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Safety and Efficacy of Tofacitinib vs Methotrexate in the Treatment of Psoriatic Arthritis (PsOLSET-BD)

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ClinicalTrials.gov Identifier: NCT03736161
Recruitment Status : Recruiting
First Posted : November 9, 2018
Last Update Posted : November 9, 2018
Sponsor:
Collaborator:
Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
Information provided by (Responsible Party):
Dr. Prayush Sharma, Globe Pharmaceuticals Limited

Brief Summary:

Title Safety and Efficacy of Tofacitinib vs Methotrexate in the treatment of Psoriatic Arthritis- An Open Label Randomized single center study Psoriatic arthritis is defined as an inflammatory arthropathy associated with skin psoriasis and usually negative for rheumatoid factor. Till date, many NSAIDs, corticosteroids, DMARDs have been used, but the safety and efficacy issues demands more researches. The prevalence of PsA worldwide is about 1%-2% and among patients with psoriasis ranges from 7% to 42%. The pathogenesis of PsA involves many cytokines. Tofacitinib is an oral Janus Kinase (JAK) inhibitor with immunomodulatory and anti-inflammatory mechanism. It binds to JAK and prevents the activation of the JAK-signal transducers and activators of transcription (STAT) signaling pathway which ultimately decreases the production of pro-inflammatory cytokines, and prevents both inflammatory response and the inflammation-induced damage. It has shown better efficacy in many diseases like Rheumatoid Arthritis, Axial spondyloarthropathies, Psoriasis, Psoriatic Arthritis, Alopecia areata, dry eye disease.

This prospective, open label, randomized study will be conducted in inpatient and outpatient departments of Rheumatology, BSMMU, Dhaka, Bangladesh in 110 adult volunteers (>18 years) of both genders diagnosed as psoriatic arthritis. Patients will be divided equally into two groups, Group A will be put on Tofacitinib 5 mg twice daily and Group B will be put on Methotrexate weekly in increasing dose with maximum dose of 25 mg weekly. Groups will be divided on the basis of randomization by random number table. Patients with inadequate response to highest dose of MTX or Tofacitinib 5 mg BD at the end of 3 months will be put on Tofacitinib 5 mg BD or Tofacitinib 10 mg BD respectively. The patients not eligible for therapy will not be included in the study. Patients will be followed up at 1, 3 and 6 months. Baseline characteristics will be monitored and recorded at 3 and 6 months.

The clinical information of the study subjects will be recorded in a structured history, clinical examination and questionnaire. All subjects will be enrolled after having informed written consent. The participants will enjoy every right to participate or withdraw from the study at any point of time. Response to Tofacitinib will be expressed in mean, standard deviation and percentage. Ethical clearance will be taken from the Institutional Review Board (IRB) of BSMMU.


Condition or disease Intervention/treatment Phase
Psoriatic Arthritis Drug: Group A- Tofacitinib Drug: Group B- Methotrexate Phase 3

Detailed Description:

Background:

Psoriatic arthritis is an inflammatory arthropathy associated with skin psoriasis and usually negative for rheumatoid factor. Till date, many non-steroidal anti-inflammatory drugs(NSAIDs), corticosteroids and disease modifying anti rheumatic drugs(DMARDs) have been used, but the safety and efficacy issues demands more researches.

EULAR 2015 guidelines recommends early consideration of csDMARDs(conventional synthetic DMARDs) in patients with peripheral arthritis, particularly in those with adverse prognostic factors and therapy with bDMARD(biological DMARD) in patients with predominantly axial disease that is active and has insufficient response to NSAIDs. Use of NSAIDs is considered the first choice in both peripheral as well as axial disease, but many patients fail to respond to multiple NSAIDs.

Methotrexate is an antifolate drug recommended as first line treatment and has so far shown a promising result in peripheral joint, skin as well nail disease in PsA but its use in axial involvement, enthesitis or dactylitis is yet not recommended. Tofacitinib is an oral Janus kinase inhibitor. It was approved by FDA, USA in 2012 and has shown better efficacy in many diseases like Rheumatoid Arthritis, Axial spondyloarthritis, Psoriasis, Psoriatic Arthritis, Alopecia areata, dry eye disease.

Method:

This prospective open label randomized study will be held in Department of Rheumatology and Department of Dermatology, Bangabandhu Sheikh Mujib Medical University (BSMMU) from September, 2017 to August, 2018 in 110 volunteers aged more than 18 yrs of both genders with the diagnosis of Psoriatic Arthritis (PsA). Patients with PsA for more than 3 months, fulfilling Classification for Psoriatic Arthritis (CASPAR) criteria and not responding to at least 2 NSAIDs at maximum recommended dose over a duration of 1 month will be the basic inclusion criteria.

Sample size was calculated using previous data on the basis of formula for comparative study. The baseline demographic data will be recorded. Patients will be randomized into two groups according to random number table. Group A patients will receive Tofacitinib 5mg BD and Group B patients will receive Methotrexate in increasing dose weekly. All the patients will go through baseline investigations before receiving treatment. Group A patients will be followed up at 1, 3 and 6 months. Group B patients will be followed up monthly for the first 2 months for close monitoring of dose (starting from 15 mg weekly to a maximum dose of 25 mg weekly) and then at 3 and 6 months. Patients with inadequate response to highest dose of MTX or Tofacitinib 5 mg BD at the end of 3 months will be put on Tofacitinib 5 mg BD or Tofacitinib 10 mg BD respectively. Primary endpoint for efficacy will be determined by ACR 20 response. Secondary endpoint will be determined by Disease activity in psoriatic arthritis (DAPSA), Disease Activity Score-28 joints-ESR (DAS-28 ESR), ASDAS-CRP, HAQ-DI Psoriasis Area and Severity Index (PASI), Maastricht Ankylosing Spondylitis Enthesitis Score (MASES), and Visual Assessment Scale(VAS).

Safety will be monitored by clinical examination and laboratory investigations at each follow up.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Open label randomized trial
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Safety and Efficacy of Tofacitinib vs Methotrexate in the Treatment of Psoriatic Arthritis
Actual Study Start Date : November 15, 2017
Estimated Primary Completion Date : February 28, 2019
Estimated Study Completion Date : February 28, 2019


Arm Intervention/treatment
Experimental: Group A- Tofacitinib
Tofacitinib 5mg twice daily orally. Patients will be followed up at 1, 3 and 6 months. Patients with inadequate response to highest dose of MTX or Tofacitinib 5 mg BD at the end of 3 months will be put on Tofacitinib 5 mg BD or Tofacitinib 10 mg BD respectively. Primary endpoint for efficacy will be determined by ACR 20 response.
Drug: Group A- Tofacitinib
Group A patients will receive Tofacitinib 5mg BD. Patients will be followed up at 1, 3 and 6 months. Patients with inadequate response to Tofacitinib 5 mg BD at the end of 3 months will be put on Tofacitinib 10 mg BD. Primary endpoint for efficacy will be determined by ACR 20 response.
Other Name: Tofacitinib

Placebo Comparator: Group B- Methotrexate

Methotrexate in increasing dose weekly with maximum dose up to 25 mg/week orally.

Patients will be followed up monthly for the first 2 months for close monitoring of dose (starting from 15 mg weekly to a maximum dose of 25 mg weekly) and then at 3 and 6 months. Patients with inadequate response to highest dose of MTX or Tofacitinib 5 mg BD at the end of 3 months will be put on Tofacitinib 5 mg BD or Tofacitinib 10 mg BD respectively.

Drug: Group B- Methotrexate
Group B patients will receive Methotrexate in increasing dose weekly with maximum dose up to 25 mg/week. Patients will be followed up at 1, 3 and 6 months. Patients with inadequate response to highest dose of MTX at the end of 3 months will be put on Tofacitinib 5 mg BD. Primary endpoint for efficacy will be determined by ACR 20 response.
Other Name: Methotrexate




Primary Outcome Measures :
  1. American college of Rheumatology 20 (ACR 20) response [ Time Frame: 3 months ]

    This response criteria is achieved if there is 20% improvement in tender or swollen joint counts along with 20% improvement in three of the following five parameters:

    1. Erythrocyte sedimentation rate in mm in 1st hour
    2. Patient assessment in numerical scale of 10 (range: 0-10)
    3. Physician assessment in numerical scale of 10 (range: 0-10)
    4. Visual analog pain scale (range: 0-10)
    5. Disability/functional questionnaire with maximum score of 3 (range: 0-3)


Secondary Outcome Measures :
  1. Ankylosing Spondylitis Disease Activity Score- CRP (ASDAS- CRP) [ Time Frame: 1, 3 and 6 months ]

    This score measures patient reported outcome with the use of following parameters:

    1. Visual analog back pain scale (range: 0-10), greater score with poor outcome
    2. Visual analog peripheral pain/swelling scale (range: 0-10), greater score with poor outcome
    3. Duration of morning stiffness (range: 1-10), greater score with poor outcome
    4. Patient global assessment of disease activity (range 1-10), greater score with poor outcome
    5. C-reactive protein in mg/L, greater score with poor outcome Calculation is done using the formula- 0.12 x Back Pain + 0.06 x Duration of Morning Stiffness + 0.11 x Patient Global + 0.07 x Peripheral Pain/Swelling + 0.58 x Ln(CRP+1)

    A value below 1.3 is considered low disease activity, between 1.3 and 2.1 as moderate disease activity, between 2.1 and 3.5 as high disease activity, and above 3.5 as very high disease.


  2. Disease activity score-28 joint-ESR score (DAS-28) [ Time Frame: 1, 3 and 6 months ]

    Disease activity score for assessment of disease activity of rheumatoid arthritis. It is calculated using the following parameters:

    1. Tender joint count- 28 joints
    2. Swollen joint count- 28 joints
    3. Patient global assessment (range 1-10)
    4. Erythrocyte sedimentation rate in mm in 1st hour Greater score means poor prognosis.A score of greater than 5.1 implies active disease, less than 3.2 low disease activity, and less than 2.6 remission.

  3. Disease activity index for psoriatic Arthritis (DAPSA) [ Time Frame: 1, 3 and 6 months ]

    The DAPSA score consists of five variables: tender and swollen joints (TJC68, SJC66), patient global assessment and patient pain assessment (each on a 10-cm visual analogue scale [VAS]), and CRP. The addition of these variables is the result.

    Disease Activity: 0-4 Remission, 5-14 low, 15-28 moderate, >28 high Disease Activity


  4. Psoriasis Area and Severity Index (PASI) [ Time Frame: 1, 3 and 6 months ]

    PASI combines the assessment of the severity of lesions and the area affected into a single score in the range 0 (no disease) to 72 (maximal disease).

    The body is divided into four sections (head (H) (10% of a person's skin); arms (A) (20%); trunk (T) (30%); legs (L) (40%)). Each of these areas is scored by itself, and then the four scores are combined into the final PASI. For each section, the percent of area of skin involved, is estimated and then transformed into a grade from 0 to 6:

    1. 0% of involved area
    2. < 10% of involved area
    3. 10-29% of involved area
    4. 30-49% of involved area
    5. 50-69% of involved area
    6. 70-89% of involved area
    7. 90-100% of involved area Within each area, the severity is estimated by three clinical signs: erythema, induration and desquamation.

  5. Maastricht Ankylosing Spondylitis Enthesitis Score [ Time Frame: 1, 3 and 6 months ]

    The Maastricht Ankylosing Spondylitis Enthesitis Score uses 13 most specific and sensitive sites. These include the bilateral first and seventh costochondral joints, the anterior and posterior superior iliac spines, the iliac crests, the fifth lumbar spinous process, and the proximal insertion of Achilles tendon.

    Total score-13 Range: 0-13 Greater score implies greeater entheses involvement, and thus greater disease activity.


  6. Health Assessment Questionnaire- Disability Index [ Time Frame: 1, 3 and 6 months ]

    An assessment tool for chronic diseases. A questionnaire where a person indicates the amount of difficulty they have with: dressing and grooming, arising, eating, walking, hygiene, reaching, gripping and performing common daily activities.

    Total score- 3 Range- 0-3 Higher scores indicates higher disability.




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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female patients more than 18 years
  2. Psoriatic arthritis > 3 months with peripheral involvement diagnosed on the basis of CASPAR criteria
  3. Unresponsive to more than 2 NSAIDs at maximum recommended doses for more than 4 weeks, i.e 2 weeks for each NASID

5. Patients with active disease 6. PsA with or without extra-articular features like enthesitis, dactylitis and nail changes

Exclusion Criteria:

  1. Systemic infections requiring hospital admission during the past 6 months
  2. A history of active infectious disorders (including active or latent tuberculosis), and/or a history of chronic or recurrent serious infective diseases, opportunistic infections
  3. Hemoglobin (Hb) < 9 g/dl
  4. White blood cell count < 3000, Neutrophil count < 1000, Platelet count < 100000
  5. Live vaccines within 3 months prior to the first dose
  6. Serum creatinine > upper limit of normal reference range
  7. GFR less than 50 mL/min
  8. Alanine aminotransaminase (ALT) more than 2 times of ULN
  9. Pregnant or breast feeding, females of child-bearing potential not using highly effective contraception
  10. New York Heart Association Class III and IV congestive heart failure
  11. Evidence or history of malignancy, with the exception of adequately treated or excised non-metastatic basal or squamous cell cancer of the skin or cervical carcinoma in situ
  12. Any lymphoproliferative disorder, history of lymphoma, leukemia, or signs and symptoms suggestive of current lymphatic disease

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03736161


Contacts
Contact: Prayush Sharma, MBBS +8801535157897 drprayush@gmail.com
Contact: Md. Asadul Islam, MBBS +8801721446630 asad.kmc13@gmail.com

Locations
Bangladesh
Bangabandhu Sheikh Mujib Medical University Recruiting
Dhaka, Bangladesh, 1205
Contact: Prayush Sharma, MBBS    +8801535157897    drprayush@gmail.com   
Sponsors and Collaborators
Globe Pharmaceuticals Limited
Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
Investigators
Principal Investigator: Prayush Sharma, MBBS BSMMU

Additional Information:
Publications:

Responsible Party: Dr. Prayush Sharma, Principal investigator, Globe Pharmaceuticals Limited
ClinicalTrials.gov Identifier: NCT03736161     History of Changes
Other Study ID Numbers: PsOLSET-BD
First Posted: November 9, 2018    Key Record Dates
Last Update Posted: November 9, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Dr. Prayush Sharma, Globe Pharmaceuticals Limited:
PsA

Additional relevant MeSH terms:
Arthritis
Arthritis, Psoriatic
Joint Diseases
Musculoskeletal Diseases
Spondylarthropathies
Spondylarthritis
Spondylitis
Spinal Diseases
Bone Diseases
Psoriasis
Skin Diseases, Papulosquamous
Skin Diseases
Methotrexate
Tofacitinib
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Protein Kinase Inhibitors