Bioequivalence Study of Coated Cesol Tablet Formulation Versus Biltricide

Study Overview
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Brief Summary
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The purpose of this study is to assess the bioequivalence (BE) of new coated Cesol tablet (Test) versus Biltricide tablets (Comparator) in healthy male participants. Praziquantel (rac-PZQ) is the active ingredient for Cesol and Biltricide tablets.

Official Title
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A Phase I, Open-label, Randomized, Four-period, Crossover, Fully Replicated, Reference-scaled, Single Center Study to Assess the Bioequivalence of a Single Oral Dose of 1200 mg of the Coated Cesol Tablet Formulation Versus Comparator Biltricide® in Healthy Male Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: Cesol (Test)
* Drug: Biltricide (Reference)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants who are overtly healthy as determined by medical evaluation, including medical history, physical examination, laboratory tests, and cardiac monitoring Nonsmoker (=0 cigarettes, pipes, cigars or others) since at least 3 months Have a body weight within 55.0 to 95.0 kilogram (kg) and body mass index within the range of 18.5 to 29.9 kilogram per meter squared (kg/m^2) Electrocardiogram recording (12-lead) without signs of clinically relevant pathology in particular heart-rate corrected [QTc] (Bazett) <450 milliseconds (ms) Vital signs should be in normal range (systolic blood pressure: 90 to 140 millimeters of mercury [mmHg]; diastolic blood pressure: 50 to 90 mmHg; pulse rate: 50 to 90 beats per minute [bpm]; auricular body temperature between 35.9 degree centigrade [°C] to 37.6°C) Are males agreeing to refrain from donating sperm, Use a male condom when having sexual intercourse with a woman of child-bearing potential, who is not currently pregnant, and advise her to use a highly effective contraceptive method with a failure rate of less than (< )1 percent (%) per year Other protocol defined inclusion criteria could apply Exclusion Criteria: Any condition, including any clinically relevant abnormality in the safety laboratory parameters as judged by the Investigator, that in the Investigator's opinion constitutes an inappropriate risk or a contraindication for participation in the study or that could interfere with the study objectives, conduct, or evaluation Have positive results from serology examination for Hepatitis B surface antigen (indicative of active Hepatitis B), Hepatitis C Virus or Human Immunodeficiency Virus (Human Immunodeficiency Virus 1/2 antibodies) Participants who have used drugs that may affect the pharmacokinetics of rac-PZQ from 15 days before dosing until the last PK sample, example., phenytoin, barbiturates, primidone, carbamazapine, oxcarbazepine, topiramate, felbamate, rifampicin, nelfinavir, ritonavir, griseofulvin, oral ketoconazole Positive test for drugs of abuse (including alcohol) at Screening and prior to each dosing Unlikely to comply with the protocol requirements, instructions and study-related restrictions; example, uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study Participant is the Principal Investigator or any Sub investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the study Inability to communicate or cooperate with the Investigator (example. language problem, illiterates, poor mental status) or to comply with the requirements of the entire study, including dietary restrictions Vulnerable participants (example., persons kept in detention). Legal incapacity or limited legal capacity Other protocol defined exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence 1 (T1-R1-T2-R2)<br>Participants will receive first dose of Cesol on Day 1 in treatment period 1 followed by first dose of Biltricide on Day 8 in treatment period 2 followed by second dose of Cesol on Day 15 in treatment period 3 followed by second dose of Biltricide on Day 22 in treatment period 4. A washout period of 7 days will be maintained between 4 treatment periods. | Drug: Cesol (Test)<br>* Participant will receive coated cesol tablet in sequence 1 (Day 1 and Day 15) and in sequence 2 (Day 8 and Day 22). A washout period of 7 days will be maintained between 4 treatment periods.<br>* Other names: Praziquantel;Drug: Biltricide (Reference)<br>* Participant will receive biltricide tablet in Sequence 1 (Day 8 and Day 22) and in sequence 2 (Day 1 and Day 15). A washout period of 7 days will be maintained between 4 treatment periods.<br>* Other names: Praziquantel;|
