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CTRI Number  CTRI/2015/06/005925 [Registered on: 17/06/2015] Trial Registered Prospectively
Last Modified On: 18/02/2016
Post Graduate Thesis  No 
Type of Trial  BA/BE 
Type of Study   Patient Pharmocokinetic and safety study. 
Study Design  Randomized, Crossover Trial 
Public Title of Study   Steady - State Bioequivalence Study of Felbamate Tablets 600 mg (Fasting) 
Scientific Title of Study   A multicenter, open label, multiple-dose, randomized, two-treatment, two-period, two-sequence, two-way crossover, steady-state bioequivalence study of Felbamate Tablets 600 mg of Getz Pharma Research Pvt. Ltd., India with that of FELBATOL® (Felbamate) Tablets 600 mg of MEDA Pharmaceuticals Inc., Somerset, New Jersey, 08873-4120,USA.,in adult male and non-pregnant female epilepsy (partial seizures with and without generalization) patients already established (run-in) on Felbamate as an monotherapy/adjunctive therapy under fasting condition. 
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
C14214 Version No: 01. Date 15 SEP 2014  Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr Chakravarthy K MBBS MD  
Designation  CROs Medical Expert 
Affiliation  Aizant Drug Research Solutions Pvt. Ltd., 
Address  Aizant Drug Research Solutions Pvt Ltd Survey No 172 173 Apparel Park Road Dulapally Village Quthbullapur Mandal Hyderabad
Survey No 172 173 Apparel Park Road Dulapally Village Quthbullapur Mandal Hyderabad
Rangareddi
ANDHRA PRADESH
500100
India 
Phone  040-23792190  
Fax  040-23792223  
Email  Chakravarthy.k@aizant.com  
 
Details of Contact Person
Scientific Query  
Name  Dr Chakravarthy K MBBS MD  
Designation  CROs Medical Expert 
Affiliation  Aizant Drug Research Solutions Pvt. Ltd., 
Address  Aizant Drug Research Solutions Pvt Ltd Survey No 172 173 Apparel Park Road Dulapally Village Quthbullapur Mandal Hyderabad
Survey No 172 173 Apparel Park Road Dulapally Village Quthbullapur Mandal Hyderabad

ANDHRA PRADESH
500100
India 
Phone  040-23792190  
Fax  040-23792223  
Email  Chakravarthy.k@aizant.com  
 
Details of Contact Person
Public Query  
Name  Dr Venkatesh MBBS 
Designation  CRO Medical Officer 
Affiliation  Aizant Drug Research Solutions Pvt. Ltd., 
Address  Aizant Drug Research Solutions Pvt Ltd Survey No 172 173 Apparel Park Road Dulapally Village Quthbullapur Mandal Hyderabad
Survey No 172 173 Apparel Park Road Dulapally Village Quthbullapur Mandal Hyderabad
Rangareddi
ANDHRA PRADESH
500100
India 
Phone  040-23792190  
Fax  040-23792223  
Email  venkatesh.pandiri@aizant.com  
 
Source of Monetary or Material Support  
Getz Pharma Research Pvt. Ltd. Plot # PL-11, Anand Nagar M.I.D.C. Addl. Ambernath, Ambernath (East), Dist. Thane-421 506, Maharashtra, India.  
 
