| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Active Rheumatoid Arthritis incompletely responsive to methotrexate |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
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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 compare the efficacy of 3 dose levels of ARRY-438162 (10 mg BID, 40 mg QD, and 20 mg BID) versus placebo, administered over 12 weeks for the treatment of the signs and symptoms of patients with RA.
• To determine the American College of Rheumatology 20% (ACR20) best response rate at Week 12 of patients treated with any well-tolerated dose.
• To evaluate the safety and tolerability of ARRY-438162 in patients with active RA on stable doses of methotrexate (≥10 mg ≤ 25 mg) for ≥ 6 weeks.
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the pharmacokinetic profiles of multiple doses of ARRY-438162 administered for 12 weeks to patients with active RA;
• To evaluate the dose- and concentration-response of ARRY-438162 against measures of disease activity through 12 weeks of treatment.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the trial:
1. Has provided written informed consent and is willing to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures;
2. Male or female ≥18 years of age;
3. Has received a stable dose of methotrexate (≥10 mg ≤ 25 mg weekly) for ≥ 6 weeks prior to screening and is willing to continue on this regimen for duration of study;
4. Has never received biological agents [Enbrel® (etanercept), Remicade® (infliximab), Humira® (adalimumab), Kineret® (anakinra), Orencia® (abatacept), Rituxan (rituximab)] for the treatment of RA and agree not to do so for duration of study;
5. Has been diagnosed with RA prior to the Screening visit based upon the American College of Rheumatology (ACR) 1987 Revised Criteria, fulfilling at least 4 of the following 7 criteria. The first 4 criteria must have been present for at least 6 weeks:
a. Morning stiffness in and around any joint for more than 1 hour;
b. Soft tissue swelling of 3 or more joint areas;
c. Swelling of the proximal interphalangeal (PIP), metacarpophalangeal (MCP), or wrist joints;
d. Symmetrical joint swelling;
e. Rheumatoid nodules;
f. Serum rheumatoid factor positive;
g. Radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints.
6. The diagnosis of RA must have been present for at least 3 months.
7. Has a minimum current level of disease activity characterized by:
a. ≥ 6 tender joints: Tender Joint Count (TJC) (28-joint count), AND
b. ≥ 6 swollen joints: Swollen Joint Count (SJC) (28-joint count), AND
c. C-reactive protein (CRP) ≥1.0 mg/dL (10 mg/L)
8. Meets the ACR 1991 Revised Criteria for Global Functional Status in RA, Class I, II, or III (Appendix 2);
9. Has completed a 4-week washout period, unless otherwise indicated (calculated from first dose of study drug) if treated with any of the following therapies:
a. DMARDs—leflunomide (Arava) (See additional washout information for leflunomide in Section 6.7), auranofin (oral gold), injectable gold (aurothioglucose or aurothiomalate), sulfasalazine, or d-penicillamine;
b. Immunosuppressive/Immunomodulatory therapies—azathioprine, cyclosporine, minocycline, and PROSORBA® device/column;
c. Any experimental therapy for RA (within or outside a clinical trial setting) within 8 weeks of screening;
d. Participation in another clinical trial within 30 days of screening;
e. Other—herbal medications, immunization with any live virus vaccination (e.g., FluMist.), intra-articular, intramuscular, or intravenous corticosteroids;
f. Vitamin D supplements > 800 IU per day.
10. Patients may continue on stable background therapy for RA (Doses should be stable for at least 6 weeks prior to first dose of study drug and remain unchanged during the 12-week Treatment Period, unless patient stops due to documented disease improvement, with Sponsor approval), if it includes:
a. Non-investigational NSAIDs or COX-2 inhibitors;
b. Low-dose oral corticosteroids (≤10 mg prednisone or equivalent per day);
c. Opioid analgesics (≤ 30 mg oral morphine or equivalent per day – Appendix 6);
d. Acetaminophen (paracetamol) ≤ 2600 mg/day (2.6 g/day)
e. Aspirin if taken for nonarthritic reasons, ≤ 325 mg/day;
f. Antimalarials (hydroxychloroquine or chloroquine).
11. Has received a stable dose of folate (≥ 5 mg weekly) for ≥ 6 weeks and is willing to continue in this regimen for duration of study;
12. If female, has met either of criterion “a.” or “b.” below:
a. If of nonchildbearing potential, has met one of the following criteria:
i. Amenorrheic for at least 2 years with an FSH in the postmenopausal range, or
ii. Has had a hysterectomy and/or bilateral oophorectomy at least 8 weeks prior to screening;
All other female patients (including those with tubal ligation) will be considered of childbearing potential.
b. If of childbearing potential, must be willing to use the acceptable methods of contraception and abide by the timelines of each method as outlined in Section 5.3.1;
13. If male, must be willing to use the acceptable methods of contraception and abide by the timelines as outlined in Section 5.3.1;
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| E.4 | Principal exclusion criteria |
Patients presenting with any of the following will not be included in the trial:
1. Patients with a diagnosis of any other inflammatory or non-inflammatory arthritis (e.g. spondyloarthropathies; fibromyalgia, psoriatic arthritis, crystal proven gout) that may interfere with disease activity assessments or clinically apparent osteoarthritis which would affect subsequent efficacy measures;
2. Patients with a history of:
a. Severe, progressive, and/or uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurological disease or severe systemic involvement with rheumatoid arthritis including rheumatoid vasculitis, Felty’s syndrome or pulmonary fibrosis within 6 months of first dose of study drug;
b. Significant associated cardiac disease:, myocardial infarction within 6 months of screening, unstable angina, congestive heart failure (New York Heart Association (NYHA) Class III-IV), known arrhythmias of ventricular etiology, unexplained syncope or syncope/seizures related to arrhythmia (Appendix 4);
c. Chronic or recent serious or life-threatening infection within 6 months of first dose (defined as requiring parenteral antibiotics or hospitalization);
d. Active tuberculosis or history of tuberculosis without documented curative treatment and/or positive tuberculin reaction to PPD (Purified Protein Derivative) without known vaccination with the bacillus Calmette-Guerin vaccine (BCG). Prior history of BCG with clearly defined scar, are exempt from PPD test and chest X-ray. Refer to Section 9.2.5. for further clarification;
e. A positive T-SPOT™TB, where used or comparable diagnostic test;
f. Significant trauma or major surgery within 8 weeks of first dose of study medication;
g. History of alcohol abuse with less than 12 months of sobriety; or any drug abuse within 3 years of screening visit;
h. Cancer, which has been in remission for ≤ 5 years excluding patients with adequately treated or excised nonmetastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.
3. Patients presenting with:
a. Any condition possibly affecting oral drug absorption (e.g. gastrectomy, any malabsorption syndrome or clinically significant diabetic gastroenteropathy);
b. Any clinically significant skin lesions as described in CTCAE Version 3.0 (Appendix 3);
c. A documented body temperature >37°C (98.6°F) at Baseline;
d. An infection with human immunodeficiency virus (HIV) or hepatitis B or C;
e. Any clinically significant active infection including herpes lesions;
f. A confirmed mean of the Screening triplicate QTc interval >450 ms;
4. Evidence of organ dysfunction or hematopoietic disorder based on any of the following assessments:
a. Hgb ≤10 g/dL, Hct ≤ 32%;
b. Absolute WBC count ≤ 3.0 × 109/L (<3000/mm3);
c. Neutrophil count ≤ 1.2 × 109/L (<1200/mm3);
d. Platelet count ≤ 100 × 109/L (<100,000/mm3);
e. AST (aspartate aminotransaminase), ALT (alanine aminotransaminase) ≥ 1.5 ULN;
f. Total bilirubin ≥ 1.5 × ULN;
g. Alkaline phosphatase ≥ 1.5 × ULN;
h. Albumin ≤ 3.5 g/dL or 35 g/L in the absence of liver disease;
i. Serum creatinine ≥ 1.2 x ULN;
j. Hyperphosphatemia or hypercalcemia [>1x the upper limit of normal (ULN)];
k. TSH ≥ 1.2 ULN unless clinically euthyroid and receiving a stable dose of thryroxine
5. Patients requiring prohibited concomitant medications including CYP3A inhibitors, CYP3A inducers, DMARDs, and BRMs, while on study (Appendix 5);
6. Pregnant or breastfeeding patients. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| • American College of Rheumatology 20% (ACR20) response rate at Week 12 |
|
| 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 | No |
| 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 | 20 |
| 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 |
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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
| |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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