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

Primary Purpose

Strongyloides Stercoralis Infection

Status
Unknown status
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Moxidectin
Ivermectin
Placebo oral tablet
Sponsored by
Jennifer Keiser
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Strongyloides Stercoralis Infection

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • National Centre for Parasitology, Entomology and Malaria Control
  • National Institute of Public Health

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm 10

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Placebo Comparator

Experimental

Active Comparator

Placebo Comparator

Arm Label

Phase 2a - Arm A

Phase 2a - Arm B

Phase 2a - Arm C

Phase 2a - Arm D

Phase 2a - Arm E

Phase 2a - Arm F

Phase 2a - Arm G

Phase 2b - Arm A

Phase 2b - Arm B

Phase 2b - Arm P

Arm Description

2 mg Moxidectin at day 0 administered orally

4 mg Moxidectin at day 0 administered orally

6 mg Moxidectin at day 0 administered orally

8 mg Moxidectin at day 0 administered orally

10 mg Moxidectin at day 0 administered orally

12 mg Moxidectin at day 0 administered orally

matching Placebo tablet(s) at day 0 administered orally

the recommended dose moxidectin (i.e. the most promising dosage identified in trial A; between 2-12 mg) at day 0 administered orally

200 µg/kg ivermectin at day 0 administered orally

matching Placebo tablet(s) at day 0 administered orally

Outcomes

Primary Outcome Measures

Cure rate against Strongyloidiasis stercoralis
The conversion from being larvae positive pre-treatment to larvae negative post-treatment, or cure rate (CR).

Secondary Outcome Measures

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)
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.
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.
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.
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.
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.
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.

Full Information

First Posted
July 22, 2019
Last Updated
March 19, 2021
Sponsor
Jennifer Keiser
Collaborators
National Institute of Public Health, Vientiane, Laos, National Centre for Parasitology, Entomology and Malaria Control, Cambodia
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1. Study Identification

Unique Protocol Identification Number
NCT04056325
Brief Title
Efficacy, Safety, and PK of Ascending Dosages of Moxidectin Versus Ivermectin Against Strongyloides Stercoralis
Acronym
StrongMoxi
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

2. Study Status

Record Verification Date
March 2021
Overall Recruitment Status
Unknown status
Study Start Date
November 27, 2019 (Actual)
Primary Completion Date
September 15, 2021 (Anticipated)
Study Completion Date
December 1, 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Jennifer Keiser
Collaborators
National Institute of Public Health, Vientiane, Laos, National Centre for Parasitology, Entomology and Malaria Control, Cambodia

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Strongyloides Stercoralis Infection

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
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
Participant
Masking Description
Phase 2a: single-blinded (participant and lab technician) Phase 2b: double-blinded (participant, Care Provider) PK sub-studies are single-blinded (participant)
Allocation
Randomized
Enrollment
210 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Phase 2a - Arm A
Arm Type
Experimental
Arm Description
2 mg Moxidectin at day 0 administered orally
Arm Title
Phase 2a - Arm B
Arm Type
Experimental
Arm Description
4 mg Moxidectin at day 0 administered orally
Arm Title
Phase 2a - Arm C
Arm Type
Experimental
Arm Description
6 mg Moxidectin at day 0 administered orally
Arm Title
Phase 2a - Arm D
Arm Type
Experimental
Arm Description
8 mg Moxidectin at day 0 administered orally
Arm Title
Phase 2a - Arm E
Arm Type
Experimental
Arm Description
10 mg Moxidectin at day 0 administered orally
Arm Title
Phase 2a - Arm F
Arm Type
Experimental
Arm Description
12 mg Moxidectin at day 0 administered orally
Arm Title
Phase 2a - Arm G
Arm Type
Placebo Comparator
Arm Description
matching Placebo tablet(s) at day 0 administered orally
Arm Title
Phase 2b - Arm A
Arm Type
Experimental
Arm Description
the recommended dose moxidectin (i.e. the most promising dosage identified in trial A; between 2-12 mg) at day 0 administered orally
Arm Title
Phase 2b - Arm B
Arm Type
Active Comparator
Arm Description
200 µg/kg ivermectin at day 0 administered orally
Arm Title
Phase 2b - Arm P
Arm Type
Placebo Comparator
Arm Description
matching Placebo tablet(s) at day 0 administered orally
Intervention Type
Drug
Intervention Name(s)
Moxidectin
Intervention Description
Monotherapy, oral administration, single dose, fixed dose
Intervention Type
Drug
Intervention Name(s)
Ivermectin
Intervention Description
Monotherapy, oral administration, single dose, weight dependent
Intervention Type
Drug
Intervention Name(s)
Placebo oral tablet
Intervention Description
Monotherapy, oral administration, single dose, matching number of tablets
Primary Outcome Measure Information:
Title
Cure rate against Strongyloidiasis stercoralis
Description
The conversion from being larvae positive pre-treatment to larvae negative post-treatment, or cure rate (CR).
Time Frame
14-21 days after treatment
Secondary Outcome Measure Information:
Title
Larvae-reduction rate (LRR) against Strongyloidiasis stercoralis
Description
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
Title
CRs and LRRs against concomitant soil-transmitted helminth infections
Description
CRs and LRRs will be calculated for T. trichiura, A. lumbricoides and hookworm infections as described in primary and secondary outcome.
Time Frame
14-21 days after treatment
Title
Number of participants reporting adverse events
Description
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.
Time Frame
14-21 days after treatment
Title
Maximum concentration (Cmax) of moxidectin in adults
Description
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.
Time Frame
0, 2, 4, 8, 24, and 72 hours, 7 and 21 days post treatment
Title
Time to reach Cmax (tmax) of moxidectin in adults
Description
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.
Time Frame
0, 2, 4, 8, 24, and 72 hours, 7 and 21 days post treatment
Title
Area under the curve (AUC) of moxidectin in adults
Description
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.
Time Frame
0, 2, 4, 8, 24, and 72 hours, 7 and 21 days post treatment
Title
Elimination half life (t1/2) of moxidectin in adults
Description
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.
Time Frame
0, 2, 4, 8, 24, and 72 hours, 7 and 21 days post treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jennifer Jennifer, Prof. Dr.
Organizational Affiliation
STPH
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Centre for Parasitology, Entomology and Malaria Control
City
Phnom Penh
Country
Cambodia
Facility Name
National Institute of Public Health
City
Vientiane
Country
Lao People's Democratic Republic

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
34296417
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.
Results Reference
derived
PubMed Identifier
33798487
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.
Results Reference
derived

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

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