| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to severe active rheumatoid arthritis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic inflammatory disease causing pain and swelling in the joints |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate equivalence of change in DAS28-CRP score from baseline to week 24 between patients treated with GP2015 and patients treated with EU-authorized Enbrel |
|
| E.2.2 | Secondary objectives of the trial |
Efficacy:
In the first part of the study, GP2015 and EU-authorized Enbrel will be compared up to week 24. Continuous GP2015 treatment versus a treatment transition from EU-authorized Enbrel to GP2015 after week 24 up to week 48 of treatment will be compared in the second part of the study for following efficacy parameters:
* DAS28-CRP and DAS28-ESR scores
* Changes from baseline in DAS28-CRP and DAS28-ESR scores
* Proportion of patients achieving EULAR good and moderate response and proportion of patients achieving DAS28 ≤2.6
* For other objectives please see protocol
Safety and tolerability:
* Evaluation of the clinical safety of GP2015 and EU-authorized Enbrel.
* Evaluation of the local tolerability at the injection sites of both products as assessed by the investigator.
* Assessment of the immunogenicity of GP2015 and EU-authorized Enbrel by measuring the rate of anti-drug antibody (ADA) positive patients at baseline, and at weeks 2, 4, 12, 24, 30, 36 and 48. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients at least 18 years of age at screening with RA diagnosed according to the ACR 1987 or ACR/EULAR 2010 criteria for ≥ 6 months at the time of baseline visit.
2. Patients must have active disease defined as DAS28-CRP ≥ 3.2.
3. Patients must haveCRP level above upper limit of normal (> 5 mg/l) or erythrocyte sedimentation rate (ESR) ≥28 mm/h.
4. Patients must have inadequate clinical response to MTX at a dose of 10 - 25 mg/week after proper dose escalation according to local standards. Patients are required to have been on MTX therapy for ≥ 3 months and to be on a stable dose for ≥ 4 weeks prior to baseline. Patients who failed a DMARD treatment other than MTX, and any other DMARD used in combination with MTX, will be allowed to enter into the study after an appropriate wash-out period prior to baseline (except for MTX).
5. Patients (male and female) who have been compliant and are willing to remain compliant throughout the study and after study completion with the safety precautions in accordance with the local MTX label, particularly in relation to contraception requirements to prevent fathering a child or becoming pregnant.
6. Patients should be taking adequate folic acid supplementation in a stable dose (≥ 5 mg per week) during the last 4 weeks before baseline and until the end of the study.
7. Patients taking systemic corticosteroids have to be on a stable dose of ≤ 7.5 mg/d prednisone or equivalent for at least 4 weeks before baseline and have to continue on this stable dose during the study.
8. Patients taking regular NSAIDs, COX-2 inhibitors, paracetamol/acetaminophen or low strengths opioids as part of their RA therapy are required to be on stable dose for at least 4 weeks before baseline.
9. Patients taking NSAIDs or COX-2 inhibitors or paracetamol/acetaminophen/low strength opioids on a PRN basis (as required, meaning not as a fixed dose schedule) within 4 weeks before randomization have to stop their medication at least 24 hours before a study vist.
10. Patients must show the following laboratory results obtained at Visit 1:
* Hemoglobin ≥ 8.5 g/dl
* White blood cell count (WBC) ≥ 3,500/µl and neutrophils > 2,000/μL and platelets >100,000/μL
* AST, ALT and AP ≤ 2.5 x ULN
* Serum creatinine level ≤ 176.8 µmol/L (2.0 mg/dL)
11. Patients must give written, signed and dated informed consent before any study-related assessment is performed.
12. Must be able to understand and communicate with the investigator and comply with the requirements of the study. Where relevant, a legal representative will also sign the informed study consent according to local laws and regulations.
13. Patient is affiliated to social security or equivalent system (France only). |
|
| E.4 | Principal exclusion criteria |
1. Previous exposure to etanercept in the past.
2. Treatment with any other biologic therapy for RA, including TNFα inhibitors, anti-CD20, immune-modulator drug(s), other investigational drug(s) and /or device(s) within three months or five half-lives at the time of enrollment whichever is longer.
3. Previous use of >2 biologics.
4. Primary and secondary biologic therapy failures in the opinion of the investigator (e.g. patients with biologic treatment stopped because of safety and/or efficacy issues).
5. Subjects taking high potency opioid analgesics, or any intramuscular corticosteroid injection, or any therapy by intra-articular injection required for treatment of acute RA flare within 4 weeks before baseline.
6. History of known hypersensitivity to any ingredients of the IMPs, to any recombinant human protein or any of the excipients used in GP2015 or Enbrel.
7. Patients who are allergic to rubber or latex (the needle cover on the prefilled syringes for both GP2015 and Enbrel contains dry natural rubber).
