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
- Trial ID
- 2022-501361-44-00
- Protocol
- TC-01-003
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase III, randomized, double-blind, multicenter study is to compare the **efficacy** of a proposed tocilizumab biosimilar (DRL_Tocilizumab) with the reference product (RoActemra®) in patients with moderate to severe **rheumatoid arthritis**. This is measured by the change from baseline to Week 13 in the Disease Activity Score 28 - Erythrocyte Sedimentation Rate (DAS28-ESR) in patients who are concurrently receiving methotrexate (MTX). This objective is clinically relevant as it aims to establish the therapeutic equivalence of the biosimilar to the reference product, potentially offering a more accessible treatment option for patients.
Secondary objectives include:
- **Efficacy**: Comparing the time course of efficacy using DAS28 (both ESR and C-reactive protein) from baseline to Week 25, and evaluating American College of Rheumatology (ACR) 20/50/70 responses at 4-week intervals up to Week 25. Additionally, the time to first achievement of the European League Against Rheumatism (EULAR) response criteria (moderate or good response) will be compared.
- **Safety**: Assessing the safety and tolerability of DRL_TC and RMP from Week 1 to Week 24, Week 25 to Week 32, and Week 33 to Week 52, including patients transitioning between treatments.
- **Immunogenicity**: Comparing the immunogenicity of DRL_TC and RMP over the same periods as the safety assessment.
- **Pharmacokinetics**: Evaluating the pharmacokinetics of DRL_TC and RMP using population pharmacokinetics methodology.
- **Pharmacodynamics**: Comparing the effect of DRL_TC and RMP on pharmacodynamic biochemical and inflammatory markers.
Participants
The clinical trial involves a total of **91 participants** who are adult patients of either gender, aged between 18 and 80 years, diagnosed with active moderate to severe **rheumatoid arthritis**. These individuals have had the condition for at least six months and have shown an inadequate response to conventional disease-modifying antirheumatic drugs (cDMARDs). All participants are currently on stable doses of methotrexate (MTX) for a minimum of eight weeks prior to randomization. Up to 25% of the participants may have been previously exposed to biological DMARDs (bDMARDs), but those with prior exposure to JAK pathway inhibitors are excluded. The selection criteria ensure that participants are capable of self-administering the study treatment or have assistance from a caregiver. Additionally, participants must adhere to a stable regimen of folic acid and, if applicable, glucocorticoids and NSAIDs, with specific dosage requirements. The trial does not include a vulnerable population, and both male and female subjects are eligible, provided they meet the necessary contraceptive measures if of childbearing potential. The study population was carefully selected to ensure compliance with all study requirements as determined by the investigator.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, multicenter study designed to evaluate the efficacy, safety, and immunogenicity of a proposed **tocilizumab** biosimilar compared to the reference product, RoActemra, in patients with moderate to severe **rheumatoid arthritis**. The trial involves the administration of the study drugs via **subcutaneous injection** as an add-on to methotrexate. The trial is expected to commence on September 25, 2023, and conclude by March 31, 2025, with an estimated duration of 62 weeks for each participant.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, disease severity, and previous treatment history. The inclusion criteria specify that participants must be adults aged 18 to 80 years with active rheumatoid arthritis for at least six months and an inadequate response to conventional DMARDs. They must also be on stable doses of methotrexate for at least eight weeks prior to randomization. Exclusion criteria include previous exposure to JAK pathway inhibitors.
Following the screening, eligible participants will be randomized to receive either the biosimilar or the reference product. The primary endpoint is the change in DAS28-ESR from baseline to Week 13. Secondary endpoints include changes in DAS28-CRP, ACR response rates, and safety assessments such as the incidence of adverse events. Study visits will occur at baseline, Weeks 5, 9, 13, 17, 21, and 25, with additional visits for safety and immunogenicity assessments extending to Week 33.
The end-of-study visit will assess the overall treatment outcomes and any long-term effects. Participants are expected to remain in the study for the full duration unless they experience significant adverse events, fail to comply with study protocols, or choose to withdraw consent. The trial is structured to ensure rigorous monitoring and data collection to support the evaluation of the biosimilar's performance relative to the reference product.
Treatment
The clinical trial involves the administration of two **tocilizumab** formulations. The experimental medication, referred to as DRL_TC, is a **solution for injection** containing the active substance tocilizumab. This formulation is provided by Dr. Reddy’s Laboratories Ltd., Biologics. The pharmaceutical form is a solution for injection, and it is administered via **subcutaneous injection**. The dosage is set at 162 mg per administration, with a maximum daily dose of 162 mg. The treatment period is limited to a maximum of 62 days. DRL_TC is characterized as a humanized monoclonal antibody, originating from protein sources other than human or animal. Participant compliance with the dosing schedule will be monitored throughout the study.
