A 12-WEEK, PHASE 2, RANDOMIZED, DOUBLE-BLIND, MULTICENTER, PLACEBO CONTROLLED STUDY TO INVESTIGATE THE SAFETY, PHARMACOKINETICS AND EFFICACY OF ARRY-438162, ADMINISTERED ORALLY DAILY IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS INCOMPLETELY RESPONSIVE TO METHOTREXATE

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2007-007859-14-PL
• Date of registration: 09/05/2008
• Prospective Registration: Yes
• Primary sponsor: Array BioPharma Inc.
• Public title: A 12-WEEK, PHASE 2, RANDOMIZED, DOUBLE-BLIND, MULTICENTER, PLACEBO CONTROLLED STUDY TO INVESTIGATE THE SAFETY, PHARMACOKINETICS AND EFFICACY OF ARRY-438162, ADMINISTERED ORALLY DAILY IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS INCOMPLETELY RESPONSIVE TO METHOTREXATE
• Scientific title: A 12-WEEK, PHASE 2, RANDOMIZED, DOUBLE-BLIND, MULTICENTER, PLACEBO CONTROLLED STUDY TO INVESTIGATE THE SAFETY, PHARMACOKINETICS AND EFFICACY OF ARRY-438162, ADMINISTERED ORALLY DAILY IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS INCOMPLETELY RESPONSIVE TO METHOTREXATE
• Date of first enrolment: 11/06/2008
• Target sample size: 200
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2007-007859-14
• 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

Countries of recruitment

Hungary, Poland

Key inclusion & exclusion criteria

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 con
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,

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

Health Condition(s) or Problem(s) studied

Active Rheumatoid Arthritis incompletely responsive to methotrexate
MedDRA version: 9.1 Level: LLT Classification code 10039073 Term: Rheumatoid arthritis

Intervention(s)

Product Name: ARRY-438162
Pharmaceutical Form: Film-coated tablet
Current Sponsor code: ARRY-438162
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: ARRY-438162
Pharmaceutical Form: Film-coated tablet
Current Sponsor code: ARRY-438162
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Primary end point(s): • American College of Rheumatology 20% (ACR20) response rate at Week 12

Secondary Objective: • 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.

Main Objective: • 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.

Secondary ID(s)

2007-007859-14-HU

ARRAY-162-201