A phase III, multicenter, randomized, double-blind, parallel-group clinical trial to compare the efficacy and safety of the Cenobamate tablets as adjunctive therapy versus Eslicarbazepine in focal seizures

Study Title: A phase III, multicenter, randomized, double-blind, parallel-group clinical trial to compare the efficacy and safety of the Cenobamate tablets as adjunctive therapy versus Eslicarbazepine in focal seizures

Details of Investigational medicinal product:

Test Product: Cenobamate tablets of Bajaj Healthcare Limited

Active- Control: Eslicarbazepine acetate tablets

Study Objective(s):

Primary Objective: The primary objective of this study is to evaluate the efficacy of Cenobamate tablets vis-à-vis active control medication, i.e. Eslicarbazepine acetate on the basis of primary and secondary efficacy endpoints

Secondary Objective: The secondary objective of this study is to evaluate the safety of Cenobamate tablets vis-à-vis active control medication, i.e. Eslicarbazepine acetate by comparing treatment-emergent adverse events or serious adverse events as well as comparison of baseline and end-of-study assessment by virtue of physical examination and clinical laboratory investigations.

Sample Size: 230 Male or female patients [Age: 18 to 70 years (both inclusive)]

Study Design:

1.    It will be a phase III, multicenter, randomized, double blind, parallel-group, active-controlled study clinical trial to test the safety and efficacy of Cenobamate tablets vis-à-vis active control medication, i.e. eslicarbazepine tablets in focal seizures as an adjuvant therapy.

The definition of drug-resistant focal seizure: Drug resistant focal seizure is defined as failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom.

2.    The study will be conducted in the hospital set-up as per NDCT rules. The patients could be treated on outpatient [OP] basis or may be in need of in-patient admission [IP].

3.    The investigator will identify the patient of epilepsy as per points stated in the recruitment flyer. The patients will be called to the clinical trial site and this will be day 0 of the trial. On day 0, patient/ patient’s legally acceptable representative [LAR] will be informed by the delegated staff of clinical trial site under supervision of investigator about the objectives and procedure and duration of this trial along with entire information about the study drugs along with possible adverse events as well as responsibilities of the patient throughout the trial. Sufficient time would be given to the patient for understanding the procedures of the trial and following his/ her voluntary informed consent, they will be provided with a seizure diary to record seizure frequency. This is baseline phase and it will last for 4 weeks. During the baseline phase, the Subjects will be screened after at least 2 weeks of baseline phase after checking the seizure diary. The screening will be done as per section 11.1 to decide eligibility.

4.    If any Subject is already and adequately maintaining seizure diary for a 4-week period, he/ she can be screened immediately to decide eligibility for the trial. In this case, there is no need for separate baseline phase. Following decision of eligibility, Subject will be called for participation in the study.

5.    This will be followed by randomization into one of the two arms, i.e. Test or Active-control in 1:1 ratio in a double-blind manner.

6.    Subjects will then enter titration phase of 8-weeks in a double-blind manner, which will start from

12.5 mg in case of Test/ 200 mg in case of active-control in the first week

25 mg in case of Test/ 400 mg in case of active-control in the second week

50 mg in case of Test/ 600 mg in case of active-control in the 3rd and 4th week

100 mg in case of Test/ 800 mg in case of active-control in the 5th and 6th week

150 mg in case of Test/ 1200 mg in case of active-control in the 7th to 8th week and

200 mg in case of Test/ 1600 mg in case of active-control from the 9th week, which is maintenance dose

7.    This will be followed by a maintenance phase of 6 weeks, i.e. from week 9 to week 14, the Subjects will be continued on 200 mg of the Test medication or 1600 mg or the active-control medication in double-blind manner.

8.    If a Subject could not tolerate the next higher dose during titration phase, the Subject’s dose will be reduced to the previous dose and he/ she will continue the maintenance phase of 6 weeks on that dose, e.g. if any Subject could not tolerate 150 mg/ 1200 mg dose of Test or Active-control medication, that Subject’s dose will be reduced to 100 mg/ 800 mg and 6-weeks’ maintenance phase will continue from then onwards

9.    If it is noted that the Subject who has reached the maximum dose of 200 mg/ 1600 mg of Test/ Active-control medication and shows signs of intolerance, the dose will be reduced as per investigator’s discretion for the remaining period of maintenance phase.

10.  No dose changes to concomitant AEDs will be allowed during the double-blind study. Patients will continue taking their allowed concomitant AEDs without any dose changes throughout the double-blind treatment period.

11.  At the end of the maintenance phase, the efficacy and safety endpoints will be checked.

12.  Total maximum duration of the clinical trial will be of 18 weeks including 4-weeks baseline phase. The maximum duration of double-blind treatment period is 14 weeks for any Subject who is enrolled and randomized. This duration could be shorter for patient who shows intolerance to any dose during titration phase as his/ her maintenance phase will begin from the tolerated dose.

13.  The trial could end prior to week 18 for an individual Subject, who voluntarily drops out.

14.  In case of adverse event/ serious adverse event irrespective of whether it is due to study procedure or study drug and anytime within 14 weeks from the enrolment, the investigator could withdraw the patient and switch to appropriate medical management of the said AE/ SAE.

15.  Since the study is blinded, the patient, investigator or any study staff would not know the nature of the treatment [Test or Active-control] until end of the study or until after the code is broken in case of AE or SAE.

16.  End-of-study [EOS] assessment would be performed after 6-weeks of maintenance phase is completed or at the time of early discontinuation or withdrawal of the patient.

17.  All Subjects will be telephonically followed 15 days after the end-of-study and inquired about the safety.