Schistosomiasis
Conditions
Keywords
Praziquantel ODT formulation, Biltricide
Brief summary
The Phase II study consisted of two parts, part 1 is open label, randomized, controlled and exploratory dose finding in children aged between 2 and 6 years infected with S. mansoni. Part 2 investigated efficacy and safety with the selected formulation and dosage in S. mansoni infected children aged between 3 months - 2 years.
Interventions
DRUGBiltricide (racemate praziquantel) oral tablets
Biltricide (600 mg tablet) was administered to participants at a dose of 20 mg/kg in Part 1, Cohort 1 and at a dose of 40mg/kg in Part 1, Cohort 2.
DRUGRacemate Praziquantel ODT
Racemate Praziquantel (PZQ) (150) mg was administered at a dose of 40 mg/kg in Part 1, Cohort 3 and at a dose of 60 mg/kg in Part 1, Cohort 4.
DRUGLevo Praziquantel ODT
Levo PZQ (150 mg) was administered at a dose of 30 mg/kg in Part 1 Cohort 5, 45 mg/kg Part 1 Cohort 6, 60 mg/kg Part 1 Cohort 7, 50 mg/kg Part 2 Cohort 8, and 50 mg/kg Part 2 Cohort 9.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Months to 6 Years
Healthy volunteers
No
Inclusion criteria
* Male and female children aged 2 to 6 years (Part 1) and 3 to 24 months (Part 2) * S. mansoni positive diagnosis defined as positive egg counts in stool (greater than \[\>\]1 egg/1 occasion) according to World Health Organization (WHO) classification : light (1-99 eggs per gram of faeces), moderate (100-399 eggs per gram of faeces) and heavy (greater than or equal to \[\>=\]400 eggs per gram of faeces) infections * Minimum weight of 8.0 kg in 2- to 6-year-old children and of 4.0 kg in 3- to 24-month infants • Parents/legal representative ability to communicate well with the Investigator, to understand the protocol requirements and restrictions, and willing their children to comply with the requirements of the entire trial, i.e. * To be examined by a study physician at screening and 14-21 days after treatment * To provide stool and urine samples at screening, 24 hours and 8 days after treatment, as well as 14-21 days after treatment * To provide finger prick blood samples for Pharmacokinetics (PK) studies and blood samples for safety assessments
Exclusion criteria
* Treatment in the 4 weeks prior to study screening with Praziquantel (PZQ) , other anti-helminthic, antimalarial or anti-retroviral compounds or any other medication that might affect the PK of PZQ such as certain antiepileptics (e.g., carbamazepine or phenytoin), glucocorticosteroids (e.g., dexamethasone), chloroquine, rifampicin or cimetidine * For children being breast fed, treatment of the mothers/wet nurses with PZQ in the 3 days prior to administration of Investigational medicinal product * Previous history of adverse reactions associated with PZQ treatment * Marked increases of the liver transaminases (alanine aminotransferase and/or aspartate aminotransferase) above 3x Upper Limit of Normal (ULN) * History of acute or severe chronic disease including hepato-splenic schistosomiasis * Fever defined as temperature above 38.0 degree centigrade * Debilitating illnesses such as tuberculosis, malnutrition, etc. as well as a medical history of seizures * Mixed S. haematobium and S. mansoni infections * Findings in the clinical examination of schistosome-infected children participating in the study as performed by the study clinician on the treatment day, that in the opinion of the Investigator constitutes a risk or a contraindication for the participation of the subject in the study or that could interfere with the study objectives, conduct or evaluation * Unlikelihood to comply with the protocol requirements, instructions and trial-related restrictions, e.g., uncooperative attitude, inability to return for follow-up visits, and improbability of completing the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Cure Determined by Kato-Katz Method | 14-21 days post treatment | Clinical cure was defined as zero egg counts at 14-21 days post treatment as determined by the Kato-Katz method. Number of participants with clinical cure were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Egg Reduction Rate (Percent) | Baseline, 14-21 days post treatment | Percent reduction in egg count was calculated as geometric mean egg count at post-treatment minus geometric mean egg count at baseline (before treatment) divided by geometric mean egg count at baseline. |
| Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | Day 2, Day 8 and 14-21 days post treatment | Clinical Cure defined as no parasite eggs in the stools as assessed by the commercially available POC-CCA assay for S. mansoni. Number of participants with clinical cure were reported. |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part 1, Cohort 1: Biltricide (Racemate Praziquantel) 20 mg/kg Participants received Biltricide (600 mg tablet) administered orally at a dose of 20 milligram per kilogram (mg/kg), three times a day on treatment Day 1. | 60 |
| Part 1, Cohort 2: Biltricide (Racemate Praziquantel) 40 mg/kg Participants received Biltricide (600 mg tablet) administered orally at a dose of 40 mg/kg as a single dose on treatment Day 1. | 60 |
| Part 1, Cohort 3: Racemate Praziquantel 40 mg/kg Participants received Racemate Praziquantel oral dispersible tablet (ODT) (150 mg) administered orally at a dose of 40 mg/kg as a single dose on treatment Day 1. | 60 |
| Part 1, Cohort 4: Racemate Praziquantel 60 mg/kg Participants received Racemate Praziquantel ODT (150 mg) administered orally at a dose of 60 mg/kg as a single dose on treatment Day 1. | 60 |
| Part 1, Cohort 5: Levo Praziquantel 30 mg/kg Participants received Levo Praziquantel ODT (150 mg tablet) administered orally at a dose of 30 mg/kg as a single dose on treatment Day 1. | 60 |
| Part 1, Cohort 6: Levo Praziquantel 45 mg/kg Participants received Levo Praziquantel ODT (150 mg tablet) administered orally at a dose of 45 mg/kg as a single dose on treatment Day 1. | 60 |
| Part 1, Cohort 7: Levo Praziquantel 60 mg/kg Participants received Levo Praziquantel ODT (150 mg tablet) administered orally at a dose of 60 mg/kg as a single dose on treatment Day 1. | 60 |
| Part 2, Cohort 8: Levo Praziquantel 50 mg/kg Participants aged 13-24 months received Levo Praziquantel ODT (150 mg) administered orally at a dose of 50 mg/kg as a single dose on treatment day 1. | 20 |
| Part 2, Cohort 9: Levo Praziquantel 50 mg/kg Participants aged 3 to 12 months received Levo Praziquantel ODT (150 mg) administered orally at a dose of 50 mg/kg as a single dose on treatment day 1. | 4 |
| Total | 444 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 2 | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 0 | 0 | 2 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Part 2, Cohort 9: Levo Praziquantel 50 mg/kg | Part 2, Cohort 8: Levo Praziquantel 50 mg/kg | Part 1, Cohort 7: Levo Praziquantel 60 mg/kg | Part 1, Cohort 6: Levo Praziquantel 45 mg/kg | Part 1, Cohort 5: Levo Praziquantel 30 mg/kg | Part 1, Cohort 4: Racemate Praziquantel 60 mg/kg | Part 1, Cohort 3: Racemate Praziquantel 40 mg/kg | Part 1, Cohort 2: Biltricide (Racemate Praziquantel) 40 mg/kg | Part 1, Cohort 1: Biltricide (Racemate Praziquantel) 20 mg/kg |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 4.1 years STANDARD_DEVIATION 1.3 | 0.6 years STANDARD_DEVIATION 0.2 | 1.7 years STANDARD_DEVIATION 0.3 | 4.4 years STANDARD_DEVIATION 1.3 | 4.3 years STANDARD_DEVIATION 1.1 | 4.2 years STANDARD_DEVIATION 1.2 | 4.2 years STANDARD_DEVIATION 1.2 | 4.4 years STANDARD_DEVIATION 1.2 | 4.3 years STANDARD_DEVIATION 1.3 | 4.1 years STANDARD_DEVIATION 1.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 444 Participants | 4 Participants | 20 Participants | 60 Participants | 60 Participants | 60 Participants | 60 Participants | 60 Participants | 60 Participants | 60 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 205 Participants | 1 Participants | 7 Participants | 25 Participants | 32 Participants | 23 Participants | 35 Participants | 32 Participants | 28 Participants | 22 Participants |
| Sex: Female, Male Male | 239 Participants | 3 Participants | 13 Participants | 35 Participants | 28 Participants | 37 Participants | 25 Participants | 28 Participants | 32 Participants | 38 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 | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 60 | 0 / 60 | 0 / 60 | 0 / 60 | 0 / 60 | 0 / 60 | 0 / 60 | 0 / 20 | 0 / 4 |
| other Total, other adverse events | 25 / 60 | 30 / 60 | 29 / 60 | 31 / 60 | 28 / 60 | 33 / 60 | 37 / 60 | 10 / 20 | 4 / 4 |
| serious Total, serious adverse events | 1 / 60 | 0 / 60 | 1 / 60 | 0 / 60 | 0 / 60 | 0 / 60 | 0 / 60 | 0 / 20 | 0 / 4 |
Outcome results
Primary
Number of Participants With Clinical Cure Determined by Kato-Katz Method
Clinical cure was defined as zero egg counts at 14-21 days post treatment as determined by the Kato-Katz method. Number of participants with clinical cure were reported.
