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A Study of the EP4 Antagonist CR6086 in Combination With Methotrexate, in DMARD-naïve Patients With Early Rheumatoid Arthritis

Primary Purpose

Rheumatoid Arthritis, DMARD-naive and Early Disease Patients

Status

Completed

Phase

Phase 2

Locations

Czechia

Study Type

Interventional

Intervention

CR6086

Methotrexate

Placebo

About this trial

This is an interventional treatment trial for Rheumatoid Arthritis, DMARD-naive and Early Disease Patients

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Male or female aged ≥18 years.
Patients with diagnosis of definite Rheumatoid Arthritis (RA) according to the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria.
Disease duration no longer than 1 year (early RA).
Patients must be naïve to any DMARDs (csDMARDs, or bDMARDs, or tsDMARDs) other than hydroxychloroquine.
Patients with "moderate" disease activity as documented by a Disease Activity Score 28 (DAS28) (C-Reactive Protein - CRP) index score > 3.2.
Patients with serum C-Reactive Protein (hsCRP) higher than the upper limit of normal.
Patients positive for serum rheumatoid factor (RF) or anti-cyclic citrullinated peptide antibodies (ACPA).

Exclusion Criteria:

Rheumatic autoimmune disease other than RA, or current inflammatory joint disease other than RA, or 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 study procedures.
History of gastric/duodenal ulcers and gastrointestinal bleeding, or gastrointestinal diseases known to interfere with the absorption or excretion of medications.
Severe, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal, metabolic, endocrine, pulmonary, cardiac or neurologic disease.
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.
Acute hepatitis (during the 3 months preceding the Screening Visit), chronic hepatitis, or HIV infection.
History of alcohol or drug abuse, or
allergy/sensitivity to lactose.
Vaccination with live vaccines during the 6 weeks preceding the Screening Visit.
Clinically significant abnormalities in haematology, serum alkaline-phosphatase, gamma-glutamyl-transferase, alanine aminotransferase, aspartate aminotransferase, total bilirubin, creatinine clearance, 12-lead ECG.
Use of hydroxychloroquine during the 4 weeks preceding the Screening Visit.
Treatment with oral corticosteroids, unless maintained at doses equivalent to ≤10 mg/day prednisone ≥7 days before the Screening Visit.
Use of nonsteroidal anti-inflammatory drugs (NSAIDs).
Use of other investigational drugs/treatments, or enrolment in a clinical trial during the 6 months preceding the Screening Visit.
For women of childbearing potential:
1. Pregnancy (i.e. positive pregnancy test at Screening) or breastfeeding
2. Failure to agree to practice a highly effective method of contraception.
For sexually active men with a female partner of childbearing potential: failure to agree to use contraception.

Sites / Locations

Institute of Rheumatology

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

CR6086 30 mg

CR6086 90 mg

CR6086 180 mg

Placebo

Arm Description

CR6086 30 mg bid for 12 weeks as add-on to methotrexate (MTX) once weekly. MTX uptitrated to stable dosing as per standard guidelines

CR6086 90 mg bid for 12 weeks as add-on to MTX once weekly. MTX uptitrated to stable dosing as per standard guidelines

CR6086 180 mg bid for 12 weeks as add-on to MTX once weekly. MTX uptitrated to stable dosing as per standard guidelines

CR6086 matching placebo bid for 12 weeks as add-on to MTX once weekly. MTX uptitrated to stable dosing as per standard guidelines

Outcomes

Primary Outcome Measures

American College of Rheumatology 20% improvement (ACR20) responder rate

Secondary Outcome Measures

ACR50 responder rate

ACR70 responder rate

Disease Activity Score on 28-joint count (DAS28)

Clinical Disease Activity Index (CDAI)

Simplified Disease Activity Index (SDAI)

ACR/EULAR remission criteria

Adverse Events

number of patients with Adverse Events

Routine Laboratory determinations

Pharmacokinetics (PK) of Methotrexate and CR6086 in combination

Main PK endpoint: AUCinf (ng.h/mL). Area under the plasma concentration vs time curve extrapolated to infinity

Biochemical markers

Serum biomarkers of disease activity

Imaging biomarkers

Dynamic Contrast-Enhanced MRI (DCE-MRI)

Full Information

NCT ID

NCT03163966

First Posted

May 8, 2017

Last Updated

October 4, 2021

Sponsor

Rottapharm Biotech

1. Study Identification

Unique Protocol Identification Number

NCT03163966

Brief Title

A Study of the EP4 Antagonist CR6086 in Combination With Methotrexate, in DMARD-naïve Patients With Early Rheumatoid Arthritis

Official 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

Study Type

Interventional

2. Study Status

Record Verification Date

December 2017

Overall Recruitment Status

Completed

Study Start Date

October 5, 2017 (Actual)

Primary Completion Date

January 8, 2019 (Actual)

Study Completion Date

January 8, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Rottapharm Biotech

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

CR6086 is a new, potent and selective, orally available, small molecule prostaglandin EP4 receptor antagonist, endowed with immunomodulatory properties. The pharmacological properties of CR6086, along with its oral bioavailability, predictable pharmacokinetics and good safety, make it the ideal candidate to be tested alone or in combination with methotrexate (MTX) in patients with early Rheumatoid Arthritis who are naïve to Disease-Modifying Antirheumatic Drugs (DMARDs). The compound has indeed the potential to provide a safer and more effective treatment than MTX (or other conventional synthetic DMARDs - csDMARDs), and could significantly improve the proportion of responder patients and avoid/delay the recourse to biological DMARDs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs).

Detailed Description

There is growing evidence that EP4 receptors play an important role in the altered immune response observed in autoimmune diseases. These findings point to the EP4 receptor as a rational target for the development of novel Disease-Modifying Antirheumatic Drugs (DMARDs)/immunomodulators which, in addition, have direct anti-inflammatory properties. The potential for CR6086 to act as a DMARD was extensively demonstrated in a series of widely accepted models of arthritis in rodents, where oral CR6086 was effective in all the parameters examined, including oedema, clinical arthritis score, and histology. CR6086 performed much better than nonsteroidal anti-inflammatory drugs (NSAIDs, that lack the immunomodulatory properties of an EP4 receptor antagonist and are scarcely effective), better than first-line csDMARDs such as MTX, and similarly to immunosuppressive bDMARDs such as TNF-blockers, or tsDMARDs such as JAK inhibitors. In the present study, CR6086 (or placebo) will be administered in a dose-response fashion for 12 weeks to DMARD-naïve patients with early Rheumatoid Arthritis, in combination with oral MTX. The treatment duration and study design will allow to test the effects of the new treatment on clinical outcomes of disease activity, laboratory biomarkers and imaging parameters.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Rheumatoid Arthritis, DMARD-naive and Early Disease Patients

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

248 (Actual)

8. Arms, Groups, and Interventions

Arm Title

CR6086 30 mg

Arm Type

Experimental

Arm Description

CR6086 30 mg bid for 12 weeks as add-on to methotrexate (MTX) once weekly. MTX uptitrated to stable dosing as per standard guidelines

Arm Title

CR6086 90 mg

Arm Type

Experimental

Arm Description

CR6086 90 mg bid for 12 weeks as add-on to MTX once weekly. MTX uptitrated to stable dosing as per standard guidelines

Arm Title

CR6086 180 mg

Arm Type

Experimental

Arm Description

CR6086 180 mg bid for 12 weeks as add-on to MTX once weekly. MTX uptitrated to stable dosing as per standard guidelines

Arm Title

Placebo

Arm Type

Experimental

Arm Description

CR6086 matching placebo bid for 12 weeks as add-on to MTX once weekly. MTX uptitrated to stable dosing as per standard guidelines

Intervention Type

Drug

Intervention Name(s)

CR6086

Intervention Description

oral CR6086 capsules

Intervention Type

Drug

Intervention Name(s)

Methotrexate

Intervention Description

oral Methotrexate tablets

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

oral CR6086 Placebo capsules

Primary Outcome Measure Information:

Title

American College of Rheumatology 20% improvement (ACR20) responder rate

Time Frame

12 weeks

Secondary Outcome Measure Information:

Title

ACR50 responder rate

Time Frame

12 weeks

Title

ACR70 responder rate

Time Frame

12 weeks

Title

Disease Activity Score on 28-joint count (DAS28)

Time Frame

12 weeks

Title

Clinical Disease Activity Index (CDAI)

Time Frame

12 weeks

Title

Simplified Disease Activity Index (SDAI)

Time Frame

12 weeks

Title

ACR/EULAR remission criteria

Time Frame

12 weeks

Title

Adverse Events

Description

number of patients with Adverse Events

Time Frame

12 weeks

Title

Routine Laboratory determinations

Time Frame

12 weeks

Title

Pharmacokinetics (PK) of Methotrexate and CR6086 in combination

Description

Main PK endpoint: AUCinf (ng.h/mL). Area under the plasma concentration vs time curve extrapolated to infinity

Time Frame

12 weeks

Title

Biochemical markers

Description

Serum biomarkers of disease activity

Time Frame

12 weeks

Title

Imaging biomarkers

Description

Dynamic Contrast-Enhanced MRI (DCE-MRI)

Time Frame

12 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male or female aged ≥18 years. Patients with diagnosis of definite Rheumatoid Arthritis (RA) according to the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria. Disease duration no longer than 1 year (early RA). Patients must be naïve to any DMARDs (csDMARDs, or bDMARDs, or tsDMARDs) other than hydroxychloroquine. Patients with "moderate" disease activity as documented by a Disease Activity Score 28 (DAS28) (C-Reactive Protein - CRP) index score > 3.2. Patients with serum C-Reactive Protein (hsCRP) higher than the upper limit of normal. Patients positive for serum rheumatoid factor (RF) or anti-cyclic citrullinated peptide antibodies (ACPA). Exclusion Criteria: Rheumatic autoimmune disease other than RA, or current inflammatory joint disease other than RA, or 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 study procedures. History of gastric/duodenal ulcers and gastrointestinal bleeding, or gastrointestinal diseases known to interfere with the absorption or excretion of medications. Severe, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal, metabolic, endocrine, pulmonary, cardiac or neurologic disease. 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. Acute hepatitis (during the 3 months preceding the Screening Visit), chronic hepatitis, or HIV infection. History of alcohol or drug abuse, or allergy/sensitivity to lactose. Vaccination with live vaccines during the 6 weeks preceding the Screening Visit. Clinically significant abnormalities in haematology, serum alkaline-phosphatase, gamma-glutamyl-transferase, alanine aminotransferase, aspartate aminotransferase, total bilirubin, creatinine clearance, 12-lead ECG. Use of hydroxychloroquine during the 4 weeks preceding the Screening Visit. Treatment with oral corticosteroids, unless maintained at doses equivalent to ≤10 mg/day prednisone ≥7 days before the Screening Visit. Use of nonsteroidal anti-inflammatory drugs (NSAIDs). Use of other investigational drugs/treatments, or enrolment in a clinical trial during the 6 months preceding the Screening Visit. 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. For sexually active men with a female partner of childbearing potential: failure to agree to use contraception.

Facility Information:

Facility Name

Institute of Rheumatology

City

Prague

Country

Czechia

12. IPD Sharing Statement

Learn more about this trial

A Study of the EP4 Antagonist CR6086 in Combination With Methotrexate, in DMARD-naïve Patients With Early Rheumatoid Arthritis

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