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CTRI Number  CTRI/2018/09/015815 [Registered on: 24/09/2018] Trial Registered Prospectively
Last Modified On: 11/07/2019
Post Graduate Thesis  No 
Type of Trial  BA/BE 
Type of Study    
Study Design  Randomized, Crossover Trial 
Public Title of Study   Bioequivalence study Felbamate Tablets 600mg in adult epilepsy patients. 
Scientific Title of Study   A multi-center, open-label, balanced, randomized, two-treatment, two-period, two-sequence, two-way crossover, steady-state bioequivalence study of Felbamate Tablets 600mg of Lannett Company Inc., USA with FELBATOL® (Felbamate) Tablets 600mg of MEDA Pharmaceuticals Inc., USA among adult epilepsy (partial seizures with or without generalization) subjects already established on a stable adjunctive therapy. 
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
BE/18/020 version 01 dated 26-Mar-2018   Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr Amrut Jadhav  
Designation  Medical Monitor  
Affiliation  Raptim Research Ltd.  
Address  Raptim Research Ltd. Clinical Pharmacology Unit (A-226), Bioanalytical and Biostatistical Unit (A-242) T.T.C., Industrial Area, Mahape M.I.D.C., Navi Mumbai
Clinical Pharmacology Unit (A-226), Bioanalytical and Biostatistical Unit (A-242) T.T.C., Industrial Area, Mahape M.I.D.C., Navi Mumbai
Thane
MAHARASHTRA
400701
India 
Phone  02227781889   
Fax    
Email  amrut.jadhav@raptimresearch.com  
 
Details of Contact Person
Scientific Query  
Name  Dr Amrut Jadhav  
Designation  Medical Monitor  
Affiliation  Raptim Research Ltd.  
Address  Raptim Research Ltd. Clinical Pharmacology Unit (A-226), Bioanalytical and Biostatistical Unit (A-242) T.T.C., Industrial Area, Mahape M.I.D.C., Navi Mumbai
Clinical Pharmacology Unit (A-226), Bioanalytical and Biostatistical Unit (A-242) T.T.C., Industrial Area, Mahape M.I.D.C., Navi Mumbai
Thane
MAHARASHTRA
400701
India 
Phone  02227781889   
Fax    
Email  amrut.jadhav@raptimresearch.com  
 
Details of Contact Person
Public Query  
Name  Mustafa Pardiwala  
Designation  Senior Project Manager  
Affiliation  Raptim Research Ltd.  
Address  Raptim Research Ltd. Clinical Pharmacology Unit (A-226), Bioanalytical and Biostatistical Unit (A-242) T.T.C., Industrial Area, Mahape M.I.D.C., Navi Mumbai
Clinical Pharmacology Unit (A-226), Bioanalytical and Biostatistical Unit (A-242) T.T.C., Industrial Area, Mahape M.I.D.C., Navi Mumbai
Thane
MAHARASHTRA
400701
India 
Phone  02227781889   
Fax    
Email  mustafa.pardiwala@raptimresearch.com  
 
Source of Monetary or Material Support  
Lannett Company Inc., 13200 Townsend road, Philadelphia, PA 19154, U.S.A. 
 
Primary Sponsor  
Name  Lannett Company Inc 
Address  13200 Townsend road, Philadelphia PA 19154 U.S.A. 
Type of Sponsor  Pharmaceutical industry-Global 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 4  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Tushit Mevada  Bodyline Hospital  Room 01, First Floor, Opp. Annapurna Hall, Nr. Dev Status, New Vikas Gruh. 380007. India.
Ahmadabad
GUJARAT 		 917069781147

tmewada@gmail.com 
Dr Amit Yeole  Dr. Amit Yeole  Supe Heart & Diabetes Hospital & Research Center, 1st floor, Clinical Research Department, Opposite Adharashram, Gharpure Ghat, Near Rungtha School, Ashok Stambh, Nasik-422002, Maharashtra, India.
Nashik
MAHARASHTRA 		 919819651753

amit_yeole37@rediffmail.com 
Dr Bakul Buch  Dr. Bakul Buch  Shri Hatkesh Healthcare Foundation, 3rd floor, Department of Psychiatry, Saraswati Mandir Complex Near Bhutnath Temple College Road Junagadh 362001
Junagadh
GUJARAT 		 919825220330

bakulbuch@gmail.com 
Dr Rajendra Anand  Kanoria Hospital and Research Centre  Ground floor, Head of Department Chamber, Kanoria Hospital and Research Centre, Airport-Gandhinagar Highway, Village- Bhat, -382428. India
Gandhinagar
GUJARAT 		 919824017400

