Efficacy and Safety Evaluation of Oral Resomelagon with Methotrexate in DMARD-Naïve Patients with Early Rheumatoid Arthritis: A Phase II Multicenter Study
- Trial ID
- 2024-514981-37-00
- Protocol
- CS008
- Sponsor
- Synact Pharma ApS
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the **efficacy** of oral AP1189 in combination with oral Methotrexate (MTX) over a 12-week treatment period in Disease-Modifying Anti-Rheumatic Drug (DMARD)-naïve participants with newly diagnosed **Rheumatoid Arthritis** (RA), in comparison with oral MTX alone. This is clinically relevant as it aims to assess the potential of AP1189 to enhance treatment outcomes in early RA, a condition characterized by active inflammation and joint damage, which can significantly impact patient quality of life if not effectively managed.
Secondary objectives include:
- To determine the **safety** and tolerability of oral AP1189 in combination with oral MTX, in comparison with oral MTX alone.
Participants
The clinical trial involves a total of **37 participants** diagnosed with **Rheumatoid Arthritis**. The study population includes both male and female subjects aged 18 years and older. Participants are required to be newly diagnosed with the disease, with a disease duration of no longer than 6 months from diagnosis and a history of symptoms not exceeding 18 months. All participants must be **Disease-Modifying Anti-Rheumatic Drug (DMARD)-naïve**. The trial population was selected based on specific criteria, including a high disease activity as indicated by a Disease Activity Score 28 (DAS28) index score greater than 5.1 and a Clinical Disease Activity Index (CDAI) greater than 22. Participants must also have at least 6 tender and 6 swollen joints at screening and baseline, and a serum high sensitive C-Reactive Protein (hsCRP) level of 3 mg/L or higher. Both male and female participants of childbearing potential are required to use a highly effective method of birth control during the study and for 90 days after the last dose. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not provided information regarding the inclusion of vulnerable populations.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled**, dose-response, phase II study to evaluate the efficacy and safety of oral AP1189 administered at doses of 40, 70, or 100 mg for 12 weeks in combination with **methotrexate** in participants with early **rheumatoid arthritis**. The trial aims to determine the efficacy of AP1189 in combination with methotrexate over a 12-week treatment period in Disease-Modifying Anti-Rheumatic Drug (DMARD)-naïve participants, compared to methotrexate alone. The study will involve multiple visits, starting with a screening visit to assess eligibility based on inclusion criteria such as age, diagnosis, and disease activity. Participants will be required to provide informed consent and comply with study procedures, including the use of effective birth control methods if applicable.
The trial will include a baseline visit where participants will be randomized to receive either AP1189 at one of the specified doses or a matching placebo, in addition to methotrexate. Follow-up visits will occur at regular intervals to monitor safety, efficacy, and adherence to the treatment regimen. The primary endpoint is the change from baseline in the Disease Activity Score 28 (DAS28) after 12 weeks of treatment. Secondary endpoints include ACR20, ACR50, and ACR70 responder rates, changes in individual components of the ACR criteria, and the proportion of participants achieving remission or a good EULAR response.
The expected duration of participant involvement is approximately 12 weeks, with the possibility of early termination if participants experience adverse events, fail to comply with study procedures, or withdraw consent. The trial is estimated to conclude by December 2025, with recruitment starting in November 2024. Participants will be closely monitored throughout the study to ensure their safety and the integrity of the trial data.
Treatment
The clinical trial involves the administration of **Methotrexate**, marketed as Methotrexat-Ebewe, in a tablet form with a dosage strength of 2.5 mg. The pharmaceutical form is a tablet, and the route of administration is oral. The maximum daily dose is 2.9 mg, with a total maximum dose of 240 mg over a 12-week treatment period. Methotrexate is a chemical substance, and its use in this trial is to evaluate its efficacy in combination with other treatments for participants with early rheumatoid arthritis. The product is manufactured by EBEWE PHARMA and is not a paediatric formulation.
The experimental medication **Resomelagon**, known by the sponsor product code AP1189, is also administered in tablet form. It is provided in three different dosages: 40 mg, 70 mg, and 100 mg. The maximum daily doses for these formulations are 40 mg, 70 mg, and 100 mg, respectively, with corresponding total maximum doses of 3360 mg, 5880 mg, and 8400 mg over the 12-week treatment period. The route of administration is oral. Resomelagon is a chemical substance developed by SYNACT PHARMA APS, and it is not a paediatric formulation. The trial aims to assess the dose response and efficacy of Resomelagon in combination with Methotrexate.
A matching placebo in tablet form is used as a comparator in this trial. The placebo is designed to mimic the appearance of the active treatment tablets to maintain the double-blind nature of the study. The placebo does not contain any active pharmaceutical ingredients and serves as a control to evaluate the efficacy of the active treatments.
Efficacy
The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the change from baseline in the Disease Activity Score 28 (DAS28) using **C-Reactive Protein (CRP)** after 12 weeks of combined treatment with AP1189 or placebo and Methotrexate (MTX). Secondary endpoints include the ACR20, ACR50, and ACR70 responder rates at Week 12, as well as changes from baseline in the seven individual components of the ACR criteria at each time point. These components include tender/painful joint count, swollen joint count, patient's assessment of arthritis pain, Patient Global Assessment of arthritis (PtGA), Physician Global Assessment of arthritis (PhGA), Health Assessment Questionnaire Disability Index (HAQ-DI), and serum CRP levels.