The comparator treatment in this study is RoActemra, a reference product also containing the active substance tocilizumab. RoActemra is provided by Roche Registration GmbH and is available as a **solution for injection in a pre-filled syringe**. Similar to DRL_TC, RoActemra is administered via subcutaneous injection at a dosage of 162 mg per administration, with a maximum daily dose of 162 mg. The treatment duration is also capped at 62 days. RoActemra is described as a recombinant humanized, anti-human monoclonal antibody. Both treatments are used as an add-on to methotrexate in patients with moderate to severe **rheumatoid arthritis**. The study is designed to compare the efficacy, safety, and immunogenicity of the proposed tocilizumab biosimilar (DRL_TC) with the reference product (RoActemra).
Efficacy
The efficacy of the clinical trial will be assessed by measuring the change in the Disease Activity Score 28 - Erythrocyte Sedimentation Rate (**DAS28-ESR**) from baseline to Week 13. This primary endpoint will compare the efficacy of the proposed tocilizumab biosimilar (DRL_TC) with the reference product (RoActemra®) in patients with moderate to severe rheumatoid arthritis who are also receiving methotrexate. Secondary efficacy endpoints include changes from baseline in DAS28-ESR and DAS28-C-reactive protein (CRP) at multiple time points, including Weeks 5, 9, 13, 17, 21, and 25. Additionally, the proportion of patients achieving American College of Rheumatology (ACR) 20/50/70 responses and the time to European League Against Rheumatism (EULAR) moderate or good response will be evaluated at these time points.
The efficacy parameters will be collected and analyzed using validated scales and laboratory tests. The DAS28-ESR and DAS28-CRP scores will be calculated based on joint counts and laboratory values, while ACR response rates will be determined by assessing improvements in tender and swollen joint counts, as well as patient and physician global assessments. The study will also assess the proportion of patients reaching moderate or good EULAR response based on DAS28-ESR. These assessments will be conducted at specified intervals throughout the trial to monitor the progression and response to treatment.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.
- 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.
- Patients with: a. Swollen Joint Count (SJC) ≥ 6 b. Tender Joint Count (TJC) ≥ 8 c. Erythrocyte Sedimentation Rate (ESR) ≥ 28 mm/ hour
- 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- Patient must be able to self-administer or must have help to administer the study treatment by caregiver.
- Patient must be able to comply with all study requirements in the opinion of the Investigator.
Exclusion Criteria
- 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.).
- 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.
- 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.
- Patients with functional class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Patients with any history or current presence of known demyelinating disease.
- 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.
- 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.
- 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.
- Patients with absolute neutrophil count (ANC) < 2 x 109/ L or platelet count < 100 x 109/ L at the time of screening.
- 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.
- Patients who have received treatment with IV gamma globulin or plasmapheresis within 6 months of randomisation.
- 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).
- 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.
- Patients with positive screening for hepatitis B, hepatitis C or HIV.
- Patients with active diverticulitis or other GI condition having high risk of perforation as per investigator’s judgement.
- Patients with unhealed clinically significant external wounds.
- Female patients who are currently pregnant or breastfeeding.
- Patients with known history of or current abuse of alcohol or illegal drugs (testing not required).
- Patients who are considered unreliable to follow study requirements and restrictions, in the opinion of the Investigator.
- Patients who had major surgery including joint surgery within 8 weeks prior to randomisation or planned major surgery within 6 months following randomisation.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Yet Recruiting | 25 Sept 2023 | 50 |
 Czechia | Not Yet Recruiting | 25 Sept 2023 | 39 |
 Estonia | Not Yet Recruiting | 25 Sept 2023 | 30 |
 Hungary | Not Yet Recruiting | 25 Sept 2023 | 50 |
 Lithuania | Not Yet Recruiting | 25 Sept 2023 | 18 |
 Poland | Not Yet Recruiting | 25 Sept 2023 | 140 |
 Romania | Not Yet Recruiting | 25 Sept 2023 | 30 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
DRL_TC | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 162 | 62 | PRD9870624 |
RoActemra 162 mg solution for injection in pre-filled syringe. | Comparator | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS INJECTION | 162 | 62 | PRD1576593 |