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

Study Overview
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Brief Summary
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The study is an extension to the study StrongMoxi NCT04056325 and entails modifications based on the outcome of NCT04056325 part A. The study is a phase 3, double-blinded and randomized clinical trial conducted in Cambodia. It aims at providing evidence on efficacy, safety and pharmacokinetic measures of 8 mg of moxidectin compared to 200 μg/kg ivermectin in adults infected with S. stercoralis. The efficacy of the treatment will be assessed by collecting three stool samples once per-treatment and once 21-28 days post-treatment. The stool samples will be analyzed by a quantitative duplicate Baermann assay.

Detailed Description
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The study is a phase 3 trial and will determine the efficacy and safety of: 8 mg of moxidectin in comparison to the standard treatment dose of ivermectin (200 μg/kg) in adults infected with S. stercoralis and to measure moxidectin disposition in adults using a microsampling device. Our primary objective is to demonstrate non-inferiority in terms of cure rate (CR) against S. stercoralis in adults of an oral 8 mg of moxidectin compared to 200 μg/kg of ivermectin. The secondary objectives of the trial are: to evaluate the safety and tolerability of moxidectin to compare the larval reduction rate (LRR) of the two different treatment groups against S. stercoralis to evaluate the CRs and egg reduction rates (ERRs) of the different treatment drugs and regimens against soil-transmitted helminths (STH) co-infections. to determine the population pharmacokinetics (popPK) of moxidectin administered to S. stercoralis-infected in adolescents, as well as normal and underweight adults. to investigate potential extended effects on follow-up helminth prevalence at 42-49 and 63-70 days post-treatment to relate socioeconomic characteristics (SES), access to sanitation, water facilities, hygiene to baseline infection intensity. to determine the larval excretion pattern till day 70 in the moxidectin treatment arm, determined at every second day between day zero and 70 post-treatment in a subset of 50 adults. to determine the origin of the remaining worm burden after treatment to treatment failure and reinfection based on genetic profiling. Three stool samples will be collected at baseline analysed in duplicates by a quantitative Baermann method for S. stercoralis infection. Co-infection with other Helminths species will be identified using duplicate Kato-Katz thick smears on two stool samples. The medical history of the participants will be assessed with a standardized questionnaire, in addition to a clinical and physical examination carried out by the study physician shortly before the treatment day. Each participant will be asked to provide a finger-prick blood sample for haemoglobin measurements at baseline. Enrolled participants will be treated with either 8 mg of moxidectin or with the standard treatment ivermectin (200 μg/kg). The adults will be interviewed a) before treatment, 3 and 24 hours as well as 21-28, 42-49 and 63-70 days after treatment about the occurrence of adverse events. The efficacy of the treatment will be determined 21-28 days of post-treatment. All stool samples will be examined with quantitative sixtuplicate Baermann assays and quadruplet Kato-Katz thick smears. At 42-49 and 63-70 days post-treatment another three stool samples will be collected and quantified for S. stercoralis larvae using Baermann assay to assess potential long-term benefits of the study drugs and treatment regimen. Of 50 adults in the moxidectin arm only, additional stool samples will be collected every second day between treatment and 70 days post treatment to evaluate larval secretion patterns. To determine the PK parameters of the study drug, a subsample of 10 willing youngest adults (aged 18 20 years old) and voluntary 20 adults (aged 18-65) in the moxidectin arm will further be asked to provide 3 finger pricks of blood per participant. The finger pricks will be collected within three consecutive days of post-treatment application. Not more than two finger pricks will be taken on the same day. To all participating households, a brief questionnaire will be administered assessing information on socioeconomic characteristics (SES) and access to sanitation, water facilities, and hygiene behaviour. An available case analysis (full analysis set according to the intention to treat principle) will be performed, including all participants with primary endpoint data. CRs will be calculated as the percentage of larvae-positive subjects at baseline who become larvae-negative after treatment, assessed 21-28 days post-treatment by sextuplicate Baermann. Uncertainty estimates around the differences among CRs will be assessed using melded confidence intervals with mid-p correction. The non-inferiority.

