Efficacy, Safety and Acceptability of Ivermectin ODT in PSAC

Efficacy, Safety and Acceptability of Ascending Doses of Ivermectin in Combination With Albendazole for Trichuris Trichiura Infections in Preschool-aged Children: a Single-blind Randomised Controlled Dose-ranging Trial

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT06184399

Acronym

Iverped

Enrollment

260

Registered

2023-12-28

Start date

2024-06-05

Completion date

2024-08-09

Last updated

2025-09-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Ascariasis, Hookworm Infections, Trichuriasis

Keywords

Ivermectin, Albendazole, Anthelminthics, Trichuris trichiura, Ascaris lumbricoides, Hookworm, Whipworm, Soil-transmitted helminths

Brief summary

This study is a single-blind randomized controlled dose-ranging trial aiming at providing evidence on the on the optimal dose of co-administered ivermectin and albendazole in terms of efficacy, safety and acceptability in preschool-aged children (PSAC; aged 2-5 years) infected with whipworm (Trichuris trichiura) on Pemba Island, Tanzania. Additionally, the pharmacokinetics of the newly developed oro-dispersible tablets (ODTs) and the standard ivermectin tablets (Stromectol®) will be compared in this age group. As measure of efficacy of the treatment the cure rate (percentage of egg-positive participants at baseline who become egg-negative after treatment) will be determined 14-21 days post-treatment.

Detailed description

This study is a single-blind randomized controlled dose-ranging trial aiming at providing evidence on the optimal dose of co-administered ivermectin and albendazole in terms of efficacy, safety and acceptability in preschool-aged children (PSAC; aged 2-5 years) infected with whipworm (Trichuris trichiura) on Pemba Island, Tanzania. Additionally, the pharmacokinetics of the newly developed ODTs and the standard ivermectin tablets (Stromectol®) will be compared in this age group. The primary objective of the trial is to comparatively assess the efficacy in terms of cure rate (CR) against T. trichiura infections among PSAC receiving different doses of ivermectin. The secondary objectives of the trial are to compare the egg reduction rates (ERRs) of the treatment regimens against T. trichiura, to determine the CRs and ERRs of the drugs in study participants co-infected with A. lumbricoides and hookworm, and to evaluate the safety and tolerability of the treatment regimens. In addition, this study aims to characterize population pharmacokinetics of the ivermectin ODTs compared to standard tablets in T. trichiura infected individuals, and to assess the acceptability of the treatments. After obtaining informed consent from parents and/or caregivers, 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 two stool samples, which will be collected, if possible, on two consecutive days or otherwise within a maximum of 5 days. All stool samples will be examined with duplicated Kato-Katz thick smears by experienced laboratory technicians. Randomization of participants into the six treatment arms will be stratified according to intensity of infection and age. All participants will be interviewed before treatment, and at 3 and 24 hours and 14-21 days after treatment about the occurrence of adverse events. The efficacy of the treatment will be determined 14-21 days post-treatment by collecting another two stool samples. The primary analysis will include all participants with primary end point data (available case analysis). Supplementary, a per-protocol analysis will be conducted. CRs will be calculated as the percentage of egg-positive participants at baseline who become egg-negative after treatment. Differences among CRs between treatment arms will be analysed using crude and adjusted logistic regression modeling (adjustment for age, sex and weight). Geometric and arithmetic mean egg counts will be calculated for the different treatment arms before and after treatment to assess the corresponding ERRs. Bootstrap resampling method with 5,000 replicates will be used to calculate 95% confidence intervals (CIs) for differences in ERRs.Using the DoseFinding package of the statistical software environment R, Emax models will be implemented to predict the dose-response curves based on CRs and ERRs. Adverse events will be compiled into frequency tables and compared between treatment groups using descriptive summary statistics.

Interventions

DRUGIvermectin 1.5 mg ODT

Oro-dispersible tablets of 1.5 mg ivermectin

DRUGIvermectin 3 mg Oral Tablet

Tablets of 3 mg ivermectin

DRUGAlbendazole 400 mg Oral Tablet

Tablets of 400 mg albendazole

DRUGPlacebo Ivermectin ODT

Placebo for ivermectin ODT

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

SINGLE (Subject)

Masking description

Single (Participant) Treatment allocation will be masked using appearance-matched placebos.

