A randomised, double-blind, multicentre study comparing the efficacy, safety and immunogenicity of proposed Abatacept biosimilar (DRL_AB) with Orencia® administered by the intravenous route as an add-on to methotrexate in the treatment of patients with moderate to severe rheumatoid arthritis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Dr Reddy's Laboratories Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

24 Oct 2024 → 3 Dec 2025

Decision date (initial)

2024-04-26

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Dr. Reddy’s Laboratories Ltd.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Others, Safety, Pharmacodynamic, Pharmacokinetic

To compare efficacy measured as change from baseline till Week 25 in DAS28-CRP following treatment with DRL_AB or RMP in a population of patients with moderate to severe rheumatoid arthritis on treatment with MTX.

Secondary objectives 1

1. Efficacy •To compare the time, course of efficacy as measured by evaluating DAS28 [both ESR and CRP] from baseline till Week 25. •To compare the time course of efficacy as measured by ACR20/50/70 at 4 weeks intervals till Week 25. •To compare the time to first achievement of the EULAR response criteria (moderate or good response). Safety •To compare the safety and tolerability during the following periods: from Baseline to Week 25 (all patients on treatment with DRL_AB to those on RMP); Week 25 to Week 33 (all patients transitioning from RMP to DRL_AB with patients continuing treatment with RMP); from Baseline to Week 53 (patients included in long term safety extension phase). Immunogenicity •To compare the immunogenicity during the following periods: from Baseline to Week 25 (all patients on treatment with DRL_AB to those on RMP); Week 25 to Week 33 (all patients transitioning from RMP to DRL_AB with patients continuing treatment with RMP); from Baseline to Week 53 (patients included in long term safety extension phase). Pharmacodynamics •To compare the effect on pharmacodynamic inflammatory markers.

Conditions and MedDRA coding

Rheumatoid Arthritis

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 1) Patients should provide a written informed consent (as per the local regulations applicable to the study site and general good clinical practice (GCP) guidelines.
2. 2) Male or female patient aged ≥ 18 years and ≤ 80 years at the time of signing informed consent.
3. 3) Patients with moderately to severely active RA for at least 6 months’ duration, defined as per the ACR Criteria, 1987 revision. Active RA is defined as having:: • SJC ≥10 out of the 66 joints count • TJC ≥12 out of the 68 joints count, and • CRP of at least 1.0 mg/dl determined using a highly sensitivity assay.
4. 4) Patient must be on MTX and folic acid for at least 3 months prior to the first dose of study drug with the below requirements. o Must have been treated with stable doses of MTX (at least 15 mg/ week; at least 6 mg/ week for patients from other Eastern Asia countries, not exceeding allowed maximum dose in the country-specific label) for at least 4 weeks prior to randomisation. o Patients who cannot tolerate higher dose of MTX should be on stable and tolerable dose of MTX for 4 weeks prior to randomisation (there should be documented evidence of intolerance to MTX). o Patients taking MTX must be on a stable dose of folic acid (≥5 mg per week) or equivalent for at least 4 weeks prior to randomisation
5. 5) Patient should not be on cDMARDs other than MTX for at least 4 weeks prior to the first dose of study drug (4 weeks’ prior for azathioprine, sulfasalazine; 8 weeks for hydroxychloroquine and chloroquine; 12 weeks for leflunomide; 24 weeks for cyclophosphamide).
6. 6) Patients should not be on bDMARDs: these agents should have been discontinued at least 4 weeks (4 weeks prior for TNF alpha inhibitors; 24 weeks for rituximab; 4 weeks or half of biological half-life for other bDMARDs whichever is longer) prior to the first dose of study drug.
7. 7) Patient on glucocorticoids should not be receiving more than 10 mg oral prednisone/ prednisolone or equivalent per day, and those receiving should be using stable dose for at least 6 weeks prior to randomisation.
8. 8) For patient receiving non-steroidal anti-inflammatory drugs (NSAIDs) for the last 4 weeks prior to randomisation: a. Should be taking a stable dose NOT higher than the maximum recommended dose for the agent in the Prescribing Information of the country where the study centre is located. b. NSAIDs are allowed except for the 12h before the efficacy scheduled assessment visit (24h for oxicams and other single daily dose or less frequently administered agents); Details of permitted and prohibited medication in the current study has been captured at Section 6.9.
9. 9) Women of childbearing potential should have a negative pregnancy test and should agree to use highly effective measures of contraception and not to donate or cryopreserve ova during the course of the study and for at least 6 months after the last dose of the study drug. OR Male patient permanently sterile by bilateral orchidectomy or agree to use appropriate contraception methods (see list in the Note below) and not to donate or cryopreserve sperm during the study and for at least 6 months after the last dose of study drug.
10. 10) Patients should have the ability to comply with all study requirements.

