E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10003268 |
E.1.2 | Term | Arthritis rheumatoid |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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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 |
Safety and tolerability of multiple doses of MOR103 in patients with active rheumatoid arthritis. |
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E.2.2 | Secondary objectives of the trial |
1. Signs of efficacy
2. Pharmcokinetics of multiple doses
3. Potential immunogenicity |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Outpatients > 18 years of age
2. BMI between 19.0 and 35.0 kg/m2 (extremes included).
3. Diagnosis of rheumatoid arthritis (RA), according to the revised criteria of the American College of Rheumatology (ACR), 1987.
4. Active disease at screening defined as:
- At least 3 swollen and 3 tender joints with at least 1 swollen joint involvement of the hand excluding the proximal interphalangeal (PIP) joint (using the DAS28 joint count).
- Elevated CRP level > 5 mg/l (in RF and anti-CCP sero-negative patients) or > 2 mg/l (in RF and/or anti-CCP sero-positive patients).
- disease activity score "DAS28" </= 5.1
5. Functional status class I-III classified according to ACR 1991 revised criteria.
6. Concomitant use of the following RA treatments is allowed:
- NSAIDs (with a stable dosage for at least 2 weeks prior to randomization)
- Oral corticosteroids (maximum of 10 mg of prednisolone or equivalent per day with a stable dosage for at least 4 weeks prior to randomization)
- DMARDS: Concomitant DMARD treatment for at least 3 months with stable dosage for at least 4 weeks prior to randomization. Allowable treatments include:
• Methotrexate (maximum of 25 mg/week) either oral, s.c., or i.v. Change of the administered formulation is allowed but not within 4 weeks prior to randomization.
• Leflunomide (maximum 20 mg/day)
• Antimalarials (hydroxychloroquine: maximum 400 mg/day, chloroquine: maximum 500 mg/day, quinacrine [mepacrine]: maximum 100 mg/day, compounded antimalarial drugs in which no individual component exceeds the maximum dose mentioned)
• Sulfasalazine (maximum: 3 g/day)
• A combination of any two of these DMARDs. Combination of methotrexate and leflunomide is not allowed due to liver toxicity.
7. Male patients must be willing to use an effective contraception method during the study and for at least 2 months following the completion/discontinuation of the study.
8. Negative purified protein derivative (PPD) tuberculin skin test reaction or a negative tuberculosis enzyme-linked immuno sorbent assay (ELISA) test, according to the local standard practices.
9. Possibility to evaluate pulmonary status for (latent) tuberculosis or other pulmonary infections by a chest x-ray not older than 3 month prior to screening.
10. Provide written informed consent and be able to comply with the patient’s assessment questionnaires.
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E.4 | Principal exclusion criteria |
1. Previous treatment with immunosuppressive agents and non-compliance with min wash-out periods
required prior to first dosing of study drug: 1m for etanercerpt, anakinra, ciclosporin, MMF, tacrolimus; 2m for adalimumab and certolizumab and 3m for infliximab, abatacept, golimumab and tocilizumab
2. Previous treatment with rituximab within 9m prior to first dose of study drug
3. History of therapy with cell depleting agent(s) incl. IMPs (Campath, anti-CD3, -CD4, -CD5, -CD11a, -CD19, -CD22, -Blys/BAFF)
4. Any therapy with human, chimeric or murine Abs (except for above) or any experimental therapy within 3m or 5 half-lives (whichever is longer) prior to screening
5. In case patient has been discontinued from other DMARDs due to toxicity or lack of efficacy, time since last dose at least 1m and effects of that agent should have dissipated as indicated by recognized duration of effect (e.g. hydroxychloroquine, sulfasalazine), or standard wash-out procedure (cholestyramine for leflunomide)
6. Patients who received systemic steroids, epidural steroid injections, intra-articular or systemic corticosteroid injections within 4w before screening
7. Known allergy to murine, chimeric or human antibodies
8. Body weight >150 kg
9. History of anaphylaxis/severe anaphylactic reaction/shock to any drug administered parentarally & suspected allergies to protein based therapeutics. In all other cases, subjects should be pre-treated with anti-histamines and H-1 receptor inhibitors
10. Pregnant/breast-feeding women & pre-menopausal women not receiving methotrexate or leflunomide a/o not willing to use at least 2 methods of effective contraception during and for a specific period after studyparticipation
11. Any findings indicative of tuberculosis or history of tuberculosis or a positive PPD- or tuberculosis ELISA test at screening
12. Presence or history of major chronic inflammatory autoimmune diseases
13. Positive hepatitis B surface antigen (HBs-Ag)test, hepatitis C (anti HCV antibody) test a/o confirmed HIV infection
14. Any type of infection requiring use of antibiotics & which does not resolve completely within 3w before sudy drug administration
15. History of recurrent pulmonary infections , recurrent abscesses, intra-abdominal infections or chronic infections
16. Procalcitonin serum level >0.5 ng/ml at screening
17. IgG level below lower limit of reference range at screening
18. History of reactivation of Epstein Barr (EB) viral infection or >1,000 EBV genome equivalent/10E6 cells in peripheral blood mononuclear cell preparations
19. History of malignancy with exception of basal cell/squamous cell carcinoma of skin/carcinoma of cervix
successfully treated within the last 3y
20.Significant cardiac disease on ECG
21. History of severe pulmonary disease
22. WBC <3.0x10E9/l, neutrophils <1.5x10E9/l, haemoglobin <10.0 g/dl, hematocrit <30%, platelets
<100x10E9/l or absolute lymphocyte count </=0.5x10E9/l at screening
23. Any signs of excretory hepatic (tot bilirubin >/= 1.5xULN) or renal insufficiency (creatinine clr/EGFR
<50ml/min) at screening.
24. Abnormal AST or ALT levels, i.e., >2x upper limit of reference range at screening
25. Live vaccines within 8w of study drug administration
26. Presence of contra-indications to MRI or contrast agents
27. Any condition/laboratory findings/medical history/pre-study assessments, that in the opinion of the
investigator constitute a risk or a contra-indication for the patient's participation in the study or that could
interfere with study objectives, conduct or evaluation
28. Participation in any interventional clinical trial with an IMP within 6m before start of study (or within 5 halflives of the IMP before study D1, whichever is longer)
29. Any neurological, psychiatric, vascular or systemic disorder which could affect any of the efficacy
assessments
30. Active alcohol/drug abuse or history of within 24w before baseline
31. History of deep space tissue infection within 48w of baseline
32. Uncontrolled disease states where flares are treated with oral or parenteral corticosteroids
For full list please refer to protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety and tolerability of MOR103 as assessed by the safety measures. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At end of each cohort and at the end of study |
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E.5.2 | Secondary end point(s) |
1. Change in the DAS28 score from baseline to Days 29 and 57
2. Proportion of patients achieving ACR20, ACR50, and ACR70 response on Day 29 and Day 57.
3. EULAR28 responder index on Day 29 and Day 57 (compared to baseline).
5. Change in individual components of the ACR core set of measures from baseline to Day 29 and Day 57.
5. Change from screening to Day 29 and Day 57 of the joint scoring on MRI according to the Rheumatoid Arthritis MRI Scoring system (RAMRIS) for synovitis and bone edema.
6. Immunogenicity of MOR103 (anti-MOR103 antibodies)
7. Pharmacokinetics (PK) endpoint: MOR103 serum concentrations and PK parameters (trough levels after each dose, exposure and terminal elimination after the last dose, accumulation and dose proportionality based on estimated AUCtau)
8. Health Assessment Questionnaire (HAQ), SF36, FACIT-F questionaires
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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) | 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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 |
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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
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Last visit of last subject undergoing the trial |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |