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

Phase 1

Recruiting

• Conditions: Rheumatoid arthritis, unspecified,

• Registration Number: CTRI/2013/05/003678
• Lead Sponsor: Cadila Healthcare Limited

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2013-04-25
• Last Update Posted: 2019-05-20

Recruitment & Eligibility

• Status: Open to Recruitment
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

• Adults subjects of either gender in age group of ≥ 18 year and ≤70 years.
• History of rheumatoid arthritis, as defined by the American College of Rheumatology (ACR) Classification1, for atleast 6 months.
• Moderate to severe active seropositive disease.
• 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.
• 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.
• Able and willing to give written informed consent and comply with the requirements of the study protocol.

Exclusion Criteria

• Patients with significant systemic manifestations of RA.
• Female nursing patients.
• Rheumatic autoimmune disease other than RA.
• History of diagnosis of juvenile idiopathic arthritis (also known as juvenile rheumatoid arthritis) and/or RA before age 16.
• History of inflammatory arthritis other than RA (e.g., inflammatory bowel disease, systemic lupus erythematosus (SLE), or psoriatic arthritis).
• Any surgical procedure, including bone/joint surgery or planned surgery within 8 weeks prior to screening or during the study period.
• Functional Class IV as defined by the American College of Rheumatology (ACR) classification of functional status in RA2.
• 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).
• Treatment with any investigational agent within 4 weeks of screening or 5 half-lives of the investigational drug (whichever is longer).
• Previous treatment with Rituximab.
• Previous treatment with any cell-depleting therapies, including investigational agents.
• Treatment with IV gamma-globulin or plasma filtering device like Prosorba (R) Column within the previous 6 months.
• Receipt of a vaccine within 4 weeks prior to Day 1 infusion.
• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies.
• 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.
• Known active bacterial, viral, fungal, mycobacterial, or other infection (including tuberculosis or atypical mycobacterial disease, but excluding fungal infections of nail beds).
• 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.
• 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).
• Lack of peripheral venous access.
• History of alcohol, drug, or chemical abuse within 6 months prior to screening.
• Positive Hepatitis B surface antigen or antibodies to Hepatitis C.
• History of significant cytopenias or other bone marrow disorders.
• Serum creatinine > 1.4 mg/dL for women or 1.6 mg/dL for men.
• AST or ALT > 2.5 times upper limit of normal (UNL).
• Platelet count < 100,000/µL.
• Hemoglobin < 8.0 g/dL.
• Neutrophils < 1.5 × 103/µL.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (4)

Andhra Hospital; 🇮🇳 Hyderabad, ANDHRA PRADESH, India

Kasturba Medical College Hospital; 🇮🇳 Bangalore, KARNATAKA, India

Omkar Heart Institute and nursing home and rheumatology Clinic; 🇮🇳 Nashik, MAHARASHTRA, India

Rathi Orthopedic & Research Centre; 🇮🇳 Ahmadabad, GUJARAT, India

Andhra Hospital

🇮🇳Hyderabad, ANDHRA PRADESH, India

DrAtchuta Ramaiah

Principal investigator

9502551321

veluriatchuta@rediffmail.com