Efficacy and Safety of Moxidectin Versus Ivermectin Against Strongyloides Stercoralis

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:

1. to evaluate the safety and tolerability of moxidectin
2. to compare the larval reduction rate (LRR) of the two different treatment groups against S. stercoralis
3. to evaluate the CRs of the different treatment drugs and regimens against soil-transmitted helminths (STH) co-infections.
4. to investigate potential extended effects on follow-up helminth prevalence at 42-49 and 63-70 days post-treatment
5. to relate socioeconomic characteristics (SES), access to sanitation, water facilities, hygiene to baseline infection intensity.
6. 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.
7. 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, 2-3 and 24 hours as well as 14-21, 42-49 and 63-70 days after treatment about the occurrence of adverse events. The efficacy of the treatment will be determined 14-21 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 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 14-21 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.

• Moxidectin 2 mg (Drug): Monotherapy, oral administration, single-dose, fixed-dose, 4 tablets of 2 mg each to yield an 8 mg final dose.
• Ivermectin 3 mg (Drug): 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.
• Placebo (Drug): Monotherapy, oral administration, single dose, matching number of tablets to either moxidectin or ivermectin

Primary outcomes

• Cure Rate Against Strongyloides Stercoralis [14-21 days after treatment]: The conversion from being larvae positive pre-treatment to larvae negative post-treatment, or cure rate (CR).

Secondary outcomes

• Larvae Reduction Rate (LRR) Against Strongyloidiasis Stercoralis [14-21 days after treatment. The originally planned follow-ups at 42-49 days and 63-70 days as well as the sample collection every second day between day 0 and day 70 (Moxidectin arm, n=50) was not performed.]: 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)
• CRs Against Concomitant Soil-transmitted Helminth Infections - Ascaris Lumbricoides [14-21 days after treatment]: CRs will be calculated for Ascaris lumbricoides, Trichuris trichiura and hookworm infections as described in primary outcome.
• CRs Against Concomitant Soil-transmitted Helminth Infections - Trichuris Trichiura [14-21 days after treatment]: CRs will be calculated for Ascaris lumbricoides, Trichuris trichiura and hookworm infections as described in primary outcome.
• CRs Against Concomitant Soil-transmitted Helminth Infections - Hookworm [14-21 days after treatment]: CRs will be calculated for Ascaris lumbricoides, Trichuris trichiura and hookworm infections as described in primary outcome.
• Number of Participants Reporting Adverse Events [2-3 hours, 24 hours and 14-21 days after treatment. The originally planned follow-ups at 42-49 days and 63-70 days after treatment were not conducted.]: Participants will be monitored on site for at least 3 hours following treatment for any acute adverse events. In addition, participants will be interviewed 2-3 and 24 hours and at several weeks 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, diarrhea, allergic reaction as well as any further mentioned event by the participant.

Other outcomes

• Socioeconomic Characteristics (SES) [Pre-treatment]: 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.
• Genetic Profiling of S. Stercoralis Positive Stool Samples [Pre-treatment]: 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.

Sex: All, ages: 18 Years to 65 Years

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)

Participant flow

Outcome results

• Cure Rate Against Strongyloides Stercoralis (Primary), Number, percentage of participants: Moxidectin 94.8 (90.0 to 97.7); Ivermectin 99.4 (96.6 to 100)
• Larvae Reduction Rate (LRR) Against Strongyloidiasis Stercoralis (Secondary), Geometric mean, percent change: Moxidectin 98.8 (96.0 to 99.9); Ivermectin 100 (100 to 100)
• CRs Against Concomitant Soil-transmitted Helminth Infections - Ascaris Lumbricoides (Secondary)
• CRs Against Concomitant Soil-transmitted Helminth Infections - Trichuris Trichiura (Secondary)
• CRs Against Concomitant Soil-transmitted Helminth Infections - Hookworm (Secondary), Number, percentage of participants: Moxidectin 82.0 (74.7 to 89.2); Ivermectin 81.0 (73.2 to 88.8)
• Number of Participants Reporting Adverse Events (Secondary), Count of participants, Participants: Moxidectin 4; Ivermectin 10
• Socioeconomic Characteristics (SES) (Other pre specified)
• Genetic Profiling of S. Stercoralis Positive Stool Samples (Other pre specified)

Adverse events

Time frame: 14-21 days

Other adverse events by term

• Results publication: Sprecher VP, Hofmann D, Savathdy V, Xayavong P, Norkhankhame C, Huy R, Khieu V, Sayasone S, Hattendorf J, Keiser J. Efficacy and safety of moxidectin compared with ivermectin against Strongyloides stercoralis infection in adults in Laos and Cambodia: a randomised, double-blind, non-inferiority, phase 2b/3 trial. Lancet Infect Dis. 2024 Feb;24(2):196-205. doi: 10.1016/S1473-3099(23)00507-8. Epub 2023 Nov 7. PMID 37949090

• Study Protocol and Statistical Analysis Plan (PDF, 2022-02-10)

• Jennifer Keiser, Prof. Dr, Principal investigator, STPH