| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Rheumatoid Arthritis (RA) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 establish proof of concept and identify the optimal efficacious dose for namilumab in RA by assessing change from baseline in disease activity (DAS28-CRP) at week 12 in patients with an inadequate response to methotrexate (MTX-IR) and in patients with an inadequate response to one TNF-inhibitor (TNF-IR). |
|
| E.2.2 | Secondary objectives of the trial |
To investigate:
- Efficacy assessed as signs and symptoms (ACR20/50/70, ACRn) at week 12 and 24
- Efficacy assessed as disease activity (DAS28-CRP) at week 2, 6 and 24
- Efficacy assessed as pain relief at weeks 2, 12 and 24
- Safety and tolerability over 40 weeks post baseline |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacogenomic Study.
Exploratory investigation of pharmacogenomic samples (DNA and RNA) for drug response, mode of action (MOA), safety, disease, as well as the potential development of diagnostic tests as appropriate. |
|
| E.3 | Principal inclusion criteria |
1. In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements.
2. The subject or, when applicable, the subject's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
3. The subject is male or female and aged 18 years (20 yers in Japan) or older (65 years maximum in Czech Republic) at time of signing the informed consent form.
4. The subject must have adult onset RA as defined by the 2010 ACR/EULAR criteria for the classification of RA for at least 6 months prior to Screening Visit.
5. The subject must have active disease defined as:
a) At least moderately active disease defined by DAS28(CRP)≥3.2 at screening and DAS28(ESR) ≥3.2 at baseline visit [Day 1] and Swollen joint count (SJC) ≥4 (within the 28 joints from DAS28) at both the Screening and baseline [Day 1] Visits.
6. VAS pain >40 mm as measured using the 100 mm study site electronic VAS scale at the Screening Visit and baseline [Day 1] visit.
7. Currently receiving treatment for RA with MTX, and
• Has received MTX on a weekly basis for at least 3 months prior to the Baseline (Day 1) Visit AND
• Has received treatment with 15 mg/week ≤MTX ≤25 mg/week (6
mg/week ≤MTX≤16 mg/week in Japan) at a stable dose via the same route of administration and formulation for at least 8 weeks prior to baseline [Day 1] Visit OR For patients outside of Japan, a stable dose for at least 8 weeks of MTX of ≥7,5 mg/week is acceptable, if the MTX dose has been reduced for reasons of documented intolerance to MTX, eg hepatic or hematological toxicity documented in eCRF, or per local requirement.
8. Willing to continue or initiate treatment with oral folic acid (at least 5 mg/week) or equivalent and be treated during the entire study (mandatory co-medication for MTX treatment).
9. Must have a posterior, anterior (PA) and lateral chest x-ray either obtained within 3 months prior to screening, or recorded during screening.
10. A female subject of childbearing potential who is sexually active with a nonsterilized male partner agrees to routinely use adequate contraception from signing of the informed consent throughout the duration of the study until the end of the safety follow up (18 weeks after last dose), see Section 9.1.15.
11. A male subject who is non-sterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of the informed consent throughout the duration of the study until the end of the safety follow up (18 weeks after last dose), see Section 9.1.15.
12. The subject is able and willing to complete questionnaires at home using an electronic device in an approved language.
13. Either MTX-IR subject per definition on section 6.1 of the protocol or
TNF-IR subject per definition on section 6.1 of the protocol.
|
|
| E.4 | Principal exclusion criteria |
1. Subjects <18 years of age ( <20 years in Japan) or less than the legal adult age in the country of the study site, whichever is higher. Subjects > 65 years of age in Czech Republic.
2. The subject has received any investigational compound within 30 days, or within
5 half lives (whichever is longer) prior to the Screening Visit, or is participating or plans to participate in any other clinical study during this study.
3. The subject has a history of or currently has any inflammatory joint disease other than RA (eg gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy or Lyme disease) or other systemic autoimmune disorder (eg systemic lupus erythematosus (SLE), inflammatory bowel disease, scleroderma, inflammatory myopathy, mixed connective tissue disease or other overlap syndrome).
4. The subject has any major systemic features of RA, eg Felty's syndrome, vasculitis or interstitial fibrosis of the lungs.
