L-PZQ ODT in Schistosoma Infected Children

Phase 3

Completed

Conditions: Schistosomiasis

Interventions: Drug: L-PZQ ODT 50 mg/kg
Drug: Biltricide®
Drug: L-PZQ ODT 60 mg/kg

Registration Number: NCT03845140

Lead Sponsor: Merck KGaA, Darmstadt, Germany

Brief Summary: The study would evaluate the safety and efficacy of L-praziquantel orodispersible (L-PZQ ODT) tablets in Schistosoma infected children aged 3 months to 6 years.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 288

Inclusion Criteria

Age of the participant is 4 to 6 years of age (Cohorts 1 and 4), 2 to 3 years of age (Cohorts 2 and 4) 3 to less than 24 months of age (Cohorts 3 and 4)
Participants are; Schistosoma (S.) mansoni positive (Cohorts 1, 2, and 3); diagnosis defined as positive egg counts in stool greater than or equal to ( >=) 1 egg per 1 occasion) according to World Health Organization (WHO) classification [1]: light (1 to 99 eggs per gram of feces), moderate (100 to 399 eggs per gram of feces) and heavy (>= 400 eggs per gram of feces) infections; S. haematobium positive (Cohort 4); diagnosis defined as positive egg counts in urine (>= 1 egg per 10 milliliter(mL) urine) according to WHO classification (Prevention and Control of Schistosomiasis and Soil Transmitted Helminthiasis. WHO Technical Report Series No. 912. WHO, Geneva, Switzerland, 2002).light (less than (<) 50 eggs per 10 mL of urine) and heavy (>=50 eggs per 10 mL of urine) infections
Participants have a minimum body weight of 8.0 Kilograms (Kg) in 2 to 6 years of age children and 5.0 Kg in 3 months to < 24 months of age infants and toddlers
Parent's or guardian/legally authorized representative's ability to communicate well with the Investigator and his/her delegate, to understand the protocol requirements and restrictions, and to be willing to have their children comply with the requirements of the entire study, that is:
- To be examined by a study physician at screening and 17 to 21 days after treatment
- To provide stool samples at screening and 17 to 21 days after treatment
- To provide urine samples at screening and 17 to 21 days after treatment
- To provide venous blood samples for laboratory assessments
- To be housed in the clinic for 12 to 24 hours
- To provide venous blood samples for pharmacokinetics (PK) assessments (for participants in the PK subset)
Participants have a minimum hemoglobin level of 10 gram per deciliter

Exclusion Criteria

Participants with following medical conditions are excluded from the study; Findings in the clinical examination and/or laboratory safety examination on the treatment day, that in the opinion of the Investigator constitute a risk or a contraindication for the child's participation in the study or that could interfere with the study objectives, conduct or evaluation. This includes but is not restricted to bacterial or viral infections, such as dysentery, gastroenteritis, ascites, jaundice, etc.; Participants with seizures and/or medical history of seizures and/or other signs of potential central nervous system involvement; Participants with known cysticercosis, or with signs or symptoms (for example: subcutaneous nodules) suggestive of cysticercosis; Participants with an acute infection or other acute illness within the 7 days prior to study screening; Debilitating illness such as tuberculosis, malnutrition, etc.
Treatment with PZQ within the 4 weeks prior to the study screening
Concomitant treatment (within 2 weeks prior to enrollment) with medication that might affect the metabolism of PZQ, such as certain anti epileptics (for example: carbamazepine or phenytoin), glucocorticosteroids (for example: dexamethasone), chloroquine, rifampicin or cimetidine (see Biltricide® Summary of Product Characteristics [SmPC])
Treatment within the 2 weeks prior to the study screening with anti malarial medications
For infants and toddlers being breast fed, treatment of the mothers/wet nurses with PZQ in the 3 days prior to PZQ ODT administration
Participation in any clinical study within 4 weeks prior to administration of PZQ ODT, or anticipated at any time until completion of the End of study visit
Participants with marked increases of the liver enzymes: alanine aminotransferase and/or aspartate aminotransferase above 3 times the upper limit of normal (ULN); total bilirubin level above 1.5 times the ULN
Participants with hepatosplenic schistosomiasis
Fever, defined as temperature above 37.5 degree Celsius axillary or oral mixed S. haematobium and S. mansoni infections

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 3: 3 to 24 months L-PZQ ODT 50 mg/kg	L-PZQ ODT 50 mg/kg	Participants aged 3 to 24 months infected with S. mansoni received L-PZQ ODT (150 mg) tablet orally at a dose of 50 mg/kg as a single oral dose after food-intake on Day 1.
Cohort 1a: 4 to 6 years L-PZQ ODT 50 mg/kg	L-PZQ ODT 50 mg/kg	Participants aged 4 to 6 years infected with Schistosoma (S.) mansoni received Levorotatory enantiomer of praziquantel (L-PZQ) orodispersible tablets (ODT) (150 milligrams \[mg\]) orally at a dose of 50 milligram per kilogram (mg/Kg) as a single oral dose after food-intake on Day 1.
Cohort 1b: 4 to 6 years Biltricide® 40 mg/kg	Biltricide®	Participants aged 4 to 6 years infected with S. mansoni received Racemate Praziquantel tablets (Biltricide®) (600 mg) orally at a dose of 40 mg/kg as a single oral dose after food-intake on Day 1.
Cohort 2: 2 to 3 years L-PZQ ODT 50 mg/kg	L-PZQ ODT 50 mg/kg	Participants aged 2 to 3 years infected with S. mansoni received L-PZQ ODT (150 mg) tablet orally at a dose of 50 mg/kg as a single oral dose after food-intake on Day 1.
Cohort 4b: 3 months to 6 years L-PZQ ODT 60 mg/kg	L-PZQ ODT 60 mg/kg	Participants aged 3 months to 6 years infected with S. haematobium received L-PZQ ODT (150 mg) tablet orally at a dose of 60 mg/kg as a single oral dose after food-intake on Day 1.
Cohort 4a: 3 months to 6 years L-PZQ ODT 50 mg/kg	L-PZQ ODT 50 mg/kg	Participants aged 3 months to 6 years infected with S. haematobium received L-PZQ ODT (150 mg) tablet orally at a dose of 50 mg/kg as a single oral dose after food-intake on Day 1.

Primary Outcome Measures

Name	Time	Method
Cohort 1a and Cohort 1b: Number of Participants With Clinical Cure Determined by Kato-Katz Method	at Week 3	Clinical cure was defined as no parasite egg in the stool at Week 3 as determined by the Kato-Katz method. Number of participants with clinical cure were reported.

Secondary Outcome Measures

Name	Time	Method
Cohort 2 and Cohort 3: Number of Participants With Clinical Cure Determined by Kato-Katz Method	at Week 3	Clinical cure was defined as no parasite egg in the stool at Week 3 as determined by the Kato-Katz method. Number of participants with clinical cure were reported.
Cohort 1a, Cohort 1b, Cohort 2, and Cohort 3: Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test	at Week 3	Clinical cure is defined as absence of test line in the POC-CCA test cassette (that is no Schistosoma antigens detected). Number of participants with clinical cure were reported.
Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin	Baseline, Day 1	Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: erythrocytes mean corpuscular hemoglobin. Change from baseline in hematology parameter: erythrocytes mean corpuscular hemoglobin at Day 1 were reported.
Change From Baseline in Hematology Parameter: Erythrocytes	Baseline, Day 1	Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: erythrocytes. Change from baseline in hematology parameter: erythrocytes at Day 1 were reported.
Change From Baseline in Hematology Parameters: Hematocrit, Lymphocytes/Leukocytes, Mixed Cells/Leukocytes, Neutrophils/Leukocytes	Baseline, Day 1	Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameters: hematocrit, lymphocytes/leukocytes, mixed cells/leukocytes, neutrophils/leukocytes. Change from baseline in hematology parameters: hematocrit, lymphocytes/leukocytes, mixed cells/leukocytes, neutrophils/leukocytes at Day 1 were reported.
Change From Baseline in Chemistry Parameter: C Reactive Protein	Baseline, Day 1	Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the chemistry parameter: C reactive protein. Change from baseline in chemistry parameter: C reactive protein at Day 1 were reported.
Change From Baseline in Chemistry Parameter: Total Protein	Baseline, Day 1	Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the chemistry parameter: total Protein. Change from baseline in chemistry parameter: total Protein at Day 1 were reported.
Change From Baseline in Urinalyses Parameter: Specific Gravity of Urine	Baseline, Day 1	Urine samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the urinalyses parameters: specific gravity. Change from baseline in urinalyses parameter: specific gravity Day 1 was reported.
Change From Baseline in Urinalyses Parameter: Potential of Hydrogen (pH) of Urine	Baseline, Day 1	Urine samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the urinalyses parameter: pH. Change from baseline in urinalyses parameter: pH at Day 1 was reported.
Change From Baseline in Urinalyses Parameter: Urobilinogen	Baseline, Day 1	Urine samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the urinalyses parameter: urobilinogen. Change from baseline in urinalyses parameter: urobilinogen at Day 1 were reported.
Change From Baseline in Hematology Parameters: Erythrocytes Mean Corpuscular Hemoglobin (HGB) Concentration and Hemoglobin	Baseline, Day 1	Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameters: erythrocytes mean corpuscular HGB concentration and hemoglobin. Change from baseline in hematology parameters: erythrocytes mean corpuscular HGB concentration and hemoglobin at Day 1 were reported.
Cohort 1a, Cohort 1b, Cohort 2 and Cohort 3: Egg Reduction Rate (Percent [%]) Determined by Kato-Katz Method	Pre-treatment, Week 3 post-treatment	Percentage of reduction in group mean egg count was calculated as relative difference between the post-treatment arithmetic mean egg count and pre-treatment arithmetic mean egg count at baseline count, (pre-treatment mean egg count minus post-treatment mean egg count divided by pre-treatment mean egg count) \*100. Egg counts were determined by the Kato-Katz method.
Cohort 4a and Cohort 4b: Egg Reduction Rate (Percent [%]) Determined by Urine Filtration Technique	Pre-treatment, Weeks 3 and 5 post-treatment	Percentage of reduction in group mean egg count was calculated as relative difference between the post-treatment arithmetic mean egg count and pre-treatment arithmetic mean egg count at baseline count, (pre-treatment mean egg count minus post-treatment mean egg count divided by pre-treatment mean egg count) \*100. Egg counts were determined by the urine filtration technique.
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs and Treatment-Related TEAEs	up to Day 40	Adverse Event (AE) was defined any untoward medical occurrence in a participant administered with a study drug, which does not necessarily had a causal relationship with this treatment. Serious AE was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs: TEAEs were defined as those events with onset dates/time occurring after study intervention administration or events that worsen after study intervention administration. TEAEs included serious TEAEs and non-serious TEAEs. Treatment-related TEAEs: reasonably related to the study intervention.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity According to Qualitative Toxicity Scale	up to Day 40	Severity of TEAEs were graded using Qualitative Toxicity Scale, as follows: Mild: Participant is aware of the event or symptom, but the event or symptom is easily tolerated; Moderate: Participant experiences sufficient discomfort to interfere with or reduce his or her usual level of activity; Severe: Significant impairment of functioning: the participant is unable to carry out his or her usual activities. Number of participants with TEAEs by severity were reported.
Change From Baseline in Hematology Parameters: Leukocytes and Platelets	Baseline, Day 1	Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameters: leukocytes and platelets. Change from baseline in hematology parameters: leukocytes and platelets at Day 1 were reported.
Change From Baseline in Chemistry Parameters: Alanine Aminotransferase and Aspartate Aminotransferase	Baseline, Day 1	Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the chemistry parameters: Alanine Aminotransferase and Aspartate Aminotransferase. Change from baseline in chemistry parameters: Alanine Aminotransferase and Aspartate Aminotransferase at Day 1 were reported.
Change From Baseline in Chemistry Parameters: Glucose, Urea and Urea Nitrogen	Baseline, Day 1	Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the chemistry parameters: glucose, urea and urea nitrogen. Change from baseline in chemistry parameters: glucose, urea and urea nitrogen at Day 1 were reported.
Change From Baseline in Chemistry Parameters: Bilirubin, Creatinine and Direct Bilirubin	Baseline, Day 1	Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the chemistry parameters: bilirubin, creatinine and direct bilirubin. Change from baseline in chemistry parameters: bilirubin, creatinine and direct bilirubin at Day 1 were reported.
Change From Baseline in Vital Signs: Pulse Rate	Baseline, Week 3	Pulse rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Change from baseline in vital sign: pulse rate at Week 3 was reported.
Change From Baseline in Vital Sign: Respiratory Rate	Baseline, Week 3	Respiratory rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Change from baseline in vital sign: respiratory rate at Week 3 was reported.
Maximum Observed Plasma Concentration (Cmax) of Praziquantel (PZQ) Enantiomers: R-PZQ and S-PZQ	Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours post-dose	Cmax was obtained directly from the plasma concentration versus time curve.
Number of Participants With Reaction to Study Intervention Administration	Day 1	Reaction to study intervention administration were recorded to describe tolerability as assessed by nurse/site staff for all children enrolled in the study. Reactions categorized as spitting, crying, diarrheas, sleepiness, abdominal pain, fever, vomiting and other. Number of participants with reaction to study intervention administration reported.
Change From Baseline in Vital Signs: Diastolic Blood Pressure and Systolic Blood Pressure	Baseline, Week 3	Diastolic blood pressure and systolic blood pressure were measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Change from baseline in vital signs: diastolic blood pressure and systolic blood pressure at Week 3 were reported.
Change From Baseline in Vital Signs: Temperature	Baseline, Week 3	Temperature was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions. Change from baseline in vital sign: temperature at Week 3 was reported.
Cohort 1a, Cohort 1b, Cohort 4a and Cohort 4b: Palatability Assessment Based on Visual Analog Scale (VAS) Score	Day 1	Palatability of the study intervention was assessed using a human gustatory sensation test (100-millimeter \[mm\] visual analog scale \[VAS\]) incorporating a facial hedonic scale, where lower score (0) indicates "not acceptable/not liked at all" and higher score (100) indicates "very acceptable/liked very much".
Time to Reach Maximum Plasma Concentration (Tmax) of Praziquantel (PZQ) Enantiomers: R-PZQ and S-PZQ	Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours post-dose	Tmax was obtained directly from the plasma concentration versus time curve.
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Praziquantel (PZQ) Enantiomers: R-PZQ and S-PZQ	Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours post-dose	Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule.
Cohort 4a and Cohort 4b: Number of Participants With Clinical Cure Determined by Urine Filtration Technique	Week 3 and Week 5	Clinical cure was defined as no parasite egg in the urine samples at follow up as determined by the urine filtration technique. Number of participants with clinical cure were reported.
Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume	Baseline, Day 1	Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: erythrocytes mean corpuscular volume. Change from baseline in hematology parameter: erythrocytes mean corpuscular volume at Day 1 were reported.