| Experimental: Sequence 2 (R1-T1-R2-T2)<br>Participants will receive first dose of Biltricide on Day 1 in treatment period 1 followed by first dose of Cesol on Day 8 in treatment period 2 followed by second dose of Biltricide on Day 15 in treatment period 3 followed by second dose of Cesol on Day 22 in treatment period 4. A washout period of 7 days will be maintained between 4 treatment periods. | Drug: Cesol (Test)<br>* Participant will receive coated cesol tablet in sequence 1 (Day 1 and Day 15) and in sequence 2 (Day 8 and Day 22). A washout period of 7 days will be maintained between 4 treatment periods.<br>* Other names: Praziquantel;Drug: Biltricide (Reference)<br>* Participant will receive biltricide tablet in Sequence 1 (Day 8 and Day 22) and in sequence 2 (Day 1 and Day 15). A washout period of 7 days will be maintained between 4 treatment periods.<br>* Other names: Praziquantel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of Racemic-Praziquantel (Rac-PZQ) | Cmax was obtained directly from the concentration versus time curve. | Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Racemic-Praziquantel (Rac-PZQ) | 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 (LLQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule. | Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Related TEAEs | Adverse event (AE): any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. Serious AE: an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after the treatment start date. TEAEs included both serious and non-serious TEAEs. Treatment-related TEAEs: reasonably related to the study intervention. Number of participants with TEAEs and treatment related TEAEs were reported. | Baseline up to Day 27 | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity According to Qualitative Toxicity Scale | 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. | Baseline up to Day 27 | 
| Number of Participants With Clinically Relevant Changes From Baseline in Laboratory Parameters | Laboratory investigation included hematology, biochemistry and urinalysis. Clinical relevance was determined by the investigator. The number of participants with clinically relevant changes from baseline in laboratory parameters were reported. | Baseline up to Day 27 | 
| Number of Participants With Clinically Relevant Changes From Baseline in Vital Signs | Vital signs included body temperature, systolic and diastolic blood pressure and pulse rate. Clinical relevance was determined by the investigator. The number of participants with clinically relevant changes from baseline in vital signs were reported. | Baseline up to Day 27 | 
| Number of Participants With Clinically Significant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings | 12-lead ECG recordings included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration and QT interval. The corrected QT interval (QTcF) was calculated using Fridericia's formula. 12-lead ECG recordings were obtained after the participants have rested for at least 10 minutes in semisupine position. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in 12-Lead ECG findings were reported. | Baseline up to Day 27 | 
| Maximum Observed Plasma Concentration (Cmax) of Praziquantel (PZQ) Enantiomers: R-(-)-PZQ and S-(+) PZQ | Cmax was obtained directly from the concentration versus time curve. | Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period | 
| 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 | 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 (LLQ). AUC0-t was calculated according to the mixed log-linear trapezoidal rule. | Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period | 
| Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Racemic-Praziquantel (Rac-PZQ), R-(-)-PZQ and S-(+)-PZQ | AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. | Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period | 
| Time to Reach Maximum Plasma Concentration (Tmax) of Racemic-Praziquantel (Rac-PZQ), R-(-)-PZQ and S-(+)-PZQ | Tmax was obtained directly from the concentration versus time curve. | Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period | 
| Time Prior to the First Measurable (Non-zero) Concentration (Tlag) of Racemic-Praziquantel (Rac-PZQ), R-(-)-PZQ and S-(+)-PZQ | Time prior to the first measurable (non-zero) concentration; calculated as last time point at which the concentration is less than (<) Lower Limit of Quantification (LLQ) before the occurrence of the first quantifiable concentration. | Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period | 
| Terminal Elimination Half-Life (T1/2) of Racemic-Praziquantel (Rac-PZQ), R-(-)-PZQ and S-(+)-PZQ | Elimination Half Life (T1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. | Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period | 
| Terminal Rate Constant (Lambda z) of Racemic-Praziquantel (Rac-PZQ), R-(-)-PZQ and S-(+)-PZQ | Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. | Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period | 
| Apparent Clearance (CL/f) of Racemic-Praziquantel (Rac-PZQ), R-(-)-PZQ and S-(+)-PZQ | CL/f was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-t + Clast pred/Lambda Z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the lower limit of quantification (LLQ) and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. | Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period | 
| Apparent Volume of Distribution During Terminal Phase (Vz/f) of Racemic-Praziquantel (Rac-PZQ), R-(-)-PZQ and S-(+)-PZQ | Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf*Lambda Z), where AUC0-inf = (AUC0-t + Clast pred/Lambda Z). Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z = the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. | Pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours post-dose in each treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bioavailability, Bioequivalence, Praziquantel, Cesol, Pharmacokinetics