemented to predict the dose-response curves in terms of CRs and LRRs.

Official Title
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Efficacy, Safety and Pharmacokinetics of Ascending Dosages of Moxidectin Alone and in Comparison to Ivermectin Against Strongyloides Stercoralis in Adults: a Randomized Controlled Trial

Conditions
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Strongyloides Stercoralis Infection

Intervention / Treatment
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* Drug: Moxidectin
* Drug: Ivermectin
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults (≥ 18 years) infected with S. stercoralis Absence of major systemic illnesses Written informed consent signed by individual Exclusion Criteria: Any abnormal medical conditions or chronic disease Negative diagnostic result for S. stercoralis No written informed consent by individual. Pregnant and lactating women. Recent use of anthelmintic drug (within past 4 weeks), attending other clinical trials during the study Known allergy to study medications (i.e. moxidectin, ivermectin) Currently taking medications with known interaction (i.e. for warfarin)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Phase 2a: Parallel study with 7 treatment arms (including a placebo arm) Phase 2b: Parallel study with 3 treatment arms (including a placebo arm)
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 2a - Arm A<br>2 mg Moxidectin at day 0 administered orally | Drug: Moxidectin<br>* Monotherapy, oral administration, single dose, fixed dose<br>|
| Experimental: Phase 2a - Arm B<br>4 mg Moxidectin at day 0 administered orally | Drug: Moxidectin<br>* Monotherapy, oral administration, single dose, fixed dose<br>|
| Experimental: Phase 2a - Arm C<br>6 mg Moxidectin at day 0 administered orally | Drug: Moxidectin<br>* Monotherapy, oral administration, single dose, fixed dose<br>|
| Experimental: Phase 2a - Arm D<br>8 mg Moxidectin at day 0 administered orally | Drug: Moxidectin<br>* Monotherapy, oral administration, single dose, fixed dose<br>|
| Experimental: Phase 2a - Arm E<br>10 mg Moxidectin at day 0 administered orally | Drug: Moxidectin<br>* Monotherapy, oral administration, single dose, fixed dose<br>|
| Experimental: Phase 2a - Arm F<br>12 mg Moxidectin at day 0 administered orally | Drug: Moxidectin<br>* Monotherapy, oral administration, single dose, fixed dose<br>|
| Placebo Comparator: Phase 2a - Arm G<br>matching Placebo tablet(s) at day 0 administered orally | Drug: Placebo oral tablet<br>* Monotherapy, oral administration, single dose, matching number of tablets<br>|
| Experimental: Phase 2b - Arm A<br>the recommended dose moxidectin (i.e. the most promising dosage identified in trial A; between 2-12 mg) at day 0 administered orally | Drug: Moxidectin<br>* Monotherapy, oral administration, single dose, fixed dose<br>|
| Active Comparator: Phase 2b - Arm B<br>200 µg/kg ivermectin at day 0 administered orally | Drug: Ivermectin<br>* Monotherapy, oral administration, single dose, weight dependent<br>|
| Placebo Comparator: Phase 2b - Arm P<br>matching Placebo tablet(s) at day 0 administered orally | Drug: Placebo oral tablet<br>* Monotherapy, oral administration, single dose, matching number of tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cure rate against Strongyloidiasis stercoralis | The conversion from being larvae positive pre-treatment to larvae negative post-treatment, or cure rate (CR). | 14-21 days after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Larvae-reduction rate (LRR) against Strongyloidiasis stercoralis | Larvae per gram (LPG) stool sample will be assessed by calculating the mean of the larvae counts from the three duplicate Baermann assays and divided by the mean weighted amount of these stool samples. The LRR will be calculated following: (LRR = (1-(mean at follow-up/mean at baseline))*100) | 14-21 days after treatment | 
| CRs and LRRs against concomitant soil-transmitted helminth infections | CRs and LRRs will be calculated for T. trichiura, A. lumbricoides and hookworm infections as described in primary and secondary outcome. | 14-21 days after treatment | 
| Number of participants reporting adverse events | Subjects will be kept for observation for at least 3 hours following treatment for any acute AEs. If there is any abnormal finding, the local study physician will perform a full clinical, physical and biochemical examination and findings will be recorded. An emergency kit will be available on site to treat any medical conditions that warrant urgent medical intervention. In addition patients will also be interviewed 3 and 24 hours and again 3 weeks after treatment about the occurrence of AEs. A standardized symptom questionnaire is used, that includes the recording of headache, abdominal pain, itching, nausea, vomiting, diarrhea, allergic reaction as well as any further mentioned event by the participant. | 14-21 days after treatment | 
| Maximum concentration (Cmax) of moxidectin in adults | Upon oral intake moxidectin levels in blood will be quantified with time using a micro sampling device. Moxidectin will be quantified using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Drug concentrations will be calculated by interpolation from a calibration curve with a foreseen limit of quantification of approximately 5 ng/ml. The PK analysis will be undertaken fitting a structural compartmental PK model. | 0, 2, 4, 8, 24, and 72 hours, 7 and 21 days post treatment | 
| Time to reach Cmax (tmax) of moxidectin in adults | Upon oral intake moxidectin levels in blood will be quantified with time using a micro sampling device. Moxidectin will be quantified using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Drug concentrations will be calculated by interpolation from a calibration curve with a foreseen limit of quantification of approximately 5 ng/ml. The PK analysis will be undertaken fitting a structural compartmental PK model. | 0, 2, 4, 8, 24, and 72 hours, 7 and 21 days post treatment | 
| Area under the curve (AUC) of moxidectin in adults | Upon oral intake moxidectin levels in blood will be quantified with time using a micro sampling device. Moxidectin will be quantified using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Drug concentrations will be calculated by interpolation from a calibration curve with a foreseen limit of quantification of approximately 5 ng/ml. The PK analysis will be undertaken fitting a structural compartmental PK model. | 0, 2, 4, 8, 24, and 72 hours, 7 and 21 days post treatment | 
| Elimination half life (t1/2) of moxidectin in adults | Upon oral intake moxidectin levels in blood will be quantified with time using a micro sampling device. Moxidectin will be quantified using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Drug concentrations will be calculated by interpolation from a calibration curve with a foreseen limit of quantification of approximately 5 ng/ml. The PK analysis will be undertaken fitting a structural compartmental PK model. | 0, 2, 4, 8, 24, and 72 hours, 7 and 21 days post treatment |