Exclusion criteria 24

1. 1 Patients who have received prior treatment with abatacept.
2. 2 Patients who have received prior treatment with JAK inhibitors within the last 16 weeks of first dose of study drug administration (e.g. tofacitinib, abrocitinib, baricitinib, upadacitinib, filgotinib etc.).
3. 3 Patients who have received treatment with IV gamma globulin or plasmapheresis within 6 months of randomisation.
4. 4 Patients with known contraindication to treatment with abatacept, including, but not restricted to hypersensitivity to abatacept, or any excipients (maltose, monobasic sodium phosphate and sodium chloride).
5. 5 Patients who need concomitant RA therapies other than a. MTX with folic acid (at a dose of at least 5 mg per week [or equivalent]) (MTX and folic acid will be kept at a stable dose during the study); Folinic acid at the same dose of folic acid, can be given in place of folic acid if it is allowed by the local label. Patient should take the same folate supplementation throughout the duration of the study. b. NSAIDs at approved doses kept at stable doses during the study; c. Corticosteroids at a maximum daily dose of 10 mg of oral prednisone or equivalent kept stable during the study; or Also, patients who cannot maintain an analgesics-free period of appropriate duration (12 hr for analgesics in general; 24 hr for oxicams and other single daily or less frequently administered drugs) before patient evaluation visit. Note: Aspirin at anti-aggregant doses (up to 325 mg per day) is not considered as an analgesic.
6. 6 Patients who have received any treatment with intra-articular injections (e.g., corticosteroids) required for a flare-up within 4 weeks prior to randomisation.
7. 7 Patients with functional class IV as defined by the ACR Classification of Functional Status in RA.
8. 8 Patients with other inflammatory diseases that might confound the evaluation of the efficacy (e.g., Crohn’s disease, ulcerative colitis). Note: Sjogren syndrome secondary to RA is allowed.
9. 9 Patients who have received any investigational drug within 30 days or 5 times half-life. Patients participating/ participated in another clinical trial evaluating a bDMARD for RA within the last year before Screening are not eligible for this trial.
10. 10 Patients with a known history of or presence of clinically significant cardiovascular (any patient with New York Heart Association (NYHA) III/ IV functional status is to be excluded), haematological, renal, or liver disease
11. 11 Patients with any history or current presence of known demyelinating disease.
12. 12 Patients with any history of or presence of an active neoplasia
13. 13 Patients with renal impairment or liver function impairment at screening
14. 14 Patients with history of chronic alcoholism or drug abuse or other addictions
15. 15 Patients with diseases that have immune suppression in their clinical course and/ or require immune suppressive treatments
16. 16 Clinically significant (COPD)
17. 17 Patients with latent tuberculosis (TB)
18. 18 Patients with active TB, unrecovered hepatitis B, herpes zoster including the period of post-herpetic neuralgia within 1 year of randomisation, or any other ongoing active infection
19. 19 Patients with positive screening for hepatitis B surface antigen (HBsAg), hepatitis C or human immunodeficiency virus (HIV)
20. 20 Patients who received live virus vaccination within 3 months prior to randomisation or planned for during the trial or up to 3 months after the end
21. 21 Patients with acute or chronic unhealed clinically significant external wounds
22. 22 Female patients who are currently pregnant or breastfeeding
23. 23 Patients who are considered unreliable to follow study requirements and restrictions
24. 24 Patients who had major surgery including joint surgery within 8 weeks prior to randomisation or planned major surgery within 6 months following randomisation

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary endpoint for EMA • Change in DAS28-CRP from Baseline to Week 13 [Time Frame: Baseline; Week 13].

Secondary endpoints 5

1. 1. Change from baseline in DAS28-ESR 2. Change from baseline in DAS28-CRP 3. Proportion of patients with ACR20/50/70 response
2. 4. Time to EULAR moderate or good response 5. Proportion of patients reaching moderate or good EULAR response based on DAS28-CRP
3. 6. Incidence of AEs and SAEs 7. Incidences of anaphylactic reactions, hypersensitivity reactions, infections (requiring intravenous antibiotic therapy), infusion related reactions and new malignancies
4. 8. Incidence of ADAs including NAb and ADA Titres 9. Incidence of ADAs including NAb and ADA Titres during transition phase
5. 10. Change in PD endpoints (ESR and CRP) from baseline to selected time points till Week 25

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 3

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Dr Reddy's Laboratories Limited

Sponsor organisation

Dr Reddy's Laboratories Limited

Address

Biologics Survey No 47 44 Part Bachupally Village Bachupally Mandal, Medchal Malkajgiri District Medchal Malkajgiri District

City

Hyderabad

Postcode

500090

Country

India

Scientific contact point

Organisation

Dr Reddy's Laboratories Limited

Contact name

Dr. Piyushbhai Patel

Public contact point

Organisation

Dr Reddy's Laboratories Limited

Contact name

Naveen Reddy

Third parties 7

Locations

8 EU/EEA countries · 61 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 6 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 85 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications