| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 20.0 |
| 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 |
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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 determine the efficacy of oral CR6086 in combination with oral MTX over a 12-week treatment period in DMARD-naïve patients with early RA, in comparison with oral MTX alone. |
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| E.2.2 | Secondary objectives of the trial |
| To determine the safety, tolerability and pharmacokinetics of oral CR6086 in combination with oral MTX and the effects on selected biological and imaging biomarkers of disease activity, in comparison with oral MTX alone. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PK sub-study: A subset of approximately 24 patients will participate in this sub-study, aimed at investigating the plasma and urinary pharmacokinetics of CR6086 and MTX and of its metabolite 7-hydroxy-MTX for any possible relevant pharmacokinetic interactions between the two drugs. To do so, patients will undergo multiple blood and urine samples during visit 2, 3 and 4.
MRI sub-study: A subset of approximately 80 patients will participate in a sub-study aimed at evaluating dynamic changes in inflammation and joint features by MRI imaging techniques. These patients will undergo three Dynamic Contrast-Enhanced MRI (DCE-MRI) examinations during visit 2, 4 and 6 (End of Study). |
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| E.3 | Principal inclusion criteria |
1. Signed and dated informed consent obtained before undergoing any trial-specific procedure.
2. Male or female aged ≥18 years.
3. Patients with definite RA diagnosis according to the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria.
4. Disease duration no longer than 1 year (early RA). Disease duration is defined as the patient self-reported duration of signs and symptoms of synovitis (e.g. pain, swelling, tenderness) of any joints.
5. Patients must be naïve to any DMARDs (csDMARDs, or bDMARDs, or tsDMARDs), other than hydroxychloroquine, as long as this is discontinued at least 4 weeks prior to the screening visit.
6. Patients with at least 6/68 tender and 6/66 swollen joints, of which at least one joint must be in the hand/wrist (to be imaged in patients participating into the MRI sub-study).
7. Patients with “moderate” disease activity as documented by a Disease Activity Score 28 (DAS28) (C-Reactive Protein – CRP) index score > 3.2.
8. Patients with serum C-reactive protein (hsCRP) higher than the upper limit of normal (ULN), i.e. 3 mg/L.
9. Patients positive for serum rheumatoid factor (RF) or anti-cyclic citrullinated peptide antibodies (ACPA).
10. Willing and able to comply with the scheduled study visits, the treatment plan, and all study procedures. |
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| E.4 | Principal exclusion criteria |
Medical history and Concomitant diseases:
1. Functional class IV of Global Functional Status (GFS) in RA, as defined by the ACR Classification.
2. Rheumatic autoimmune disease other than RA, i.e. systemic lupus erythematosus, mixed connective tissue disease, scleroderma, polymyositis, or significant systemic involvement secondary to RA (vasculitis, pulmonary fibrosis or Felty's syndrome).
3. Current inflammatory joint disease other than RA.
4. Non-inflammatory type of musculoskeletal condition (e.g., osteoarthritis or fibromyalgia) that in the Investigator's opinion is symptomatic and/or severe enough to interfere with the subject's primary diagnosis of RA or the evaluation of the effect of the study drug.
5. History of gastric/duodenal ulcers and gastrointestinal bleeding.
6. Gastrointestinal diseases known to interfere with the absorption or excretion of medications.
7. Severe, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal, metabolic, endocrine, pulmonary, cardiac or neurologic disease.
8. Malignancy (with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ) active during the 12 months preceding the Screening Visit.
9. Acute hepatitis (during the 3 months preceding the Screening Visit), chronic hepatitis (previous documented diagnosis of viral or autoimmune hepatitis, or detection of any unexplained elevation of serum ALT or AST greater than 1.5-fold ULN, at least twice in the 6 months before the Screening Visit) and HIV infection.
10. History of alcohol or drug abuse during the 12 months preceding the Screening Visit.
11. Allergy/hypersensitivity/intolerance to any components in CR6086 and MTX, including excipients such as lactose (patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-
galactose malabsorption should be excluded), starch, magnesium stearate, cellulose.
12. Vaccination with live vaccines during the 6 weeks preceding the Screening Visit.
Laboratory and examinations
13. Hemoglobin <9 g/dL or Hematocrit <30%
14. White blood cell (WBC) count <3.0 x 10^9/L
15. Absolute neutrophil count <1.2 x 10^9/L
16. Platelet count <100 x 10^9/L
17. Serum alkaline-phosphatase, or gamma-glutamyl-transferase greater than 3-fold ULN; alanine aminotransferase, or aspartate aminotransferase, or total bilirubin greater than 2-fold ULN.
18. Estimated creatinine clearance less than 60 mL/min/1.73 m2 (MDRD).
19. 12-lead electrocardiogram (ECG) with clinically relevant findings, as judged by the Investigator.
Medications
20. Use of hydroxychloroquine during the 4 weeks preceding the Screening Visit.
21. Treatment with oral corticosteroids, unless maintained at doses equivalent to ≤10 mg/day prednisone ≥7 days before the Screening Visit. Use of steroids by other administration route before screening visit is allowed, with the exception of i.a. administration during the four weeks preceding the screening visit.
22. Use of non-steroidal anti-inflammatory drugs (NSAIDs) if the patient cannot suspend therapy for the whole duration of the study (from Screening Visit to EOS).
23. Use of other investigational drugs/treatments, or enrolment in a clinical trial during the 6 months preceding the Screening Visit.
Other
24. For women of childbearing potential:
- Pregnancy (i.e. positive pregnancy test at Screening) or breastfeeding.
- Failure to agree to practice a highly effective method of contraception, from enrolment up to at least 3 months after the study end.
25. For sexually active men with a female partner of childbearing potential: failure to agree to use condom, from enrolment up to at least 3 months after the study end.
26. Any other clinically relevant disease and condition that, in the opinion of the Investigator, may jeopardize efficacy or safety assessments or may compromise the subject’s safety during trial participation. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| ACR20 responder rate after 12 weeks of combined treatment with CR6086/Placebo and MTX (week 13). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After 12 weeks of combined treatment with CR6086/Placebo (week 13) |
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| E.5.2 | Secondary end point(s) |
• ACR50 responder rate at week 13.
• ACR70 responder rate at week 13.
• Change from baseline of the 7 individual components of the ACR criteria (tender/painful joint count, swollen joint count, Patient's assessment of arthritis pain, PtGA of arthritis, PhGA of arthritis, HAQ-DI, serum CRP) at each time point.
• Change from baseline in DAS28 at each time point.
• Proportion of patients with Low, Moderate, or High Disease Activity based on DAS28 at each time point.
• Proportion of patients fulfilling DAS28 remission criteria at each time point (DAS28<2.6).
• Proportion of patients achieving a Good EULAR response (a DAS28 score≤3.2 at the considered visit, together with an improvement from baseline in DAS28>1.2) at each time point.
• Change from baseline in SDAI and CDAI at each time point.
• Proportion of patients with Low, Moderate, or High Disease Activity based on SDAI and CDAI at each time point.
• Proportion of patients fulfilling the ACR/EULAR remission criteria at each time point. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The ACR50 and ACR70 Responder rate will be both assessed at week 13. All the other secondary endpoints will be assessed at each timepoint. |
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| 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 | 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 | 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 38 |
| 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 |
| Bulgaria |
| Czech Republic |
| Denmark |
| Moldova, Republic of |
| Poland |
| Romania |
| United Kingdom |
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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
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| 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 | 16 |
| 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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