Official Title
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Efficacy, Safety and Pharmacokinetics of Moxidectin and Its Comparison to Ivermectin Against Strongyloides Stercoralis in Adults: a Randomized Controlled Non-inferiority Trial

Conditions
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Strongyloides Stercoralis Infection

Intervention / Treatment
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* Drug: Moxidectin 2 mg
* Drug: Ivermectin 3 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults (18-65 years) Infected with S. stercoralis (positive) Absence of major systemic illnesses Written informed consent Exclusion Criteria: Any abnormal medical conditions or chronic disease Negative diagnostic result for S. stercoralis No written informed consent by the individual. Pregnant and lactating women. Recent use of an 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: 65 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: Parallel study with 2 treatment arms
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Moxidectin<br>8 mg Moxidectin at day 0 administered orally | Drug: Moxidectin 2 mg<br>* Monotherapy, oral administration, single-dose, fixed-dose, 4 tablets a 2 mg to yield an 8 mg final dose.<br>Drug: Placebo<br>* Monotherapy, oral administration, single dose, matching number of tablets to either moxidectin or ivermectin<br>|
| Experimental: Ivermectin<br>200 ug/kg Ivermectin at day 0 administered orally | Drug: Ivermectin 3 mg<br>* Monotherapy, oral administration, single-dose, weight dependent, The number of tablets will be adjusted according to the patients' weight to yield 200 ug/kg final dose.<br>Drug: Placebo<br>* Monotherapy, oral administration, single dose, matching number of tablets to either moxidectin or ivermectin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cure rate against Strongyloides stercoralis | The conversion from being larvae positive pre-treatment to larvae negative post-treatment, or cure rate (CR). | 21-28 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) | 21-28, 42-49 and 63-70 days after treatment (All) or every second day between day 0 and day 70 (Arm Moxidectin, n=50) | 
| CRs against concomitant soil-transmitted helminth infections | CRs will be calculated for T. trichiura, A. lumbricoides and hookworm infections as described in primary outcome. | 21-28 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 adverse events. 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 at several points after treatment about the occurrence of adverse events. A standardized symptom questionnaire is used, that includes the recording of headache, abdominal pain, itching, nausea, vomiting, diarrhoea, allergic reaction as well as any further mentioned event by the participant. | 3 hours, 24 hours, 21-28 days, 42-49 days , 63-70 days after treatment | 
| Maximum concentration (Cmax) of moxidectin in adults, young adults and adults with a BMI <19 | 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. | 0-24 hours after treatment | 
| Time to reach Cmax (tmax) of moxidectin in adults, young adults and adults with a BMI <19 | 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. | 0-24 hours after treatment | 
| Area under the curve (AUC) of moxidectin in adults, young adults and adults with a BMI <19 | Upon oral intake, moxidectin levels in the blood will be quantified with time using a microsampling 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 pharmacokinetic analysis will be undertaken fitting a structural compartmental PK model. | 0-24 hours after treatment | 
| Elimination half life (t1/2) of moxidectin in adults, young adults and adults with a BMI <19 | Upon oral intake, moxidectin levels in the blood will be quantified with time using a microsampling 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 pharmacokinetic analysis will be undertaken fitting a structural compartmental pharmacokinetic model. | 0-24 hours after treatment | 
| Genetic profiling of S. stercoralis positive stool samples | From all S. stercoralis positive stool samples, the extracted larvae will be stored in 70% Ethanol after examination by Baermann. Samples will be shipped to the investigating laboratory (La Trobe University) at room temperature. | Pre-treatment | 
| Socioeconomic characteristics (SES) | To all participating households, a brief questionnaire will be administered assessing information on socioeconomic characteristics (SES) and access to sanitation, water facilities, and hygiene behaviour. | Pre-treatment |