E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Rheumatoid Arthritis (RA) |
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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 | 18.0 |
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 |
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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 |
To explore the effect on structural damage image markers measured as change from Baseline in synovitis, erosion, and bone marrow edema (osteitis), in metacarpophalangeal (MCP) joints and wrist at Week 24 on magnetic resonance imaging (MRI) using the RA-MRI scoring (RAMRIS) Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) score. |
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E.2.2 | Secondary objectives of the trial |
• To explore the effect on structural damage imaging markers measured as change from Baseline in DCE-MRI parameters at Week 24 on MCP joints and wrist using the DCE-MRI.
• To explore other clinical efficacy outcomes of namilumab in RA such as Disease Activity Score 28 based on C-reactive protein (DAS28-CRP) and American College of Rheumatology (ACR) 20, 50, and 70 criteria.
• To explore the speed of onset of efficacy measured as effect on synovitis, bone marrow edema, erosion (RAMRIS), and synovial perfusion using static and DCE-MRI at Weeks 6 and 12.
• To evaluate the safety and tolerability of namilumab/MTX coadministration. |
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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 research Study
To perform exploratory investigation of pharmacogenomic samples (DNA and RNA) for drug response, mode of action, safety, disease, as well as the potential development of diagnostic tests as appropriate.
Specific purposes of this study include:
• Identifying genetic reasons why certain people respond differently to namilumab.
• Finding out more information about how namilumab works.
• Generating information needed for research, development, and regulatory approval of tests to predict response to namilumab.
• Identifying variations in genes related to the biological target of namilumab.. |
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E.3 | Principal inclusion criteria |
Subject eligibility is determined according to the following criteria prior to entry into the study:
The subject is male or female and aged 18 years, or above (<65 years of age in Czech Republic).
The subject is diagnosed with adult onset RA as defined by the 2010 ACR/EULAR criteria for the classification of RA within 6 months prior to Screening Visit. Subjects with onset of signs and symptoms more than 12 months prior to Screening will not be allowed into the study.
The subject has active disease defined as:
a) Swollen joint count (SJC) ≥ 4 and tender joint count (TJC) ≥ 4 (referred to the 28 joint-count system) at Screening and Baseline Visit
and
b) C-reactive protein (CRP) ≥4.3 mg/L at Screening Visit and erythrocyte sedimentation rate (ESR) ≥28 mm/hr at Baseline Visit.
and
c) Imaging (US power doppler) evidence of moderate to severe inflammation of at least 1 MCP joint of the dominant hand and/or 1 joint of the dominant wrist at Screening and Baseline Visit.
A male subject who is nonsterilized* and sexually active with a female partner of childbearing potential* agrees to use adequate contraception* from signing of informed consent throughout the duration of the study until the end of the safety follow up (20 weeks after last dose).
A female subject of childbearing potential* who is sexually active with a nonsterilized* male partner agrees to use routinely adequate contraception* from signing of informed consent throughout the duration of the study until the end of the safety follow up (20 weeks after last dose).
The subject is receiving current treatment with MTX for RA:
• Received weekly MTX for at least 3 months prior to the Screening Visit, AND
• Received treatment with MTX ≥ 15 mg/week but ≤ 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.
The subject is willing to continue or initiate treatment with oral folic acid (at least 5 mg/week) or equivalent and be treated during the entire trial (mandatory comedication for MTX treatment).
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E.4 | Principal exclusion criteria |
Subjects <18 years of age 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.
The subject has received biologic DMARDs for the treatment of RA.
The subject has a history of or currently 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, inflammatory bowel disease, scleroderma, inflammatory myopathy, mixed connective tissue disease, or other overlap syndrome).
The subject has any major systemic features of RA, for example, Felty’s syndrome, vasculitis, or interstitial fibrosis of the lungs.
The subject has a history of juvenile idiopathic arthritis or RA onset prior to age 16 years.
The subject has an underlying condition that predisposes to infections (eg, immunodeficiency, poorly controlled diabetes history, splenectomy).
The subject has a history of clinically significant interstitial lung disease, for example, history of chronic or recurrent pulmonary infection where macrophages are important for the clearance of the infection, for example, pneumocystis jiroveci pneumonia (PJP), formerly known as pneumocystis carinii pneumonia (PCP), allergic bronchopulmonary aspergillosis, nocardia infections, Actinomyces infection.
The subject has a positive QuantiFERON-TB Gold test and/or evidence of active or latent TB by chest x-ray at Screening Visit, not accompanied by initiation of an approved regimen of anti-TB therapy at least 12 months prior to the Baseline Visit.
The subject has a known history of infection with hepatitis B virus, hepatitis C virus, or human immunodeficiency virus (HIV), or has serological findings at the Screening Visit which indicate active or latent hepatitis B, hepatitis C or HIV infection.
The subject has a clinically relevant decrease in lung function at Screening, as defined by an oxygen saturation as measured by pulse oximetry (SpO2) <94% at rest.
The subject has evidence of clinically significant respiratory disease on the basis of review the data from subjects’ respiratory assessments including chest x-ray, lung function test (forced expiratory volume in 1 second [FEV1] and forced vital capacity [FVC]) by spirometry performed at Screening). To be eligible for the study, subjects must have SpO2 ≥94%, FEV1 and/or FVC ≥60 % of predicted values at Screening or at Baseline and no uncontrolled lung disease. A subject’s treatment that has been modified to control lung disease within 24 weeks prior to Screening is exclusionary.
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, within the last 12 months prior to the Screening Visit.
The subject has an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73m2.
The subjects 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 Takeda physician, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
The subject has any significant cardiac disease (eg, coronary artery disease with 7. unstable angina, coronary heart failure New York Heart Association Class III and IV, familial long QT syndrome).
The subject has a history of cancer within the last 10 years except for basal cell or squamous cell carcinomas of the skin or in situ carcinoma of the cervix treated and considered cured.
The subject has a severe psychiatric or neurological disorder.
If female, the subject is pregnant or lactating or intends to become pregnant before, during, or within 20 weeks after the last treatment visit; or intends to donate ova during such time periods.
If male, the subject intends to donate sperm during or within 20 weeks after the last treatment visit.
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E.5 End points |
E.5.1 | Primary end point(s) |
• Change from Baseline in synovitis, erosion and bone marrow edema (osteitis), on MRI of the MCP and wrist using the RAMRIS OMERACT at Week 24. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Vascular perfusion of the synovium measured as a change from Baseline in DCE-MRI parameters at Week 24. The ability to induce synovial remission (absence of synovial inflammation) will be assessed at Weeks 6 and 12 using static (RAMRIS OMERACT synovitis score) and DCE-MRI parameters.
• Proportion of subjects who achieved DAS28-CRP (<2.6) remission at Week 24.
• Proportion of subjects who achieved DAS28-CRP (<3.2) low disease activity by at Week 24.
• Proportion of subjects who achieved ACR 20, 50, and 70 at Week 24.
• Clinical disease activity improvement measured as decrease in DAS28-CRP from Baseline at all applicable postbaseline visits. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please see E.5.2 for timepoints corresponding to each secondary
endpoint. |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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.8.2.4 | 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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
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 |
Czech Republic |
Estonia |
Russian Federation |
Spain |
United Kingdom |
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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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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 | 3 |
E.8.9.1 | In the Member State concerned days | 11 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 11 |