Eligibility

Sex/Gender

ALL

Age

2 Years to 5 Years

Healthy volunteers

Inclusion criteria

* individuals aged 2-5 years (24-71 months; confirmed by birth certificate or similar document) * having given written informed consent signed by parents/caregivers * being able and willing to provide two stool samples at baseline and at follow-up assessment (14-21 days) * having at least two out of four Kato-Katz slides positive for T. trichiura at baseline * being able and willing to be examined by a study physician before and after treatment

Exclusion criteria

* presence or signs of major systemic illness, e.g. fever (temporal body temperature of \>38.0°C), severe anaemia (haemoglobin level of \<70 g/l) * history of severe acute disease or unmanaged, severe chronic disease (i.e., condition is not as therapeutically controlled as necessary) * use of anthelminthic drugs during study period * known allergy to study medication (i.e., ivermectin or albendazole) * being prescribed or taking concomitantly medication with known contraindications or drug interactions with the study medication * concurrent participation in other clinical trials

Design outcomes

Primary

Measure	Time frame	Description
Cure Rate (CR) Against T. Trichiura	14-21 days post-treatment	The CR will be calculated as the proportion of participants converting from being egg-positive pre-treatment to egg-negative post-treatment.

Secondary

Measure	Time frame	Description
Egg Reduction Rate (ERR) Against T. Trichiura (Geometric Mean ERR)	14-21 days post-treatment	Eggs per gram of stool (EPG) will be assessed by adding up the egg counts from the quadruplicate Kato-Katz thick smears and multiplying this number by a factor of six. Geometric and arithmetic mean egg counts will be calculated for the two treatment arms before and after treatment to assess the corresponding ERRs.
Egg Reduction Rate (ERR) Against T. Trichiura (Arithmetic Mean ERR)	14-21 days post-treatment	Eggs per gram of stool (EPG) will be assessed by adding up the egg counts from the quadruplicate Kato-Katz thick smears and multiplying this number by a factor of six. Geometric and arithmetic mean egg counts will be calculated for the two treatment arms before and after treatment to assess the corresponding ERRs.
Cure Rate (CR) Against A. Lumbricoides	14-21 days post-treatment	The CR will be calculated as the proportion of participants converting from being egg-positive pre-treatment to egg-negative post-treatment.
Egg Reduction Rate (ERR) Against A. Lumbricoides (Geometric Mean ERR)	14-21 days post-treatment	Eggs per gram of stool (EPG) will be assessed by adding up the egg counts from the quadruplicate Kato-Katz thick smears and multiplying this number by a factor of six. Geometric and arithmetic mean egg counts will be calculated for the two treatment arms before and after treatment to assess the corresponding ERRs.
Egg Reduction Rate (ERR) Against A. Lumbricoides (Arithmetic Mean ERR)	14-21 days post-treatment	Eggs per gram of stool (EPG) will be assessed by adding up the egg counts from the quadruplicate Kato-Katz thick smears and multiplying this number by a factor of six. Geometric and arithmetic mean egg counts will be calculated for the two treatment arms before and after treatment to assess the corresponding ERRs.
Egg Reduction Rate (ERR) Against Hookworm (Arithmetic Mean ERR)	14-21 days post-treatment	Eggs per gram of stool (EPG) will be assessed by adding up the egg counts from the quadruplicate Kato-Katz thick smears and multiplying this number by a factor of six. Geometric and arithmetic mean egg counts will be calculated for the two treatment arms before and after treatment to assess the corresponding ERRs.
Number of Participants Reporting Adverse Events (AEs)	3 hours, 24 hours and 14-21 days post-treatment	Participants will be monitored at the site for 3 hours following treatment for any acute AEs and reassessment will be done at 24h post-treatment. In addition, participants will be interviewed 3 and 24 hours after treatment and retrospectively at days 14-21 about the occurrence of AEs.
Cure Rate (CR) Against Hookworm	14-21 days post-treatment	The CR will be calculated as the proportion of participants converting from being egg-positive pre-treatment to egg-negative post-treatment.
Egg Reduction Rate (ERR) Against Hookworm (Geometric Mean ERR)	14-21 days post-treatment	Eggs per gram of stool (EPG) will be assessed by adding up the egg counts from the quadruplicate Kato-Katz thick smears and multiplying this number by a factor of six. Geometric and arithmetic mean egg counts will be calculated for the two treatment arms before and after treatment to assess the corresponding ERRs.

Other

Measure	Time frame	Description
Blood Concentration of Ivermectin	0 to 24 hours post-treatment	For characterization of population pharmacokinetics (PK), ivermectin concentration 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 lower limit of quantification of 1-5 ng/ml.
Acceptability of ODT Assessed by Visual Analogue Scale (0-100 mm)	15 min post-treatment	To determine the acceptability of ivermectin ODTs compared to standard tablets, the palatability of each formulation will be rated by children aged 4-5 years using a visual analogue scale with continuous scores from 0 mm (worst taste) to 100 mm (best taste).

