A randomized, double blind, placebo-controlled, dose response, phase II, multicentre trial to evaluate the efficacy, safety and pharmacokinetics of oral CR6086 administered at the doses of 30, 90 or 180 mg bid for 12 weeks in combination with methotrexate, in DMARD-naïve patients with early rheumatoid arthritis

• Register: EUCTR
• Last refreshed on: 30 April 2019
• Main ID: EUCTR2016-004834-11-DK
• Date of registration: 11/05/2017
• Prospective Registration: Yes
• Primary sponsor: Rottapharm Biotech S.r.l.
• Public title: A randomized, double blind, placebo-controlled, dose response, phase II, multicentre trial to evaluate the efficacy, safety and pharmacokinetics of oral CR6086 administered at the doses of 30, 90 or 180 mg bid for 12 weeks in combination with methotrexate, in DMARD-naïve patients with early rheumatoid arthritis
• Scientific title: A randomized, double blind, placebo-controlled, dose response, phase II, multicentre trial to evaluate the efficacy, safety and pharmacokinetics of oral CR6086 administered at the doses of 30, 90 or 180 mg bid for 12 weeks in combination with methotrexate, in DMARD-naïve patients with early rheumatoid arthritis
• Date of first enrolment: 06/07/2017
• Target sample size: 240
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-004834-11
• 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; Number of treatment arms in the trial: 4
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Bulgaria, Czech Republic, Denmark, Moldova, Republic of, Poland, Romania, United Kingdom

Contacts

• Name: Regulatory Affairs Department
• Affiliation: Nordic Bioscience Clinical Development VII A/S

• Name: Regulatory Affairs Department
• Affiliation: Nordic Bioscience Clinical Development VII A/S

Key inclusion & exclusion criteria

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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 160
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 80

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 p

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

Health Condition(s) or Problem(s) studied

Rheumatoid Arthritis
MedDRA version: 20.0 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 - Musculoskeletal and connective tissue disorders

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Intervention(s)

Product Name: CR6086
Product Code: CR6086Z
Pharmaceutical Form: Capsule
INN or Proposed INN: see D.3.9.3 'Other descriptive name' below
CAS Number: 1417742-86-9
Current Sponsor code: CR6086Z
Other descriptive name: CR6086
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 30-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Product Name: CR6086
Product Code: CR6086Z
Pharmaceutical Form: Capsule
INN or Proposed INN: see D.3.9.3 'Other descriptive name' below
CAS Number: 1417742-86-9
Current Sponsor code: CR6086Z
Other descriptive name: CR6086
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 90-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Trade Name: Methotrexate® 2.5 mg tablets
Pharmaceutical Form: Tablet
INN or Proposed INN: Methotrexate
CAS Number: 59-05-2
Other descriptive name: METHOTREXATE 2.5 mg tablets
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2.5-

Primary Outcome(s)

Primary end point(s): ACR20 responder rate after 12 weeks of combined treatment with CR6086/Placebo and MTX (week 13).

Main Objective: 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.

Secondary Objective: 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.

Timepoint(s) of evaluation of this end point: After 12 weeks of combined treatment with CR6086/Placebo (week 13)

Secondary Outcome(s)

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.

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.

Secondary ID(s)

CR6086-2-02

Source(s) of Monetary Support

Rottapharm Biotech S.r.l.

Ethics review

Status: Approved
Approval date:
Contact: