A phase III, randomised, double-blind, multicentre study comparing the efficacy, safety, and immunogenicity of proposed tocilizumab biosimilar (DRL_Tocilizumab) with tocilizumab reference product (RoActemra®) administered by the subcutaneous 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]

Decision date (initial)

2023-10-09

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Dr. Reddy’s Laboratories Ltd., Biologics

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Pharmacodynamic, Safety, Pharmacokinetic, Efficacy

To compare efficacy measured as change from baseline to Week 13 in DAS28-ESR following treatment with DRL_TC 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 & CRP] from baseline till Week 25 during treatment with DRL_TC or RMP. • 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 of DRL_TC and RMP during the following periods: from Week 1 to Week 24, Week 25 to Week 32 (all patients including patients continuing on DRL_TC to those on RMP; patients transitioning from RMP to DRL_TC with patients continuing treatment with RMP); from Week 33 to Week 52 (patients included in long-term extension phase). Immunogenicity: • To compare the immunogenicity of DRL_TC and RMP during the following periods: from Week 1 to Week 24, Week 25 to Week 32 (all patients including patients continuing on DRL_TC to those on RMP; patients transitioning from RMP to DRL_TC with patients continuing treatment with RMP); from Week 33 to Week 52 (patients included in long-term extension phase). Pharmacokinetics: • To compare the pharmacokinetics of DRL_TC and RMP using population pharmacokinetics methodology and sparse sampling schedule. Pharmacodynamics: • To compare the effect of DRL_TC and RMP on pharmacodynamic biochemical/ inflammatory markers.

Conditions and MedDRA coding

Adult patients of either gender with active moderate to severe rheumatoid arthritis (1987 revised ACR criteria; Arnett et al. 1987) of at least 6 months duration, with an inadequate response to cDMARDs and currently on treatment with stable doses of MTX for at least 8 weeks prior to randomisation will be eligible for the study. Up to 25% of patients might have also been previously exposed to bDMARDs. Patients with previous exposure to other cDMARD and bDMARD would enter the study after an adequate washout period. Patients previously exposed to JAK pathway inhibitors will not be allowed in the study.

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 1. Male or female patient aged ≥ 18 years and ≤ 80 years and willing to voluntarily provide informed consent for participation as per the locally applicable regulations.
2. 2. Patient with active moderate to severe rheumatoid arthritis of at least 6 months duration, as per ACR 1987 revised criteria for the classification of Rheumatoid Arthritis.
3. 3. Patients with: a. Swollen Joint Count (SJC) ≥ 6 b. Tender Joint Count (TJC) ≥ 8 c. Erythrocyte Sedimentation Rate (ESR) ≥ 28 mm/ hour
4. 4. Patient must have been treated with stable doses of MTX (at least 15 mg/ week, not exceeding allowed maximum dose in the country-specific label; at least 6 mg/ week for patients from other Eastern Asia countries) for at least 8 weeks prior to randomisation. a. Patients who cannot tolerate higher dose of MTX should be on stable dose of tolerable dose of MTX for 8 weeks prior to study entry (there should be documented evidence of intolerance to MTX).
5. 5. Patient taking MTX must be on a stable dose of folic acid (≥ 5 mg per week) or equivalent. Patient must have received folic acid or equivalent for at least 2 months and at a stable dose for 4 weeks prior to randomisation.
6. 6. If the patient is on any of these cDMARDs or bDMARDs, an adequate washout period needs to be completed before first dose of study drug: hydroxychloroquine, chloroquine, azathioprine, leflunomide, sulfasalazine, cyclophosphamide, TNF inhibitors, abatacept, rituximab. Refer Section 10.3 for further details on washout periods.
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 NSAIDs, a stable dose not higher than the maximum recommended dose for the agent in the Prescribing Information of the country where the centre is located for the last 4 weeks prior to randomisation.
9. 9. Woman of childbearing potential should have a negative pregnancy test and should agree to use reliable means 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. Patient must be able to self-administer or must have help to administer the study treatment by caregiver.
11. 11. Patient must be able to comply with all study requirements in the opinion of the Investigator.

Exclusion criteria 26

1. 1. Patients who have received prior treatment with tocilizumab (even if tocilizumab was used for COVID-19 treatment, patient should be excluded), or other agents directly acting on the IL-6 signalling axis (e.g. sirukumab, olokizumab etc.).
2. 4. Patients who need concomitant rheumatoid arthritis therapies other than a. methotrexate with folic acid (at a dose of at least 5 mg per week [or equivalent]) (methotrexate and folic acid will be kept at a stable dose during the study); b. nonsteroidal anti-inflammatory drugs 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; or d. 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) cannot be maintained before patient evaluation visit. Note: Aspirin at anti-aggregant doses (up to 325 mg per day) is not considered an analgesic.
3. 5. Patients who have received any treatment with intra-articular injections (e.g., corticosteroids) required for a flare-up and up to 4 weeks prior to randomization.
4. 6. Patients with functional class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis.
5. 7. 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 rheumatoid arthritis is allowed.
6. 8. Patients who have received any investigational drug within 30 days or 5 times half-life, whichever is longer, prior to the first dose of study drug (or longer as per the local regulation of the country). Patients participating/ participated in another clinical trial evaluating a bDMARD for RA in the last year before Screening are not eligible for this trial.
7. 9. Patients with a known history of or presence of clinically significant haematological, cardiovascular (any patient with NYHA III/ IV functional status is to be excluded), renal, or liver disease.
8. 16. Patients with diseases that have immune suppression in their clinical course and/ or need for treatment with immune suppressive treatments such as patients with an organ graft requiring maintenance immune suppression.
9. 17. Patients with latent tuberculosis including patients with positive and indeterminate QuantiFERON-TB test at screening (QuantiFERON-Gold TB or other validated tuberculosis screening Interferon Gamma Release Assay). Note: For indeterminate results, two repeats are allowed. In emergent situations, when the patient needs quick therapy for RA, patient may be re-tested and randomised after completing at least 4 weeks of prophylactic treatment. As a standard approach, optimal prophylactic therapy should last 3 months with relevant medications and treatment confirmed as effective in patient documentation before randomization.
10. 18. Patients with active tuberculosis, unrecovered hepatitis B, herpes zoster including the period of post-herpetic neuralgia within 1 year of randomisation, or any other ongoing clinically relevant active infection, even if localised.
11. 10. Patients with any history or current presence of known demyelinating disease.
12. 11. Patients with any history of or presence of an active neoplasia except for successfully treated (at least five years in advance) non-metastatic cutaneous squamous cell or basal cell carcinoma and ⁄or localised carcinoma in situ of the cervix.
13. 12. Patients with renal impairment (Cockcroft-Gault creatinine clearance < 60 ml/ min) or liver function impairment (bilirubin > 1.25 x ULN, albumin < 3.5 g/ dL, INR > 1.25, ALT or AST > 1.5 x ULN) at screening.
14. 13. Patients with any disorder or treatment that, in the Investigator’s opinion, may interfere with the safety of the patient, the study evaluations, or the patient compliance to the study procedures and limitations, such as history of chronic alcohol or drug abuse, or significant (for the purposes of the study in the opinion of the Investigator) endocrinological, cardiac, respiratory, mental, or nervous disorder or other diseases. Special focus should be given to lung conditions to ensure it is sufficiently close to normal to avert excessive risks upon study participation.
15. 14. Patients with absolute neutrophil count (ANC) < 2 x 109/ L or platelet count < 100 x 109/ L at the time of screening.
16. 15. Patients with clinically relevant hyperlipidaemia (fasting serum LDL cholesterol higher than 190 mg/ dL or fasting serum triglycerides higher than 200 mg/ dL despite treatment with antihyperlipidemic drugs) at the time of screening. Note: Repeat tests up to two times are allowed as per Investigator’s discretion.
17. 2. Patients who have received treatment with IV gamma globulin or plasmapheresis within 6 months of randomisation.
18. 3. Patients with known contraindication to treatment with tocilizumab, including, but not restricted to hypersensitivity to tocilizumab, other monoclonal antibodies, or any excipients (L-arginine hydrochloride, L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbate 80).
19. 19. Patients who received live virus vaccination within 3 months prior to randomization or intention to receive live virus vaccination during the trial or up to 3 months after the end of administration of the study drug.
20. 20. Patients with positive screening for hepatitis B, hepatitis C or HIV.
21. 21. Patients with active diverticulitis or other GI condition having high risk of perforation as per investigator’s judgement.
22. 22. Patients with unhealed clinically significant external wounds.
23. 23. Female patients who are currently pregnant or breastfeeding.
24. 24. Patients with known history of or current abuse of alcohol or illegal drugs (testing not required).
25. 25. Patients who are considered unreliable to follow study requirements and restrictions, in the opinion of the Investigator.
26. 26. 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. The following parameters will be compared between patients treated with DRL_TC and RMP: Primary endpoint for EMA: • Change in DAS28-ESR from Baseline to Week 13 [Time Frame: Baseline; Week 13]

Secondary endpoints 8

1. The following parameters will be compared between patients treated with DRL_TC and RMP:Efficacy: • Change from Baseline in DAS28-ESR [Time Frame: Baseline; Week 5; Week 9; Week 13 (for US FDA); Week 17; Week 21; and Week 25 (for EMA)]
2. • Change from Baseline in DAS28-CRP [Time Frame: Baseline; Week 5; Week 9; Week 13; Week 17; Week 21; and Week 25] • Proportion of patients with ACR20/ 50/ 70 response [Time Frame: Week 5; Week 9; Week 13; Week 17; Week 21; and Week 25]
3. • Time to EULAR moderate or good response [Time Frame: Week 5; Week 9; Week 13; Week 17; Week 21; and Week 25] • Proportion of patients reaching moderate or good EULAR response based on DAS28-ESR [Time Frame: Week 5; Week 9; Week 13; Week 17; Week 21; and Week 25]
4. Safety: • Incidence of AEs and SAEs [Time Frame: Baseline till EOS; different study periods will be separately considered] • Incidence of AEs and SAEs during transition phase [Time Frame: Week 25; Week 33]
5. • Incidences of anaphylactic reactions, hypersensitivity reactions, and injection site reactions [Time Frame: Baseline till EOS; different study periods will be separately considered] • Incidence of anaphylactic reactions, hypersensitivity reactions, and injection site reactions during transition phase [Time Frame: Week 25; Week 33]
6. Immunogenicity: • Incidence of ADAs including NAb and ADA Titres [Time Frame: Baseline through scheduled time points till EOS; different study periods will be separately considered] • Incidence of ADAs including NAb and ADA Titres during transition phase [Time Frame: Week 25; Week 33]
7. Pharmacokinetics: • Population pharmacokinetic parameters [Time Frame: Baseline through scheduled time points till EOS]
8. Pharmacodynamics: • Change in PD endpoints from baseline to selected time points [Time Frame: Baseline through scheduled time points]

Investigational products

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

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Dr. Reddy's Laboratories Limited

Sponsor organisation

Dr. Reddy's Laboratories Limited

Address

No 47 Bachupally Village, Malkajgiri District 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

K. Ranjith

Third parties 8

Locations

7 EU/EEA countries · 53 investigational sites

By country

Investigational sites

Application history

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