8. Patients with functional status class IV according to the ACR 1991 revised criteria.
9. Systemic manifestation of RA, with the exception of Sjögren’s syndrome.
10. Active ongoing inflammatory diseases other than RA that might confound the evaluation of the efficacy.
11. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL).
12. Women of child-bearing potential not willing to use highly effective contraception throughout.
13. Pre-existing or recent-onset central or peripheral nervous system demyelinating disorders according to investigator's discretion and taking into account a neurological assessment; patients who are considered to have an increased risk of developing a demyelinating disease.
14. Any serious illness or uncontrolled medical condition, including but not limited to significant hepatic or renal disease, uncontrolled hypertension (defined as ≥ 160/95), congestive heart failure (NYHA class III or IV), or other severe, uncontrolled cardiac disease.
15. Patients who have body mass index (BMI) ≥ 29.9.
16. History of active tuberculosis (TB) or presence of latent (inactive) TB detected by imaging (Chest X-ray [PA or PA and lateral according to local practice], Computerized Tomography [CT] scan or MRI) and/or by the QuantiFERON®-TB Gold test at screening.
17. Chronic infectious disease or history of recurrent infectious disease or active systemic infection within 2 weeks prior to selection or during the screening period (except for common cold) and patients with a history or evidence of opportunistic infections (e.g. histoplasmosis, listeriosis, legionellosis).
18. Known immunodeficiency, history of positive serology to human immunodeficiency virus (HIV), or is immunocompromised.
19. Positive serology to hepatitis B (HBsAg or anti-HBc) or hepatitis C (HCV RNA) at screening or baseline
20. History of lymphoproliferative disease or any known malignancy or history of malignancy of any organ system (except for basal cell carcinoma or actinic keratosis that have been treated with no evidence of recurrence in the past 3 months, and except for carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been removed with no evidence of recurrence), treated or untreated, within the past 5 years.
21. Any medical or psychiatric condition which, in the Investigator’s opinion, would preclude the participant from adhering to the protocol or completing the study per protocol.
22. History or evidence of ongoing alcohol or drug abuse, within the last six months before baseline.
23. Plans for administration of live vaccines during the study period or vaccination within 3 months prior to baseline.
24. Patients who are legally institutionalized, or patients under judicial protection (France and any other country where stipulated by local regulations).
25. Patients with an immediate family member (i.e., spouse, parent/legal guardian, sibling or a child) being a member of study site staff or being a member of the sponsor’s study team. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in DAS28-CRP |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy endpoints:
1) DAS28-CRP and DAS28-ESR scores
2) DAS28-CRP and DAS28-ESR score change from baseline
3) EULAR good and moderate response and proportion of patients achieving DAS28 ≤2.6
4) EULAR/ACR boolean remission criteria
5) ACR20/50/70 response
6) ACR-N scores
7) SDAI and CDAI: high, moderate, low disease activity and remission
8) Health-related Quality of life (HAQ)
9) Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue scale
10) CRP/ESR levels
Safety endpoints:
11) Physical examination and vital signs
12) Laboratory assessments: hematology, clinical chemistry, urine analysis
13) ECG
14) Immunogenicity (development of anti-drug-antibodies (ADA))
15) Assessment of injection site reactions (ISRs)
16) AEs and SAEs |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy endpoints:
1) Weeks 0, 4, 12, 24 and up to week 48
2) Weeks 4, 12, 24 and up to week 48
3) Weeks 4, 12 and 24, 36 and 48
4) Weeks 4, 12 and 24, 36 and 48
5) Weeks 4, 12, 24, 36 and 48
6) Weeks 0, 4, 12, 24, 36 and 48
7) Weeks 4, 12, 24, 36 and 48
8) Weeks 0, 4, 12, 24, 36 and 48
9) Weeks 4, 12, 24, 36 and 48
10) Weeks 0, 4, 12, 24, 36 and 48
Safety and tolerability endpoints:
11) Weeks 0, 2, 4, 8, 12, 18, 24, 30, 36, 42 and 48
12) Weeks 0, 2, 4, 8, 12, 18, 24, 30, 36, 42 and 48
13) Weeks 24 and 48
14) Weeks 0, 2, 4, 12, 24, 30, 36 and 48
15) Weeks 0, 2, 4, 8, 12, 18, 24, 30, 36, 42 and 48
16) Weeks 0, 2, 4, 8, 12, 18, 24, 30, 36, 42 and 48 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | Yes |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Parallel group with open label phase after week 24 |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 74 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Czech Republic |
| Estonia |
| Germany |
| Hungary |
| Italy |
| Latvia |
| Lithuania |
| Mexico |
| Poland |
| Russian Federation |
| Serbia |
| Slovakia |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
Print