5. The subject has a diagnosis of primary fibromyalgia that would make it difficult to appropriately assess RA activity for the purposes of this study.
6. History of juvenile idiopathic arthritis or arthritis onset prior to age 16.
7. The subject is required to take or has taken excluded medications, see Section 7.3.
8. Subjects with any of the following laboratory abnormalities at the screening visit (identified by the central laboratory):
a) Hemoglobin <8.5 g/dL
b) Neutrophils <1500/mm3.
c) Platelet count <75 000 cells/mm3.
d) AST or ALT >1.5 x ULN.
e) Bilirubin (total) >ULN, unless Gilbert's disease has been determined by genetic testing and has been documented.
9. The subject has a history of hypersensitivity or allergies to any of the contents of the formulation (see investigator's brochure]) [13].
10. The subject has any clinically significant illness, including infection requiring antibiotics, within 4 weeks prior to the first dose of study medication, which may influence the outcome of the study.
11. The subject has an underlying condition that predisposes to infections (eg immunodeficiency, poorly controlled diabetes history, splenectomy).
12. Evidence of clinically significant respiratory disease, on the basis of
review the data from subjects' respiratory assessments, including chest
x-ray, lung function tests (forced expiratory volume in one second
[FEV1] and forced vital capacity [FVC]) by spirometry performed at
screening). The subjects must have SpO2 ≥94%, FEV1 and FVC ≥60 %
of predicted values and an MRC Breathlessness Scale score of less than 4
at Screening and at Baseline and no uncontrolled lung disease. A
subject's treatment which has been modified to control lung disease
within 24 weeks prior to screening is exclusionary.
13. History of clinically significant interstitial lung disease (ILD) eg
history of chronic or recurrent pulmonary infection where macrophages
are important for the clearance of the infection eg pneumocystis jiroveci
pneumonia (PJP) formerly known as pneumocystis carinii pneumonia
(PCP), allergic bronchopulmonary aspergillosis (ABPA), nocardia
infections, Actinomyces infection, Japanese and Korean patients will be
tested using Beta glucans test and subjects will be excluded unless the
Beta-Glucans test is negative.
14. Presence or history of active tuberculosis (TB) or latent TB infection, where no anti-TB treatment has been given or where successful completion of an appropriate course of anti- TB therapy cannot be documented.
15. A positive QuantiFERON-TB Gold test and / or evidence of active or latent TB by chest X-ray, not accompanied by initiation of an approved regimen of anti-TB therapy at least 12 months prior to the baseline visit.
16. The subject has a known history of infection with hepatitis B virus, hepatitis C virus, or human immunodeficiency virus, or has serological findings at the Screening Visit which indicate active or latent hepatitis B, hepatitis C or HIV infection.
17. The subject has a history of severe chronic obstructive pulmonary disease (COPD) and / or history of severe COPD exacerbation(s), or a history of asthma with exacerbations requiring hospitalization (including emergency or acute care treatments), within the last 12 months prior to the Screening visit.
18. History of MTX-associated lung toxicity.
19. The subject has a history or evidence of a clinically significant disorder (including but not limited to cardiopulmonary, oncologic, renal, metabolic, hematologic or psychiatric), condition or disease that, in the opinion of the investigator and/or Medical monitor, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
20. Any significant cardiac disease (eg coronary artery disease with
unstable angina, coronary heart failure New York Heart Association [NYHA] Class III and IV, familial long QT syndrome).
See protocol for complete list.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the mean change from baseline in DAS28-CRP at week 12 comparing (superiority) each of the three dose levels of namilumab to placebo. This endpoint will be analyzed controlled for strata combined (TNF IR and MTX IR) and for each stratum separately. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Proportion of subjects with an ACR20/50/70 and ACRn response at weeks 12 and 24
- The change from baseline in DAS28-CRP at weeks 2, 6 and 24
- Proportion of subjects with a reduction of pain, ie, a ≥40% change from baseline as measured using a 100 mm VAS (study site electronic instrument) at weeks 2, 12 and 24 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please see E.5.2 for timepoints corresponding to each secondary
endpoint. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | 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 | 4 |
| 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 | 31 |
| 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 |
| Japan |
| Poland |
| Russian Federation |
| Spain |
| United Kingdom |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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