| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Active Rheumatoid Arthritis |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | PT |
| 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 |
The Primary Objectives of this study are to determine the:
• Safety and tolerability of 3 months of dosing of INCB028050 in patients with active rheumatoid arthritis who have had inadequate response to any DMARD therapy.
• Efficacy of INCB028050 at 3 months in patients with active rheumatoid arthritis who have had inadequate response to any DMARD therapy. |
|
| E.2.2 | Secondary objectives of the trial |
The Secondary Objectives of this study are to determine the:
• Safety and tolerability of 6 months of dosing of INCB028050 in patients with active rheumatoid arthritis who have had inadequate response to any DMARD therapy.
• Efficacy of INCB028050 at 6 months in patients with active rheumatoid arthritis who have had inadequate response to any DMARD therapy.
• Population pharmacokinetics (PK) of INCB028050 in patients with active rheumatoid arthritis who have had inadequate response to any DMARD therapy.
• Effect of INCB028050 on additional non-genotypic pharmacodynamic markers of rheumatoid disease activity in patients with active rheumatoid arthritis who have had inadequate response to any DMARD therapy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects may be included in the study if they are:
1. Male or female subjects over 18 years of age (or the legal age of consent, whichever is older).
2. Females may be enrolled following a negative urine pregnancy test. Subjects must agree to take appropriate precautions to avoid pregnancy or fathering a child (with at least 99% certainty) from screening through follow-up. (Note: Permitted methods which are at least 99% effective in preventing pregnancy should be communicated to the subjects and their understanding confirmed).
3. Have an established diagnosis of rheumatoid arthritis based on the 1987 American College of Rheumatology (ACR) Criteria
4. Must have rheumatoid arthritis which has been inadequately controlled with at least one DMARD including gold, penicillamine, dapsone, azathioprine,
6-mercaptopurine, cholorambucil, cyclophosphamide, cyclosporin, mycophenolate mofetil, methotrexate, leflunomide, sulfasalazine or a biologic.
5. For subjects receiving antimalarials (hydroxychloroquine, chloroquine or quinacrine), they must be treated with antimalarials for at least 6 months, and receiving a stable daily dose (hydroxychloroquine no more than 200 mg BID, chloroquine no more than 250 mg QD, or quinacrine no more than 100 mg QD) for at least 8 consecutive weeks prior to randomization.
6. For subjects receiving sulfasalazine, they must be treated with SSZ for at least 6 months, and receiving a stable daily dose of no more than 3 grams per day for at least 8 consecutive weeks prior to randomization.
7. For subjects on methotrexate, they must be treated with methotrexate for at least 6 months, and receiving a stable weekly dose of methotrexate between 7.5 and 25 mg per week for at least 8 consecutive weeks prior to study entry.
8. For subjects on leflunomide, they must be treated with leflunomide for at least 6 months, and receiving a stable dose of leflunomide between 10 to 20 mg per day for at least 8 consecutive weeks prior to randomization.
9. For subjects receiving corticosteroids, they must be on a dose not to exceed 10 mg of prednisone daily (or equivalent) and on a stable dose for at least 6 weeks prior to randomization.
10. Active rheumatoid arthritis at the time of screening defined by the following:
• 6 or more joints tender or painful on motion and
• 4 or more swollen joints and
• At least one of the following two:
o ESR above 28 mm/hr.
o CRP above 10 mg/liter.
11. Have evidence of lack of risk for tuberculosis, as determined by one of the following:
- Negative PPD test (< 5 mm induration) or, for subjects with a history of BCG vaccination within the 10 years prior to Screening, a negative chest X-ray, or
- Negative QuantiFERON-TB Gold test
- Note that if both tests are done, both must be negative.
12. Have negative serology tests for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb). (Note: Subjects with a negative HBsAg and a positive HBcAb may be permitted in the study if they also have a positive hepatitis B surface antibody (HBsAb) and normal hepatic transaminases.