Primary Sponsor  
Name  Getz Pharma Research Pvt Ltd 
Address  Getz Pharma Research Pvt. Ltd. Plot # PL-11, Anand Nagar M.I.D.C. Addl. Ambernath, Ambernath (East), Dist. Thane-421 506, Maharashtra, India.  
Type of Sponsor  Pharmaceutical industry-Indian 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study
Modification(s)  
No of Sites = 3  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr B Hemeswar rao MD DM   Praveen Cardiac center  4th Floor, CR Division. Neurology Department. 32-9-18, Madhu garden center, Moghalarajpuram, Vijayawada-520010.
Krishna
ANDHRA PRADESH 		 9000348262
08666662024
bioexperts21@gmail.com 
Dr Vikram Sharma  St. Theresas Hospital  Neurology Dept, First Floor. Sanathnagar, Hyderabad-500018.
Rangareddi
ANDHRA PRADESH 		 9866960555
04023814556
drvikramsharma@gmail.com 
Dr Neehar Potluri  Surakshaka Diabetic centre (P) Ltd.  MIG-218, K.P.H.B Main Road, Kukatpally, Hyderabad
Rangareddi
ANDHRA PRADESH 		 9246207969
04040061930
neeharpotluri@gmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 3  
Name of Committee  Approval Status 
Ethics Committee St. Theressa Hospital  Approved 
Institutional Ethics Committee Ppraveen cardiac centre  Approved 
surakshaka Institutional Ethics Committee  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  adult male and non-pregnant female epilepsy patients already established (run-in) on Felbamate as an monotherapy/adjunctive therapy under fasting condition,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  Felbamate Tablets 600 mg Oral Tablets  Patients will be titrated upwards with Felbamate (reference product) starting with 600mg OD with increments up to 600mg Q8h. The total study duration for patient participation will be 20 days. Getz Pharma Research Pvt. Ltd., India 
Comparator Agent  FELBATOL® (Felbamate) Tablets 600 mg Oral Tablets  Patients will be titrated upwards with Felbamate (reference product) starting with 600mg OD with increments up to 600mg Q8h. the total study duration for patient participation will be 20 days. MEDA Pharmaceuticals Inc., Somerset, New Jersey, 08873-4120,USA 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  45.00 Year(s)
Gender  Both 
Details  i. Patients should be in the range of 18 - 45 years of age (both inclusive).
ii. BMI should be in the range of 18.5 to 24.9 kg/m2.
iii. Patients having refractory partial seizures with and without generalization not controlled on standard antiepileptic drugs at therapeutic levels.
iv. Patients with normal findings as determined by baseline history, physical examination and vital signs (seated blood pressure, radial pulse rate, respiratory rate and axillary temperature).
v. Patients with normal / not significant laboratory values as determined by hematological tests, biochemistry, urine analysis, ECG and chest X-ray(P/A view) in correlation with clinical findings.
vi. Willingness to follow the protocol requirement as evidenced by voluntary written informed consent.
vii. Agreeing to, not using or conforming to not having any medication (prescription and over the counter, herbal products), including vitamins and minerals for 15 days prior to study & during the course of the study except any one of Valproic acid, Gabapentin, Levetiracetam or Pregabalin for ongoing therapy of any of their illnesses.
viii. No history or presence of significant alcoholism(> 3 units of alcohol per day) within one year prior to drug administration.
ix. No history of smoking and of drug abuse.
x. All female patients who are of child bearing potential or those within the first two years of the onset of menopausal syndrome using acceptable methods of birth control at least 30 days prior to onset of screening period and till 30 days post last dose of study drug in period-II. Acceptable birth control methods include Barrier methods such as diaphragm/condom with spermicide, foams, jellies, diaphragm, intrauterine device (IUD), or abstinence. Unacceptable methods include oral or implanted or is surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy has been performed on the study patient)
 
