A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study of the Efficacy, Safety, and Pharmacokinetics of MLN3897 in Patients with Rheumatoid Arthritis Taking Methotrexate - NA

• Register: EUCTR
• Last refreshed on: 25 November 2019
• Main ID: EUCTR2005-006165-14-GB
• Date of registration: 11/05/2006
• Prospective Registration: Yes
• Primary sponsor: Millennium Pharmaceuticals Inc,
• Public title: A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study of the Efficacy, Safety, and Pharmacokinetics of MLN3897 in Patients with Rheumatoid Arthritis Taking Methotrexate - NA
• Scientific title: A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study of the Efficacy, Safety, and Pharmacokinetics of MLN3897 in Patients with Rheumatoid Arthritis Taking Methotrexate - NA
• Date of first enrolment: 03/08/2006
• Target sample size: 186
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2005-006165-14
• 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
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Czech Republic, Netherlands, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
Each patient must meet all of the following inclusion criteria to be enrolled into the study:
1. Be male or female aged 18 to 70 years (inclusive)
2. Meet the ACR diagnostic criteria for RA (see section 16.1 for details). Patients with rheumatological disorders other than RA, where arthritis may be a prominent feature, such as systemic lupus erythematosus, mixed connective tissue disease, scleroderma, poly-dermatomytosis, Sjogren’s syndrome, etc, will be excluded. Patients with RA who have conditions associated secondarily with RA, such as osteoarthritis of affected joint(s) or sicca syndrome, may be enrolled.
3. Have an RA Global Functional Class of I, II, or III (see section 16.2 for details).
4. Be taking MTX for a minimum of 6 months before screening with a stable, once weekly oral dose of 7.5 to 25 mg for at least 3 months prior to screening and plan to continue that regimen for the duration of the study
5. If taking oral corticosteroids, be taking no more than 10 mg/day of prednisone or its equivalent at a dose that has been unchanged for at least 4 weeks prior to screening
6. If taking NSAIDs, be taking a stable regimen of NSAIDs that has been unchanged for at least 2 weeks prior to screening
7. Be willing and able to comply with the protocol for the duration of the study
8. If female of childbearing potential (less than one year post-menopausal or not surgically sterile [tubal ligation does not qualify]), must not be pregnant or breast-feeding. Confirmation that a female patient is not pregnant must be established by a negative serum ßhCG pregnancy test at screening and a negative urine pregnancy test on Day 1, prior to study drug administration.
9. Female patients of childbearing potential and all male patients must use two complementary methods of contraception while enrolled in the study (e.g. condoms plus diaphragm, condom plus oral contraceptives, etc). All patients should use appropriate contraceptives before and after the study as long as they continue taking the background drug, MTX, in accordance with their physician's advice. Abstinance will be considered as an acceptable method of contraception on a case-by-case basis upon discussion with the Millennium or Covance medical monitor.
10. Have =6 swollen joints and =6 tender joints, plus at least 2 of the following:
• CRP >1.5 mg/dL (measured twice, at least 10 days apart, during screening)
• Morning stiffness with a duration of at least 45 minutes
• ESR =28 mm/h (measured twice, at least 10 days apart, during screening)
11. Provide written informed consent prior to any study-related procedures not conducted as part of normal medical care.

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

Exclusion criteria:
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Be taking any DMARD other than MTX concomitantly or within 1 month prior to study enrollment (Note: If patient had previously been taking leflunomide [Arava®], his/her last dose must have been taken a minimum of 3 months prior to enrollment, or he/she must have undergone washout with cholestyramine). If patient has previously been taking hydroxychloroquine (Plaquenil®) or chloroquine, his/her last dose must have been a minimum of 3 months prior to enrollment.
2. Currently being treated with TNF-antagonists (e.g., etanercept, infliximab, or adalimumab) or any other biologic anti-rheumatic agents. If a patient had previously been treated with etanercept, his/her last dose must have been taken a minimum of 4 weeks prior to enrollment. If a patient had previously been treated with infliximab or adalimumab, his/her last dose must have been taken a minimum of 12 weeks prior to enrollment.
3. Have a tuberculosis (TB) infection of any kind (pulmonary or extra-pulmonary, active or latent), regardless of history of anti-TB treatment. Patients must be screened for TB by customary clinical measures (history, chest X-ray, and skin test as appropriate) at screening. Those patients who appear to be negative for TB must be confirmed free of TB by an ELISPOT blood test.
4. Have received any investigational drug or experimental procedure in the 30 days before Day 1
5. Have received intra-articular or systemic corticosteroid injections within 1month prior to screening
6. Have an acute or chronic active infection or be at high risk of developing an infection due to a compromised immune system (with the exception of patients receiving corticosteroids or MTX as defined in the inclusion criteria)
7. Have a known or suspected human immunodeficiency virus (HIV) infection, or be at high risk of being HIV-infected due to risk factors in medical or social history, including a known history of intravenous illicit drug use.
8. Test positive for hepatitis B or hepatitis C infection at screening
9. Have evidence of an infectious or acute cardiopulmonary process on chest X-ray completed at screening (or on chest X-ray performed within 6 months prior to screening, if available), or any other clinically significant finding that could confound study conduct or results, in the opinion of the investigator.
10. Have baseline QTc duration >450 msec in males or >460 msec in females or have any other abnormality on a 12-lead ECG that is clinically significant in the opinion of the investigator
11. Use medications that prolong QT/QTc interval 30 days prior to study drug administration.
12. History of risk factors for Torsade de Pointes, including but not limited to:
• family history of long QT syndrome
• history of congestive heart failure, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocarditis, or Kawasaki syndrome
• significant electrolyte disorder, especially hypokalemia, hypocalcemia, or hypomagnesemia
• bradycardia, atrioventricular (AV) block
13. Have a creatinine clearance as calculated by the Cockcroft-Gault formula of <30 mL/min (see section 16.3 for details)


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

Health Condition(s) or Problem(s) studied

Rheumatoid Arthritis
MedDRA version: 8.1 Level: LLT Classification code 10039073 Term: Rheumatoid arthritis

Intervention(s)

Product Name: MLN3897
Product Code: N/A
Pharmaceutical Form: Capsule*
INN or Proposed INN: N/A
CAS Number: N/A
Current Sponsor code: MLN3897
Other descriptive name: AVE9897
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10 -
Pharmaceutical form of the placebo: Capsule*
Route of administration of the placebo: Oral use

Trade Name: Methotrexate(MTX) administration is at the discretion of the rheumatologist and no tradename is fixed by the protocol.
Product Name: Methotrexate
Product Code: N/A
Pharmaceutical Form: Tablet
INN or Proposed INN: Methotrexate
CAS Number: N/A
Current Sponsor code: N/A
Other descriptive name: N/A
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 7.5-25

Primary Outcome(s)

Primary end point(s): The primary endpoint for efficay will be the percentage of patients achieving ACR20 at Day 84 in MLN3897 versus placebo-treated patients.

Study Endpoints:-

Efficacy: ACR response criteria assessment, DAS28-CRP assessment, time to
ACR20 response, HAQ-DI, European League Against Rheumatism (EULAR)
response criteria, and duration of morning stiffness will be evaluated.

Safety: AEs, vital signs, clinical laboratory assessments, physical examinations,
vision examinations, ECGs, peripheral blood leukocyte immunophenotyping

Pharmacokinetics: MTX, 7-hydroxy MTX, and MLN3897 PK parameters including
maximum plasma concentration (Cmax), time to reach maximum plasma concentration
(Tmax), and area under the plasma concentration-time curve from 0 to 24 hours
(AUC0-24) will be estimated from plasma concentration data using noncompartmental
methods. Additional PK parameters may be estimated and reported as appropriate. PK parameters for the 2 treatment groups will be compared statistically to assess whether concurrent use of MLN3897 has any effect on MTX and 7-hydroxy MTX PK, and also to determine whether MTX has any effect on the steady-state PK of MLN3897.

Pharmacodynamics: C-C chemokine receptor-1 (CCR1) internalization will be
assessed.

Secondary Objective:

Main Objective: This is the first study of MLN3897 in any disease population. It seeks to establish:
• The ability of MLN3897 to modify the signs and symptoms of rheumatoid arthritis (RA)
• The safety and tolerability of MLN3897 in combination with methotrexate (MTX)
• The pharmacokinetic (PK)/pharmacodynamic (PD) profile of MLN3897 in the RA population, and comparison to that in the healthy volunteer population with respect to CCR1 receptor blockade
• MTX PK and MLN3897 PK and PD when these drugs are used in combination

Secondary ID(s)

C08005

Ethics review

Status: Approved
Approval date:
Contact:

Results

• Results available: Yes
• Date Posted: 01/01/2017
• Date Completed: 12/09/2007
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2005-006165-14/results