A Rheumatoid Arthritis Study to Test the Safety, Tolerability, and Efficacy of MK-8457 in Patients with an Inadequate Response or Intolerance to Anti-TNF-alpha Therapy

Phase 2

• Conditions: Rheumatoid Arthritis; Inflammatory and Immune System - Rheumatoid arthritis

• Registration Number: ACTRN12612000774820
• Lead Sponsor: MSD - Merck Sharp & Dohme (Australia) Pty Limited

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2012-07-20
• Last Update Posted: 13 January 2020

Recruitment & Eligibility

• Status: Stopped early
• Sex: All
• Target Recruitment: 178

Inclusion Criteria

A subject must meet all the criteria listed below to participate in the trial:
1Subject must be greater than or equal to 18 years of age on the day of signing the informed consent.
RA diagnosis and disease activity:
2.Subject has a diagnosis of RA (according to revised 1987 criteria of the ARA) for at least 6 months prior to screening
3.Subject has active RA as defined by the presence of greater than or equal to 6 swollen joints (of 66 joint count) AND greater than or equal to 6 tender joints (of 68 joint count) at screening (Visit 1) and baseline (Visit 2).
4.Subject has a C-reactive protein (CRP) blood level >0.9 mg/dL from the central reference laboratory at screening.
5.Subject is anti-citrullinated protein antibody (ACPA) positive and/or rheumatoid factor positive at screening.
6.Subject is ACR functional Class I, II, or III.
7.Subject must have received MTX for a minimum of 3 months prior to screening with a regionally appropriate stable weekly dose for at least 4 weeks prior to screening (15-25 mg/wk for regions outside of Asia, and 6-25 mg/week for Asia). The subject's dose of weekly MTX must remain stable through week 24 of the study.
8.Subject must have either failed treatment with 1 or 2 anti-TNF-a therapies or was intolerant to anti-TNF-a therapy prior to screening. For subjects who have failed therapy, the treatment with anti-TNF-a therapies must have been for at least 3 months.
Note: The inadequate response or intolerance to anti-TNF therapy will be defined by the Investigator's assessment and will be recorded. Typically, an inadequate response is based on clinical reasons (e.g., no improvement or worsening of RA). Lack of access to the medication or financial reasons are not considered an inadequate response.
9.If using NSAIDs or other analgesics, subject must be on stable doses (minimum of 2 weeks prior to the first dose of study medication).
10.If using oral corticosteroids, must be on a stable dose of less than or equal to10 mg prednisone per day (or equivalent) for at least 2 weeks prior to first administration of study medications.
Tuberculosis:
11.Subject is considered to be eligible according to the following tuberculosis (TB) screening criteria:
a.Has no history of either untreated latent or active TB prior to Baseline. Prophylactic treatment for latent TB (as per American Thoracic Society 1999 or local guidelines) must be initiated for at least 4 weeks prior to first administration of study medication.
b.Has no signs or symptoms suggestive of active TB upon medical history and/or physical examination.
c.Has had no recent close contact with a person with active TB or, if there has been such contact, will be referred to a physician specializing in TB to undergo additional evaluation and, if warranted, receive appropriate treatment for latent TB at least 4 weeks prior to the first administration of study medication.
d.Within 8 weeks prior to the first administration of study medication, either has a negative diagnostic TB test result (defined as either a negative tuberculin skin test or negative QuantiFERON-TB Gold test). In the US and Canada, an induration of 5 mm or greater in response to the intradermal tuberculin skin test is considered to be a positive result and evidence for either latent or active TB. In countries outside the United States and Canada, country-specific guidelines for immunocompromised patients should be consulted for the interpretation of tuberculin skin

Exclusion Criteria

A subject meeting any of the exclusion criteria listed below must be excluded from participating in the study:
1.Subject has inflammatory disease other than RA, including but not limited to psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, or Lyme disease.
2.Subject who has signs or symptoms of severe, progressive, or uncontrolled renal, hepatic, hematologic, endocrine, pulmonary, cardiac, neurologic, or cerebral disease, that affects the subject’s ability to participate in the trial.
3.Subject has been hospitalized due to an acute cardiovascular event, cardiovascular illness or cardiovascular surgery within 6 months of screening.
4. Subject has sustained, uncontrolled hypertension (systolic blood pressure of greater than or equal to 160 mm Hg and/or diastolic blood pressure of greater than or equal to 100 mm Hg at baseline), or uncontrolled diabetes.
5.Subject who has a transplanted organ, excluding corneal transplant performed >3 months prior to first dose of trial medication.
6.Subject has had a prior malignancy or concurrent malignancy (excluding successfully treated basal cell carcinoma, squamous cell carcinoma of the skin in situ, squamous cell carcinoma with no evidence of recurrence within 5 years, or carcinoma in situ of the cervix that has been adequately treated).
7.Subject has any infection requiring treatment with systemic antibiotics within 2 weeks prior to first dose of trial medication or serious infection (e.g., hepatitis, pneumonia or pyelonephritis) requiring hospitalization or treatment with IV antibiotics within 8 weeks prior to first dose of trial medication.
8.Subject with history of opportunistic infection (e.g., cytomegalovirus, aspergillosis, etc.) within 6 months prior to screening.
9.Subject with a history of, or ongoing, chronic or recurrent infectious disease, including but not limited to, chronic renal infection, chronic chest infection, sinusitis, recurrent urinary tract infection (e.g., recurrent pyelonephritis), an open, draining, or infected skin wound, or an ulcer. Subjects with chronic conjunctivitis on stable therapy can be enrolled per investigator discretion.
10.Subject has a positive hepatitis B surface antigen or hepatitis C test result
11.Subject known to be HIV positive.
12.Female subject of childbearing potential is pregnant, intends to become pregnant (within 3 months of completing the trial), or is lactating.
13.Subject is, at the time of signing informed consent, a user of recreational or illicit drugs or has had a history (within the previous 2 years) of drug or alcohol abuse or dependence.
14.Subject is allergic or intolerant to MK-8457 or any components in its formulation.
Previous or Concurrent Medication
15.Previous exposure to fostamatinib or other spleen tyrosine kinase (SYK) inhibitors.
16.Previous exposure to 3 or more anti-TNF therapeutic agents.
17.Previous exposure to any biological agents other than anti-TNF therapeutic agents, including but not limited to abatacept, tocilizumab, rituximab or other biological agents used for the treatment of RA.
18.Subject has received any treatment listed below more recently than the indicated washout period prior to randomization.
Washout Period for Medications Prior to Randomization
Anti-TNF-a Therapies:
* Adalimumab 8 weeks,
* Certolizumab 8 weeks,
* Etanercept 4 weeks,
* Golimumab 8 weeks,
* Infliximab 8 weeks.
* Cyclosporine, corticosteroids (parenteral, intra-articu

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To determine the effects of MK-8457 100 mg twice a day compared to placebo over 12 weeks of treatment as measured by ACR20 response.[12 weeks after randomisation.];To determine the safety and tolerability of MK-8457 100 mg twice a day compared to placebo over 12 weeks of treatment.[12 weeks after randomisation.<br>There will be two planned interim analyses for this study.<br>The first interim analysis occurs when approx 50% subjects (45 per arm) have either completed 12 weeks of the study or dropped out. This interim analysis will check for futility based on ACR20 response rate at Week 12. The study will stop for futility if the observed treatment difference is less than or equal to 7.5%. The futility boundary corresponds to an alpha-spending of 0.1% and beta-spending of 10.1%, non-binding. The overall power of the primary analysis<br>accounting for the futility interim analysis is approximately 78%.]