Bioequivalence Study of Two Formulations of Propafenone 300 mg Film-coated Tablets in Healthy Adult Volunteers After a Single Oral Dose Administration Under Fasting Conditions

Bioequivalence Clinical Trial

Official title: Single Dose, Full Replicate, Crossover Comparative Bioavailability Study of Propafenone 300 mg Film-Coated Tablets in Healthy Adult Subjects / Fasting State

Status Completed

Clinical Trial Summary

This bioequivalence study will be conducted in healthy male and female volunteers in order to determine the bioequivalence of two different formulations of propafenone after a single oral dose administration under fasting conditions.

Clinical Trial Description

This is a single center, randomized, single dose, laboratory-blinded, 2-treatment, 4-period, 2-sequence, full replicate crossover design, in which 32 healthy adult subjects will receive one of the study treatments during each study period.

The intra-subject variation following a single dose of propafenone appears to be around 36% for maximum observed concentration (Cmax) in plasma and around 34% for cumulative area under the concentration time curve calculated from 0 to time of last observed quantifiable concentration using the linear trapezoidal method (AUC0-T). Statistically, given that the expected Test to Reference ratio of geometric least-squares means (LSmeans) should fall within 95 and 105%, it is estimated that the lowest number of subjects to meet the 80 to 125% bioequivalence range with a statistical a priori power of at least 80% is about 28 in a full replicate design study. Therefore, the inclusion of 32 subjects in a full replicate design should be sufficient to account for the possibility of drop-outs, variations around the estimated intra-subject coefficient of variation (CV) and to conclude in favor of the hypothesis of bioequivalence with sufficient statistical power.

Subject eligibility for this study will be determined at the screening visit and eligible subjects will be admitted to the clinical research unit at least 10 hours prior to drug administration for each study period. Food and fluid intake other than water will be controlled for each confinement period and for all subjects. Water will be provided as needed until 1 hour predose. Water will be allowed beginning 1 hour after the administration of the drug.

A subject who withdraws or is withdrawn during the pretrial evaluations but before receiving the investigational product will not be considered as a drop-out and will not be included in the final database. Standbys should be recruited and available to replace any subject who withdraws prior to the first drug administration. On-study drop-outs will not be replaced.

For each study period, subjects will receive a single 300 mg oral dose of propafenone, under fasting conditions and undergo a 36-hour sample collection. Study participants will be aware they will receive different formulations of the same drug, without being informed which product (Test or Reference) is being administered. A total of 21 blood samples will be collected in each study period for pharmacokinetic (PK) assessments. The time of PK blood sample collection will be calculated relative to the time of treatment administration. The actual time of all PK blood draws will be recorded and reported for all subjects.

Subjects are to be discharged from the clinic after the 24-hour postdose PK sample collection, and following medical approval. However, they may be advised to stay at the clinical site for safety reasons, if judged necessary by the physician in charge. Subjects will return to the clinic for blood collection at 36 hours postdose. The drug administrations in each period will be separated by at least 7 calendar days.

The duration of the clinical portion of this study (excluding the screening period) is expected to be approximately 24 days. The actual overall study duration may vary.

Blood samples for PK determination will be processed, split, stored, and shipped according to the sample processing instructions supplied by the bioanalytical facility. Propafenone plasma concentrations will be measured according to a validated bioanalytical method.

Samples from all subjects who received at least one of the investigational products will be assayed and propafenone plasma levels will be reported. The decision of which subjects will be included in the PK analysis is to be documented by the pharmacokineticist (or delegate) and approved by the sponsor before the start of the sample analysis by the bioanalytical facility. The evaluation of plasma PK parameters will take into account all actual PK sampling times.

For the average bioequivalence (unscaled) approach, the calculation of the within-subject standard deviation (Swr), and the scaled-average-bioequivalence analyses, data from those subjects who have at least one evaluable period of Test product and at least one evaluable period of Reference product will be included in the PK and statistical analysis. An unequal number of subjects per sequence may be used. Concentration data of the remaining subjects will be presented separately.

Subjects who do not complete the sampling schedule of one or more study periods may be included in the PK and statistical analysis and bioequivalence determination for only the PK parameters that are judged not to be affected by the missing sample(s).

Statistical inference of propafenone will be based on a bioequivalence (BE) approach using the following standards:

• Average bioequivalence: The ratio of geometric LSmeans with corresponding 90% confidence interval calculated from the exponential of the difference between the Test and Reference product for the ln-transformed parameters Cmax and AUC0-T should all be within the 80.00 to 125.00% bioequivalence range.

• Scaled-average-bioequivalence: In the event that the Cmax Reference-to-Reference within-subject CV is greater than 30%, that its Test-to-Reference geometric LSmeans ratio is within the bioequivalence range of 80.00-125.00% and the average BE criteria is not met, a scaling approach to the bioequivalence assessment will be used. The 90% confidence interval calculated from the exponential of the difference between the Test and Reference product for the ln-transformed parameter Cmax should be within the widened acceptance criteria using scaled-average-bioequivalence.

The safety population will include all subjects who received at least one dose of one of the investigational products. Safety assessments will include physical examination, vital signs, 12-lead ECG, clinical laboratory tests, and adverse event (AE) monitoring. Additional safety measurements may be performed at the discretion of the investigator for reasons related to subject safety. The safety endpoints are the incidence of AEs, laboratory abnormality assessments, vital signs and ECG findings. Any significant changes will be recorded as adverse events only if they are judged clinically significant by the qualified investigator or delegate. ;

Related Conditions & MeSH terms

• Bioequivalence

• NCT number: NCT03915340
• Study type: Interventional
• Source: Pharmtechnology LLC
• Status: Completed
• Phase: Phase 1
• Start date: March 23, 2019
• Completion date: May 8, 2019