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Trial registered on ANZCTR


Registration number
ACTRN12612000774820
Ethics application status
Approved
Date submitted
20/07/2012
Date registered
20/07/2012
Date last updated
23/10/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
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
Scientific title
A Phase IIa, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Worldwide, Proof-of-Concept Clinical Trial to Evaluate the Safety, Tolerability, and Efficacy of MK-8457 in Subjects with Active Rheumatoid Arthritis and an Inadequate Response or Intolerance to Anti-TNF-alpha Therapy
Secondary ID [1] 280882 0
MK-8457-010-00
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Rheumatoid Arthritis 286951 0
Condition category
Condition code
Inflammatory and Immune System 287289 287289 0 0
Rheumatoid arthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
SUMMARY OF STUDY DESIGN
Study Design for Base Study:
In the base study, ~178 subjects will be randomized to treatment with MK-8457 100 mg twice a day (oral tablet) or placebo for a total of 24 weeks. Subjects are required to be on background methotrexate (MTX) therapy at stable doses prior to and during the study.
Subjects will continue in a safety extension at the end of the base study. After approximately ~50% of subjects have completed 12 weeks of treatment in the base study, an interim analysis (IA) will be conducted to evaluate for futility. While the IA is being conducted, enrollment will continue. A second IA will be performed to assess for efficacy after ~100% of subjects complete 12 weeks of treatment (or otherwise discontinue). If efficacy is not demonstrated, the study may be discontinued.
Early Escape:
Subjects in the base study will be eligible for early escape at Week 12 or any point after, if they demonstrate a <20% improvement in both tender and swollen joint counts. Subjects may choose to either withdraw from the study or to continue into the safety extension portion of the study and receive MK-8457 100 mg twice a day (oral tablet) for up to a total of 100 weeks of treatment.
Study Design for Safety Extension
Subjects who complete 24 weeks of treatment in the base study will continue in a safety extension for up to a total of 100 weeks. The safety extension will begin at Visit 9 (Extension). Subjects who meet the criteria for early escape may opt to continue onto the safety extension starting at Week 12.
Intervention code [1] 285314 0
Treatment: Drugs
Comparator / control treatment
Placebo-controlled (oral tablet).
Subjects are required to be on background methotrexate (MTX) therapy at stable doses prior to and during the study.
Control group
Placebo

Outcomes
Primary outcome [1] 287563 0
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.
Timepoint [1] 287563 0
12 weeks after randomisation.
Primary outcome [2] 287564 0
To determine the safety and tolerability of MK-8457 100 mg twice a day compared to placebo over 12 weeks of treatment.
Timepoint [2] 287564 0
12 weeks after randomisation.
There will be two planned interim analyses for this study.
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
accounting for the futility interim analysis is approximately 78%.
Secondary outcome [1] 298403 0
To determine the effects of MK-8457 100 mg twice a day compared to placebo as measured by ACR20 at Week 24.
Timepoint [1] 298403 0
24 weeks following randomisation.
Secondary outcome [2] 298405 0
To determine the effects of MK-8457 100 mg twice a day compared to placebo as measured by DAS28CRP change from baseline at Week 12.
Timepoint [2] 298405 0
12 weeks following randomisation.
Secondary outcome [3] 298406 0
To determine the effects of MK-8457 100 mg twice a day compared to placebo as measured by ACR50 at Week 12.
Timepoint [3] 298406 0
12 weeks following randomisation.
Secondary outcome [4] 298407 0
To determine the effects of MK-8457 100 mg twice a day compared to placebo as measured by change from baseline in DAS28CRP at Week 24.
Timepoint [4] 298407 0
24 weeks following randomisation.
Secondary outcome [5] 298408 0
To determine the effects of MK-8457 100 mg twice a day compared to placebo as measured by ACR50 at Week 24.
Timepoint [5] 298408 0
24 weeks following randomisation.
Secondary outcome [6] 298409 0
To determine the effects of MK-8457 100 mg twice a day compared to placebo as measured by HAQ change from baseline at Weeks 12 and 24.
Timepoint [6] 298409 0
12 and 24 weeks following randomisation.
Secondary outcome [7] 298410 0
Safety Extension: To assess the safety and tolerability of MK-8457 during the safety extension period through Week 100.
Timepoint [7] 298410 0
100 weeks following randomisation.
There will be two planned interim analyses for this study.
The second interim analysis occurs when 100% subjects (89 per arm) have either completed 12 weeks of the study or dropped out. This interim analysis will check for efficacy based on ACR20 response rate at Week 12. If MK-8457 100 mg twice a day does not demonstrate efficacy then the study may be discontinued.

Eligibility
Key inclusion criteria
A subject must meet all the criteria listed below to participate in the trial:
1 Subject 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 test results. If no local guidelines for immunocompromised patients exist, US guidelines must be followed.
e. Has a chest radiograph (both posterior-anterior and lateral views) within 2 months prior to Screening and read by a qualified radiologist, with no evidence of current active TB or old inactive TB. If a negative chest radiograph is not available, then subject must have a chest radiograph performed during the screening phase showing no evidence of active TB or old inactive TB.
General:
12. Subject understands the purpose and risks of the trial, is willing and able to comply with the protocol (able to adhere to dose and visit schedules) and voluntarily agrees to participate in the study by giving written informed consent. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
13. Subject is able to read, understand, and complete study questionnaires.
14. Subjects must be free of any clinically significant condition or situation, other than RA that, in the opinion of the investigator, would interfere with the study evaluations or optimal participation in the study.
15. A subject (male or female) of reproductive potential agrees to remain abstinent or use 2 acceptable methods of birth control starting from Visit 1 until at least 3 months after last dose of methotrexate or at least 14 days after the last dose of study medication, whichever is later. Longer periods of birth control may be required per local requirements. Acceptable methods of birth control are: hormonal contraceptives, intrauterine device (IUD), diaphragm with spermicide, contraceptive sponge, condom, and vasectomy OR use appropriate double barrier contraception as per local regulations or guidelines. Abstinence is acceptable if this is the established and preferred contraception for the subject. Female subjects of reproductive potential must demonstrate a negative serum pregnancy test at Screening (Visit 1) and a negative urine pregnancy test 24 hours prior to the first dose of study medication and throughout the study. Women who are postmenopausal or have had a hysterectomy or bilateral tubal ligation or bilateral oophorectomy are exempt from this requirement. (Postmenopausal is defined as no menses for the previous 1 year.)
Note: Serum FSH sample will be obtained only from women with cessation of menses within 1 year prior to Visit 1. If a subject’s Visit 1 FSH result is not within the postmenopausal range (as defined by the central laboratory), serum beta-hCG level consistent with a non-gravid state at screening must be demonstrated to continue in the study. These women will be considered to be of childbearing potential during the course of the study (i.e., they should be administered the urine pregnancy tests).
16. Subject must have results of a physical examination, including vital signs, within normal limits or clinically acceptable limits to the investigator and medical monitor (or appropriate designee) prior to the first dose of study medication.
Laboratory Assessments:
17. Subject's screening clinical laboratory tests (CBC and blood chemistry) must be within the following parameters:
a. white blood cells (WBCs) greater than or equal to 3.5 x 109/L
b. neutrophils greater than or equal to 1.5 x 109/L
c. platelets greater than or equal to 100 x 109/L
d. hemoglobin >8.5 g/dL
e. serum creatinine <1.5 mg/dL (or <133 micromol/L)
f. aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase and gammaglutamyl transferase less than or equal to 2 x ULN
g. total bilirubin less than or equal to 1.5 x ULN
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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-articular), azathioprine, sulfasalazine, hydroxychloroquine 4 weeks.
*Leflunomide 8 weeks unless subject undergoes standard cholestyramine or activated charcoal washout in which case 4 weeks washout is required.
*Cytotoxic agents including chlorambucil, cyclophosphamide, nitrogen mustard, or other alkylating agents 3 months.
*Live vaccinations 1 month.
*Investigational medications 30 days or 5 half lives of the investigational agent whichever is longer.
*Bacille Calmette-Guerin (BCG) vaccination 1 month.
a. Subjects will be allowed to take stable doses of oral corticosteroids as specified in inclusion criterion #10; i.e., subjects must be on a stable dose of less than or equal to 10 mg prednisone per day (or equivalent) for at least 2 weeks prior to first administration of study medications.
b. Subjects may be allowed to use leflunomide instead of methotrexate on or after Week 24 of study treatment.

19. Subject taking concomitant doses of statins exceeding those listed below (due to potential drug-drug interaction):
*atorvastatin 40mg daily
*fluvastatin 40mg daily
*pravastatin 40mg daily
*rosuvastatin 20mg daily
*simvastatin 20mg daily
Laboratory Abnormalities
20. Subject has clinically significant abnormalities on screening clinical laboratory safety tests.
Other
21. Subject who is currently participating in another interventional clinical trial or has participated in an interventional clinical trial within 4 weeks prior to screening.
22. The subject or a family member is among the personnel of the investigational or sponsor staff directly involved with this trial.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by phone/fax/computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The treatment assignment in the base study will be assigned by chance (like the flip of a coin) by Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation).
Randomization will be stratified by C-reactive protein (CRP) level at screening and geographical area.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 4414 0
New Zealand
State/province [1] 4414 0
Christchurch
Country [2] 4415 0
New Zealand
State/province [2] 4415 0
Timaru

Funding & Sponsors
Funding source category [1] 285671 0
Commercial sector/Industry
Name [1] 285671 0
MSD - Merck Sharp & Dohme (Australia) Pty Limited
Address [1] 285671 0
MSD - Merck Sharp & Dohme (Australia) Pty Limited
54-68 Ferndell St South Granville NSW 2142
Country [1] 285671 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
MSD - Merck Sharp & Dohme (Australia) Pty Limited
Address
MSD - Merck Sharp & Dohme (Australia) Pty Limited
54-68 Ferndell St South Granville NSW 2142
Country
Australia
Secondary sponsor category [1] 284502 0
Commercial sector/Industry
Name [1] 284502 0
MSD - Merck Sharp & Dohme (New Zealand) Limited
Address [1] 284502 0
Merck Sharp & Dohme (New Zealand) Limited
109 Carlton Gore Rd, Newmarket, Auckland 1023
Country [1] 284502 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 287660 0
Cabrini Human Research Ethics Committee
Ethics committee address [1] 287660 0
183 Wattletree Road
Malvern, VIC 3144
Australia
Ethics committee country [1] 287660 0
Australia
Date submitted for ethics approval [1] 287660 0
20/07/2012
Approval date [1] 287660 0
30/11/2012
Ethics approval number [1] 287660 0
HREC approval ID: CHREC number 07-06-08-12

Summary
Brief summary
In subjects with active Rheumatoid Arthritis (RA), MK-8457 100 mg twice a day will be superior to placebo as measured by the proportion of subjects who achieve ACR20 (American College of Rheumatology Rheumatoid Arthritis Clinical Response Criteria) response after 12 weeks of treatment.
Trial website
Nil
Trial related presentations / publications
Nil
Public notes

Contacts
Principal investigator
Name 34462 0
A/Prof Stephen Hall
Address 34462 0
Emeritus Research
291 Wattletree Road
Malvern East
VIC 3145
Country 34462 0
Australia
Phone 34462 0
+613 95096166
Fax 34462 0
Email 34462 0
StephenHall@emeritusresearch.com
Contact person for public queries
Name 17709 0
Mrs Zoe Armstrong
Address 17709 0
Clinical Research Director, Australia and New Zealand
Global Clinical Trial Operations Merck Sharp & Dohme (Australia) Pty Limited Level 1 – Building A, 26 Talavera Road, Macquarie Park NSW 2113 North Ryde Business Centre Locked Bag 2234 North Ryde NSW 1670 Australia
Country 17709 0
Australia
Phone 17709 0
+61 2 8988 8358
Fax 17709 0
+61-2-89888001
Email 17709 0
zoe.armstrong@merck.com
Contact person for scientific queries
Name 8637 0
Ms Jeny Paul
Address 8637 0
Clinical Project Manager, ANZ - Global Clinical Trials Operations MSD - Merck Sharp & Dohme (Australia) Pty Limited Level 1 – Building A, 26 Talavera Road, Macquarie Park NSW 2113 North Ryde Business Centre Locked Bag 2234 North Ryde NSW 1670 Australia
Country 8637 0
Australia
Phone 8637 0
+61-2-89888152
Fax 8637 0
+61-2-89888001
Email 8637 0
jeny.paul@merck.com

No information has been provided regarding IPD availability
Summary results
No Results