CTRI/2013/12/004248 [Registered on: 26/12/2013] Trial Registered Retrospectively
Last Modified On:
07/04/2014
Post Graduate Thesis
No
Type of Trial
BA/BE
Type of Study
Study Design
Randomized, Crossover Trial
Public Title of Study
Bioequivalence Study of Fludarabine Tablets.
Scientific Title of Study
Multicenter open-label randomized crossover bioequivalence study of Flugarda® tablets (CJSC BIOCAD, Russia) and Fludara® tablets (Genzyme Europe B.V., the Netherlands) in patients with B-cell chronic lymphocytic leukemia.
Trial Acronym
Secondary IDs if Any
Secondary ID
Identifier
BCD-028, Version 1.0 dated 06 Nov 2012
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Closed joint stock company BIOCAD (CJSC BIOCAD), Russia. Mailing address: Petrovo-Dalneye, Krasnogorsky District, Moscow Region, 143422, Russia
Primary Sponsor
Name
Biocad India Private Limited
Address
Biocad India Private Limited.
163/C, 3rd cross, 3rd Phase,
JP Nagar, Bangalore-560078, Karnataka, India
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
NIL
NIL
Countries of Recruitment
India
Sites of Study
No of Sites = 8
Name of Principal
Investigator
Name of Site
Site Address
Phone/Fax/Email
Dr V Satya Suresh Attili
Bibi General Hospital and Cancer Center
3rd Floor, Room No 308, Clinical Research Division, 16-3-991/1/C, Government Printing Press Road, Malakpet, Hyderabad – 500024,Andhra Pradesh, India
Hyderabad ANDHRA PRADESH
09246243034 04024528144 sureshattili@yahoo.com
Dr Chetan Deshmukh
Deenanath Mangeshkar Hospital & Research Centre
Department of Oncology,
Erandwane, Pune,
Maharashtra 411004
Pune MAHARASHTRA
91-9850811449
drchetandeshmukh@gmail.com
Dr ChandrakalaS
KEM Hospital
KEM Hospital,
Department of Hematology,
Ward 42, 10th floor, new multistory building,
Parel, Mumbai,
Maharashtra 400012
Mumbai (Suburban) MAHARASHTRA
91-9699087654
drchandra1s@gmail.com
Dr Krishna Kumar Rathnam
Meenakshi Mission Hospital and Research Centre
Radiation Oncology
Lake Area, Melur Road, Madurai-625107
Tamil Nadu
Madurai TAMIL NADU
91-9842113003
kkrathnam@gmail.com
Dr Minish Mahendra Jain
Noble Hospital Pvt Ltd
Department of Pathology, Nobel Hospital
153, Magarpatta City Road, PMC,
Pune - 411013 Pune MAHARASHTRA
91-9823133390
minishjain009@rediffmail.com
Dr Chiradoni Tungappa Satheesh
Sri Venkateshwara Hospital
3rd Floor, Clinical Research department, # 86, Hosur Main Road, Madiwala, Bangalore – 560068 Bangalore KARNATAKA
Bangalore
KARNATAKA
Karnataka, India
Bangalore KARNATAKA
91-9242698750
drsatheeshct@gmail.com
Dr Kuntegowdennahalli Chinnagiriyappa Lakshmaiah
Srinivasam Cancer Care Hospitals India Pvt.Ltd
Board Room , 4th Floor, Srinivasam Cancer Care Hospitals India Pvt. Ltd., # 236/ 1, Vijayashree Layout, Arekere , Bannerghatta Main Road, Bangalore-560076 Bangalore KARNATAKA
09448055949
kcluck@gmail.com
Dr Cecil Ross
St. Johns Medical College and Hospital,
Department of Medicine, Ground floor, Sarjapur Main Road,
Koramangala, Bangalore – 560034
Bangalore KARNATAKA
91-9448493705
cecilross@sify.com
Details of Ethics Committee
No of Ethics Committees= 8
Name of Committee
Approval Status
"Institutional Ethics Committee, Deenanath Mangeshkar Hospital and research center "
Submittted/Under Review
"INSTITUTIONAL REVIEW BOARD (IRB) Seth GS Medical College and KEM Hospital"
Submittted/Under Review
BiBi General Hospital and Cancer Center Ethics Committee, Hyderabad, PI-Dr. V Satya Suresh Attili
Approved
Institutional Ethics Committee (IEC), Meenakshi Mission Hospital and Research Centre
Approved
Institutional Ethics Committee, Srinivasam Cancer Care Hospital, Bangalore, PI- Dr. K.C. Lakshmaiah
Approved
Institutional Ethics Committee, St.Johns Medical College & Hospita
Approved
NOBLE HOSPITAL, Institutional Ethics Committee, Pune
Approved
Sri Venkateshwara Hospital Ethics Committee, Bangalore
Approved
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Patients
Patients with B-cell chronic lymphocytic leukemia,
Intervention / Comparator Agent
Type
Name
Details
Comparator Agent
Fludara® (Genzyme Europe B.V., the Netherlands)
In study of the concentration fludarabine metabolite (2-fluoro-arabinofuranosyladenine – 2- fluoro-ara-Ð) within 24 hours after a single oral administration of Fludara® (Genzyme Europe B.V, Netherlands) at a dose of 40 mg/m2 under fasting condition 18 patients with B-cell CLL will be recruited into the study. After informed consent form signing and screening examination, subjects will be randomly assigned into one of two groups (#1 or #2) in a 1:1 ratio. In the group #1 the patients will first receive the test drug Flugarda® at a dose of 40 mg/m2 once daily for 5 straight days and then the reference drug Fludara® at a dose of 40 mg/m2 once daily for 5 straight days; in the group #2 the patients will first receive Fludara® and then Flugarda®, respectively. The interval between the last dose of the first period and the first dose of the second period will be 23 days, which is more than 5 days and ensures complete excretion of fludarabine from participants’ body.
Intervention
Flugarda® tablets (CJSC BIOCAD, Russia)
In study of the concentration fludarabine metabolite (2-fluoro-arabinofuranosyladenine – 2- fluoro-ara-Ð) within 24 hours after a single oral administration of Flugarda® (CJSC BIOCAD, Russia) at a dose of 40 mg/m2 under fasting condition 18 patients with B-cell CLL will be recruited into the study. After informed consent form signing and screening examination, subjects will be randomly assigned into one of two groups (#1 or #2) in a 1:1 ratio. In the group #1 the patients will first receive the test drug Flugarda® at a dose of 40 mg/m2 once daily for 5 straight days and then the reference drug Fludara® at a dose of 40 mg/m2 once daily for 5 straight days; in the group #2 the patients will first receive Fludara® and then Flugarda®, respectively. The interval between the last dose of the first period and the first dose of the second period will be 23 days, which is more than 5 days and ensures complete excretion of fludarabine from participants’ body.
Inclusion Criteria
Age From
18.00 Year(s)
Age To
75.00 Year(s)
Gender
Both
Details
1.Signed informed consent form.
2.Patients with documented stage A or B of B-cell CLL according to Binet classification requiring treatment.
3.18-75 years of age inclusive.
4.ECOG(0-2).
5.Life expectancy greater than 6 months from the date of study enrollment.
6. Pre-specified laboratory values: hemoglobin ≥ 100 g/L, white blood cells (WBC) ≥ 2.5 х 109/L, absolute neutrophil count ≥ 1.5 х 109/L, platelet count ≥ 100 х 109/L, liver enzymes (AST, ALT, ALP, GGT) ≤ 2.5 x upper limit of normal (ULN), total bilirubin ≤ 2.0 mg/dL, creatinine level ≤ ULN.
7.Negative test results for hepatitis B, C, HIV, and syphilis dated no more than 4 weeks before the screening examination.
8.Body Mass Index (BMI) within the normal range (18.5-24.99 kg/m2).
9.Hemodynamic parameters within normal range: systolic blood pressure (SBP) within 100-130 mm Hg, diastolic blood pressure (DBP) within 60-90 mm Hg, heart rate within 50-90 beats per minute.
10.Body temperature ≤ 38°С for a week before the study inclusion.
11.Patient’s ability to comply with the requirements of the Protocol (according to an Investigator’s opinion).
12.Male and female subjects with normal reproductive function and their sexual partners are aware and willing to use voluntarily reliable methods of contraception starting from 1 week prior to study entry and 4 weeks after administration of the last dose of the test drug. This requirement does not apply to patients who had operative sterilization or those defined as post-menopausal (documented) within last 2 years. Reliable methods of contraception suggest using 1 barrier method in combination with 1 of the following methods: spermicides, intra-uterine device.
13.Willingness not to drink alcohol within 24 hours prior to the first dosing of the test drug/the reference drug and within 48 hours after the last dosing.
14.Willingness not to drink grapefruit juice or grapefruit-containing foods within 72 hours prior to the first dosing of test drug/reference drug and within 72 hours after the last dosing in each study period.
ExclusionCriteria
Details
1.Aggravated allergological anamnesis (e.g., history of multi-drug allergy, anaphylactic shock, etc).
2.Known hypersensitivity or idiosyncratic reaction to fludarabine or any other ingredients of the test drug or the reference drug.
3.Confirmed lactose intolerance or other rare hereditary diseases such as saccharose and fructose intolerance, lactase and sucrase-isomaltase deficiency or glucose-galactose malabsorption.
4.Psychiatric disorders and other conditions that might interfere with ability of a patient to follow the study Protocol.
5.History of gastrointestinal surgery (with the exception of appendectomy performed no later than 30 days prior to the screening examination). Other surgeries should be performed not later than 30 days prior to the screening examination.
6.Any acute or chronic infection at the moment of screening examination; acute bacterial, viral, or mycotic infection (for example, cystitis) less than 4 weeks prior to the screening examination.
7.Urinary retention in the past medical history or at screening examination.
8.Inability to insert the venous catheter for blood sampling (e.g., due to a skin disease at the venipuncture sites).
9.Any diseases or other conditions that might affect the pharmacokinetics of the test drug/the reference drug, for example:
- intestinal malabsorption;
- severe hepatic or renal dysfunction (liver enzymes level (AST, ALT, ALP, GGT) > 2.5 x ULN, total blood bilirubin level > 2.0 mg/dL, plasma creatinine level > ULN);
- cardiovascular disorders (severe refractory idiopathic hypertension, decompensated cardiac disorders (III-IV class of chronic heart failure according to NYHA);
- decompensated respiratory insufficiency, tumor infiltration of lungs;
- neuroendocrine disorders (e.g., severe refractory diabetes mellitus);
- autoimmune disorders;
10.A history of any other neoplasm with the exception of adequately treated basal-cell carcinoma or cervical carcinoma in situ and cases with the remission period not less than 5 years.
11.Bone marrow radiation exposure (> 30%) in a history.
12.The use of the medicines including non-prescription and dietary supplements, which have pronounced influence on hemodynamics, liver function etc. (barbiturates, omeprazole, cimetidine etc.), less than 30 days prior to the study initiation; received blood less than 2 weeks prior to the screening examination.
13.Conditions requiring the constant use of systemic corticosteroids.
14.Pregnancy and lactation.
15.Smoking more than 10 cigarettes per day.
16.Consumption of more than 10 units of alcohol per week (1 unit is equivalent to 0.5 L of beer, 200 mL of wine or 50 mL of pure alcohol) or a history of alcoholism, narcomania or drug abusing.
17.Donation of ≥ 450 mL of blood or plasma within 3 months prior to the study enrollment.
18.Participation in any clinical trials less than 3 months prior to the study enrollment.
19.Simultaneous participation in other clinical trials.
20.Previous participation in this study.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Sequentially numbered, sealed, opaque envelopes
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
The assessment of the investigational products’ bioequivalence will be performed by comparing the following PK parameters: the maximal plasma concentration of 2-fluoro-ara-Р(the main fludarabine metabolite) Cmax, area under concentration-time curve (AUC) from the moment of drug administration till 24 hours and till infinity (AUC (0-24) and AUC(0-∞), respectively) after a single oral administration of the test drug and the reference drug.
0 min, 15 mins, 30 mins, 45 mins,50 mins, 1hr, 1hr 30 mins, 2 hrs, 3 hrs, 4 hrs,6 hrs, 8 hrs, 10 hrs and 24 hrs after administration of the test or reference drug.
Secondary Outcome
Outcome
TimePoints
•AEs and SAEs incidence;
•Grade 3-4 AEs incidence according to CTCAE 4.03;
•Incidence of treatment discontinuation due to AEs.
AEs: recorded from the beginning of the therapy until day 28 after the patients withdrawal or study termination.
SAEs: recorded from the moment of signing informed consent from till end of study.
Target Sample Size
Total Sample Size="18" Sample Size from India="18" Final Enrollment numbers achieved (Total)= "" Final Enrollment numbers achieved (India)=""
Fludarabine
is an effective drug that is well tolerated by patients suffering from lymphoproliferative
diseases. Fludarabine is a cytostatic agent with no significant negative impact
on the quality of patients’ life.The main objective of the study is to compare the concentration of the main fludarabine
metabolite (2-fluoro-arabinofuranosyladenine – 2- fluoro-ara-Ð) within 24 hours after a single oral administration of Flugarda® at a dose of 40 mg/m2 under fasting condition
or Fludara® at the same dose
in patients with B-cell CLL. and to evaluate the rate and severity of adverse
events after oral administration of Flugarda® at a dose of 40 mg/m2 and Fludara® at the same dose for 5 straight days.