Dose Finding Study of Namilumab in Combination With Methotrexate in Participants With Moderate to Severe Rheumatoid Arthritis (RA)

NCT02379091 | Completed Phase 2 Results

• 6 other identifiers: M1-1188_202U1111-1151-69312013-002805-7614/SC/1252153300410A0071JapicCTI-152979
• Study Type: interventional
• Target: 108
• Locations: 8 countries
• Sites: 31

Brief Summary

The purpose of this study is to establish proof of concept and identify the optimal efficacious dose for namilumab in RA in patients with an inadequate response to methotrexate (MTX-IR) and in patients with an inadequate response to one tumor necrosis factor (TNF)-inhibitor (TNF-IR).

Conditions

Rheumatoid Arthritis

Keywords

Drug therapy

Outcome Measures

Primary Outcomes (1)

• Change From Baseline in Disease Activity Score 28 C-Reactive Protein (DAS28-CRP) at Week 12

  The DAS28-CRP score is a measure of the participant's disease activity calculated using the tender joint count (TJC) \[28 joints\], swollen joint count (SJC) \[28 joints\], general health: patient's global assessment of disease activity \[visual analog scale: 0=no disease activity to 100=maximum disease activity\] and acute phase response: C-Reactive Protein (CRP) for a total possible score of 0 (best) to approximately 10 (worst). Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A negative change from Baseline indicates improvement. A mixed model repeated measures (MMRM) model with main effects for study site, treatment, visit, and previously failed medication with interactions between visit and treatment, visit and previously failed medication, and visit and baseline value as a covariate and participant as a random effect with an unstructured covariance structure was used for analysis.

  Baseline and Week 12

Secondary Outcomes (6)

• Percentage of Participants Achieving American College of Rheumatology 20% (ACR20), 50% (ACR 50) and 70% (ACR70) Response at Weeks 12 and 24

  Baseline and Weeks 12 and 24

• ACR Numeric (N) Index (ACRn) at Week 12

  Baseline and Week 12

• ACR Numeric (N) Index (ACRn) at Week 24

  Baseline and Week 24

• Change From Baseline in DAS28-CRP at Weeks 2, 6, and 10

  Baseline and Weeks 2, 6 and 10

• Change From Baseline in DAS28-CRP at Week 24

  Baseline and Week 24

Study Arms (4)

Placebo

PLACEBO COMPARATOR

Namilumab placebo-matching, SC injection, once on Days 1, 15, 43, 71 and every 4 weeks for 12 weeks. Participants were assessed for response (a 20% improvement from Baseline in both swollen and tender joint counts). If the participant was a responder, the current treatment continued every 4 weeks up to Week 24. If the participant was a non-responder, the participant entered an open-label period and received namilumab 150 mg/mL, SC injection, every 4 Weeks up to Week 24. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.

Drug: Placebo; Drug: Methotrexate; Drug: Folic/folinic acid

Namilumab 20 mg/mL

EXPERIMENTAL

Namilumab 20 mg/mL, subcutaneous (SC) injection, once on Days 1, 15, 43, 71 and every 4 weeks for 12 Weeks. Participants were assessed for response (a 20% improvement from Baseline in both swollen and tender joint counts). If the participant was a responder, the current treatment continued every 4 weeks up to Week 24. If the participant was a non-responder, the participant entered an open-label period and received namilumab 150 mg/mL, SC injection, every 4 Weeks up to Week 24. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.

Drug: Namilumab; Drug: Methotrexate; Drug: Folic/folinic acid

Namilumab 80 mg/mL

EXPERIMENTAL

Namilumab 80 mg/mL, SC injection, once on Days 1, 15, 43, 71 and every 4 weeks for 12 Weeks. Participants were assessed for response (a 20% improvement from Baseline in both swollen and tender joint counts). If the participant was a responder, the current treatment continued every 4 weeks up to Week 24. If the participant was a non-responder, the participant entered an open-label period and received namilumab 150 mg/mL, SC injection, every 4 Weeks up to Week 24. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.

Drug: Namilumab; Drug: Methotrexate; Drug: Folic/folinic acid

Namilumab 150 mg/mL

EXPERIMENTAL

Namilumab 150 mg/mL, SC injection, once on Days 1, 15, 43, 71 and every 4 weeks for 12 Weeks. Participants were assessed for response (a 20% improvement from Baseline in both swollen and tender joint counts). If the participant was a responder, the current treatment continued every 4 weeks up to Week 24. If the participant was a non-responder, the participant was discontinued from the study. All participants were on a stable dose of methotrexate tablets (15-25 mg weekly) and folic acid (at least 5 mg/week) orally throughout the duration of the study.