13. Have negative serology tests for hepatitis C virus antibody (HCVAb).
14. Have negative serology tests for human immunodeficiency virus antibody (HIVAb).
15. Be able and willing to provide written, informed consent.
16. Be able and willing to comply, in the opinion of the investigator, with the requirements of this study. |
|
| E.4 | Principal exclusion criteria |
Subjects will be excluded from the study if they have:
1. Current or recent (< 30 days prior to screening and/or 45 days prior to randomization) viral, bacterial, fungal, parasitic or mycobacterial infection requiring systemic therapy (including diverticulitis).
2. Subjects who are, in the opinion of the investigator, unable to comply with the dosing schedule and protocol evaluations.
3. Pregnant women or women who are breast-feeding.
4. Current alcohol or drug use that, in the expert judgment of the investigator, will interfere with the subject’s ability to comply with the protocol requirements. In patients receiving methotrexate or leflunomide, alcohol use is excluded.
5. Subjects with a history of known or currently suspected systemic lupus erythematosus, periarteritis nodosa, dermatomyositis, progressive systemic sclerosis, rheumatic fever, gouty arthritis, psoriatic arthritis, acute infectious arthritis, Reiter’s syndrome, hypertrophic pulmonary osteoarthropathy, neuroarthropathy, sarcoidosis, multiple myeloma, erythema nodosum, ankylosing spondylitis, psoriasis, Lyme disease, inflammatory bowel disease, leukemia or lymphoma, or agammaglobulinemia.
6. Subjects who have a history of infected joint prosthesis.
7. Subjects who have a history of malignancy within the past 10 years, except completely excised basal or squamous cell skin cancers.
8. Subjects who have a current or recent history of severe, progressive, uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, cardiac, neurological or cerebral disease or, who in the opinion of the investigator have a medical condition that precludes inclusion in this study.
9. Subjects who have a history of unstable ischemic heart disease or uncontrolled hypertension, or a myocardial infarction or cerebrovascular accident within 6 months prior to screening.
10. Subjects who have received treatment with the following drugs or drug classes within the specified timeframe:
• Prior treatment with rituximab within 12 months.
• Prior treatment with an oral JAK inhibitor.
• DMARDs or other anti-rheumatic therapies not specified above including but not limited to: gold, penicillamine, dapsone, azathioprine, 6-mercaptopurine, cholorambucil, cyclophosphamide, cyclosporin, mycophenolate mofetil within 12 weeks prior to the first dose of study medication.
• Treatment with any investigational medication within 12 weeks or 5 half-lives (whichever is longer) prior to the first dose of study medication.
• Treatment with a biologic agent within 12 weeks prior to the first dose of study medication.
11. Subjects who have received a systemic (oral, intramuscular or intravenous) corticosteroid that contains more than 10 mg prednisone equivalent, or intra-articular corticosteroids, within 6 weeks prior to the first dose of study medication.
12. Subjects currently enrolled in other investigational drug protocols.
13. Subjects with malabsorption syndromes possibly affecting drug absorption (eg, Crohn’s disease, chronic pancreatitis, etc.).
14. Subjects who are clinically obese (body mass index (BMI) > 38 kg/m2) or asthenic (BMI < 18 kg/m2).
15. Subjects with a heart rate corrected QT interval (Fridericia correction, QTcF) of > 460 msec.
16. Subjects with a past history of neutropenia, thrombocytopenia or anemia requiring transfusion other than at the time of trauma or surgery, and subjects with the following laboratory parameters at Screening:
− Hemoglobin < 10.0 g/dL.
− White blood cell (WBC) count < 3000/mm3.
− Absolute neutrophil count (ANC) < 2000/mm3.
− Platelet count < 140,000/mm3.
− Alanine aminotransferase (ALT) > 1.5 times the upper limit of normal. For subjects receiving concomitant methotrexate or leflunomide, ALT and AST >1.25 times the upper limit of normal is exclusionary.
− Calculated creatinine clearance (using the MDRD method1) < 60 mLs/minute or serum creatinine > 1.2 times upper limit of normal |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Safety and tolerability of INCB028050 as measured by adverse events, vital signs, clinical laboratory tests and ECGs after 3 months of treatment.
2. Efficacy as determined by percent of subjects achieving ACR 20 improvement at 3 months. |
|
| 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 | Yes |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | Yes |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 | No |
| 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 | |
| E.8.9.1 | In the Member State concerned months | 14 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 16 |
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