| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| moderately to severely active rheumatoid arthritis |
|
| 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 | 16.0 |
| 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 of the study is to evaluate the efficacy in terms of the percentage of subjects achieving an ACR20 response, of different doses of GLPG0634 given once daily compared with placebo at Week 12. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
• To evaluate the efficacy in terms of the percentage of subjects achieving an ACR20, ACR50, ACR70, ACR N, DAS28(CRP), EULAR response and ACR/EULAR remission, CDAI, and SDAI with different doses of GLPG0634 given once daily compared with placebo at every visit.
• To evaluate the safety and tolerability of different doses of GLPG0634 in comparison with placebo.
• To characterize the population PK and PD of GLPG0634 and its metabolite (G254445) in subjects with rheumatoid arthritis and investigate the relationship between exposure and efficacy/safety/PD.
• To evaluate the effects of different doses of GLPG0634 administration on subjects’ disability, fatigue, and quality of life.
|
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be eligible for study entry subjects must fulfil all of the following criteria:
1. Male or female subjects who are ≥18 years of age on the day of signing informed consent.
2. Diagnosis of RA since at least 6 months and meeting the 2010 ACR/EULAR criteria of RA and ACR functional class I III.
3. Have ≥6 swollen joints (from a 66 joint count) and ≥8 tender joints (from a 68 joint count) at Screening and Baseline
4. Screening serum CRP ≥ 1.5 x ULN
5. Have shown an inadequate response in terms of either lack of efficacy or toxicity to MTX.
6. Have agreed to be washed out from MTX for a period of at least 4 weeks before or during the Screening period.
7. If taking oral steroids, these should be at a dose ≤10 mg/day of prednisone or prednisone equivalent and stable for at least 4 weeks prior to Screening.
8. If taking non-steroidal anti-inflammatory drugs (NSAIDs), these must be at a stable dose for at least 2 weeks prior to Screening.
9. The results of the following laboratory tests performed at the central laboratory at Screening must be within the limits specified below:
a) Hemoglobin ≥9 g/dL (International System of Units [SI]: ≥90 g/L);
b) WBCs ≥3.0 x 103 cells/mm3 (SI: ≥3.0 x 109 cells/L);
c) Neutrophils ≥1.5 x 103 cells/mm3 (SI: ≥1.5 x 109 cells/L);
d) Platelets ≥100 x 103 cells/mm3 (SI: ≥100 x 109 cells/L);
e) Serum ALT and aspartate aminotransferase (AST) ≤1.5 x ULN;
f) Total bilirubin level ≤1.25 x ULN;
g) Lipase ≤1.5 x ULN and amylase ≤1.5 x ULN;
h) Creatinine clearance >60 mL/min and blood urea nitrogen (BUN) within normal ranges. Creatinine clearance will be calculated using the Cockroft-Gault formula.
10. Female subjects must have a negative pregnancy test unless they are surgically sterile or have been post-menopausal for at least one year (12 consecutive months without menses); in case of doubt a determination of serum FSH can be done with FSH levels above 35 mIU/mL being confirmative for menopause.
11. Women of childbearing potential must use a medically acceptable means of birth control and agree to continue its use during the study and for at least 12 weeks after the last dose of study medication. Medically acceptable forms of birth control include oral contraceptives, injectable or implantable methods, intrauterine devices, tubal ligation (if performed more than one year before Screening), and double barrier contraception.
12. Sexually active men must agree to use a medically acceptable form of contraception (double barrier) during the study and continue its use for at least 12 weeks after the last dose of study medication.
13. Able and willing to sign the informed consent as approved by the Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to Screening evaluations and agree to the schedule of assessments.
14. Judged to be in good health, except for their RA, as determined by the investigator based upon the results of medical history, laboratory profile, physical examination, chest X-ray, and a 12-lead ECG performed during Screening.
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|
| E.4 | Principal exclusion criteria |
Subjects will be excluded from the study if one or more of the following statements are applicable:
1. Current therapy with any non-biological DMARD, with the exception of antimalarials, which must be at a stable dose for at least 12 weeks prior to Screening.
2. Current or previous RA treatment with a biologic DMARD, with the exception of biologic DMARDs:
• administered in a single clinical study setting, and;
• more than 6 months prior to Screening (12 months for rituximab or other B cell depleting agents), and;
• where the biologic DMARD was effective, and if discontinued, this should not be due to lack of efficacy.
3. Previous treatment at any time with a cytotoxic agent, other than MTX, before Screening. These agents include, but are not limited to chlorambucil, cyclophosphamide, nitrogen mustard, or other alkylating agents.
4. Previous use of JAK or SYK inhibitors.
5. Receipt of an intra-articular or parenteral corticosteroid injection within 4 weeks prior to Screening.
6. Known hypersensitivity to study medication ingredients or a significant allergic reaction to any drug as determined by the investigator, such as anaphylaxis requiring hospitalization.
7. Positive serology for human immunodeficiency virus (HIV) 1 or 2 or hepatitis B or C or any history of hepatitis from any cause with the exception of hepatitis A.
8. History of any inflammatory rheumatological disorder other than RA except secondary Sjögren Syndrome.
9. Have undergone surgical treatments for RA, including synovectomy or arthroplasty.
10. History of moderate to severe congestive heart failure (New York Heart Association class III or IV), recent (within 24 hours prior to study entry) cerebrovascular accident and any other condition that in the opinion of the investigator, would put the subject at risk by participation in the study.
11. History of malignancy within the past 5 years (except for basal cell carcinoma of the skin or cervical carcinoma in situ that has been treated with no evidence of recurrence).
12. History of tuberculosis (TB) infection as determined by either:
a) positive QuantiFERON TB Gold test result OR
b) chest radiograph (both posterior-anterior and lateral views), taken within 3 months prior to Screening and read by a qualified radiologist, with evidence of current active TB or old inactive TB symptoms of clinically significant illness in the 3 months before the initial study medication administration.
13. History of invasive infection (eg, listeriosis and histoplasmosis).
14. Treatment with any drug known to have a well-defined potential for toxicity to a major organ in the last 3 months preceding the initial study drug administration.
15. Administration of a live vaccine within 90 days or an attenuated vaccine within 30 days prior to the initial study medication administration.
16. Participation in any investigational drug/device clinical study within 4 weeks prior to Screening.
17. History within the previous 2 years or current evidence of drug or alcohol abuse.
18. Breastfeeding during the study.
19. Any condition or circumstances that, in the opinion of the investigator, may make a subject unlikely or unable to complete the study or comply with study procedures and requirements.
20. Significant blood loss (including blood donation [> 500 mL]) or a transfusion of any blood product within 12 weeks prior to the initial study medication administration.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the percentage of subjects achieving an ACR20 response at Week 12. Other time points will be regarded as secondary endpoints |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| Percentage of subjects achieving ACR20 response at Week 24, percentage of subjects achieving ACR50, ACR70, ACR N, DAS28(CRP), EULAR response and ACR/EULAR remission, CDAI, SDAI response, the change in Baseline in Quality of Life (functional assessment of chronic illness therapy [FACIT] and short form 36 [SF-36]) scores at Weeks 1, 2, 4, 8, 12, and 24, as appropriate. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| weeks 1, 2, 4, 8, 12 and week 24. |
|
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 4 |
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Chile |
| Colombia |
| Czech Republic |
| Germany |
| Guatemala |
| Hungary |
| Israel |
| Latvia |
| Lithuania |
| Mexico |
| New Zealand |
| Peru |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Spain |
| Ukraine |
| United States |
|
| 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
|
| Last contact of the last subject in the study |
|
| 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 | 8 |
| 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 | 8 |
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