| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Rheumatoid arthritis, a chronic systemic autoimmune inflammatory disease characterized by persisten synovial inflammations. |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039073 |
| E.1.2 | Term | Rheumatoid arthritis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
| 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 objective is to evaluate the efficacy of two doses of apremilast (20 mg BID and 30 mg BID) compared with placebo on the reduction of signs and symptoms of RA at 24 weeks of treatment |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the following in subjects with active RA who are treated with
2 doses of apremilast compared with placebo for up to 24 weeks:
- Safety and tolerability
- Physical function
To evaluate the following in subjects with active RA who are treated with
2 doses of apremilast for up to 52 weeks:
- Safety and tolerability
- Signs and symptoms
- Physical function
- To evaluate the efficacy, safety and tolerability of 2 doses of apremilast for up to
2 years of administration in subjects with active RA |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
General Subject Population:
1. Male or female, must be age ≥ 18 years at the time of consent.
2. Must understand and voluntarily sign an informed consent form prior to any study related assessments/procedures are conducted.
3. Must be able to adhere to the study visit schedule and other protocol requirements. Disease Specific Parameters:
4. Must have a documented diagnosis of RA (1987 ACR Criteria, Appendix A) with onset of signs/symptoms of disease ≥ 4 months of duration from randomization.
5. Must be receiving treatment on an outpatient basis.
6. Must have active disease despite current methotrexate treatment as defined below:
≥ 6 swollen joints (66 swollen joint count) at randomization (Visit 2) AND
≥ 6 tender joints (68 tender joint count) at randomization (Visit 2)
7. Must meet at least one of the four lab requirements below:
- hsCRP ≥ 10 mg/L
- ESR > 28 mm after the first 1 hour
- Positive for RF
- Positive for anti-CCP antibodies
8. For subjects participating in the MRI assessment:
-Must have RA joint involvement, as assessed by swollen joint counts in: 1) at least
two MCP swollen joints on the same hand, or 2) at least one swollen MCP joint and
swollen wrist on the same hand.
Current Treatment:
9. Must have been treated with methotrexate for at least 4 months prior to randomization, and must be on stable dose between 7.5 and 25 mg/week (oral or parenteral) for at least 4 weeks prior to randomization. Subjects will be required to maintain their stable dose through Week 52 of the study. Oral folate (folic acid) supplementation is required with a minimum dose of 5 mg/week, or instead leucovorin may be used up to 10 mg/week orally.
10. NSAIDs and pain medications are allowed, however, must be on stable regimen for at least 7 days prior to randomization and through Week 52 of the study.
11. Oral corticosteroids (if taken) are allowed, however, must be on stable dose of prednisone ≤ 10 mg/day or equivalent for at least 28 days prior to randomization and through Week 52 of the study.
Laboratory Measures:
12. Must meet the following laboratory criteria at screening:
- White blood cell count ≥ 3000/mm3 (≥ 3.0 x 109/L) and < 14,000/mm3 (< 14 x
10^9/L)
- Platelet count ≥ 100,000/μL (≥ 100 x 109/L)
- Serum creatinine ≤ 1.5 mg/dL (≤ 132.6 μmol/L)
- AST (SGOT) and ALT (SGPT) ≤ 2 x upper limit of normal (ULN). If initial test
shows ALT or AST > 2 times the ULN, one repeat test is allowed during the
screening period.
- Total bilirubin ≤ 2 mg/dL (≤ 34 μmol/L). If initial test result is > 2 mg/dL, one repeat
test is allowed during the screening period.
- Hemoglobin ≥ 9 g/dL (≥ 5.6 mmol/L)
- Hemoglobin A1c ≤ 9.0%
- Negative for hepatitis B surface antigen
- Negative for hepatitis C antibody
Contraception Requirement:
13. Male subjects (including those who have had a vasectomy) who engage in activity in which conception is possible must use barrier contraception (male latex condom or nonlatex condom NOT made out of natural [animal] membrane [for example, polyurethane]) while on IP and for at least 28 days after the last dose of IP.
14. Females of childbearing potential (FCBP)† must have a negative pregnancy test at Screening and Baseline. FCBP who engage in activity in which conception is possible must use contraception‡ while on IP and for at least 28 days after taking the last dose of IP with either: 1) one highly effective form (non-oral hormonal, intrauterine device [IUD], tubal ligation, vasectomized partner); or 2) an oral hormonal contraceptive PLUS one additional form of barrier contraception (male or female latex condom or nonlatex condom NOT made out of natural [animal] membrane [for example, polyurethane], diaphragm with spermicide, cervical cap with spermicide, contraceptive sponge with spermicide); or 3) two forms of barrier contraception (male or female latex condom or nonlatex condom NOT made out of natural [animal] membrane [for example, polyurethane]) PLUS one of the following (diaphragm with spermicide, cervical cap with spermicide, contraceptive sponge with spermicide). |
|
| E.4 | Principal exclusion criteria |
Disease Specific Requirements:
1. Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization.
2. Rheumatic autoimmune disease other than RA, including systemic lupus erythematosus, mixed connective tissue disease, scleroderma, polymyositis or significant systemic involvement secondary to RA (eg, vasculitis, pulmonary fibrosis or Felty syndrome). Sjögren syndrome secondary to RA is allowable.
3. Functional Class IV as defined by the ACR Classification of Functional Status in
Rheumatoid Arthritis (Appendix B).
4. Prior history of, or current, inflammatory joint disease other than RA (eg, gout, reactive arthritis, psoriatic arthritis, ankylosing spondylitis, Lyme disease).
Previous and Current Medications/Therapy:
5. Receiving treatment with DMARDs (other than MTX), including biologic DMARDs.
Previous use is only allowed after adequate washout prior to randomization.
6. Inadequate response to treatment with an anti-TNF agent. Patients who terminated previous anti-TNF treatment due to cost or safety reason, such as discomfort with the subcutaneous injections, may participate in this study after adequate washout.
7. Treatment with any investigational agent within four weeks (or five half-lives of the investigational drug, whichever is longer) of screening.
8. Previous treatment with any cell depleting therapies, including investigational agents (eg, CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19 and anti-CD20).
9. Treatment with intravenous gamma globulin, plasmapheresis or Prosorba® column within 6 months of baseline.
10. Intra-articular or parenteral corticosteroids are not allowed within 6 weeks prior to randomization.
11. Any previous treatment with alkylating agents such as cyclophosphamide or
chlorambucil, or with total lymphoid irradiation.
General Health:
12. Pregnant women or nursing (breast feeding) mothers.
13. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including severe or very severe chronic obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus as defined by HbA1c > 9.0%) or gastrointestinal (GI) disease.
14. Uncontrolled disease states, such as asthma, psoriasis or inflammatory bowel disease, where flares are commonly treated with oral or parenteral corticosteroids.
15. Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis and atypical mycobacterial disease, Hepatitis B and C, and herpes zoster, but excluding onychomycosis) or any major episode of infection requiring hospitalization or treatment with IV or oral antibiotics within 4 weeks of screening.
16. History of positive Human Immunodeficiency Virus (HIV), or congenital or acquired
immunodeficiency (eg, Common Variable Immunodeficiency Disease).
17. History of malignancy, including solid tumors and hematologic malignancies (except basal cell carcinoma of the skin that has been excised and cured).
18. History of alcohol, drug or chemical abuse within the 6 months prior to screening.
19. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
20. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
21. Any condition that in the investigator’s opinion would interfere significantly with the efficacy evaluations, including the pain and joint assessments (eg, fibromyalgia).
For MRI Only:
22. Receiving medication(s) or will require medication(s) during the
study that impact on vascular flow (eg, nitrates, calcium channel blockers, ergot
containing drugs) on the day of the MRI test and in the investigator’s judgement the
subject cannot hold back from taking these medications on the day of the MRI prior to
the MRI test. The subject can continue taking the medication(s) at any time after the
MRI test is completed, as clinically indicated and scheduled. Exclusions of
antihypertensive and migraine medications can be determined after discussion with the
Sponsor.
23. Unable to undergo an MRI examination, including but not limited to the presence of a pacemaker, defibrillator, or other implanted device such as anterior interbody cages, aneurysm clip, pedicle screws, or any other metal contained in the body (eg, such as tattoos that contain metallic pigment, or metal in the eyes from metal grinding [eg, a metal worker, etc.]), or severe claustrophobia, or any other contraindication to an MRI as per local imaging center guidelines.
24. Allergic or adverse reactions to gadolinium
25. Estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73m2 (based on the MDRD formula).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Proportion of subjects in each treatment group who achieve an American College of
Rheumatology criteria for at least 20% improvement (ACR20) from baseline at
Week 24 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| SEE PROTOCOL FOR ALL SECONDARY END POINTS |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| SEE PROTOCOL FOR ALL SECONDARY ENDPOINT TIMEPOINTS |
|
| 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 | No |
| 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 | 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 36 |
| 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 | No |
| 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
|
Subjects will participate for a maximum of 112 weeks (2 years and 2 months) in this study comprised of 5 phases:
- 1 to 4 weeks in the Screening Phase
- 24 weeks in the Double-blind, Placebo-controlled Treatment Phase
- 28 weeks in the Double-blind, Active Treatment Phase
- 52 weeks in the Double-blind, Active Treatment Extension Phase
- 4 weeks in the Observational Follow-up Phase |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 | 2 |
| 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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