Clinical trial NCT04056325: Efficacy, Safety, and PK of Ascending Dosages of Moxidectin Versus Ivermectin Against Strongyloides Stercoralis
Official title: Efficacy, Safety and Pharmacokinetics of Ascending Dosages of Moxidectin Alone and in Comparison to Ivermectin Against Strongyloides Stercoralis in Adults: a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Strongyloides Stercoralis Infection
Lead sponsor: Swiss Tropical & Public Health Institute
Sponsor class: OTHER
Collaborators: name: National Institute of Public Health, Vientiane, Laos
First posted: 2019-08-14
Enrollment: 617
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase 2a: Parallel study with 7 treatment arms (including a placebo arm) Phase 2b: Parallel study with 2 treatment arms
Primary purpose: TREATMENT

Brief summary: 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: 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 350 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Observed Cure Rate Against Strongyloides Stercoralis
timeFrame: Phase 2a: 21-28 days after treatment; phase 2b: 14-21 days after treatment
Secondary outcomes:
measure: Observed Larvae-reduction Rate (LRR) Against Strongyloides Stercoralis
timeFrame: Phase 2a: 21-28 days after treatment; phase 2b: 14-21 days after treatment
measure: Observed CRs Against Concomitant Soil-transmitted Helminth Infections - Ascaris Lumbricoides
timeFrame: Phase 2a: 21-28 days after treatment; phase 2b: 14-21 days after treatment
measure: Observed CRs Against Concomitant Soil-transmitted Helminth Infections - Trichuris Trichiura
timeFrame: Phase 2a: 21-28 days after treatment; phase 2b: 14-21 days after treatment
measure: Observed CRs Against Concomitant Soil-transmitted Helminth Infections - Hookworm
timeFrame: Phase 2a: 21-28 days after treatment; phase 2b: 14-21 days after treatment
measure: Number of Participants Reporting Adverse Events
timeFrame: 2-3 hours, 24 hours, and retrospectively 21-28 days (phase 2a) or 14-21 days (phase 2b Arm A and Arm B) after treatment.
measure: Maximum Concentration (Cmax) of Moxidectin in Adults
timeFrame: 0, 2, 4, 6, 7, 24, and 72 hours, and 28 days after treatment.
measure: Time to Reach Cmax (Tmax) of Moxidectin in Adults
timeFrame: 0, 2, 4, 6, 7, 24, and 72 hours, and 28 days after treatment.
measure: Area Under the Curve (AUC) of Moxidectin in Adults
timeFrame: 0, 2, 4, 6, 7, 24, and 72 hours, and 28 days after treatment.
measure: Elimination Half Life (T1/2) of Moxidectin in Adults
timeFrame: 0, 2, 4, 6, 7, 24, and 72 hours, and 28 days after treatment.
Other outcomes:
Locations:
city: Vientiane
country: Lao People's Democratic Republic
facility: National Institute of Public Health
Study officials:
affiliation: Swiss TPH
name: Jennifer Keiser, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Smit C, Hofmann D, Sayasone S, Keiser J, Pfister M. Characterization of the Population Pharmacokinetics of Moxidectin in Adults Infected with Strongyloides Stercoralis: Support for a Fixed-Dose Treatment Regimen. Clin Pharmacokinet. 2022 Jan;61(1):123-132. doi: 10.1007/s40262-021-01048-4. Epub 2021 Jul 23.
citation: Hofmann D, Sayasone S, Sengngam K, Chongvilay B, Hattendorf J, Keiser J. Efficacy and safety of ascending doses of moxidectin against Strongyloides stercoralis infections in adults: a randomised, parallel-group, single-blinded, placebo-controlled, dose-ranging, phase 2a trial. Lancet Infect Dis. 2021 Aug;21(8):1151-1160. doi: 10.1016/S1473-3099(20)30691-5. Epub 2021 Mar 30.