CTRI/2020/08/027254 [Registered on: 19/08/2020] Trial Registered Prospectively
Last Modified On:
17/02/2021
Post Graduate Thesis
No
Type of Trial
BA/BE
Type of Study
Study Design
Randomized, Crossover Trial
Public Title of Study
A clinical trial of two products Vigabatrin 500 mg tablets compared to SABRIL(Vigabatrin) Tablets 500mg to study the pharmacokinetics and safety in adult refractory complex partial-seizure patient’s who are already on stable dose of Vigabatrin.
Scientific Title of Study
A Multicentric, Open-label, Randomized, Two Treatment, Two Sequence, Two Period, Crossover, Steady state Bioequivalence Study of Vigabatrin 500 mg Immediate-Release Tablets of Aucta Pharmaceuticals, LLC (Test) With SABRIL (Vigabatrin) Tablets 500mg of Lundbeck Pharmaceuticals LLC, USA (Reference) in adult refractory complex partial-seizure/ focal epilepsy patients who are already on established Vigabatrin adjunctive therapy under fasting conditions.
Trial Acronym
Secondary IDs if Any
Secondary ID
Identifier
Version 1.0 Amendment 03 Dated 05.11.2019
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Dr Subhra Lahiri
Designation
Associate Vice President
Affiliation
Axis Clinicals Limited
Address
AXIS Clinicals Ltd
1 121 1 Miyapur Hyderabad500049
Telangana INDIA
AXIS Clinicals Ltd
1 121 1 Miyapur Hyderabad500049
Telangana INDIA Hyderabad TELANGANA 500049 India
Phone
8886221089
Fax
Email
Subhra.L@axisclinicals.com
Details of Contact Person Scientific Query
Name
Dr Subhra Lahiri
Designation
Associate Vice President
Affiliation
Axis Clinicals Limited
Address
AXIS Clinicals Ltd
1 121 1 Miyapur Hyderabad500049
Telangana INDIA
AXIS Clinicals Ltd
1 121 1 Miyapur Hyderabad500049
Telangana INDIA
TELANGANA 500049 India
Phone
8886221089
Fax
Email
Subhra.L@axisclinicals.com
Details of Contact Person Public Query
Name
Dr Subhra Lahiri
Designation
Associate Vice President
Affiliation
Axis Clinicals Limited
Address
AXIS Clinicals Ltd
1 121 1 Miyapur Hyderabad500049
Telangana INDIA
AXIS Clinicals Ltd
1 121 1 Miyapur Hyderabad500049
Telangana INDIA
TELANGANA 500049 India
Phone
8886221089
Fax
Email
Subhra.L@axisclinicals.com
Source of Monetary or Material Support
Aucta Pharmaceuticals, Inc.
Primary Sponsor
Name
Aucta Pharmaceuticals Inc
Address
71 Suttons Lane
Piscataway Township, NJ 08854
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
AXIS Clinicals Ltd
1-121/1 Miyapur Hyderabad-500049
Andhra Pradesh, INDIA
CR department Vedant Multispeciality Hospital, Sambhajinagar, Chinchwad, Pimpri-Chinchwad, Maharashtra-411 019. Pune MAHARASHTRA
9860918000
Amitpande411@gmail.com
Details of Ethics Committee
No of Ethics Committees= 2
Name of Committee
Approval Status
Anand Ethics Committee
Approved
Ethics Committee of Pulse Multispeciality Hospital
Approved
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Patients
(1) ICD-10 Condition: G402||Localization-related (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures,
Intervention / Comparator Agent
Type
Name
Details
Comparator Agent
SABRIL (Vigabatrin) Tablets 500mg
Patient needs to take either test or reference twice daily for 5 days in period-I and Period- II respectively
Intervention
Vigabatrin 500 mg
Patient needs to take either test or reference 500 mg tablets twice daily for 5 days in period-I and period-II respectively
Inclusion Criteria
Age From
18.00 Year(s)
Age To
65.00 Year(s)
Gender
Both
Details
Prior to Stabilization (Day -36):
1.Availability for the entire study
2.Male or female patients
3.Patient aged of at least 18 years but not older than 65 years.
4.The patient has refractory Complex Partial Seizure/ focal epilepsy as evidenced by the attainment of all the following criteria:
a.The patient has failed because of lack of efficacy with 2 or more anti-epileptic drugs (AEDs) of differing pharmacologic mechanisms administered as monotherapy or polytherapy at the therapeutic dose
b.The patient should be taking at least 1 AED (A vagal nerve stimulator is not counted as an AED)
5.Patients must agree not to change their use of prescription medication(s) or over-the-counter (OTC) medicines (including natural food supplements and vitamins) within 30 days prior to administration of study drug or during the study unless dose adjustment are needed for the safety of the patients in which case the participation in the study will be re-evaluate on the case-by-case basis.
6.Patients with clinically non-significant findings on ophthalmologic assessments for visual field and visual acuity.
