Strongyloides Stercoralis Infection
Conditions
Brief summary
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
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.
Interventions
DRUGMoxidectin 2 mg
Monotherapy, oral administration, single-dose, fixed-dose, 4 tablets of 2 mg each to yield an 8 mg final dose.
DRUGIvermectin 3 mg
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.
DRUGPlacebo
Monotherapy, oral administration, single dose, matching number of tablets to either moxidectin or ivermectin
Sponsors
National Centre for Parasitology, Entomology and Malaria Control, Cambodia
Jennifer Keiser
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blinded (Participant and Care provider) Additionally, the principal investigator and the statistician will be blinded. PK substudy is single-blinded (Participant)
Intervention model description
Parallel study with 2 treatment arms
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Cambodia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Moxidectin 8 mg Moxidectin at day 0 administered orally
Moxidectin 2 mg: Monotherapy, oral administration, single-dose, fixed-dose, 4 tablets of 2 mg each to yield an 8 mg final dose.
Placebo: Monotherapy, oral administration, single dose, matching number of tablets to either moxidectin or ivermectin | 166 |
| Ivermectin 200 ug/kg Ivermectin at day 0 administered orally
Ivermectin 3 mg: 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: Monotherapy, oral administration, single dose, matching number of tablets to either moxidectin or ivermectin | 166 |
| Total | 332 |
Baseline characteristics
| Characteristic | Ivermectin | Total | Moxidectin |
|---|---|---|---|
| Age, Continuous | 45.0 years STANDARD_DEVIATION 12.7 | 44.9 years STANDARD_DEVIATION 12.8 | 44.8 years STANDARD_DEVIATION 12.8 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Cambodia | 166 participants | 332 participants | 166 participants |
| Sex: Female, Male Female | 86 Participants | 165 Participants | 79 Participants |
| Sex: Female, Male Male | 80 Participants | 167 Participants | 87 Participants |
| Strongyloides stercoralis infection intensity Heavy | 19 Participants | 39 Participants | 20 Participants |
| Strongyloides stercoralis infection intensity Light | 103 Participants | 205 Participants | 102 Participants |
| Strongyloides stercoralis infection intensity Moderate | 44 Participants | 88 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 166 | 0 / 166 |
| other Total, other adverse events | 15 / 166 | 19 / 166 |
| serious Total, serious adverse events | 0 / 166 | 0 / 166 |
Outcome results
Primary
Cure Rate Against Strongyloides Stercoralis
The conversion from being larvae positive pre-treatment to larvae negative post-treatment, or cure rate (CR).
Time frame: 14-21 days after treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Moxidectin | Cure Rate Against Strongyloides Stercoralis | 94.8 percentage of participants |
| Ivermectin | Cure Rate Against Strongyloides Stercoralis | 99.4 percentage of participants |
Secondary
CRs Against Concomitant Soil-transmitted Helminth Infections - Ascaris Lumbricoides
CRs will be calculated for Ascaris lumbricoides, Trichuris trichiura and hookworm infections as described in primary outcome.
Time frame: 14-21 days after treatment
Population: No participants infected with Ascaris lumbricoides pre- or post-treatment
Secondary
CRs Against Concomitant Soil-transmitted Helminth Infections - Hookworm
CRs will be calculated for Ascaris lumbricoides, Trichuris trichiura and hookworm infections as described in primary outcome.
Time frame: 14-21 days after treatment
Population: Participants co-infected with Hookworm
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Moxidectin | CRs Against Concomitant Soil-transmitted Helminth Infections - Hookworm | 82.0 percentage of participants |
| Ivermectin | CRs Against Concomitant Soil-transmitted Helminth Infections - Hookworm | 81.0 percentage of participants |
Secondary
CRs Against Concomitant Soil-transmitted Helminth Infections - Trichuris Trichiura
CRs will be calculated for Ascaris lumbricoides, Trichuris trichiura and hookworm infections as described in primary outcome.
Time frame: 14-21 days after treatment
Population: No participants infected with Trichuris trichiura pre- or post-treatment
Secondary
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)
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Moxidectin | Larvae Reduction Rate (LRR) Against Strongyloidiasis Stercoralis | 98.8 percent change |
| Ivermectin | Larvae Reduction Rate (LRR) Against Strongyloidiasis Stercoralis | 100 percent change |
Secondary
Number of Participants Reporting Adverse Events
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.
Time frame: 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.
Population: Analysis population at 2-3 hours after drug administration: N=332. Analysis population at 24 hours after drug administration: N=332. Analysis population at 14-21 days after drug administration: N=315.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Moxidectin | Number of Participants Reporting Adverse Events | 2-3 hours: Headache | 4 Participants |
| Moxidectin | Number of Participants Reporting Adverse Events | 2-3 hours: Abdominal pain | 2 Participants |
| Moxidectin | Number of Participants Reporting Adverse Events | 2-3 hours: Itching | 3 Participants |
| Moxidectin | Number of Participants Reporting Adverse Events | 2-3 hours: Nausea | 0 Participants |
| Moxidectin | Number of Participants Reporting Adverse Events | 2-3 hours: Vomiting | 0 Participants |
| Moxidectin | Number of Participants Reporting Adverse Events | 2-3 hours: Diarrhea | 1 Participants |
| Moxidectin | Number of Participants Reporting Adverse Events | 2-3 hours: Allergic reaction | 0 Participants |
| Moxidectin | Number of Participants Reporting Adverse Events | 24 hours: Headache | 4 Participants |
| Moxidectin | Number of Participants Reporting Adverse Events | 24 hours: Abdominal pain | 1 Participants |
| Moxidectin | Number of Participants Reporting Adverse Events | 24 hours: Itching | 2 Participants |
| Moxidectin | Number of Participants Reporting Adverse Events | 24 hours: Nausea | 0 Participants |
| Moxidectin | Number of Participants Reporting Adverse Events | 24 hours: Vomiting | 0 Participants |
| Moxidectin | Number of Participants Reporting Adverse Events | 24 hours: Diarrhea | 0 Participants |
| Moxidectin | Number of Participants Reporting Adverse Events | 24 hours: Allergic reaction | 0 Participants |
| Moxidectin | Number of Participants Reporting Adverse Events | 14-21 days: Headache | 0 Participants |
| Moxidectin | Number of Participants Reporting Adverse Events | 14-21 days: Abdominal pain | 0 Participants |
| Moxidectin | Number of Participants Reporting Adverse Events | 14-21 days: Itching | 0 Participants |
| Moxidectin | Number of Participants Reporting Adverse Events | 14-21 days: Nausea | 0 Participants |
| Moxidectin | Number of Participants Reporting Adverse Events | 14-21 days: Vomiting | 0 Participants |
| Moxidectin | Number of Participants Reporting Adverse Events | 14-21 days: Diarrhea | 0 Participants |
| Moxidectin | Number of Participants Reporting Adverse Events | 14-21 days: Allergic reaction | 0 Participants |
| Ivermectin | Number of Participants Reporting Adverse Events | 14-21 days: Nausea | 0 Participants |
| Ivermectin | Number of Participants Reporting Adverse Events | 2-3 hours: Headache | 10 Participants |
| Ivermectin | Number of Participants Reporting Adverse Events | 24 hours: Nausea | 0 Participants |
| Ivermectin | Number of Participants Reporting Adverse Events | 14-21 days: Allergic reaction | 0 Participants |
| Ivermectin | Number of Participants Reporting Adverse Events | 2-3 hours: Abdominal pain | 4 Participants |
| Ivermectin | Number of Participants Reporting Adverse Events | 14-21 days: Abdominal pain | 0 Participants |
| Ivermectin | Number of Participants Reporting Adverse Events | 2-3 hours: Itching | 0 Participants |
| Ivermectin | Number of Participants Reporting Adverse Events | 24 hours: Vomiting | 1 Participants |
| Ivermectin | Number of Participants Reporting Adverse Events | 2-3 hours: Nausea | 0 Participants |
| Ivermectin | Number of Participants Reporting Adverse Events | 14-21 days: Diarrhea | 0 Participants |
| Ivermectin | Number of Participants Reporting Adverse Events | 2-3 hours: Vomiting | 0 Participants |
| Ivermectin | Number of Participants Reporting Adverse Events | 24 hours: Diarrhea | 1 Participants |
| Ivermectin | Number of Participants Reporting Adverse Events | 2-3 hours: Diarrhea | 1 Participants |
| Ivermectin | Number of Participants Reporting Adverse Events | 14-21 days: Itching | 0 Participants |
| Ivermectin | Number of Participants Reporting Adverse Events | 2-3 hours: Allergic reaction | 0 Participants |
| Ivermectin | Number of Participants Reporting Adverse Events | 24 hours: Allergic reaction | 0 Participants |
| Ivermectin | Number of Participants Reporting Adverse Events | 24 hours: Headache | 2 Participants |
| Ivermectin | Number of Participants Reporting Adverse Events | 14-21 days: Vomiting | 0 Participants |
| Ivermectin | Number of Participants Reporting Adverse Events | 24 hours: Abdominal pain | 1 Participants |
| Ivermectin | Number of Participants Reporting Adverse Events | 14-21 days: Headache | 0 Participants |
| Ivermectin | Number of Participants Reporting Adverse Events | 24 hours: Itching | 5 Participants |
Other Pre-specified
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.
Time frame: Pre-treatment
Other Pre-specified
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.
Time frame: Pre-treatment