 
ExclusionCriteria 
Details  The patients meeting with any one of the following criteria should be excluded:
i. History of aplastic anemia or hepatic failure.
ii. Requiring medication for any ailment having enzyme-modifying activity in previous one month other than Felbamate, Valproic acid, Gabapentin, Levetiracetam or Pregabalin prior to drug administration day and during the course of the study.
iii. History of cardiovascular, renal, hepatic, ophthalmic, pulmonary, neurological (other than refractory epilepsy), metabolic hematological, gastrointestinal, endocrine or immunological illness.
iv. At baseline (Prior to randomization):
• Two-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 and Status Epilepticus.
v. Participation in any other clinical study within 90 days prior to onset of screening period.
vi. History of or currently active malignancy or any other serious diseases.
vii. Any contraindication to blood sampling.
viii. Refusal to abstain from smoking or consumption of alcohol and tobacco products 72.00 hours before morning drug administration on days- 10 and 20 and until after the last blood sample collection in each study period.
ix. Use of xanthine containing food or beverages (chocolates, tea, coffee or cola drinks), grapefruit juice or products containing grapefruit and alcohol or any alcoholic products, for 72.00 hours before morning drug administration on days- 10 and 20 and until after the last blood sample collection in each study period.
x. Blood donation within 90 days prior to the commencement of the study.
xi. Patients with positive HIV I/II, HBsAg or HCV tests.
xii. Patients with positive HBsAg, positive anti-Hbc and positive anti HBs.
xiii. Positive urine screen for drugs of abuse and breath alcohol test done during check-in process.
xiv. For female patients: Positive serum pregnancy test for female patients during screening and enrolment/check-in process.
xv. A history of allergic or adverse reactions to Felbamate, its formulation excipients or any comparable or similar product (carbamates).
xvi. A history of severe hepatic impairment, drug induced leucopenia/neutropenia, congenital prolongation of the QT interval, cardiac arrhythmias, myocardial infarction or unstable heart disease
xvii. Concurrent primary psychiatric or neurological diagnosis, including organic mental disorder, severe tardive dyskinesia, or idiopathic Parkinson’s disease.
xviii. Complete blood counts below accepted normal values.
xix. Elevation in liver enzymes, above the normal limits. A history of or currently active granulocytopenia or myeloproliferative disorders (drug-induced or idiopathic).
xx. A medical or surgical condition that might interfere with the absorption, metabolism, or excretion of Felbamate.
xxi. Concurrent use of other drugs known to suppress bone marrow function or causes a significant risk of drug induced hepatitis.
xxii. Expected changes in concomitant medications during the period of study.
xxiii. A history of alcohol or drug dependence by Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria during the 6-month period immediately prior to study entry.
xxiv. Not complied with outpatient medication schedule.
xxv. History of multiple syncopal episodes.
Lactating or nursing or pregnant female patients or planning to become pregnant during 30 days prior to onset of screening period and till 30 days post last dose of study drugs in Period-II. 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   An Open list of random numbers 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
To determine the steady state bioequivalence of Felbamate Tablets 600 mg of Getz Pharma Research Pvt. Ltd., India, with Standard Reference - FELBATOL® 600 mg of MEDA Pharmaceuticals Inc., Somerset, New Jersey, 08873-4120, USA, in 32 adult epileptic (partial seizures with and without generalization) patients   2 Months Clinical Schedule 
 
Secondary Outcome  
Outcome  TimePoints 
To monitor the safety and tolerability of repeated doses of Felbamate 600 mg tablets in refractory partial epilepsy patients stabilized on Felbamate.  2 Months Clinical Schedule 
 
Target Sample Size
Modification(s)  		 Total Sample Size="38"
Sample Size from India="38" 
Final Enrollment numbers achieved (Total)= ""
Final Enrollment numbers achieved (India)="" 
Phase of Trial   N/A 
Date of First Enrollment (India)   23/06/2015 
Date of Study Completion (India) Date Missing 
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    
Individual Participant Data (IPD) Sharing Statement

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

Brief Summary
Modification(s)  
Epilepsy is a neurologic condition, which affects the nervous system. Seizures are classified in two basic groups, partial and generalized. The process of diagnosing and treating people with epilepsy is diverse from single or combination of medications to alternative therapies to surgery. As many as two out three patients treated for epilepsy have seizures that are refractory to therapy, either because they have incomplete control of their seizures or they experience treatment-related side effects that interfere with their quality of life.
Objectives :
Primary Objective: To determine the steady state bioequivalence of Felbamate Tablets 600 mg of Getz Pharma Research Pvt. Ltd., India, with Standard Reference - FELBATOL® 600 mg of MEDA Pharmaceuticals Inc., Somerset, New Jersey, 08873-4120, USA, in 32 adult epileptic (partial seizures with and without generalization) patients already receiving any of the following mentioned drugs i.e. valproic acid, levetiracetam, gabapentin, or pregabalin and are eligible to add Felbamate 600 mg Q8h as an adjunctive therapy in a stable regimen under fasting condition.
Secondary Objective: To monitor the safety and tolerability of repeated doses of Felbamate 600 mg tablets in refractory partial epilepsy patients stabilized on Felbamate.
Study Population :
Total 38 number of patients will be randomized to ensure 32 Adult patients with refractory partial-onset seizures with and without generalization already receiving Felbamate 600mg Q8H and any of the following mentioned drugs i.e. valproic acid, levetiracetam, gabapentin, or pregabalin in a stable regimen for at least 7 days prior to randomization. 
Screening Procedure (Day -28):
Informed consent form obtaining, demographic data, medical and treatment
histories   (surgical   and   obstetric   history   for female patients),       physical
examination, 12-lead ECG, Chest X-ray (P/A view), vital signs and well­being, hematology with complete differential count, biochemistry, serology, urinalysis, urine drug screen, alcohol breath test and serum pregnancy test (in case of female patients only) will be performed.
Inclusion-exclusion criteria check, monitoring for concomitant medications and safety, issuance of reference product (for up to day -7) and patient diary, up-titration treatment onset of Felbamate (FELBATOL®) and down-titration of antiepileptic drugs.
The procedure of up-titration on day -28 should only be initiated for the patients who are found to be eligible for enrollment after complete screening. Note: Patients will be instructed by the concerned personnel for filling up the diary and administration procedures of the drug.
Up-titration (Day -28 to Day -7)
Patients will be titrated upwards with Felbamate (reference product) starting with 600mg OD with increments up to 600mg Q8h and simultaneous down’
titration  of ongoing      concomitant    drugs   (valproic   acid,   levetiracetam,
gabapentin, or pregabalin) as per investigator’s sole discretion over a period of 3 weeks. During this period patients will be contacted telephonically on day -21st, day -14th for their well being, drug administration and concomitant medications details.
Note: Patients will be instructed telephonically by the concerned personnel for filling up the diary and administration procedures of the drug.
Clinical Stabilization (Day-7):
Physical examination, vital sign measurements (axillary temperature, respiratory rate, radial pulse rate and seated blood pressure) and well being, hematology with complete differential count, liver function test, checking of inclusion-exclusion criteria, concomitant medication and safety, issuance of reference product, clinical stabilization on Felbamate and concomitant medications.
Prior to enrollment into the study (for at least 7 days prior to the randomization), patients will be clinically stabilized. Stabilization will be assessed by the investigator as no further deterioration in the patient status, i.e. increase in seizures or new adverse event occurred in comparison to earlier therapeutic schedule) to a dose of 600mg Q8h of the reference product with any one of valproic acid, levetiracetam, gabapentin, or pregabalin.
Note:
·      The drug accountability and patient diary will be reviewed.
Patients will be instructed by the concerned personnel for filling up the diary and administration procedures of the drug.
Procedure on Day -1:
Physical examination, vital sign measurements (axillary temperature, respiratory rate, radial pulse rate and seated blood pressure) and well being, hematology with complete differential count, liver function test, concomitant medication and safety, clinical stabilization on Felbamate and concomitant medications.
(Based on the day -7 or day -1 results, Felbamate treatment will be stopped, if necessary in accordance with the aplastic anaemia and hepatic failure warning in the labeling of reference product or other potential safety concern. Patients requiring modification or stopping of Felbamate tablet treatment will be terminated from the study and provided with prompt medical care).
Note:
1.    Any unscheduled visits throughout the study will be documented and verified by the site investigator.
      2. The drug accountability and patient diary will be reviewed.

Randomization (Day 0):

Physical           examination,   vital     sign      measurements (axillary          temperature, respiratory rate, radial pulse rate and seated blood pressure) and well-being, , urine screen for drugs of abuse, alcohol breath test, serum pregnancy test (in case of female patient only),   checking of inclusion-exclusion criteria,concomitant medication and safety.Based on the physical examination and other diagnostic parameters respective site physician will declare the eligibility status for the study and the patients will be randomized to either test product or reference product treatments. Patients will be issued sufficient quantity of test product or reference product (for days: 1 to 7) for their consumption respectively, at their home during this visit.
Out Patient Treatment :
Patients will be instructed to consume either test product or reference product as per their randomization schedule from days 1 to 7 and 11 to 17 during Period- I and Period- II, respectively.Patients will be issued sufficient quantity of test product or reference productfor consumption at their home during Period- I (on day 0) and Period-II (on day 11).
Note:
• The drug accountability and patient diary will be reviewed.
• Patients will be instructed by the concerned personnel for filling up the
diary and administration procedures of the drug.

Check-in :
The patients will be hospitalized at least 12.00 hours prior to morning dose on day8 for Period-I and day18 for Period-II or as per the investigator discretion. Physical examination, vital signs and well-being, Alcohol breath test, urine screen for drugs of abuse and serum pregnancy test (in case of female patientonly), checking of inclusion-exclusion criteria will be performed prior tocheck-in of each study period, i.e. day 7 during Period-I and day 17 duringPeriod-II. Patients will be excluded if found positive for these tests.
Housing :
Patients will remain in hospital on day 8, day 9, day 10 in Period-I and day18, day 19, day 20 in Period-II.Vital signs and well being, concomitant medication, safety monitoring will be performed during their in-house stay.

Safety Monitoring During the Study :
Physical examination, vital sign measurements (axillary temperature,respiratory rate, radial pulse rate and seated blood pressure) and well-beingwill be done before check-in and check-out on day 7 and day 11, duringPeriod-I and on day 17 and day 21 during Period-II.Vital sign measurements (axillary temperature, respiratory rate, radial pulserate and seated blood pressure) and well-being will be assessed at 0.00 hours(within 1.00 hour prior to morning dose) and at 1.00, 2.00, 4.00, 6.00, 8.00and 12.00 hours post morning dose on day 8, day 9, day 10 in Period-I and onday 18, day 19, day 20 in Period-II. Monitoring for concomitant medication and safety will performed prior to check-in on day7 (Period-I) and day 17 (Period-II), during in-house stay (day8, day 9 and day 10 in Period-I and day 18, day 19 and day 20 in Period-II),and during check-out on day 11 (Period-I) and day 21 (Period-II).
FOOD INTAKE : The total calories of standard meals or snacks will be 2875 kilo calories/ dayserved on days 7th, 8th, 9th, 10th and 17th, 18th, 19th, 20th of pre/ post dose in each study period. The meal plan will be uniform and identical in all the periods. Information on the amount of meal consumed and the time of consumption will be recorded by the custodians in the respective sites in the respective Case Report Forms.

CHECK OUT : Patients will be checked out from hospital on day 11 in Period -I and day 21 in Period-II after 22.00 hours of morning dose.

WASHOUT PERIOD : There will be no washout period between the two treatment periods. After lastdose administration on 10th day, patient will be then switched over to the other treatment as per randomization schedule.

DRUG ADMINISTRATION : As per the randomized study code, patients will be instructed to take either test product or reference product 600 mg (three times daily at 8.00 hours interval i.e. morning, afternoon and evening dose) orally, for the first seven days (days:1-7 for Period-I and 11-17 for Period-II) in each study period.During hospitalization, patients will be fasted for at least 10.00 hours prior tomorning dose on day 8, day 9, day 10 in Period-I and day 18, day 19, day 20 in Period-II, respectively. Patients will be administered stabilized treatment of Felbamate 600 mg thrice a day (either test product or reference product) as per their randomization study code) and stable down titrated dose of antiepileptic drug with 240 ±2 mL of water. Drinking water will not be allowed 1.00 hour before and after morning drug administration on day 8, day 9, day 10 (Period-I) and on day 18, day 19, day 20 (Period-II) except for 240 ±2 mL of water administered during dosing. At all other times drinking water will be provided ad-libitum. It will be ensured by the dosing personnel that the tablet is completely swallowed by the patient with a thorough check of the oral cavity using a tongue depressor and flash light immediately after drug administration. Patients will be instructed not to chew or crush the tablet but to consume it whole with specified quantity of water. The dose will be administered in a staggered manner to maintain subsequent blood collection schedule. Record of drug administration for individual patient will be maintained in Case Report Form. Patient will remain in sitting posture for 2 hrs post morning doses on day 8,day 9, day 10 during Period-I and day 18, day 19, day 20 during Period-II.

DOWN-TITRATION :
Patients will be down-titrated for Felbamate 600 mg dose and up-titrated for concomitant anti-epileptic drugs in the same manner as in the up-titration process of Felbamate dosing as per investigator’s discretion on day 21 prior to check-out. Patients will be issued sufficient quantity of reference products for their consumption respectively, at their home (for day 21 to day 34) on day 21.prior to check-out.
Patients will be telephonically contacted for their well being, drug administration and concomitant medications details on day 27. 
Note: Patients will be instructed by the concerned personnel for filling up the diary and administration procedures of the drug.

POST-STUDY SAFETY :

At the end of the study on day 34 or in case of a patient withdrawal or termination or dropout, the following procedures will be done: Physical examination, vital sign measurement (axillary temperature, respiratory rate,radial pulse rate and seated blood pressure) and well being, hematology with complete differential count, biochemistry and urine analysis and serum pregnancy test (for Females), 12-lead ECG, and monitoring for concomitant medication and safety.

BIO-ANALYTICAL METHOD :

The plasma concentration of Felbamate will be analysed using a validated Liquid Chromatography Mass Spectrometry (LC-MS/MS) method.

PHARMACO KINETICS :

Area under the plasma concentration-time curve for a steady-state dosing interval ( AUC0- ), peak concentration at steady state (Cmaxss), time to peak concentration at steady state (Tmaxss), minimum concentration at steady state (Cminss) and percent peak - trough fluctuation (Fluctuation%) will be calculated using WinNonlin® 5.3 or higher.

STATISTICAL ANALYSIS :

Analysis of variance (ANOVA) will be performed for ln-transformed Cmaxss,Cminss and AUC0- data with factors for treatment, period, centre, sequence and patient nested within sequence. Because different dosing regimens may be used, the dose will also be included in the ANOVA model. For Tmaxss,% fluctuation and Felbamate concentrations at each sampling time will be compared. The geometric means and 90% confidence intervals of the AUC0- and Cmaxss ratio (Test/Reference) will be presented based on the 90%
confidence interval the conclusion will be drawn.

BIO-EQUIVALANCE CRITERIA : 
The acceptance range for bioequivalence is 80.00-125.00%, if the 90% confidence intervals for the ratios of the means of Cmaxss, Cminss and AUC0- are within the acceptance range then the test product is claimed to be bioequivalent with the reference product.

COOMON ADVERSE REACTIONS :

The most common adverse reactions seen in association with Felbamate:
• In adults during monotherapy are anorexia, vomiting, insomnia, nausea,
and headache.
• In adults during adjunctive therapy are anorexia, vomiting, insomnia,
nausea, dizziness, somnolence, and headache.
• In children during adjunctive therapy are anorexia, vomiting, insomnia,
headache, and somnolence.

 
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