| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Refractory rheumatoid arthritis |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
|
| 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 bioequivalence between GP2013 and rituximab in combination with MTX in patients with active RA who have not responded adequately, or have shown intolerance, to DMARDs, including MTX, and one or two anti-TNF therapies. Bioequivalence is defined as AUC(0-) and Cmax of blood concentrations of the drugs being comparable, i.e. the 90% confidence interval for the ratio of the geometric means (GP2013/rituximab) estimated based on non-compartmental analysis based on assessments up to week 24 must be within the standard bioequivalence limits 0.8 to 1.25. |
|
| E.2.2 | Secondary objectives of the trial |
PK/PD
• To evaluate pharmacokinetic parameters after the administration of two intravenous infusions of 1000 mg GP2013 and rituximab, respectively: AUC(0-24), clearance, volume of distribution and t1/2.
• To evaluate the extent and kinetics of the depletion of peripheral blood B cells in response to GP2013 or rituximab, respectively, defined as AUECs of the relative change of the peripheral blood B cell count from baseline following the first infusion of GP2013 or rituximab, until the time of the second infusion.
• Efficacy
- To compare the proportion of patients with an ACR20 response at week 24 in response to treatment with GP2013 or rituximab, respectively.
• Safety
- Overall safety and tolerability of GP2013 and rituximab up to 24 and 52 weeks
For additional secondary and exploratory objectives please see full protocol pages 20-21. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients must give written informed consent before any study-related assessment is performed.
2. Patients must be ≥18 years of age.
3. Patients must have a diagnosis of Rheumatoid Arthritis, based on the ACR 1987 criteria. At least 4 of the following 7 criteria must be fulfilled to confirm the diagnosis of RA:
• joint morning stiffness of at least one hour
• swelling of joints in at least in three joint areas, diagnosed by a doctor
• swelling of MCP and wrist joints, diagnosed by a doctor
• bilateral, symmetric swelling of joints in the same joint areas, diagnosed by a doctor
• rheumatoid nodule
• rheumatoid factor seropositivity
• positive findings in hand radiographs.
4. Patients must have had the diagnosis of RA for at least 6 months.
5. Patients must have active RA at baseline:
• ≥ 6 swollen joints (of 66 joints assessed)
• ≥ 6 tender joints (of 68 joints assessed)
• CRP ≥ 10 mg/L
OR ESR ≥ 28mm/1st hour
Note: If one of the criteria is not met at baseline, the patient is not eligible for randomization at this timepoint. Rescreening (i.e. a second baseline visit) is at the discretion of the investigator.
6. Patients must be seropositive for rheumatoid factor (RF) and/or have antibodies to cyclic citrullinated peptide (anti-CCP).
7. Patients must have inadequate response or intolerance to non-biologic DMARDs, including MTX, and one or two TNF antagonists:
• infliximab (≥ 3 mg/kg, ≥ 4 infusions),
• adalimumab (40 mg biweekly ≥ 3 months),
• etanercept (25 mg twice weekly or 50 mg weekly ≥ 3 months),
• certolizumab pegol (400 mg every 2 weeks ≥ 3 months),
• or golimumab (50 mg every 4 weeks ≥ 4 months),
and discontinued the biological treatment due to lack of efficacy, or due to being intolerant to at least 1 administration of these agents.
8. Patients may have previously received hydroxychloroquine, chloroquine, steroids, sulfasalazine, leflunomide, gold, cyclosporin but NEITHER any alkylating agents or azathioprine, NOR rituximab, abatacept, tocilizumab, anakinra or other biological treatments, apart from TNF antagonists, for RA.
9. Patients must be on a stable dose of MTX (10-25 mg per week). They must have received MTX for at least 4 months with 25 mg/week as the maximal dose, and with a stable dose for 4 weeks prior to randomization.
10. Patients must be on a stable dose of folic acid or equivalent (≥ 5 mg per week). They must have received folic acid or equivalent for at least 4 months and with a stable dose for 4 weeks prior to randomization.
11. Patients must have stopped DMARDs for at least 4 weeks. In case of leflunomide it has to be discontinued for 8 weeks prior to randomization (unless a cholestyramine washout is performed, than randomization can happen 4 weeks after). Antimalarial drugs (hydroxychloroquine, chloroquine) or sulfasalazine which are permitted in combination with MTX should be taken at least for 4 months prior to randomization and at a stable dose for at least 4 weeks prior to randomization.
12. Patients must have stopped etanercept, certolizumab pegol and adalimumab for at least 4 weeks, infliximab and golimumab for at least 8 weeks before randomization.
13. If taking glucocorticoids, patients must be on stable dose of maximally 10 mg/day prednisone or equivalent over the past 2 weeks before randomization and continue this therapy during the trial.
14. Patients requiring vaccination should be vaccinated according to current local guidance or practice at least 4 weeks prior to administration of study drugs.
15. Patients taking NSAIDs or COX-2 inhibitors or paracetamol/acetaminophen/low strength opioids as part of their RA therapy are required to be on a stable dose for at least 4 weeks before randomization.
16. Patients taking NSAIDs or COX-2 inhibitors or paracetamol/acetaminophen/low strength opioids PRN within 4 weeks before randomization have to stop their medication at least 24 hours before an ACR visit (i.e. visits 1, 2, 8 to 14 and in case of retreatment).
For additional inclusion criteria, please refer to section 4.1 of the protocol. |
|
| E.4 | Principal exclusion criteria |
1. RA patients with functional status class IV classified according to the ACR 1991 revised criteria.
2. Patients with levels of serum IgG, IgM and IgA below LLN.
3. Patients with systemic manifestations of RA, with the exception of Sjögren’s syndrome.
4. Patients taking high potency opioid analgesics (e.g. methadone, hydromorphone, morphine).
5. Female patients nursing (lactating / breast-feeding), pregnant or planning of pregnancy within 12 months after the last infusion of study drug, 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).
6. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they are using a highly effective method of birth control (i.e. one that results in a less than 1% per year failure rate when used consistently and correctly, such as implants, injectables, combined oral contraceptives and intrauterine devices (IUDs)). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) is not acceptable.
7. Patients who have had any therapy with intra-articular injections (e. g. corticoid) required by a flare up to 4 weeks before randomization.
8. Patients with underlying metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, infectious or gastrointestinal conditions, which in the opinion of the investigator immunocompromizes the patient and/or places the patient at unacceptable risk by receiving immunomodulatory therapy within the study – especially patients with clinical history of Felty’s Syndrome.
9. Patients with significant medical problems, including but not limited to the following: uncontrolled hypertension (≥ 160/95 mmHg), congestive heart failure (New York Heart Association status of class III or IV).
10. Patients with screening total WBC count < 3000/µL, platelets < 100,000/µL, neutrophils < 1,500/µL or hemoglobin < 8.5 g/dL.
11. History of clinically significant liver disease or liver injury as indicated by abnormal liver function tests such as AST, ALT, or alkaline phosphatase. Any single parameter may not exceed 3 x upper limit of normal (ULN). A single parameter elevated up to and including 3 x ULN should be re-checked once more as soon as possible, and in all cases, at least prior to randomization.
12. Patients with history of renal trauma, glomerulonephritis, a single kidney or a creatinine level exceeding 1.5 mg/dL.
13. History of lymphoproliferative disease or any known malignancy or history of malignancy within the past 5 years (except non-melanoma skin cancer which has been treated with no evidence of recurrence in the past 3 months, carcinoma in situ of the cervix, polyps (removed) in the colon with non-invasive malignancy).
14. Patients who have lost or donated 400 mL blood in the 8 weeks prior to randomization.
15. Inability or unwillingness to undergo repeated venepuncture (poor tolerability or lack of access to veins).
16. Patients with plans to receive live vaccines during the study or 4 weeks prior to randomization.
17. Known infection with HIV according to patient history.
18. Active or latent hepatitis B (HBsAg positive) or hepatitis C at screening.
19. Patients with other inflammatory diseases which might confound the evaluation of the efficacy (e.g. Crohn’s disease, ulcerative colitis).
20. History of ongoing, chronic or recurrent infectious disease or evidence of tuberculosis infection as defined by either a positive PPD skin test (the size of induration will be measured after 48-72 hours, and a positive result is defined as an induration of ≥ 5 mm or according to local guidelines) or a positive QuantiFERON TB-Gold test. Patients with evidence of latent tuberculosis may enter the study after evaluation by an appropriate specialist and after sufficient treatment has been initiated according to local medical practice.
21. Active systemic infections during the two weeks (exception: common cold) prior to randomization.
22. History of allergy (medication history) to any of the compounds used in the study.
23. Hypersensitivity to any of the study medication excipients or to murine proteins.
24. Concurrent therapy with any other investigational medicinal product within 30 days or 5 times the half-life, which ever is longer, prior to randomization.
For additional exclusion criteria, please refer to section 4.2 of the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PK bioequivalence is defined as AUC and Cmax of the drugs being comparable, i.e. the two-sided 90% confidence interval is within the predefined bioequivalence limits of 0.8 to 1.25. AUC and Cmax will be regarded as co-primary endpoints. |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | Yes |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| 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.8.2.3.1 | Comparator description |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
|
A patient will be considered to have completed the study when all scheduled study
assessments and procedures up to and including Visit 14 (week 52) or, in case of retreatment with another course of study medication, his/ her 26 weeks safety, efficacy and PD follow-up visit, whichever is later, have been concluded. |
|
| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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