Countries

Tanzania

Participant flow

Participants by arm

Arm	Count
Arm A: Ivermectin ODT Placebo & Albendazole Placebo for ivermectin (oro-dispersible tablets) and albendazole (Zentel®, 1 tablet of 400 mg) administered orally at day 0 Albendazole 400 mg Oral Tablet: Tablets of 400 mg albendazole Placebo Ivermectin ODT: Placebo for ivermectin ODT	43
Arm B: Ivermectin ODT 100 µg/kg & Albendazole Combination therapy of ivermectin (100 µg/kg using oro-dispersible tablets of 1.5 mg) and albendazole (Zentel®, 1 tablet of 400 mg) administered orally at day 0 Ivermectin 1.5 mg ODT: Oro-dispersible tablets of 1.5 mg ivermectin Albendazole 400 mg Oral Tablet: Tablets of 400 mg albendazole	44
Arm C: Ivermectin ODT 200 µg/kg & Albendazole Combination therapy of ivermectin (200 µg/kg using oro-dispersible tablets of 1.5 mg) and albendazole (Zentel®, 1 tablet of 400 mg) administered orally at day 0 Ivermectin 1.5 mg ODT: Oro-dispersible tablets of 1.5 mg ivermectin Albendazole 400 mg Oral Tablet: Tablets of 400 mg albendazole	42
Arm D: Ivermectin ODT 300 µg/kg & Albendazole Combination therapy of ivermectin (300 µg/kg using oro-dispersible tablets of 1.5 mg) and albendazole (Zentel®, 1 tablet of 400 mg) administered orally at day 0 Ivermectin 1.5 mg ODT: Oro-dispersible tablets of 1.5 mg ivermectin Albendazole 400 mg Oral Tablet: Tablets of 400 mg albendazole	44
Arm E: Ivermectin ODT 400 µg/kg & Albendazole Combination therapy of ivermectin (400 µg/kg using oro-dispersible tablets of 1.5 mg) and albendazole (Zentel®, 1 tablet of 400 mg) administered orally at day 0 Ivermectin 1.5 mg ODT: Oro-dispersible tablets of 1.5 mg ivermectin Albendazole 400 mg Oral Tablet: Tablets of 400 mg albendazole	44
Arm F: Ivermectin Standard Tablets & Albendazole Combination therapy of ivermectin (Stromectol®, 200 µg/kg using tablets of 3 mg) and albendazole (Zentel®, 1 tablet of 400 mg) administered orally at day 0 Ivermectin 3 mg Oral Tablet: Tablets of 3 mg ivermectin Albendazole 400 mg Oral Tablet: Tablets of 400 mg albendazole	43
Total	260

Baseline characteristics

Characteristic	Total	Arm F: Ivermectin Standard Tablets & Albendazole	Arm E: Ivermectin ODT 400 µg/kg & Albendazole	Arm D: Ivermectin ODT 300 µg/kg & Albendazole	Arm C: Ivermectin ODT 200 µg/kg & Albendazole	Arm B: Ivermectin ODT 100 µg/kg & Albendazole	Arm A: Ivermectin ODT Placebo & Albendazole
Age, Continuous	3.6 years STANDARD_DEVIATION 1.1	3.7 years STANDARD_DEVIATION 1.2	3.5 years STANDARD_DEVIATION 1	3.6 years STANDARD_DEVIATION 1	3.5 years STANDARD_DEVIATION 1	3.6 years STANDARD_DEVIATION 1.1	3.7 years STANDARD_DEVIATION 1.1
Ascaris lumbricoides co-infection	56 Participants	9 Participants	9 Participants	7 Participants	8 Participants	13 Participants	10 Participants
Hookworm co-infection	52 Participants	7 Participants	8 Participants	10 Participants	8 Participants	11 Participants	8 Participants
Race and Ethnicity Not Collected	0 Participants	—	—	—	—	—	—
Region of Enrollment Tanzania	260 participants	43 participants	44 participants	44 participants	42 participants	44 participants	43 participants
Sex: Female, Male Female	137 Participants	26 Participants	21 Participants	24 Participants	24 Participants	20 Participants	22 Participants
Sex: Female, Male Male	123 Participants	17 Participants	23 Participants	20 Participants	18 Participants	24 Participants	21 Participants
Trichuris trichiura infection intensity Heavy (>9999 EPG)	1 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants
Trichuris trichiura infection intensity Light (<1000 EPG)	211 Participants	34 Participants	36 Participants	35 Participants	34 Participants	36 Participants	36 Participants
Trichuris trichiura infection intensity Moderate (1000-9999 EPG)	48 Participants	9 Participants	8 Participants	9 Participants	7 Participants	8 Participants	7 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	0 / 43	0 / 44	0 / 42	0 / 44	0 / 44	0 / 43
other Total, other adverse events	4 / 43	3 / 44	1 / 42	1 / 44	7 / 44	1 / 43
serious Total, serious adverse events	0 / 43	0 / 44	0 / 42	0 / 44	0 / 44	0 / 43

Outcome results

Primary

Cure Rate (CR) Against T. Trichiura

The CR will be calculated as the proportion of participants converting from being egg-positive pre-treatment to egg-negative post-treatment.