Helminth Infections
Conditions
Keywords
Helminth infections, Helminths, Pediatric, Preschool aged, School aged, Mebendazole, Vermox, Placebo
Brief summary
The purpose of this study is to evaluate the efficacy and safety of mebendazole compared with placebo in pediatric participants with Helminth infections.
Detailed description
This will be a double-blind (neither physician nor participant knows the treatment that the participant receives), randomized (the study drug is assigned by chance), multi-center, parallel-group study (each group of participants will be treated at the same time) to evaluate the efficacy and safety of mebendazole (a drug currently being investigated for Helminth gastrointestinal infections) compared with placebo (an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical trial) in children (including pre-school and school-aged children) with Helminth infections. The study will consist of 3 phases: a screening phase, a double-blind treatment phase, and a post-treatment (or follow-up) phase. A pharmacokinetic (explores what a drug does to the body) open-label substudy (asks a separate research question from the parent study while using the same participant population but does not contribute to the parent study's objectives) will be included in the parent study to measure the level of mebendazole in the blood. Safety assessments will be performed throughout the study. Each participant will take part in the study for approximately 30 days.
Interventions
DRUGMebendazole
Mebendazole will be administered as a single-dose 500 mg chewable tablet. For children 1 year to \<36 months of age, the tablet will be placed in a teaspoon and bottled water will be poured into the remaining volume of the teaspoon. The tablet will then be allowed to absorb all water (absorption time has been observed to take less than 1 minute) to become a soft semi-solid mass without any hard particles. This semi-solid form can then be easily ingested by the child.
DRUGPlacebo
Matching placebo will be administered as a single-dose chewable tablet. For children 1 year to \<36 months of age, the tablet will be placed in a teaspoon and bottled water will be poured into the remaining volume of the teaspoon. The tablet will then be allowed to absorb all water (absorption time has been observed to take less than 1 minute) to become a soft semi-solid mass without any hard particles. This semi-solid form can then be easily ingested by the child.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
1 Years to 16 Years
Healthy volunteers
No
Inclusion criteria
* Female participants who are \>=9 years old must have a negative urine pregnancy test at screening or at the time of randomization * Participants must be an otherwise healthy child, based on medical history, physical examination, vital signs, hemoglobin, and concomitant medications * Participants \>=3 years of age must have teeth and be able to chew * Participant must be available to return to the study site for all visits, including the follow-up visit * Parent(s)/guardians of participants (or their legally-accepted representatives) must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to have their child participate in the study * Children 6 years of age and older will be asked to assent (agree) to their participation using appropriate language to their level of understanding; assent will be documented
Exclusion criteria
* Participant has active diarrhea (defined as the passage of 3 or more loose or liquid stools per day) at screening or at the time of randomization * Participant has a significant medical disorder, participant has difficulty in chewing or swallowing * Participant has significant anemia (\<8 g/dL) * Participant has significant wasting (greater than 2 standard deviations below the mean World Health Organization \[WHO\] Child Growth Standards for weight-for-height or body mass index) * Participant has a known hypersensitivity to mebendazole, any inert ingredients in the chewable formulation * Participant has preplanned surgery/procedures that would interfere with the conduct of the study during the course of study * Participants has received an investigational drug (including vaccines) or used an investigational medical device within 30 days before the planned start of treatment, or is currently enrolled in an investigational study * Employees of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator * Participant has taken any form of medication containing mebendazole or any other treatment for soil transmitted helminth infection within 30 days of entry into the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cure Rate for Ascaris Lumbricoides at the End of Double-blind Treatment Period | At Visit 3 (Day 19) of Double-blind treatment period | Cure is defined as a post-treatment egg count of zero in participants who had a positive egg count at baseline. |
| Cure Rate for Trichuris Trichiura at the End of Double-blind Treatment Period | At Visit 3 (Day 19) of Double-blind treatment period | Cure is defined as a post-treatment egg count of zero in participants who had a positive egg count at baseline. |
| Number of Participants Reporting Treatment Emergent Adverse Event (TEAE) in Double-Blind Treatment Period | Up to Visit 3 (Day 19 +/-2) | An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. |
| Number of Participants Reporting Treatment Emergent Adverse Event (TEAE) in Open-Label Treatment Period | At Visit 3 (Day 19+/-2) followed up to Visit 5 (Day 7+/-1 from Visit 3) | An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours (AUC8h) of Mebendazole | Predose, 1, 2, 3, 5, 8 and 24 hours postdose at visit 4 (Day 20; 1 day after Visit 3) | The (AUC8h) is the area under the plasma concentration-time curve from time 0 to 8 hours Post-dose. |
| Egg Count Reduction Rate (Percent) for Ascaris Lumbricoides Infestation at the End of Double-blind Treatment Period | Baseline and Day 19 (Visit 3) at the End of Double-blind Treatment Period | Percent egg count reduction is calculated as average egg count at end of treatment period of a treatment group minus average egg count at baseline of the treatment group divided by average egg count at baseline of the treatment group. |
| Area Under the Plasma Concentration-Time Curve From Time Zero to Time of the Last Quantifiable Concentration AUC(0-last) of Mebendazole | Predose, 1, 2, 3, 5, 8 and 24 hours postdose at visit 4 (Day 20; 1 day after Visit 3) | The (AUC \[0-last\]) is the area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. |
| Egg Count Reduction Rate (Percent) for Trichuris Trichiura Infestation at the End of Double-blind Treatment Period | Baseline and Day 19 (Visit 3) at the End of Double-blind Treatment Period | Percent egg count reduction is calculated as average egg count at end of treatment period of a treatment group minus average egg count at baseline of the treatment group divided by average egg count at baseline of the treatment group. |
| Maximum Plasma Concentration (Cmax) of Mebendazole | Predose, 1, 2, 3, 5, 8 and 24 hours postdose at visit 4 (Day 20; 1 day after Visit 3) | The Cmax is the maximum plasma concentration. |
| Time to Reach Maximum Plasma Concentration (Tmax) of Mebendazole | Predose, 1, 2, 3, 5, 8 and 24 hours postdose at visit 4 (Day 20; 1 day after Visit 3) | The Time to Reach Maximum Plasma Concentration (Tmax) is time to reach the maximum plasma concentration. |
Countries
Ethiopia, Rwanda
Participant flow
Recruitment details
The study was conducted from 8-Dec-2014 to 3-Sep-2015. A total of 295 participants were enrolled and randomly assigned to study treatment; 278 participants completed the study. Of the 295 participants, 167 participants were reported with Ascaris lumbricoides infestation and 243 participants were reported with Trichuris trichiura infestation.
Pre-assignment details
Of the 792 participants screened, a total of 295 were randomly assigned to study treatments, of which 278 completed the study. 17 participants were withdrawn from study with following reasons: Withdrawal by participant (12), Lost to follow-up (3), Physician decision (1) and Protocol violation (1).
Participants by arm
| Arm | Count |
|---|---|
| Double-blind Placebo Placebo Comparator: Placebo. Matching placebo was administered as a single-dose chewable tablet in a double-blind manner at the baseline visit (Day 1) followed up to Visit 3 (Day 19+/-2). | 146 |
| Double-blind Mebendazole 500 mg Experimental: Mebendazole. Mebendazole was administered as a single 500-mg chewable tablet in a double-blind manner at the baseline visit (Day 1) followed up to Visit 3 (Day 19+/-2). | 149 |
| Total | 295 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-blind | Lost to Follow-up | 3 | 0 | 0 |
| Double-blind | Physician Decision | 1 | 0 | 0 |
| Double-blind | Protocol Violation | 0 | 1 | 0 |
| Double-blind | Withdrawal by Subject | 5 | 7 | 0 |
Baseline characteristics
| Characteristic | Double-blind Mebendazole 500 mg | Total | Double-blind Placebo |
|---|---|---|---|
| Age, Continuous | 7.9 years STANDARD_DEVIATION 3.27 | 7.8 years STANDARD_DEVIATION 3.18 | 7.7 years STANDARD_DEVIATION 3.09 |
| Region of Enrollment ETHIOPIA | 128 participants | 255 participants | 127 participants |
| Region of Enrollment RWANDA | 21 participants | 40 participants | 19 participants |
| Sex: Female, Male Female | 78 Participants | 152 Participants | 74 Participants |
| Sex: Female, Male Male | 71 Participants | 143 Participants | 72 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 140 | 9 / 144 | 7 / 278 |
| serious Total, serious adverse events | 0 / 140 | 0 / 144 | 0 / 278 |
Outcome results
Primary
Cure Rate for Ascaris Lumbricoides at the End of Double-blind Treatment Period
Cure is defined as a post-treatment egg count of zero in participants who had a positive egg count at baseline.
Time frame: At Visit 3 (Day 19) of Double-blind treatment period
Population: The intent-to-treat (ITT) analysis set included all randomized participants with a pretreatment stool sample positive for 1 or more worms of interest. Here 'N' signifies number of participants analysed for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-blind Placebo | Cure Rate for Ascaris Lumbricoides at the End of Double-blind Treatment Period | 11.1 percentage of participants |
| Double-blind Mebendazole 500 mg | Cure Rate for Ascaris Lumbricoides at the End of Double-blind Treatment Period | 83.7 percentage of participants |
p-value: <0.001Cochran-Mantel-Haenszel
Primary
Cure Rate for Trichuris Trichiura at the End of Double-blind Treatment Period
Cure is defined as a post-treatment egg count of zero in participants who had a positive egg count at baseline.
Time frame: At Visit 3 (Day 19) of Double-blind treatment period
Population: The ITT analysis set included all randomized participants with a pretreatment stool sample positive for 1 or more worms of interest. Here 'N' signifies number of participants analysed for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-blind Placebo | Cure Rate for Trichuris Trichiura at the End of Double-blind Treatment Period | 7.6 percentage of participants |
| Double-blind Mebendazole 500 mg | Cure Rate for Trichuris Trichiura at the End of Double-blind Treatment Period | 33.9 percentage of participants |
p-value: <0.001Cochran-Mantel-Haenszel
Primary
Number of Participants Reporting Treatment Emergent Adverse Event (TEAE) in Double-Blind Treatment Period
An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Time frame: Up to Visit 3 (Day 19 +/-2)
Population: The safety analysis set consisted of all randomized participants who received 1 dose of study agent (mebendazole or placebo) at baseline. Here 'N' signifies number of participants analysed for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-blind Placebo | Number of Participants Reporting Treatment Emergent Adverse Event (TEAE) in Double-Blind Treatment Period | 8 participants |
| Double-blind Mebendazole 500 mg | Number of Participants Reporting Treatment Emergent Adverse Event (TEAE) in Double-Blind Treatment Period | 9 participants |
Primary
Number of Participants Reporting Treatment Emergent Adverse Event (TEAE) in Open-Label Treatment Period
An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Time frame: At Visit 3 (Day 19+/-2) followed up to Visit 5 (Day 7+/-1 from Visit 3)
Population: The open-label follow-up safety analysis set consisted of all randomized participants who received a 500-mg chewable tablet of mebendazole at Visit 3. Here 'N' signifies number of participants analysed for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-blind Placebo | Number of Participants Reporting Treatment Emergent Adverse Event (TEAE) in Open-Label Treatment Period | 7 participants |
Secondary
Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours (AUC8h) of Mebendazole
The (AUC8h) is the area under the plasma concentration-time curve from time 0 to 8 hours Post-dose.
Time frame: Predose, 1, 2, 3, 5, 8 and 24 hours postdose at visit 4 (Day 20; 1 day after Visit 3)
Population: PK population included all randomized participants who received at least 1 dose of the study drug and had valid pharmacokinetic profile. Here 'N' signifies number of participants analysed for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-blind Placebo | Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours (AUC8h) of Mebendazole | 697 nanogram hour per Milliliters(ng*h/mL) | Standard Deviation 367 |
| Double-blind Mebendazole 500 mg | Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours (AUC8h) of Mebendazole | 242 nanogram hour per Milliliters(ng*h/mL) | Standard Deviation 139 |
| Mebendazole: Group 3 (7 to 16 Years) | Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours (AUC8h) of Mebendazole | 182 nanogram hour per Milliliters(ng*h/mL) | Standard Deviation 66.3 |
Secondary
Area Under the Plasma Concentration-Time Curve From Time Zero to Time of the Last Quantifiable Concentration AUC(0-last) of Mebendazole
The (AUC \[0-last\]) is the area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration.
