CTRI

CTRI Number

CTRI/2013/05/003678 [Registered on: 27/05/2013] Trial Registered Retrospectively

Last Modified On:

20/05/2019

Post Graduate Thesis

Type of Trial

Interventional

Type of Study

Biological

Study Design

Randomized, Parallel Group, Active Controlled Trial

Public Title of Study

to evaluate pharmacokinetic, pharmacodynamic (efficacy) and safety of Rituximab (Zydus) and Rituximab (Roche) in patients with Rheumatoid Arthritis.”

Scientific Title of Study

“A randomized controlled study to evaluate pharmacokinetic, pharmacodynamic (efficacy) and safety of Rituximab (Zydus) and Rituximab (Roche) in patients with Rheumatoid Arthritis.”

Secondary IDs if Any
Modification(s)

Secondary ID	Registry
RIT.11.001.01.PROT,version 1.1,dated 06th November 2012	Protocol Number

Details of Principal Investigator or overall Trial Coordinator (multi-center study)

Name	Dr R H Jani
Address	Zydus Cadila House Plot No. 360, TPS 5, Service Road, Vile Parle (E) Mumbai MAHARASHTRA 400 057 India Mumbai MAHARASHTRA 400057 India
Phone	26186052
Fax	26151735
Email	rhjani@zyduscadila.com

Details Contact Person
Scientific Query

Name	Dr R H Jani
Address	Zydus Cadila House Plot No. 360, TPS 5, Service Road, Vile Parle (E) Mumbai MAHARASHTRA 400 057 India Mumbai MAHARASHTRA 400057 India
Phone	26186052
Fax	26151735
Email	rhjani@zyduscadila.com

Details Contact Person
Public Query

Name	Dr R H Jani
Address	Zydus Cadila House Plot No. 360, TPS 5, Service Road, Vile Parle (E) Mumbai MAHARASHTRA 400 057 India Mumbai MAHARASHTRA 400057 India
Phone	26186052
Fax	26151735
Email	rhjani@zyduscadila.com

Source of Monetary or Material Support

Primary Sponsor

Name	Cadila Healthcare Limited
Address	Zydus Cadila House Plot No. 360, TPS 5, Service Road, Vile Parle (E) Mumbai MAHARASHTRA 400 057 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 = 4
Contact Person	Name of Site	Site Address	Phone/Fax/Email
DrAtchuta Ramaiah	Andhra Hospital	Department of Orthopaedics,Andhra Hospitals,CVR Complex,Prakasam Road,Vijaywada Hyderabad	9502551321 veluriatchuta@rediffmail.com
DrRamchandra Kamath	Kasturba Medical College Hospital	Dr. Ramachandra Kamath. K., Associate Professor Dept. of Orthopaedics Kasturba Medical College Hospital Attavar, Mangalore - 575 001 Karnataka, India Bangalore	8242445858 08242425092 drkrk_ortho@yahoo.co.in
Dr Praveen Jadhav	Omkar Heart Institute and nursing home and rheumatology Clinic	Omkar Heart Institute and nursing home and rheumatology Clinic, Behind Regimental Plaza, Gaikwad Mala, Nashik Road, Nashik 4221010 Nashik	9822055612 drpraveenj@sify.com
Dr Gaurav Rathi	Rathi Orthopedic & Research Centre	Rathi Orthopedic & Research Centre, Nr. Anupam Shopping Centre, Jodhpur Crossroads, Satellite, Ahmedabad- 380 015 Ahmadabad	9824015618 drgjrathi@yahoo.co.in

Details of Ethics Committee
Modification(s)

No of Ethics Committees= 4
Name of Committee	Approval Status
Bezwada Central Ethics Committee	Approved
Dr. Praveen Jadhav ,Yash Society Ethics Committee	Approved
Dr.Ramchandra Kamath,Manipal University Ethics Committee	Approved
Rathi Ethics Committee	Approved

Regulatory Clearance Status from DCGI
Modification(s)

Status

Approved/Obtained

Health Condition / Problems Studied
Modification(s)

Health Type	Condition
Patients	Rheumatoid Arthritis
Patients	Rheumatoid arthritis, unspecified

Intervention / Comparator Agent
Modification(s)

Type	Name	Details
Comparator Agent	Rituximab (Roche)	Dose-1000mg Route-Intravenous Frequency-2 infusion 2 weeks apart. Duration of therapy:04 Months
Intervention	Rituximab (Zydus)	Dose-1000mg Route-Intravenous Frequency-2 infusion 2 weeks apart. Duration of therapy -04 months

Inclusion Criteria

Age From	18.00 Year(s)
Age To	70.00 Year(s)
Gender	Both
Details	1. Adults subjects of either gender in age group of ≥ 18 year and ≤70 years. 2. History of rheumatoid arthritis, as defined by the American College of Rheumatology (ACR) Classification1, for atleast 6 months. 3. Moderate to severe active seropositive disease. 4. History of treatment with Methotrexate (MTX) 10-25mg per week for at least 12 weeks with last 4 weeks at the stable dose before screening. 5. If female and of childbearing potential, she shall have a negative pregnancy test at the time of screening and agrees to use adequate contraception throughout the study period. 6. Able and willing to give written informed consent and comply with the requirements of the study protocol.

ExclusionCriteria

Details

1. Patients with significant systemic manifestations of RA.
2. Female nursing patients.
3. Rheumatic autoimmune disease other than RA.
4. History of diagnosis of juvenile idiopathic arthritis (also known as juvenile rheumatoid arthritis) and/or RA before age 16.
5. History of inflammatory arthritis other than RA (e.g., inflammatory bowel disease, systemic lupus erythematosus (SLE), or psoriatic arthritis).
6. Any surgical procedure, including bone/joint surgery or planned surgery within 8 weeks prior to screening or during the study period.
7. Functional Class IV as defined by the American College of Rheumatology (ACR) classification of functional status in RA2.
8. History of use of disease-modifying anti-rheumatic drugs (DMARDs) other than MTX within 4 weeks prior to randomization (8 weeks prior for infliximab, adalimumab, or leflunomide).
9. Treatment with any investigational agent within 4 weeks of screening or 5 half-lives of the investigational drug (whichever is longer).
10. Previous treatment with Rituximab.
11. Previous treatment with any cell-depleting therapies, including investigational agents.
12. Treatment with IV gamma-globulin or plasma filtering device like Prosorba (R) Column within the previous 6 months.
13. Receipt of a vaccine within 4 weeks prior to Day 1 infusion.
14. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies.
15. History of primary or secondary immunodeficiency
16. Evidence of significant uncontrolled concomitant diseases such as cardiovascular disease, nervous system, renal, hepatic, endocrine, gastrointestinal, or pulmonary disease, including any pulmonary or other condition that would preclude subject participation.
17. Known active bacterial, viral, fungal, mycobacterial, or other infection (including tuberculosis or atypical mycobacterial disease, but excluding fungal infections of nail beds).
18. History of recurrent significant infection or any significant episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening.
19. History of cancer, including solid tumors and hematologic malignancies (except basal cell and squamous cell carcinoma of the skin that have been excised and cured).
20. Lack of peripheral venous access.
21. History of chronic daily use of narcotic analgesics.
22. History of alcohol, drug, or chemical abuse within 6 months prior to screening.
23. Positive Hepatitis B surface antigen or antibodies to Hepatitis C.
24. History of significant cytopenias or other bone marrow disorders.
25. Laboratory Exclusion Criteria: Patients may not participate in this study until any of the following that are present have resolved.
a. Serum creatinine > 1.4 mg/dL for women or 1.6 mg/dL for men.
b. AST or ALT > 2.5 times upper limit of normal (UNL).
c. Platelet count < 100,000/µL.
d. Hemoglobin < 8.0 g/dL.
e. Neutrophils < 1.5 × 103/µL.

Method of Generating Random Sequence

Other

Method of Concealment

Other

Blinding/Masking

Open Label

Primary Outcome
Modification(s)

Outcome	TimePoints
1) Compare pharmacokinetics (PK- Cmax, AUC0-t)of rituximab following IV infusions of rituximab (Zydus) and Rituximab (Roche)	Day 15

Secondary Outcome

Outcome	TimePoints
1) Pharmacodynamic parameters: Assessment of CD19 level in RA patients on Day 15 as compared to baseline in both the treatment groups. 2) Immunogenicity assessment: Percentage of subjects who develop detectable anti-drug antibodies	Day 15

Target Sample Size

Total Sample Size="24"
Sample Size from India="24"

Phase of Trial

Phase 1

Date of First Enrollment (India)
Modification(s)

25/04/2013

Date of First Enrollment (Global)

No Date Specified

Estimated Duration of Trial

Years="0"
Months="6"
Days="0"

Recruitment Status of Trial (Global)
Modification(s)

Not Applicable

Recruitment Status of Trial (India)

Open to Recruitment

Publication Details

Brief Summary

This is a multicentric, randomized, open label, parallel arm study to evaluate the pharmacokinetics, pharmacodynamics (efficacy) and safety of Rituximab (Zydus) as compared to Rituximab (Reference, Roche) in patients with Rheumatoid Arthritis (RA).

Patients suffering from RA since the last 6 months and having mild- to moderate disease activity, as assessed by Disease Activity Score-28 (DAS-28) will be invited for participation in the screening program of the study. Such a patient will be required to sign an Informed Consent Form after understanding the informed consent document before any trial related activity. If the patient satisfies all the inclusion-exclusion criteria, the subject will be eligible for randomization into the study.

The study is divided into 2 parts:

Part A – This study is a single dose PK/PD study (advised by DCGI) wherein Rituximab 1000 mg via IV infusion will be given to the eligible subjects who satisfy the inclusion-exclusion criteria on the day of enrolment (Day1). This study is of 15 days duration and will assess the single dose pharmacokinetics, pharmacodynamics of Rituximab (Zydus) as compared to Rituximab (Roche).

The scheduled visits include Visit 1 - Day 1 Visit 2 - Day 3±1 Visit 3 - Day 7±1 Visit 4 - Day 15±1

Visit 2 and Visit 3 will be home visits wherein a lab personnel appointed by the sponsor will go to the patient’s home and collect pharmacokinetic samples.

Visit 1 and Visit 4 will be visits in the hospital wherein the Principal Investigator (PI) will assess the patient clinically (physical- vitals, general and systemic examination). The PI will also assess the tender joint and swollen joint count by counting the number of joints which are tender or swollen, along with pain assessment and global health assessment performed by the patient and the treating physician.

Rituximab infusion will be given on Day 1 (Visit1) after collection of baseline blood samples. Prior to infusion, premedication with analgesics, antipyretics and antihistamine is necessary. Methylprednisolone 100mg IV is recommended 30 minutes prior to infusion of Rituximab to decrease the rate and severity of infusion reactions. The infusion of Rituximab will be given under the supervision of a physician and will follow the general instructions which have been mentioned in the package insert of the originator.

For pharmacokinetics, blood sample will be collected at the following time points.

a) Part A Day 1 – 0 hrs and end of infusion Day 3 Day 7 Day 15 – 0 hrs

The study will also assess pharmacodynamics. For this, quantitative assessment of CD19 cell count will be done by the flow cytometry at the Central Laboratory, Ahmedabad. CD19 is a biomarker for efficacy analysis of Rituximab.

Immunogenicity assessment will also be carried out at baseline (predose) and Day 15 (0hours). This will involve the detection of anti-drug antibodies to Rituximab.

Part B – As per the package insert of the originator, one complete course of Rituximab includes 2 infusions of 1000mg each given via IV infusion on Day 1 and Day 15. This complete course ensures that the patient remains symptom free for a minimum of 16-24 months. The benefits may last for 1-2 years as well.

In view of the same, the sponsor believes that the second dose should be given to the patient for compassionate use on ethical considerations. The subject’s participation in receiving the second dose is completely non-obligatory. However, if they wish to receive the second dose of Rituximab they would be required to sign another Informed Consent Form (ICD – Part B), confirming their participation in receiving the second dose of Rituximab. However, this would also mean that they are willing to provide additional blood samples for pharmacokinetic, pharmacodynamic and immunogenicity assessment.