Drug: Namilumab; Drug: Methotrexate; Drug: Folic/folinic acid

Interventions

Namilumab DRUG

Namilumab subcutaneous injection

Namilumab 150 mg/mL; Namilumab 20 mg/mL; Namilumab 80 mg/mL

Placebo DRUG

Namilumab placebo-matching subcutaneous injection

Placebo

Methotrexate DRUG

Methotrexate tablets

Namilumab 150 mg/mL; Namilumab 20 mg/mL; Namilumab 80 mg/mL; Placebo

Folic/folinic acid DRUG

Folic/folinic acid tablets

Namilumab 150 mg/mL; Namilumab 20 mg/mL; Namilumab 80 mg/mL; Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
• The participant or, when applicable, the participant'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.
• Is male or female and aged 18 years (20 years in Japan) or older (65 years maximum in Czech Republic) at time of signing the informed consent form.
• Must have adult onset rheumatoid arthritis (RA) as defined by the 2010 American College of Rheumatology (ACR)/ European League against Rheumatism (EULAR) criteria for the classification of RA for at least 6 months prior to Screening Visit.
• Must have active disease defined as:
• a. At least moderately active disease defined by Disease Activity Score 28 based on C-reactive protein \[DAS28(CRP)\] ≥3.2 at screening and Disease Activity Score 28 based on Erythrocyte Sedimentation Rate \[DAS28(ESR)\] ≥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.
• Visual analog scale (VAS) pain \>40 mm as measured using the 100 mm study site electronic VAS scale at the Screening Visit and baseline \[Day 1\] Visits.
• Currently receiving treatment for Rheumatoid Arthritis (RA) with methotrexate (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 participants outside 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, e.g. hepatic or hematological toxicity documented in Electronic case report form (eCRF), or per local requirement.
• 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).
• Must have a posterior, anterior (PA) and lateral chest x-ray obtained within 3 months prior to Screening, or recorded during screening.
• A female participant 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).

You may not qualify if:

• Participants \<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. Participants \>65 years of age in Czech Republic.
• 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.
• 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).
• Has any major systemic features of RA, eg, Felty's syndrome, vasculitis or interstitial fibrosis of the lungs.
• Has a diagnosis of primary fibromyalgia that would make it difficult to appropriately assess RA activity for the purposes of this study.
• History of juvenile idiopathic arthritis or arthritis onset prior to age 16.
• Is required to take or has taken excluded medications.
• Has any of the following laboratory abnormalities at the screening visit (identified by the central laboratory):
• Hemoglobin \<8.5 g/dL;
• Neutrophils \<1500/mm\^3;
• Platelet count \<75000 cells/mm\^3;
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>1.5 x upper limit of normal (ULN);
• Bilirubin (total) \>ULN, unless Gilbert's disease has been determined by genetic testing and has been documented.
• \. Has a history of hypersensitivity or allergies to any of the contents of the formulation.
• \. 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.

Sponsors & Collaborators

• Takeda: lead

Study Sites (31)

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Plovdiv, Bulgaria

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Rousse, Bulgaria

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Sofia, Bulgaria

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České Budějovice, Czechia

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Prague, Czechia

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Uherské Hradiště, Czechia

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Zlín, Czechia

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Fukuoka, Fukuoka, Japan

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Iizuka-shi, Fukuoka, Japan

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Kitakyusyu-shi, Fukuoka, Japan

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Sapporo, Hokkaido, Japan

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Takarazuka-shi, Hyōgo, Japan

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Morioka, Iwate, Japan

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Kawasaki-shi, Kanagawa, Japan

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Kumamoto, Kumamoto, Japan

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Miyagi-gun, Miyagi, Japan

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Nagasaki, Nagasaki, Japan

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Sasebo-shi, Nagasaki, Japan

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Hamamatsu, Shizuoka, Japan

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Nishimuro-gun, Wakayama, Japan

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Bydgoszcz, Poland

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Torun, Poland

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Kazan', Russia

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Saint Petersburg, Russia

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Ulyanovsk, Russia

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Voronezh, Russia

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Seoul, Gyeonggi-do, South Korea

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A Coruña, Spain

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Seville, Spain

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Romford, Essex, United Kingdom

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London, Greater London, United Kingdom

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Related Publications (1)

• Taylor PC, Saurigny D, Vencovsky J, Takeuchi T, Nakamura T, Matsievskaia G, Hunt B, Wagner T, Souberbielle B; NEXUS Study Group. Efficacy and safety of namilumab, a human monoclonal antibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) ligand in patients with rheumatoid arthritis (RA) with either an inadequate response to background methotrexate therapy or an inadequate response or intolerance to an anti-TNF (tumour necrosis factor) biologic therapy: a randomized, controlled trial. Arthritis Res Ther. 2019 Apr 18;21(1):101. doi: 10.1186/s13075-019-1879-x.

  PMID: 30999929 DERIVED

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

namilumab; Methotrexate; Leucovorin

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Coenzymes; Enzymes and Coenzymes

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Director Clinical Science

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 28, 2014
• First Posted: March 4, 2015
• Study Start: December 17, 2014
• Primary Completion: May 11, 2016
• Study Completion: December 5, 2016
• Last Updated: September 14, 2018
• Results First Posted: September 14, 2018

Record last verified: 2018-08

Locations

RU (4); PL (2); JP (13); KR (1); CZ (4); ES (2); BU (3); GB (2)