Clinical trial NCT04268771: A Phase III Transition Study of DRL Rituximab to Reference Medicinal Products
Official title: A Randomized, Double-blind, Parallel Group, Multicenter Study to Assess the Immunogenicity and Safety of Transitioning Subjects With Rheumatoid Arthritis to Biosimilar Rituximab (DRL_RI) or Continued Treatment With Rituxan® or MabThera®
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Lead sponsor: Dr. Reddy's Laboratories Limited
Sponsor class: INDUSTRY
Collaborators: name: PPD Development, LP
First posted: 2020-02-13
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A randomized, double-blind, parallel group, multicenter study to assess the immunogenicity and safety of transitioning subjects with rheumatoid arthritis to biosimilar rituximab (DRL_RI) or continued treatment with Rituxan® or MabThera®
Primary purpose: TREATMENT

Brief summary: The objective of the current study is to assess the immunogenicity and safety of transitioning subjects with RA to DRL_RI from US-rituximab/EU-rituximab to continued treatment with US-rituximab/EU-rituximab.

The primary objective of this study is to assess the immunogenicity of transitioning subjects with RA to DRL_RI (biosimilar rituximab) from US-rituximab/EU-rituximab to continued treatment with US-rituximab/EU-rituximab

To assess the safety of transitioning subjects with RA to DRL_RI from US-rituximab/EU-rituximab to continued treatment with US-rituximab/EU-rituximab.

Detailed description: This is a randomized, double-blind, parallel group, multicenter, Phase 3 transition study in subjects with active RA who are eligible for the subsequent treatment course with US-rituximab or EU-rituximab according to the clinical judgment of the investigator.

Subjects will then be randomized by interactive web response system (IWRS) to receive either two 1000 mg infusions of DRL_RI (Arm A) or US-rituximab/EU-rituximab (Arm B) on Day 1 and Day 15.

Subjects randomized to Arm A will receive DRL_RI and subjects randomized to Arm B will continue to receive either US-rituximab or EU-rituximab.

The study will consist of a screening period (Days -14 to 0) and a double-blind period (Day 1 to Week 12). Subjects will attend a screening visit followed by a visit at Weeks 0 (Day 1), 2, 4, 8, and 12 after randomization

It is planned that approximately 50 sites will be initiated for this study in up to 7 countries (including but not restricted to United States). There has been no randomization of patients till date for this study.

The study endpoints include:

The immunogenicity endpoint is:

• The incidence of anti-drug antibodies (ADA), including titer and neutralizing antibodies (NAb).

The primary safety endpoints are:

* Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs).
* Incidence of anaphylactic reactions, hypersensitivity reactions, and IRRs.

Eligibility criteria: Inclusion Criteria:

1. Male or female subjects aged 18 years or older who have provided valid written informed consent.
2. Subjects with a diagnosis of active RA who are eligible for the subsequent treatment course with US-rituximab or EU-rituximab according to the clinical judgment of the investigator.
3. Documented evidence that subject has received at least 1 full course comprising two 1000 mg infusions of either US-rituximab at least 16 weeks prior to the randomization visit or EU-rituximab at least 24 weeks prior to the day of randomization visit.
4. Subjects receiving a stable dose of weekly methotrexate (MTX) for at least 4 weeks prior to randomization (between 7.5 mg and 25 mg) and folic acid (at least 5 mg per week.

EXCLUSION CRITERIA;

1. Subjects with RA in functional Class IV
2. Subjects with human immunodeficiency virus (positive HIV1Ab or HIV2Ab), hepatitis B virus and/or hepatitis C virus infection, including those with positive results in the viral disease screening.
3. Subjects with active tuberculosis. Subjects with evidence of latent TB or a history of TB must have completed treatment or have initiated treatment for at least 1 month before the first dose of study treatment (Day 1). TB testing is required only if it is required by local regulations or practice.
4. Active systemic infection.
5. Severely immunocompromised.
6. History of severe hypersensitivity to either US-rituximab or EU-rituximab or any of its excipients requiring drug discontinuation.
7. Any serious illness or uncontrolled medical condition, including but not limited to severe infections, significant hepatic or renal disease, uncontrolled hypertension despite treatment (defined as blood pressure ≥160/95 mmHg), congestive heart failure (New York Heart Association \[NYHA\] Class III or IV), or other severe, uncontrolled cardiac disease or uncontrolled diabetes with immediate risk of acute complications.
8. Any condition that in the opinion of the investigator represents an obstacle for study conduct and/or represents a potential unacceptable risk for subjects.
9. Requires treatment with any biological medicinal product during the study other than the study treatment.
10. Previous treatment with B-cell modulating or cell depleting biologic therapy except US-rituximab or EU-rituximab.
11. Prior participation in this clinical trial or prior participation in any clinical trial with any monoclonal antibody within 12 months of screening or prior participation in any clinical trial within 3 months of screening or within 5 half-lives of the investigational drug or until the expected PD effect has returned to baseline, whichever is longer.
12. Treatment with other biologic disease-modifying anti-rheumatic drugs, or Janus kinase (JAK) inhibitors administered within 12 weeks before the first dose of rituximab of the prior treatment course onwards till the date of randomization.
13. Subjects with the following laboratory abnormalities:

    * Subjects with screening total white blood cell count \<3000/μL, platelets \<100,000/μL, neutrophils \<1,500/μL, or hemoglobin \<8.5 g/dL
    * Abnormal liver function tests such as aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase \>2 × upper limit of normal (ULN). A single parameter \>2 × ULN can be re-checked as soon as possible, at least prior to randomization, if required as per the investigator's discretion.
    * Creatinine clearance (Cockcroft \& Gault formula) of less than 50 mL/min.
14. History of vaccination with live vaccines within 4 weeks of the first dose of study treatment (Day 1) or known to require live vaccines during the study.
15. Lactating or pregnant female.
16. Women of childbearing potential who do not consent to use highly effective methods of birth control (e.g., barrier contraceptives, oral contraceptives, intrauterine devices, true abstinence if it allowed as per the country specific regulatory requirement \[periodic abstinence {e.g., calendar ovulation, symptothermal, post-ovulation methods} and withdrawal are not acceptable methods of contraception\], or sterilization) during treatment and for at least 12 months after the last administration of study treatment.
17. For men involved in any sexual intercourse that could lead to pregnancy, subjects must agree to use 1 of the highly effective methods of birth control listed in Exclusion Criterion #16 during treatment and for at least 12 months after the last administration of study treatment.
18. Subject with serum IgG \< lower limit of normal.

Primary outcomes:
measure: Number of Subjects With Positive Anti-Drug Antibodies (ADA) on Day 1
timeFrame: ADA will be obtained before the administration of study treatment on Day 1
measure: Number of Subjects With Positive Anti-Drug Antibodies (ADA) on Day 15
timeFrame: ADA will be obtained before the administration of study treatment on Day 15
measure: Number of Subjects With Positive Anti-Drug Antibodies (ADA) at Week 4
timeFrame: ADA will be obtained before the administration of study treatment at Week 4
measure: Number of Subjects With Positive Anti-Drug Antibodies (ADA) at Week 8
timeFrame: ADA will be obtained before the administration of study treatment at Week 8
measure: Number of Subjects With Positive Anti-Drug Antibodies (ADA) at Week 12 Visits
timeFrame: ADA will be obtained at Week 12
Secondary outcomes:
measure: Number of Subjects Reporting Anaphylactic Reactions at Dosing Time Points (Either at Week 1 or Week 3)
timeFrame: Assessments of Anaphylactic reactions will be carried out at either Week 1 or Week 3
measure: Number of Subjects Reporting TEAEs (Treatment Emergent Adverse Events) That Led to Study Drug Discontinuation at Either Week 1 or Week 3 Dosing Timepoint
timeFrame: Assessment of AE's (Adverse Events) that led to study drug discontinuation were carried out at either week 1 or week 3 dosing timepoint
measure: Number of Subjects Reporting SAEs (Serious Adverse Events) From Baseline (Week 1) to End of Study (Week 26)
timeFrame: Assessment of SAE's was carried out from baseline (week 1) to end of study (week 26)
measure: Number of TEAEs Reported From Baseline (Week 1) to End of Study (Week 26)
timeFrame: Assessment of AE's will be carried out from baseline (week 1) to end of study (week 26)
measure: Number of Subjects Reporting AE From Baseline (Week 1) to End of Study (Week 26)
timeFrame: Assessment of AE's will be carried out from baseline (week 1) to end of study (week 26)
measure: Number of Subjects Reporting TEAEs From Baseline (Week 1) to End of Study (Week 26)
timeFrame: Assessment of AE's will be carried out from baseline (week 1) to end of study (week 26)
measure: Number of Subjects Reporting Hypersensitivity Reactions at Dosing Time Points (Either at Week 1 or Week 3)
timeFrame: Assessments of hypersensitivity reactions either at Week 1 or Week 3
measure: Number of Subjects Reporting Infusion-related Reactions (IRRs) at Dosing Time Points (Either at Week 1 or Week 3)
timeFrame: Assessments of IRRs were carried out at either Week 1 or Week 3
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Arizona Arthritis and Rheumatology Research, PLLC
state: Arizona
city: Palmdale
country: United States
facility: California Allergy and Asthma Medical Group - CRN - PPDS 41230 11th Street West, Suite A
state: California
city: Upland
country: United States
facility: Inland Rheumatology Clinical Trials Incorporated
state: California
city: Lewes
country: United States
facility: Rheumatology Consultant of Delaware dba Delaware Arthritis
state: Delaware
city: Aventura
country: United States
facility: MedBio Trials
state: Florida
city: Clearwater
country: United States
facility: Clinical Research of West Florida Inc - Clearwater
state: Florida
city: Miami
country: United States
facility: Medical Research Center
state: Florida
city: Miami
country: United States
facility: AppleMed Research Group, LLC
state: Florida
city: Plantation
country: United States
facility: Integral Rheumatology and Immunology Specialist, 140 Southwest 84th Avenue, Suite B
state: Florida
city: Tampa
country: United States
facility: Vicis Clinical Research INC
state: Florida
city: Springfield
country: United States
facility: Springfield Clinic (Clinic location)
state: Illinois
city: Lexington
country: United States
facility: Bluegrass Community Research Inc,330 Waller Avenue, Suite 100,
state: Kentucky
city: Freehold
country: United States
facility: Arthritis and Osteoporosis Associates
state: New Jersey
city: Charlotte
country: United States
facility: Integrative Rheumatology
state: North Carolina
city: Duncansville
country: United States
facility: Altoona Center For Clinical Research, 175 Meadowbrook Lane,
state: Pennsylvania
city: Summerville
country: United States
facility: Articularis Healthcare Group, Inc dba Low Country Rheumatology
state: South Carolina
city: Baytown
country: United States
facility: Accurate Clinical Management, LLC
state: Texas
city: Carrollton
country: United States
facility: Trinity Clinical Research LLC, 2008 East Hebron Parkway, Suites 120/114/100,
state: Texas
city: Houston
country: United States
facility: Abigail Neiman
state: Texas
city: Houston
country: United States
facility: Accurate Clinical Management, LLC
state: Texas
city: Houston
country: United States
facility: Laila A Hassan, MD, PA
state: Texas
city: Houston
country: United States
facility: Accurate Clinical Research-Houston, 11003 Resource Parkway, Suite 102
state: Texas
city: Katy
country: United States
facility: Houston Rheumatology & Arthritis Specialists
state: Texas
city: San Antonio
country: United States
facility: Clinical Associates in Research Therapeutics of America, LLC
state: Texas
city: San Antonio
country: United States
facility: Accurate Clinical Research, Inc.
state: Texas
city: Texas City
country: United States
facility: Accurate Clinical Research-League City
state: Texas
Study officials:
References: