| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
|
| 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 |
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 |
|
| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 βhCG 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.
|
|
| E.4 | Principal 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)
14. Have AST, ALT, or total bilirubin values >1.5 x ULN)
15. Have a creatine phosphokinase (CPK) value ≥1.5 x ULN
16. Be diagnosed with any type of arthritis prior to the age of 16 years
17. Have a rheumatological diagnosis other than RA
18. Use of a potent CYP3A4 inhibitor drugs or foodstuffs (especially grapefruit/grapefruit juice) or any herbal supplements within 14 days prior to Day 1. (For reference list see section 16.6)
19. Have a known history of cancer, except for a distant history of carcinoma in situ of the cervix or adequately treated basal cell carcinoma of the skin (≥5 years prior to study entry)
20. Have other serious concomitant disorders incompatible with the study (exceptions must be discussed and confirmed in writing with the Millennium Pharmaceuticals, Inc. [Millennium] medical monitor or designated delegate)
21. Have an acute illness which, in the opinion of the investigator, could pose a threat or harm to the patient
22. Have any planned surgeries or procedures during the course of the study
23. Have any other factor that, in the opinion of the investigator, could confound the conduct or interpretation of the study
24. Have received any live, attenuated vaccinations within 1 month prior to study drug administration. Note: Patients who receive study drug should not receive any type of these vaccinations within 1 month after receiving their final dose.
25. Admit to illicit drug use within 6 months of enrollment, or participation in a drug or alcohol detoxification program within the past 5 years
26. Currently consume >1 standard units/day of alcohol or admit to alcohol abuse. A standard unit of alcohol is defined as 360 mL beer, 30 mL of 80 proof alcohol, or one 180-mL glass of wine.
|
|
| E.5 End points |
| E.5.1 | 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. |
|
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
| |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 1 |
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