7.Patients with adequate hematopoeitic and liver function, defined as:
•Hemoglobin of ≥ 9.0 g/dL
•ANC ≥ 1500/mm3, Platelet count ≥ 100,000/mm3
•AST and ALT ≤ 3 times ULN, Alkaline phosphatase ≤ 2.5 times ULN, Bilirubin ≤ 1.5 times ULN
8.Patient or his/her Legally Acceptable Representative willing to adhere to the protocol requirements as evidenced by ICF duly read, signed and dated.
9.Motivated patient and absence of intellectual problems likely to limit the validity of consent to participate in the study or the compliance with protocol requirements; ability to cooperate adequately; ability to understand and observe the instructions of the physician or designee.
10.Female patient of childbearing potential must have a negative serum pregnancy test.
11.Women of childbearing potential must agree to use adequate contraception prior to study entry, and for 60 days following completion of therapy.
12.Females must use acceptable and effective methods of contraception such as the following:
• Tubal sterilization (tubal ligation performed more than one month before Study Day 1; transcervical tubal occlusion procedure performed more than six months before Study Day 1) or
• Intrauterine Device (IUD) or
• Progestin Implant (i.e. Implanon or its equivalent) or
• Progestin injection or progestin oral contraceptive pill + one barrier method (cervical cap, diaphragm, contraceptive sponge, or vaginal spermicide + a male or female condom) or
• Two barrier methods used together (cervical cap, diaphragm, contraceptive sponge, or vaginal spermicide + a male or female condom) or
• Absolute sexual abstinence (no sexual intercourse or genital contact with a male partner)
13.Male subjects agreed to use contraceptive methods prior to study entry, and for 60 days following completion of study.
At the time of Screening Period and/ or Randomization Day (Day -7 to Day 0):
1.Patient receiving twice daily doses of Vigabatrin 500 mg for over at least 28 days before the 1st drug administration of the study.
2.Patient/ LAR must be willing for switch from the Sabril® tablet to the generic formulation (test).
3.Patients with clinically non-significant findings on ophthalmologic assessments for visual field and visual acuity.
4.Patients with adequate hematopoeitic and liver function at screening, defined as:
•Hemoglobin of ≥ 9.0 g/dL
•ANC ≥ 1500/mm3, Platelet count ≥ 100,000/mm3
•AST and ALT ≤ 3 times ULN, Alkaline phosphatase ≤ 2.5 times ULN, Bilirubin ≤ 1.5 times ULN
5.Female patient of childbearing potential must have a negative serum pregnancy test.
ExclusionCriteria
Details
Prior to Stabilization (Day -36):
1.History or presence of significant cardiovascular, pulmonary, hematologic, neurological, psychiatric, endocrine, immunologic or dermatologic disease with the exception of the illness or refractory complex partial seizures/ focal seizures and conditions associated with refractory complex partial seizures/ focal seizures.
2.Pre-existing ocular or neurological disease that might affect bilateral visual fields or interfere with perimetry (e.g., aphakia, visually significant cataract, glaucoma, diabetic retinopathy, ischemic optic neuropathy, multiple sclerosis).
3.Clinically significant diseases captured in the medical history or evidence of clinically significant findings on physical examination (ECG, vital signs) other than the illness and conditions associated with refractory complex partial seizures/ focal epilepsy.
4.Concurrent exposure to medications with known or suspected retinal or optic nerve toxicity.
5.Suicidality state or suicidal behavior as per the C-SSRS baseline-screening.
6.Presence of observed abnormality that would be clinically significant in the opinion of the Investigator
7.Use of drugs associated with serious adverse ophthalmic effects such as retinopathy or glaucoma.
8.Significant history of drug dependency or alcohol abuse (> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic).
9.Concurrent use of the ketogenic or similar diet.
10.Patient on vagal nerve stimulator as a monotherapy.
11.Patients with emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
12.Patient had received any investigational drug within the past 90 days.
13.Patient had history of difficulty with donating blood or difficulty in accessibility of veins.
14.Patients with Peripheral Neuropathy.
15.Patient who are pregnant or nursing females.
16.Positive test results for HIV-1/HIV-2 Antibodies, Hepatitis B surface Antigen (HBsAg) or Hepatitis C Antibody (HCVAb).
17.Patient at high risk of ophthalmic abnormalities and other types or irreversible vision loss as per clinical symptoms or results of the visual examination in the opinion of an ophthalmologist at screening. (Visual examination will include 1) visual acuity test with their usual glasses/contact lenses or have undergone refractive surgery and 2) standardized static perimetry test 30-2 [Humphrey/Octopus or Goldman]).
18.Patient presenting visual field defects based clinical symptoms or based on the results of the visual examination in the opinion of an ophthalmologist that could lead to ophthalmologic abnormalities.
19.Donation of 500 mL or more of blood (blood donor center, clinical studies, etc.) in the previous 56 days before day 1 of this study.
At the time of Screening Period and/ or Randomization Day (Day -7 to Day 0):
1.History of significant hypersensitivity to vigabatrin or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs.
2.Suicidality state or suicidal behavior as per the C-SSRS screening.
3.Presence of observed abnormality that would be clinically significant in the opinion of the Investigator
4.Patients with history of allergic reactions to Vigabatrin.
5.Patients with emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
6.Patient who is pregnant.
7.Positive urine screen for alcohol, and/or drugs of abuse at Day 0.
8.Patient at high risk of ophthalmic abnormalities and other types or irreversible vision loss as per clinical symptoms or results of the visual examination in the opinion of an ophthalmologist at screening. (Visual examination will include 1) visual acuity test with their usual glasses/contact lenses or have undergone refractive surgery and 2) standardized static perimetry test 30-2 [Humphrey/Octopus or Goldman]).
9.Patient presenting visual field defects based clinical symptoms or based on the results of the visual examination in the opinion of an ophthalmologist that could lead to ophthalmologic abnormalities.
10.Patient with a decline in vision compared to baseline.
11.Patient with progression of previously diagnoses adverse events associated with Sabril® prior to randomization.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
1. Area under the plasma concentration – time curve over the steady state dosing interval
2. Maximum concentration over the steady state dosing interval
pre-dose blood samples collected on Day 3, 4 and 5 in Period I and on Day 8, 9 and 10 in Period II. Post dose samples 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75,2.00, 2.50, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00 and 12.00 hours post morning dose on Day 5 and Day 10
Secondary Outcome
Outcome
TimePoints
Minimum concentration over the steady state dosing interval
pre-dose blood samples collected on Day 3, 4 and 5 in Period I and on Day 8, 9 and 10 in Period II. Post dose samples 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75,2.00, 2.50, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00 and 12.00 hours post morning dose on Day 5 and Day 10
Average concentration over the steady state dosing interval
pre-dose blood samples collected on Day 3, 4 and 5 in Period I and on Day 8, 9 and 10 in Period II. Post dose samples 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00 and 12.00 hours post morning dose on Day 5 and Day 10
Percentage Fluctuation
pre-dose blood samples collected on Day 3, 4 and 5 in Period I and on Day 8, 9 and 10 in Period II. Post dose samples 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00 and 12.00 hours post morning dose on Day 5 and Day 10.
Swing [(CmaxSS-CminSS)/CminSS]
pre-dose blood samples collected on Day 3, 4 and 5 in Period I and on Day 8, 9 and 10 in Period II. Post dose samples 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00 and 12.00 hours post morning dose on Day 5 and Day 10
Pre-dose concentration observed immediately to the next successive dose
pre-dose blood samples collected on Day 3, 4 and 5 in Period I and on Day 8, 9 and 10 in Period II. Post dose samples 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00 and 12.00 hours post morning dose on Day 5 and Day 10
Time of maximum measured plasma concentration over the steady state dosing interval.
pre-dose blood samples collected on Day 3, 4 and 5 in Period I and on Day 8, 9 and 10 in Period II. Post dose samples 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00 and 12.00 hours post morning dose on Day 5 and Day 10.
Target Sample Size
Total Sample Size="24" Sample Size from India="24" Final Enrollment numbers achieved (Total)= "24" Final Enrollment numbers achieved (India)="24"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
Patient meeting all inclusion and none of the exclusion criteria will be enrolled in the study, and will under go stabilization period for 28 days with Vigabatrin 500 mg tablets, after stabilization patients will be screened again for randomization in day -7 to day -1 . Patients meeting all inclusion and none of the exclusion criteria will be randomized on Day 0.Patients will receive either Test or Reference product 500 mg twice daily from Day 1 to Day 5 and alternate study treatment as per randomization (if the subject receives Test in Period-I, then the subject will receive Reference in Period-II and vice versa) from Day 6 to Day 10 without washout period with 240mL of water.Patients shall fast overnight for at least 10.00 hours prior to morning dosing and should fast for 4.00 hours post morning dose on Day 5 and Day 10. Patients should not be allowed to drink water 1.00 hour pre dose and 1.00 hour post dose on Day 5 and Day 10. Water will be allowed in the restriction period in case of medical emergency at the discretion of investigator. Venous blood samples (~4 mL) will be withdrawn 5 minutes prior to morning (first) dosing on Day 1, 3, 4 & 5 and Day 6, 8, 9 & 10. The pre-dose blood samples collected on Day 3, 4 & 5 in Period-I and on Day 8, 9 & 10 in Period-II will be used to confirm that steady-state is achieved. Complete PK sampling will be done on day 5 and day 10 post morning dose administration.Ophthalmic assessment will be done by qualified ophthalmologist on day 11. Safety assessments (reporting of adverse events and serious adverse events if any, ECG, clinical laboratory measures and vital sign parameters) will be performed and the patients will be checked out from the facility on day 11.