A 24-week placebo-controlled clinical study to evaluate the adequate dose, efficacy and safety of 3 doses of namilumab combined with methotrexate in subjects with moderate to severe rheumatoid arthritis followed by a 48-week active extension study.

Phase 1

Conditions: Rheumatoid Arthritis (RA)
MedDRA version: 17.0Level: PTClassification code 10039073Term: Rheumatoid arthritisSystem Organ Class: 10028395 - Musculoskeletal and connective tissue disorders
Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Registration Number: EUCTR2013-002805-76-ES

Lead Sponsor: Takeda Development Centre Europe Ltd.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 324

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 or older at time of signing the informed consent form.
4. The subject must have adult onset RA as defined by the 2010 ACR 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) Swollen joint count (SJC) ?4 and tender joint count (TJC) ?4 (referred to the 28 joint-count system) at both the Screening and Baseline Visits.
b) C-reactive protein (hs-CRP) ?4.3 mg/L at the Screening Visit.
6. VAS pain > 40 mm as measured using the 100 mm study site electronic VAS scale at the Screening Visit
7. Currently receiving treatment for RA with MTX, and
- Has received weekly MTX for at least 3 months prior to the Screening Visit AND
- Has received treatment with MTX ?15-25 mg/week at a stable dose via the same route of administration and formulation for at least 8 weeks prior to Baseline Visit OR
- 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, e.g. hepatic or hematological toxicity, 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 obtained within 3 months prior to Screening, or recorded at the Baseline visit, without any signs of pulmonary disease.
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).
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).
12. The subject is able and willing to complete questionnaires at home using an electronic device in an approved language.
13. MTX-IR subjects: The subject has shown an inadequate response (insufficient initial or loss of response and/or intolerance) to MTX.
14. TNF-IR subjects: The subject has shown an inadequate response (insufficient initial or loss of response and/or intolerance) to MTX plus TNF inhibitor for at least 12 weeks. Subjects should not have received more than one TNF inhibitor.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 260
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 64

Exclusion Criteria

1. Subjects <18 years of age or less than the legal adult age in the country of the study site, whichever is higher.
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 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) White blood cells <3000/mm3.
c) Neutrophils <1500/mm3.
d) Platelet count <75 000 cells/mm3.
e) AST or ALT >1.5 x ULN.
f) 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 namilumab or any of the contents of the formulation (see investigator?s brochure).
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. 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 carinii pneumonia (PCP), allergic bronchopulmonary aspergillosis (ABPA), nocardia infections, Actinomyces infection.
13. 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.
14. 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.
15. 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.
16. The subject has a clinically relevant decrease in SpO2 <94% saturation at Screening - as measured by pulse oximetry at rest.
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 l

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: 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).;Secondary Objective: To investigate:<br>- Efficacy assessed as signs and symptoms (ACR20/50/70) at week 12 and 24<br>- Efficacy assessed as disease activity (DAS28-CRP) at week 2, 6 and 24<br>- Efficacy assessed as pain relief at weeks 2, 12 and 24<br>- Safety and tolerability over 88 weeks post baseline;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.;Timepoint(s) of evaluation of this end point: Week 12

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): - Proportion of subjects with an ACR20/50/70 response at weeks 12 and 24<br>- The change from baseline in DAS28-CRP at weeks 2, 6 and 24<br>- 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;Timepoint(s) of evaluation of this end point: Please see E.5.2 for timepoints corresponding to each secondary<br>endpoint.