Additional secondary endpoints involve changes from baseline in DAS28 at each time point, the proportion of participants with Low, Moderate, or High Disease Activity based on DAS28, and the proportion of participants fulfilling DAS28 remission criteria at each time point. The trial will also evaluate the proportion of participants achieving a Good EULAR response, changes from baseline in Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) at each time point, and the proportion of participants fulfilling the ACR/EULAR remission criteria. Furthermore, the proportion of participants achieving a minimal clinically important difference (MCID) in HAQ-DI, defined as a reduction greater than 0.22 from baseline, will be assessed.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed and dated informed consent obtained before undergoing any trial-specific procedure
- Male or female aged ≥18 years
- Participants with definite RA diagnosis according to the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria
- Disease duration no longer than 6 months from diagnosis at the time of Baseline Visit (newly diagnosed) and with a history of RA symptoms which does not exceed 18 months. RA symptoms is defined as the participant self-reported duration of signs and symptoms of synovitis (e.g. pain, swelling, tenderness) of any joints
- Participants must be naïve to any DMARDs (csDMARDs, or bDMARDs, or tsDMARDs)
- Participants with at least 6/68 tender and 6/66 swollen joints at Screening Visit and Baseline.
- Participants with “high” disease activity as documented by a Disease Activity Score 28 (DAS28) (C-Reactive Protein – CRP) index score > 5.1 at screening, and Clinical disease activity index (CDAI) >22 at Screening Visit and Baseline
- Participants with serum high sensitive C-Reactive Protein (hsCRP) ≥3 mg/L at the time of screening
- Participants positive for serum rheumatoid factor (RF), AND/OR anti-cyclic citrullinated peptide antibodies (anti-CCP). If seronegative RA, hsCRP ≥6 mg/L at the time of screening
- Willing and able to comply with the scheduled study visits, the treatment plan, and all study procedures
- Females of childbearing potential must have a negative pregnancy test at screening and again at baseline
- Sexually active female participants of childbearing potential and male participants must use a highly effective method of birth control (hormonal contraceptives, intrauterine device, vasectomy, bilateral tubal occlusion, sexual abstinence) with their partner during the study and for 90 days after the last dose of study drug or who will not remain abstinent during the study and for 90 days after the last dose. (See Appendix 1: Contraceptive Guidance and Woman of Childbearing Potential)
Exclusion Criteria
- Functional class IV of Global Functional Status in RA, as defined by the ACR Classification
- Vaccination with live vaccines during the 6 weeks preceding the Screening Visit
- Haemoglobin <9 g/dL or Haematocrit <30% at the Screening Visit
- White blood cell (WBC) count <3.0 x 109/L at the Screening Visit
- Absolute neutrophil count <1.2 x 109/L at the Screening Visit.
- Platelet count <100 x 109/L at the Screening Visit
- 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 at the Screening Visit
- Estimated creatinine clearance less than 45 mL/min/1.73 m2 (CKD-EPI) at the Screening Visit
- 12-lead electrocardiogram (ECG) with abnormal clinically significant findings, as judged by the Investigator, at the Screening Visit
- Positive or indeterminate QuantiFERON-in-Tube test (QFG-IT) (Mantoux test can be used if QFG-IT is not possible)
- Use of hydroxychloroquine during the 30 weeks preceding the Screening Visit
- 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)
- Treatment with any systemic or intraarticular corticosteroid within 6 weeks before the Screening Visit (topical or inhaled corticosteroids are allowed)
- Intermittent use of nonsteroidal anti-inflammatory drugs (NSAIDs). Use of NSAIDs is allowed if used in a stable dose regimen for at least 4 weeks prior to the Screening Visit
- Use of other investigational drugs/treatments, or enrolment in a clinical trial during the 6 months preceding the Screening Visit
- 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
- Current inflammatory joint disease other than RA
- 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
- 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 6 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) or HIV infection
- History of alcohol or drug abuse during the 12 months preceding the Screening Visit
- Females who are pregnant, lactating.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Recruiting | 01 Nov 2024 | 85 |
 Czechia | Not Recruiting | 01 Nov 2024 | 37 |
 Denmark | Not Recruiting | 01 Nov 2024 | 5 |
 Poland | Not Recruiting | 01 Nov 2024 | 40 |
 Romania | Not Recruiting | 01 Nov 2024 | 5 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
AP1189 Tablet | Test | TABLET | ORAL | 100 | 12 | PRD11481319 |
AP1189 Tablet | Test | TABLET | ORAL | 70 | 12 | PRD11481318 |
AP1189 Tablet | Test | TABLET | ORAL | 40 | 12 | PRD11481317 |
Matching Placebotablets | Placebo | N/A | — | — | — | N/A |
Methotrexat-Ebewe, 2,5 mg, tabletki | Test | TABLETKI | ORAL | 2.9 | 12 | PRD758121 |