drrajendraanand@yahoo.com 
 
Details of Ethics Committee  
No of Ethics Committees= 4  
Name of Committee  Approval Status 
Bodyline Hospitals Ethics Committee  Approved 
Kanoria Ethics Committee  Approved 
Shri Hatkesh Healthcare Foundation Ethics Committee  Approved 
Supe Hospital Ethics Committee  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  (1) ICD-10 Condition: G403||Generalized idiopathic epilepsy and epileptic syndromes,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  Felbamate Tablets 600mg of Lannett Company Inc., USA  As per randomization schedule, subjects will be instructed to receive Test or Reference products of one tablet of Felbamate 600mg three times a day 8 hrs apart for entire study duration of 20 days.  
Comparator Agent  FELBATOL® (Felbamate) Tablets 600mg of MEDA Pharmaceuticals Inc., USA.   As per randomization schedule, subjects will be instructed to receive Test or Reference products of one tablet of Felbamate 600mg three times a day 8 hrs apart for entire study duration of 20 days.  
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  45.00 Year(s)
Gender  Both 
Details  A patient fulfilling all the following criteria will be included in the present study:

1) Patients willing to provide written informed consent for participation in the study;
2) Having ability to comprehend the nature and purpose of the study;
3) Willing to be available for the entire study period and to comply with protocol requirements.
4) Disease population and treatment condition –
Subjects with documented clinical diagnosis of refractory partial seizures with or without generalization.Subjects with partial seizures with or without generalization not controlled with any of standard antiepileptic regimen of Sodium Valproate (or Valproic acid), Levetiracetam, Gabapentin or Pregabalin at therapeutic levels;
5) BMI in the range of 18.5 to 29.99 kg/m2 both inclusive.
6) Non-smoker or ex-smoker or mild / moderate smokers and willing to abstain from chewing or smoking any tobacco containing product at least 72.00 hrs prior to first dosing (onset of up-titration) of the study and throughout study.
7) Willing to abstain from alcohol or alcoholic products within 24.00 hrs prior to first dosing (onset of up-titration) of the study and throughout the study.
8) Willing to abstain from, xanthine or its derivative containing food or beverages (e.g. chocolates, tea, coffee or cola drinks) within 72.00 hrs prior to first prior to first sample collection in each study period and throughout the sampling points.
9) Willing to abstain from grapefruit or its juice within 72.00 hrs prior to first prior to first sample collection in each study period and throughout the sampling points.
10) Clinically non-significant serum electrolytes (sodium, potassium and chloride).
11) With normal or clinically non-significant laboratory values as determined by hematological, biochemistry tests, urine analysis.
12) With a normal or clinically non-significant 12-lead ECG.
13) In case of female subjects:
• Negative urine pregnancy test during screening and, negative serum β-HCG test at baseline visits and at check-in for housing during each study period.
• Patients with child bearing potential or those within their first two years of onset of menopausal syndrome must either abstain from sexual intercourse, or must be using acceptable methods of birth control during the study (Acceptable birth control methods include barrier methods such as diaphragm/condom with spermicide or who are surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy has been performed), but must not use hormonal contraceptive (either oral/implants)).
 
 
ExclusionCriteria 
Details  A patient fulfilling any one of the following criteria will be excluded from the study:
1) Institutionalized patients.
2) A history of allergic or hypersensitive reactions Felbamate or other carbamates or to any of the excipients of formulation which in the opinion of an investigator, would compromise the safety of the subject or the study.
3) History of aplastic anemia or significant hematological disorder (drug induced or idiopathic).
4) History of liver failure or significant liver disease.
5) History of suicidal thinking, imminent risk of suicide, or a danger to self or others as judged by the investigator.
6) History of psychiatric illness or depression.
7) Concurrent use of other drugs known to suppress bone marrow function.
8) Liver enzyme (SGPT and SGOT) levels >2 times the upper limit of normal values at baseline and during the entire study.
9) Clinically significant drop in the red blood cells, white blood cells and platelet counts at baseline and during the entire study.
10) Subjects with any of the following seizure criteria during the study from the date of study onset (baseline):
• 2-fold increase in the highest, 2-day pre-study seizure frequency.
• Single, generalized, tonic-clonic seizure if none occurred during pre-treatment screening, and/or
• Significant prolongation of generalized, tonic-clonic seizures.
11) A medical or surgical condition that might interfere with the absorption, metabolism, or excretion of Felbamate during the study.
12) Significant history or current evidence of malignancy or chronic infectious, cardiovascular, renal, hepatic, ophthalmic, pulmonary, neurological, metabolic (endocrine), hematological, gastrointestinal, immunological or psychiatric diseases, or organ dysfunction, which in the opinion of an investigator, would compromise the safety of the subject or the study;
13) Expected changes in the concomitant medications during the study periods.
14) Expected incompliance with outpatient medications.
15) A history of alcohol or drug dependence by DSM-V-TR criteria during the 6-month period immediately prior to study entry;
16) Positive alcohol breath or urine drug of abuse tests during randomization, or at check-in for housing during each study period.
17) Positive test for Human Immunodeficiency virus (HIV) type I/II antibodies or Hepatitis B surface antigen (HBsAg) or Hepatitis C virus (HCV) antibodies.
18) In case of female subjects:
Planning to become pregnant
Lactating or nursing subjects
19) Participated in any clinical investigation requiring repeated blood sampling, blood donation, or have blood loss of >500 mL in past 8 weeks or participated in any clinical study within the past 3 months prior to first dosing (onset of up-titration) of the study.
20) Any major illness or hospitalization within 90 days prior to first dosing (onset of up-titration) of the study.
21) History of difficulty in accessibility of veins in arms.
 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Centralized 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
The primary objective of the study is to assess whether the test product is bioequivalent to reference product based on the evaluation of Cmax,ss and AUC0-Ï„,ss  Median Tmax at 2.5 hours with range of 0 hrs to 8 hrs 
 
