AP1189 + Methotrexate for Rheumatoid Arthritis
Palo Alto (17 mi)Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: SynAct Pharma Aps
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?The study is a randomized, double blind, placebo-controlled, dose response, phase II, multicentre trial to evaluate the efficacy and safety of oral AP1189 administered at the doses of 40, 70, or 100 mg for 12 weeks in combination with methotrexate, in DMARD-naïve participants with early rheumatoid arthritis and active inflammation.
Do I need to stop taking my current medications to join the trial?The trial does not specify if you need to stop all current medications, but you must be naïve to DMARDs and cannot have used hydroxychloroquine in the last 30 weeks or corticosteroids in the last 6 weeks. NSAIDs are allowed if used consistently for at least 4 weeks before the trial.
Is the drug AP1189 a promising treatment for rheumatoid arthritis?AP1189, also known as Resomelagon, is being studied in combination with Methotrexate, which is a well-established and effective drug for rheumatoid arthritis. Methotrexate is known for its long-term effectiveness and safety, making it a strong partner in combination therapies. If AP1189 works well with Methotrexate, it could potentially enhance treatment outcomes for patients with rheumatoid arthritis.235711
What safety data exists for AP1189 + Methotrexate in treating rheumatoid arthritis?The provided research does not contain specific safety data for AP1189 (Resomelagon) combined with Methotrexate for rheumatoid arthritis. However, it does provide safety information on Methotrexate, which is commonly used in rheumatoid arthritis treatment. Methotrexate is generally considered safe and effective, with common side effects including gastrointestinal intolerance and elevated hepatic enzymes. Rare but serious side effects include severe hemocytopenia and pneumonitis. Long-term use may lead to liver fibrosis or cirrhosis, especially with higher cumulative doses. No specific safety data for AP1189 or its combination with Methotrexate is mentioned in the provided research.1241314
What data supports the idea that AP1189 + Methotrexate for Rheumatoid Arthritis is an effective treatment?The available research does not provide specific data on the effectiveness of AP1189 + Methotrexate for Rheumatoid Arthritis. Instead, it discusses other treatments like etanercept and adalimumab, which have shown improvements in patients with rheumatoid arthritis. For example, etanercept, alone or with methotrexate, reduced the number of swollen or tender joints by more than 50% in a study. However, there is no direct comparison or data available for AP1189 + Methotrexate in the provided information.6891012
Eligibility Criteria
This trial is for people who have just been diagnosed with early rheumatoid arthritis and haven't taken any disease-modifying anti-rheumatic drugs (DMARDs) yet. They should be experiencing active inflammation but can't join if they've had certain other treatments or health conditions that the study details exclude.Inclusion Criteria
I have not taken any DMARDs for my condition.
I have at least 6 tender and 6 swollen joints.
My arthritis is very active, with high scores on specific health tests.
I am using two forms of birth control or will remain abstinent during and for 90 days after the study.
Exclusion Criteria
I have an autoimmune disease like lupus, but not RA.
I have an inflammatory joint condition that is not rheumatoid arthritis.
I do not have severe or worsening conditions affecting my kidneys, liver, blood, stomach, hormones, lungs, heart, or nervous system.
My kidney function is reduced, with a creatinine clearance below 45 mL/min.
Treatment Details
The trial is testing different doses of a new pill, AP1189, to see how well it works and how safe it is when given alongside methotrexate, a common medication for rheumatoid arthritis. Participants will randomly receive either 40 mg, 70 mg, or 100 mg of AP1189 or a placebo without knowing which one they're getting.
4Treatment groups
Experimental Treatment
Group I: PlaceboExperimental Treatment1 Intervention
12 weeks daily treatment of oral AP1189 matching placebo as add-on to Methotrexate (MTX)
Group II: AP1189 70 mgExperimental Treatment1 Intervention
12 weeks daily treatment of oral AP1189 70 mg as add-on to Methotrexate (MTX)
Group III: AP1189 40 mgExperimental Treatment1 Intervention
12 weeks daily treatment of oral AP1189 40 mg as add-on to Methotrexate (MTX)
Group IV: AP1189 100 mgExperimental Treatment1 Intervention
12 weeks daily treatment of oral AP1189 100 mg as add-on to Methotrexate (MTX)
Find a clinic near you
Research locations nearbySelect from list below to view details:
Altoona Center for Clinical ResearchDuncansville, PA
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Who is running the clinical trial?
SynAct Pharma ApsLead Sponsor
NBCD A/SIndustry Sponsor
References
[Methotrexate in rheumatoid arthritis]. [2013]Methotrexate may be effective in patients with rheumatoid arthritis refractory to other treatments (gold salts, d-penicillamine and antimalarial drugs). Success rates from 39 to 88% have been reported. The mechanism of action is unknown, but is supposedly related to anti-inflammatory and immunosuppressive effects. Frequent side effects are observed on prolonged treatment. Most of these are mild and disappear with dose reduction. An exception is pneumonitis, a hypersensitivity reaction that may appear early and at low doses. Hepatotoxic effects are milder than those observed in patients with psoriasis. Intraarticular administration is not effective. No carcinogenic effects have been observed in humans. The drug should be administered with caution in fertile males and females due to possible teratogenic effects. New studies involving larger number of patients may help establish a significant role for methotrexate in the treatment of rheumatoid arthritis.
Methotrexate: its use in the rheumatic diseases. [2017]Methotrexate in a low dose intermittent regimen has become popular as a therapeutic choice for refractory psoriatic arthritis, polymyositis, Reiter's disease and more recently rheumatoid arthritis. As a folate analogue, it inhibits the formation of reduced folate cofactors which participate in a host of important reactions including DNA synthesis. It has been shown to have both immunosuppressive and anti-inflammatory properties although its precise mechanism of action in these diseases is not known. It may be variably absorbed especially in psoriatics and its action may be antagonized by folate supplements. Its major route of metabolism appears to be via the enterohepatic circulation. Numerous drugs, including salicylates, may increase serum levels by displacing the drug from protein binding sites and by competing for renal excretion. It has fewer short term side effects than the other immunosuppressives used in rheumatic disease. Its major long term toxicity is liver fibrosis or cirrhosis which appears to increase with greater cumulative dosage and treatment duration. Several recent reports of hypersensitivity pneumonitis reinforce the previous literature on this topic. Pulmonary toxicity may be more common than suggested as more patients are treated with methotrexate for rheumatic diseases. Clinical studies in general have been uncontrolled and lacking in scope and size. Nevertheless, the literature to date appears to show this to be an excellent drug for use in the diseases mentioned. Prospective double blind controlled studies on psoriatic arthritis and rheumatoid arthritis should help establish this drug as the immunosuppressive of choice in these diseases.
Methotrexate in rheumatoid arthritis. An update. [2018]Methotrexate has been approved for the treatment of refractory rheumatoid arthritis by several regulatory agencies, including the Food and Drug Administration. The tendency is now to prescribe it at earlier stages of the disease. Methotrexate is a well known antifolate. Its exact mechanism of action in rheumatoid arthritis remains uncertain. The polyglutamated derivatives of methotrexate are potent inhibitors of various enzymes, including dihydrofolate reductase and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase. Inhibitory effects on cytokines, particularly interleukin-1, and on arachidonic acid metabolism, as well as effects on proteolytic enzymes, have been reported. Some of them may be linked to the antifolate properties of methotrexate. Overall, the drug appears to act in rheumatoid arthritis as an anti-inflammatory agent with subtle immunomodulating properties. Direct inhibitory effects on rapidly proliferating cells in the synovium have also been suggested. Methotrexate is usually given orally. Marked interindividual variation in its bioavailability has been found. Food intake has no significant effect on the pharmacokinetics of oral methotrexate. Methotrexate undergoes significant metabolism. The functionally important metabolites are the polyglutamated derivatives of methotrexate, which are selectively retained in the cells. Less than 10% of a dose of methotrexate is oxidised to 7-hydroxy-methotrexate, irrespective of the route of administration. This metabolite is extensively (91 to 93%) bound to plasma proteins, in contrast to the parent drug (35 to 50% bound). Methotrexate is mainly excreted by the kidneys. It undergoes tubular secretion and may thereby compete with various organic acid compounds. Early placebo-controlled trials demonstrated that weekly low dosage methotrexate produced early symptomatic improvement in most rheumatoid arthritis patients. Two meta-analyses showed that methotrexate is among the most efficacious of slow-acting antirheumatic agents, together with parenteral gold (sodium aurothiomalate), penicillamine and sulfasalazine. Furthermore, in the short term context of clinical trials, methotrexate has one of the best efficacy/toxicity ratios. There is little evidence that methotrexate, or any available slow-acting antirheumatic agent, is a true disease-modifying drug. However, the probability that a patient will continue methotrexate therapy over time appears quite favourable compared with any other slow-acting antirheumatic drug. Combination therapy with slow-acting drugs has been advised for the management of rheumatoid arthritis, but the evidence currently available does not support general use of combination therapy including methotrexate. Almost all investigations indicated that toxic effects, rather than lack of response, were the major reason for discontinuing methotrexate therapy.(ABSTRACT TRUNCATED AT 400 WORDS)
Low-dose methotrexate in rheumatic diseases--efficacy, side effects, and risk factors for side effects. [2022]Controlled trials and observational studies have shown low-dose methotrexate (MTX) to be a second-line agent of high potency with a favorable profile of safety and tolerability in the treatment of rheumatoid arthritis (RA). Its risk-benefit ratio in psoriatic arthritis is less well documented. Preliminary reports on its beneficial effects in other disorders, including the systemic manifestations of RA, other spondyloarthritides, and collagen vascular diseases, merit more detailed examination. Gastrointestinal intolerance and hepatic enzyme elevation are the most frequent side effects of MTX; life-threatening events such as severe hemocytopenia and MTX pneumonitis are rare and amenable to prevention by recognizing risk factors and premonitory signs. Hepatotoxicity does not appear to be a major limiting factor in RA patients over the first 2 to 3 years of MTX therapy; its impact on long-term tolerance remains to be clarified.