Time frame: 14-21 days post treatment
Population: Modified intention-to-treat (mITT) analysis set included all participants who had a baseline measurement for the efficacy variable and did not use anti-malaria treatment after study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1, Cohort 1: Biltricide (Racemate Praziquantel) 20 mg/kg | Number of Participants With Clinical Cure Determined by Kato-Katz Method | 51 Participants |
| Part 1, Cohort 2: Biltricide (Racemate Praziquantel) 40 mg/kg | Number of Participants With Clinical Cure Determined by Kato-Katz Method | 43 Participants |
| Part 1, Cohort 3: Racemate Praziquantel 40 mg/kg | Number of Participants With Clinical Cure Determined by Kato-Katz Method | 47 Participants |
| Part 1, Cohort 4: Racemate Praziquantel 60 mg/kg | Number of Participants With Clinical Cure Determined by Kato-Katz Method | 46 Participants |
| Part 1, Cohort 5: Levo Praziquantel 30 mg/kg | Number of Participants With Clinical Cure Determined by Kato-Katz Method | 44 Participants |
| Part 1, Cohort 6: Levo Praziquantel 45 mg/kg | Number of Participants With Clinical Cure Determined by Kato-Katz Method | 49 Participants |
| Part 1, Cohort 7: Levo Praziquantel 60 mg/kg | Number of Participants With Clinical Cure Determined by Kato-Katz Method | 52 Participants |
| Part 2, Cohort 8: Levo Praziquantel 50 mg/kg | Number of Participants With Clinical Cure Determined by Kato-Katz Method | 14 Participants |
| Part 2, Cohort 9: Levo Praziquantel 50 mg/kg | Number of Participants With Clinical Cure Determined by Kato-Katz Method | 4 Participants |
Secondary
Egg Reduction Rate (Percent)
Percent reduction in egg count was calculated as geometric mean egg count at post-treatment minus geometric mean egg count at baseline (before treatment) divided by geometric mean egg count at baseline.
Time frame: Baseline, 14-21 days post treatment
Population: mITT analysis set included all participants who had a baseline measurement for the efficacy variable and did not use anti-malaria treatment after study treatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Part 1, Cohort 1: Biltricide (Racemate Praziquantel) 20 mg/kg | Egg Reduction Rate (Percent) | 94.6 percent reduction in egg count |
| Part 1, Cohort 2: Biltricide (Racemate Praziquantel) 40 mg/kg | Egg Reduction Rate (Percent) | 83.3 percent reduction in egg count |
| Part 1, Cohort 3: Racemate Praziquantel 40 mg/kg | Egg Reduction Rate (Percent) | 88.6 percent reduction in egg count |
| Part 1, Cohort 4: Racemate Praziquantel 60 mg/kg | Egg Reduction Rate (Percent) | 88.6 percent reduction in egg count |
| Part 1, Cohort 5: Levo Praziquantel 30 mg/kg | Egg Reduction Rate (Percent) | 88.3 percent reduction in egg count |
| Part 1, Cohort 6: Levo Praziquantel 45 mg/kg | Egg Reduction Rate (Percent) | 92.3 percent reduction in egg count |
| Part 1, Cohort 7: Levo Praziquantel 60 mg/kg | Egg Reduction Rate (Percent) | 94.1 percent reduction in egg count |
| Part 2, Cohort 8: Levo Praziquantel 50 mg/kg | Egg Reduction Rate (Percent) | 97.7 percent reduction in egg count |
| Part 2, Cohort 9: Levo Praziquantel 50 mg/kg | Egg Reduction Rate (Percent) | 100.0 percent reduction in egg count |
Secondary
Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test
Clinical Cure defined as no parasite eggs in the stools as assessed by the commercially available POC-CCA assay for S. mansoni. Number of participants with clinical cure were reported.
Time frame: Day 2, Day 8 and 14-21 days post treatment
Population: mITT analysis set included all participants who had a baseline measurement for the efficacy variable and did not use anti-malaria treatment after study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1, Cohort 1: Biltricide (Racemate Praziquantel) 20 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | 14-21 days post treatment | 33 Participants |
| Part 1, Cohort 1: Biltricide (Racemate Praziquantel) 20 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | Day 8 | 28 Participants |
| Part 1, Cohort 1: Biltricide (Racemate Praziquantel) 20 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | Day 2 | 8 Participants |
| Part 1, Cohort 2: Biltricide (Racemate Praziquantel) 40 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | 14-21 days post treatment | 21 Participants |
| Part 1, Cohort 2: Biltricide (Racemate Praziquantel) 40 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | Day 8 | 16 Participants |
| Part 1, Cohort 2: Biltricide (Racemate Praziquantel) 40 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | Day 2 | 3 Participants |
| Part 1, Cohort 3: Racemate Praziquantel 40 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | Day 2 | 3 Participants |
| Part 1, Cohort 3: Racemate Praziquantel 40 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | Day 8 | 19 Participants |
| Part 1, Cohort 3: Racemate Praziquantel 40 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | 14-21 days post treatment | 24 Participants |
| Part 1, Cohort 4: Racemate Praziquantel 60 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | Day 8 | 18 Participants |
| Part 1, Cohort 4: Racemate Praziquantel 60 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | Day 2 | 8 Participants |
| Part 1, Cohort 4: Racemate Praziquantel 60 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | 14-21 days post treatment | 32 Participants |
| Part 1, Cohort 5: Levo Praziquantel 30 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | 14-21 days post treatment | 24 Participants |
| Part 1, Cohort 5: Levo Praziquantel 30 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | Day 2 | 4 Participants |
| Part 1, Cohort 5: Levo Praziquantel 30 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | Day 8 | 16 Participants |
| Part 1, Cohort 6: Levo Praziquantel 45 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | 14-21 days post treatment | 35 Participants |
| Part 1, Cohort 6: Levo Praziquantel 45 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | Day 8 | 28 Participants |
| Part 1, Cohort 6: Levo Praziquantel 45 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | Day 2 | 6 Participants |
| Part 1, Cohort 7: Levo Praziquantel 60 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | 14-21 days post treatment | 42 Participants |
| Part 1, Cohort 7: Levo Praziquantel 60 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | Day 8 | 38 Participants |
| Part 1, Cohort 7: Levo Praziquantel 60 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | Day 2 | 11 Participants |
| Part 2, Cohort 8: Levo Praziquantel 50 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | Day 2 | 5 Participants |
| Part 2, Cohort 8: Levo Praziquantel 50 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | Day 8 | 8 Participants |
| Part 2, Cohort 8: Levo Praziquantel 50 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | 14-21 days post treatment | 10 Participants |
| Part 2, Cohort 9: Levo Praziquantel 50 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | Day 8 | 0 Participants |
| Part 2, Cohort 9: Levo Praziquantel 50 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | Day 2 | 0 Participants |
| Part 2, Cohort 9: Levo Praziquantel 50 mg/kg | Number of Participants With Clinical Cure Determined by Point-of-Care Circulating Cathodic Antigen (POC-CCA) Test | 14-21 days post treatment | 0 Participants |