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.

• Register: EUCTR
• Last refreshed on: 2 October 2017
• Main ID: EUCTR2013-002805-76-CZ
• Date of registration: 17/07/2014
• Prospective Registration: Yes
• Primary sponsor: Takeda Development Centre Europe Ltd.
• Public title: 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.
• Scientific title: A 24-week randomized, double-blind, placebo-controlled, phase 2 dose finding study to evaluate the efficacy and safety of 3 doses of namilumab (20 mg, 80 mg and 150 mg) in combination with methotrexate (MTX) in subjects with moderate to severe rheumatoid arthritis (RA) NEXUS.
• Date of first enrolment: 11/09/2014
• Target sample size: 108
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-002805-76
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 4
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Bulgaria, Czech Republic, Japan, Poland, Russian Federation, Spain, United Kingdom

Contacts

• Name: Clinical Study Manager
• Affiliation: Takeda Development Centre Europe Ltd.

• Name: Clinical Study Manager
• Affiliation: Takeda Development Centre Europe Ltd.

Key inclusion & exclusion criteria

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 years 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 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.
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 101
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 7

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 QuantiFE

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Rheumatoid Arthritis (RA)
MedDRA version: 19.0 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 - Musculoskeletal and connective tissue disorders

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Intervention(s)

Product Name: Namilumab
Product Code: MT203
Pharmaceutical Form: Solution for injection
INN or Proposed INN: namilumab
CAS Number: 1206681-39-1
Current Sponsor code: MT203
Other descriptive name: NAMILUMAB
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 150-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Product Name: Namilumab
Product Code: MT203
Pharmaceutical Form: Solution for injection
INN or Proposed INN: namilumab
CAS Number: 1206681-39-1
Current Sponsor code: MT203
Other descriptive name: NAMILUMAB
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 80-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Product Name: Namilumab
Product Code: MT203
Pharmaceutical Form: Solution for injection
INN or Proposed INN: namilumab
CAS Number: 1206681-39-1
Current Sponsor code: MT203
Other descriptive name: NAMILUMAB
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Week 12

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.

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:
- 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

Secondary Outcome(s)

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

Timepoint(s) of evaluation of this end point: Please see E.5.2 for timepoints corresponding to each secondary
endpoint.

Secondary ID(s)

M1-1188_202

Source(s) of Monetary Support

Takeda Development Centre Europe Ltd.

Takeda Development Center Americas, Inc.