Secondary Outcome  
Outcome  TimePoints 
Descriptive statistics for pharmacokinetic (PK) parameters - Cmin,ss, Cavg,ss Degree of
Fluctuation, Swing and Tmax,ss;

Assessment of safety and tolerability profile of test and reference products.
 		 During each study period, pre-dose samples will be collected on days - 8, 9, 10, 18, 19 and 20 for morning dose. Post-dose PK samples will be collected on day-10 and 20 of each study period at 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00 and 8.00 hrs post morning dose 
 
Target Sample Size   Total Sample Size="38"
Sample Size from India="38" 
Final Enrollment numbers achieved (Total)= "41"
Final Enrollment numbers achieved (India)="41" 
Phase of Trial   N/A 
Date of First Enrollment (India)   01/10/2018 
Date of Study Completion (India) 14/02/2019 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Date Missing 
Estimated Duration of Trial   Years="0"
Months="3"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  		 Not Applicable 
Recruitment Status of Trial (India)  Completed 
Publication Details   None yet  
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Brief Summary  

Felbamate (2-phenyl-1,3-propanediol dicarbamate) is a chemically unique antiepileptic agent.

The purpose of this study is to establish Bioequivalence between Felbamate Tablet 600 mg of of Lannett Company Inc., USA with Felbatol® (Felbamate) Tablet 600 mg of MEDA Pharmaceuticals in Adult Epilepsy Patients (partial seizures with or without generalization) subjects already established on a stable adjunctive therapy under Fasting Conditions.

This study will be initiated only after obtaining the approvals from Drug Controller General of India (DCGI) and from Institutional Ethics Committee (IEC) of participating sites.

Subjects qualifying inclusion and exclusion criteria will undergo up-titration from one tablet of 600mg Reference Felbamate to 3 tablets of 600mg Reference Felbamate 8 hrs apart over a period of 3 weeks followed by stabilization phase where subject will receive 3 tablets of 600mg Reference Felbamate 8 hrs apart for a week.

Upon successful completion of stabilization phase, subject will be randomized to Test or Reference 600mg Felbamate to be taken 8 hrs apart for 10 days followed by cross-over of Test or Reference 600mg Felbamate to be taken 8 hrs apart for another 10 days. Randomization will happen as per site specific randomization schedule.

Subject will be check-in on Day-7 and Day-17. On Day-8, Day-9, Day-10, Day-18, Day-19 and Day-20 pre-dose PK sample will be taken. Apart from these samples, on Day-10 and Day-20 post dose PK samples will be taken at below given time points:

0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00 and 8.00 hrs post morning dose

Subject will be discharged on Day-10 and Day-20 after completion of PK samples.

Post Day-20, down-titration with 600mg Reference Felbamate Tablet will start from two tablets per day for a week to one tablet per day for a week.

Bioanalysis: Plasma samples will be analyzed for Felbamate using a validated analytical method in  accordance with USFDA Guidelines and in-house SOPs of bioanalytical laboratory.

PK parameters and their evaluations will be performed based on:

·         Primary PK parameters: Cmax,ss and AUC0- Ï„,ss

·         Secondary PK parameters: Cmin,ss, Cavg,ss, Degree of Fluctuation, Swing and Tmax,ss.

Acceptance criteria for steady state attainment will be based on following criteria:

·         Probability value for the resultant slope should be statistically nonsignificant at 5% level of significance.

·         If the probability values for the resultant slope is statistically significant at 5% level of significance, but Day 10 - 0.00 hrs / Day 10 - 8.00 hrs ratios should be within 90.00% to 111.11% in each study period.

Test product will be considered bioequivalent to reference product, if 90% CI for ratio of geometric least square means based on log transformed primary PK parameters - Cmax,ss and AUC0- Ï„,ss fall within acceptable BE limits of 80.00% to 125.00% for Felbamate. 
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