Time frame: Predose, 1, 2, 3, 5, 8 and 24 hours postdose at visit 4 (Day 20; 1 day after Visit 3)
Population: PK population included all randomized participants who received at least 1 dose of the study drug and had valid pharmacokinetic profile. Here 'N' signifies number of participants analysed for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-blind Placebo | Area Under the Plasma Concentration-Time Curve From Time Zero to Time of the Last Quantifiable Concentration AUC(0-last) of Mebendazole | 1320 ng*h/mL | Standard Deviation 844 |
| Double-blind Mebendazole 500 mg | Area Under the Plasma Concentration-Time Curve From Time Zero to Time of the Last Quantifiable Concentration AUC(0-last) of Mebendazole | 416 ng*h/mL | Standard Deviation 215 |
| Mebendazole: Group 3 (7 to 16 Years) | Area Under the Plasma Concentration-Time Curve From Time Zero to Time of the Last Quantifiable Concentration AUC(0-last) of Mebendazole | 387 ng*h/mL | Standard Deviation 190 |
Secondary
Egg Count Reduction Rate (Percent) for Ascaris Lumbricoides Infestation at the End of Double-blind Treatment Period
Percent egg count reduction is calculated as average egg count at end of treatment period of a treatment group minus average egg count at baseline of the treatment group divided by average egg count at baseline of the treatment group.
Time frame: Baseline and Day 19 (Visit 3) at the End of Double-blind Treatment Period
Population: The ITT analysis set included all randomized participants with a pretreatment stool sample positive for 1 or more worms of interest. Here 'N' signifies number of participants analysed for this outcome measure.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Double-blind Placebo | Egg Count Reduction Rate (Percent) for Ascaris Lumbricoides Infestation at the End of Double-blind Treatment Period | -19.2 percent change in egg count | 20684.03 |
| Double-blind Mebendazole 500 mg | Egg Count Reduction Rate (Percent) for Ascaris Lumbricoides Infestation at the End of Double-blind Treatment Period | -97.9 percent change in egg count | 23476.82 |
p-value: <0.001ANCOVA
Secondary
Egg Count Reduction Rate (Percent) for Trichuris Trichiura Infestation at the End of Double-blind Treatment Period
Percent egg count reduction is calculated as average egg count at end of treatment period of a treatment group minus average egg count at baseline of the treatment group divided by average egg count at baseline of the treatment group.
Time frame: Baseline and Day 19 (Visit 3) at the End of Double-blind Treatment Period
Population: The ITT analysis set included all randomized participants with a pretreatment stool sample positive for 1 or more worms of interest. Here 'N' signifies number of participants analysed for this outcome measure.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Double-blind Placebo | Egg Count Reduction Rate (Percent) for Trichuris Trichiura Infestation at the End of Double-blind Treatment Period | -10.5 percent change in egg count | 930.05 |
| Double-blind Mebendazole 500 mg | Egg Count Reduction Rate (Percent) for Trichuris Trichiura Infestation at the End of Double-blind Treatment Period | -59.7 percent change in egg count | 1256.22 |
p-value: <0.001ANCOVA
Secondary
Maximum Plasma Concentration (Cmax) of Mebendazole
The Cmax is the maximum plasma concentration.
Time frame: Predose, 1, 2, 3, 5, 8 and 24 hours postdose at visit 4 (Day 20; 1 day after Visit 3)
Population: Pharmacokinetic (PK) population included all randomized participants who received at least 1 dose of the study drug and had valid pharmacokinetic profile. Here 'N' signifies number of participants analysed for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-blind Placebo | Maximum Plasma Concentration (Cmax) of Mebendazole | 210.0 nanogram per Milliliters (ng/mL) | Standard Deviation 212 |
| Double-blind Mebendazole 500 mg | Maximum Plasma Concentration (Cmax) of Mebendazole | 49.9 nanogram per Milliliters (ng/mL) | Standard Deviation 26.8 |
| Mebendazole: Group 3 (7 to 16 Years) | Maximum Plasma Concentration (Cmax) of Mebendazole | 34.2 nanogram per Milliliters (ng/mL) | Standard Deviation 13.8 |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax) of Mebendazole
The Time to Reach Maximum Plasma Concentration (Tmax) is time to reach the maximum plasma concentration.
Time frame: Predose, 1, 2, 3, 5, 8 and 24 hours postdose at visit 4 (Day 20; 1 day after Visit 3)
Population: PK population included all randomized participants who received at least 1 dose of the study drug and had valid pharmacokinetic profile. Here 'N' signifies number of participants analysed for this outcome measure.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Double-blind Placebo | Time to Reach Maximum Plasma Concentration (Tmax) of Mebendazole | 2.5 hours |
| Double-blind Mebendazole 500 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Mebendazole | 2 hours |
| Mebendazole: Group 3 (7 to 16 Years) | Time to Reach Maximum Plasma Concentration (Tmax) of Mebendazole | 3 hours |