[Weekly low-dose methotrexate in rheumatoid arthritis. Review of the literature]. [2016]Methotrexate (MTX) is an antifolic drug that in recent years has been largely employed in the treatment of Rheumatoid Arthritis (RA). Both short and long term clinical trials have demonstrated its efficacy and good tolerability. It induces a significant improvement of all clinical variables and a decrease in the erythrocyte sedimentation rate and other acute phase reactants with a steroid sparing effect. The probability of continuing MTX therapy for up to 5 years is 46-55% whereas that of continuing gold, hydroxychloroquine, sulfasalazine or D-penicillamine therapy is less than 20%. MTX is a rapidly acting drug with a clinical response within 4 weeks and a plateau phase after 6 months of therapy. Discontinuation of long-term MTX therapy induces a flare-up of the disease so that patients receiving long-term MTX must continue the drug to maintain clinical benefits. In spite of its clinical efficacy, MTX does not seem to have a significant effect on disease progression as determined radiographically. In this respect, MTX appears to have some superiority when compared to azathioprine, but not when compared to gold salts. MTX has been employed in patients with RA unresponsive to other Disease-Modifying Antirheumatic Drugs (DMARDs), but according to some recent views on the therapeutic strategy of RA, it could be used in early RA as a first choice drug. Toxic effects are the main reason in limiting long-term MTX treatment. Hepatic toxicity is one of the more common side-effects of MTX, but the recognition of its "risk factors" such as alcohol abuse, may reduce it. Acute pneumonitis is one of the more severe complications of MTX therapy and may be life-threatening. In RA patients treated with MTX are also reported complications of immunosuppression, such as Pneumocystis carinii pneumonia whose clinical-radiological picture may be similar to that of acute pneumonitis. The mechanism of action of low-dose weekly MTX in RA is still unclear, but it might be more antiinflammatory than immunosuppressive, as supported by the rapid clinical response. The inhibition of Interleukin-1 activity or other inflammatory cytokines and inflammatory cells may play an important role in the antiinflammatory effect of MTX. MTX effects in RA are not fully understood and further studies are needed to clarify its mechanism of action and its place in the therapeutic strategy of this disease.
Etanercept: a review of its use in rheumatoid arthritis. [2018]Etanercept, a fusion protein consisting of the extracellular ligand-binding domain of the 75kD receptor for tumour necrosis factor-alpha and the constant portion of human IgG1, is administered by subcutaneous injection and is the first specific anti-cytokine therapy approved for rheumatoid arthritis. In patients with active rheumatoid arthritis [American College of Rheumatology (ACR) functional class I to III] who had failed to respond to previous treatment with > or = 1 disease-modifying antirheumatic drug (DMARD), etanercept, alone or in combination with methotrexate, produced improvements in all components included in the ACR core set of disease activity measures. A dose-response effect was apparent with etanercept 0.25 to 16 mg/m2 twice weekly in a randomised, double-blind study in 180 patients. The mean number of swollen or tender joints at the end of the 12-week study decreased by >50% in patients treated with etanercept 16 mg/m2 twice weekly and by or =4 years with refractory juvenile rheumatoid arthritis. Although the overall frequency of infections was similar in patients treated with etanercept or placebo, upper respiratory tract infections were more common in patients treated with etanercept (29%) than placebo (16%). Injection site reactions occurred more frequently in etanercept- than placebo-treated patients, but did not bias the results of any study.
Methotrexate as the "anchor drug" for the treatment of early rheumatoid arthritis. [2022]The two major advances over the 1990s in the treatment of rheumatoid arthritis (RA) were a shift in strategy from a "pyramid", in which disease modifying anti-rheumatic drugs (DMARDs) were deferred for several years, to the early aggressive use of DMARDs and widespread acceptance of methotrexate as the DMARD with the most long-term effectiveness and safety. Methotrexate courses are continued far longer than those of any other DMARD, an excellent indicator of greater effectiveness and safety. In one recent series, methotrexate was the first DMARD used in more than 80% of patients with RA. Studies which document the superiority of combinations of methotrexate with biological agents to methotrexate monotherapy select for only a minority of contemporary patients with RA who have severe disease activity and incomplete responses to methotrexate. In one locale, only 5% of patients met criteria for the Anti-Tumor Necrosis Factor Trial in RA with Concomitant Therapy (ATTRACT) trial and only 30% met the criteria for the Early Rheumatoid Arthritis (ERA) trial. In studies comparing methotrexate directly with biological agents, the biological agents have greater efficacy in patients with very severe disease, but the best results are seen in patients who take a combination of methotrexate and biologic agents. These data establish that methotrexate is the anchor drug and probably should be the first DMARD used in the majority of patients with RA at this time.
Patient-reported health outcomes in a trial of etanercept monotherapy versus combination therapy with etanercept and methotrexate for rheumatoid arthritis: the ADORE trial. [2022]This study assessed the relative efficacy of etanercept (ETN) or etanercept and methotrexate (ETN+MTX) for patients with rheumatoid arthritis (RA) who had an unsatisfactory response to MTX, using patient-reported outcomes (PROs) of function, pain, general health, disease activity and morning stiffness.
Clinical remission and/or minimal disease activity in patients receiving adalimumab treatment in a multinational, open-label, twelve-week study. [2022]To evaluate the effect of adalimumab treatment on clinical remission and/or minimal disease activity (MDA) in 6,610 patients with active rheumatoid arthritis (RA) who were enrolled in the Research in Active RA trial, a multinational, open-label, 12-week study with an optional extension period.
Comparative effectiveness and survival of infliximab, adalimumab, and etanercept for rheumatoid arthritis patients in the Hellenic Registry of Biologics: Low rates of remission and 5-year drug survival. [2022]To compare effectiveness, drug survival, and safety between infliximab, adalimumab, and etanercept, in a nationwide cohort of rheumatoid arthritis (RA) patients.
The role of methotrexate in psoriatic arthritis: what is the evidence? [2017]Methotrexate is a popular and widely used medication for the treatment of psoriatic arthritis. Herein we review the body of evidence for its use and examine its benefits as well as its limitations, both as a monotherapy and in combination with other DMARDs and biological drugs.
Comparison between low disease activity or DAS remission as treatment target in patients with early active rheumatoid arthritis. [2022]To compare outcomes of targeted treatment aimed at either low disease activity or remission in patients with early active rheumatoid arthritis (RA).
Search of official nationwide database in Japan for adverse events associated with disease-modifying antirheumatic drug therapies: focus on therapies in combination with methotrexate. [2022]Disease-modifying antirheumatic drugs (DMARDs) are essential for rheumatoid arthritis (RA) therapy. The adverse events (AEs) evaluation should focus on that methotrexate (MTX) is frequently prescribed in combination with others (combination MTX).
Efficacy, safety and immunogenicity of etanercept biosimilars versus reference biologics in patients with rheumatoid arthritis: A meta-analysis. [2023]Background: Although with the application of etanercept biosimilars in the field of rheumatoid arthritis, the evidences of their efficacy, safety, and immunogenicity are still limited. We conducted this meta-analysis to evaluate the efficacy, safety and immunogenicity of etanercept biosimilars for treating active rheumatoid arthritis compared to reference biologics (Enbrel®). Methods: PubMed, Embase, Central, and ClinicalTrials.gov were searched for randomized controlled trials of etanercept biosimilars treated in adult patients diagnosed with rheumatoid arthritis from their earliest records to 15 August 2022. The outcomes included ACR20, ACR50, and ACR70 response rate at different time points from FAS or PPS, adverse events, and proportion of patients developed anti-drug antibodies. The risk of bias of each included study was assessed using the revised Cochrane Risk of Bias in Randomised Trials tool, and the certainty of evidence was rated according to the Grading of Recommendation Assessment, Development, and Evaluation. Results: Six RCTs with 2432 patients were included in this meta-analysis. Etanercept biosimilars showed more benefits in ACR50 at 24 weeks from PPS [5 RCTs, OR = 1.22 (1.01, 1.47), p = 0.04, I 2 = 49%, high certainty], ACR50 at 1 year from PPS [3 RCTs, OR = 1.43 (1.10, 1.86), p < 0.01, I 2 = 0%, high certainty] or FAS [2 RCTs, OR = 1.36 (1.04, 1.78), p = 0.03, I 2 = 0%, high certainty], and ACR70 at 1 year from PPS [3 RCTs, OR = 1.32 (1.01, 1.71), p = 0.04, I 2 = 0%, high certainty]. In terms of other outcomes about efficacy, safety, and immunogenicity, the results showed that there was no significant difference between etanercept biosimilars and reference biologics, and the certainty of evidences ranged from low to moderate. Conclusion: Etanercept biosimilars showed more benefits in ACR50 response rate at 1 year than reference biologics (Enbrel®), other outcomes for clinical efficacy, safety, and immunogenicity of etanercept biosimilars were comparable with originator in patients with rheumatoid arthritis. Systematic Review Registration: PROSPERO, identifier CRD42022358709.