The Immunological Basis for Treatment Resistance to Anti-TNF Treatments

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by University of Michigan
Sponsor:
Collaborator:
Amgen
Information provided by (Responsible Party):
Johann E Gudjonsson MD, PhD, University of Michigan
ClinicalTrials.gov Identifier:
NCT01971346
First received: October 23, 2013
Last updated: September 5, 2014
Last verified: September 2014
  Purpose

The purpose of this study is to determine the relationship between two types of cell signals (type I IFN and TNF) in psoriatic skin prior to and during treatment with etanercept and correlate that information with the degree of the improvement in the psoriasis.


Condition Intervention Phase
Psoriasis
Drug: etanercept
Phase 4

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: The Immunological Basis for Treatment Resistance to Anti-TNF Treatments

Resource links provided by NLM:


Further study details as provided by University of Michigan:

Primary Outcome Measures:
  • change in Psoriasis Area and Severity Index (PASI) score [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    Change in Psoriasis Area and Severity Index (PASI) score from baseline to week 12 will be calculated. The PASI Score will range from 0-72 at each timepoint. A cumulative score reflecting change in PASI during the course of etanercept treatment will be calculated for each patient. This score will then be treated as a continuous response variable, and we will use robust linear modeling to test whether scores are significantly associated with baseline TNF-α signal, baseline IFN-α signal, and/or an interaction between these two signals.


Secondary Outcome Measures:
  • TNF-alpha/IFN-alpha signal strength [ Time Frame: 12 Weeks ] [ Designated as safety issue: No ]
    Strength of TNF-alpha and IFN-alpha signatures will be measured in blood and skin of study subjects at initiation, during and after treatment. The TNF and IFN signals scores are arbitrary parameters calculated from the proportion and fold changes of TNF and IFN specific genes that are differentially expressed in psoriatic skin. These scores are represented as a ratio. The values can range from 0 to infinite but most fall within a range of 0.25 and 10-fold.The strength of these signals in skin will be done using bioinformatic approach quantifying transcriptional signature of these cytokines whereas blood-derived values will be based on serum concentration of these two cytokines. The strength of the cytokine signals in blood and skin will be treated as a response variable in a univariate repeated measure analysis of variance, with PASI response profile and time as covariates

  • Psoriasis Area and Severity Index Response profile [ Time Frame: 12 Weeks ] [ Designated as safety issue: No ]
    Subjects will be categorized according to improvement in Psoriasis Area and Severity Index (PASI) score: responders (greater than 75% reduction in PASI from baseline), intermediate-responders (those with greater than 25% and less than 75% reduction in PASI from baseline), and non-responders (less than 25% reduction in PASI from baseline).


Estimated Enrollment: 50
Study Start Date: March 2014
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Etanercept
100 mg Etanercept injections per week for 3 months.
Drug: etanercept
100 mg Etanercept injections per week (2 separate single-use pre-filled 50 mg subcutaneous injections taken on two separate days) for 3 months
Other Name: ENBREL

Detailed Description:

Hypothesis: The balance between type I IFN and TNF determines the response to anti-TNF treatment. The goal of the proposed study is to address this hypothesis and demonstrate that the strength of the type I IFN signature in psoriatic skin is the major determinant of the clinical response to anti-TNF treatment.

Purpose: Determine the strength of the type I interferon and TNF signal in psoriatic skin prior to and during treatment with etanercept and correlate with degree of clinical improvement.

Study Population: up to 50 subjects, men or women over the age of 18 with clinically stable plaque psoriasis, who meet the wash out requirements and other exclusion criteria

Psoriatic patients will receive 100 mg etanercept per week (2 separate single-use pre-filled 50 mg subcutaneous injections taken on two separate days) for 3 months.

Procedures: Urine pregnancy test, TB test, photography, Physical Examinations, Skin Examinations, Study Drug, Peripheral blood and biopsies

Anticipated Results: We expect that patients with strong IFN-α signature in psoriatic skin along with weak TNF-α signature will have minimal response to anti-TNF treatment, while patients with the opposite pattern, weak IFN and strong TNF signature, will have significant clinical improvement.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • At least 18 years of age at screening.
  • Clinically stable moderate to severe plaque psoriasis at screening and baseline.
  • Subject must be:

    • A man or
    • A woman who is surgically sterile or at least 3 years postmenopausal or
    • A woman of childbearing potential who has had a negative pregnancy test within 7 days before the first dose of study drug.
  • If the subject is sexually active, (s)he must agree to use a medically acceptable form of contraception during screening and throughout the study.

Exclusion Criteria:

  • Grade 3 or 4 adverse events or infections within 28 days before screening, or between the screening visit and drug initiation.
  • Active or chronic infection within 4 weeks before screening visit, or between the screening and baseline visits.
  • Evidence of skin conditions other than psoriasis that would interfere with the evaluations of the effect of study medication on psoriasis.
  • Use of PUVA, oral retinoids, cyclosporine, alefacept, or any other systemic anti-psoriasis therapy within 28 days study drug initiation.
  • Use of UVB therapy, topical steroids at no higher than moderate strength, topical vitamin A or D analog preparations, or anthralin with 14 days of study initiation.
  • Prior or concurrent use of cyclophosphamide therapy
  • Concurrent sulfasalazine therapy.
  • Known hypersensitivity to Enbrel® (etanercept) or any of its components or known to have antibodies to etanercept.
  • Current enrollment in any other investigational device or investigational drug trial(s), or receipt of any other investigational agent(s) within 28 days before baseline visit.
  • Use of any biologic drugs within 28 days of study drug initiation.
  • Concurrent use of Anakinra.
  • Severe comorbidities (diabetes mellitus requiring insulin; CHF of any severity or myocardial infarction or cerebrovascular accident or transient ischemic attack within 3 months of screening visit; unstable angina pectoris, uncontrolled hypertension (sitting systolic BP <80 mm Hg or > 160 or diastolic BP > 100 mm Hg), oxygen-dependent severe pulmonary disease, history of cancer within 5 years (other than resected cutaneous basal or squamous cell carcinoma of the skin or in situ cervical cancer)
  • Known history of tuberculosis (TB), or previous positive purified protein derivative (PPD) test. Any mycobacterial disease or high risk factors for tuberculosis (TB), such as family member with TB, positive purified protein derivative (PPD) or taking anti-tuberculosis medication.
  • Known HIV-positive status or known history of any other immuno-suppressing disease.
  • Concurrent or history of psychiatric disease that would interfere with ability to comply with study protocol or give informed consent.
  • History of alcohol or drug abuse within 12 months of screening visit.
  • Latex sensitivity [NB: only applicable if they are using prefilled syringe or prefilled SureClick™ autoinjector presentations]
  • Exposure to hepatitis B or hepatitis C or to high risk factors for hepatitis B or C, such as intravenous drug use in patient.
  • Systemic lupus erythematosus, history of multiple sclerosis, transverse myelitis, optic neuritis or seizure disorder.
  • Use of a live vaccine 90 days prior to screening visit, or concurrent use of a live vaccine.
  • Any condition or circumstances judged by the patient's physician[or the investigator or medically qualified study staff] to render this clinical trial detrimental or otherwise unsuitable for the patient's participation.
  • History of non-compliance with other therapies.
  • Pregnant or nursing females.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01971346

Contacts
Contact: Kathryn Keeley 734-936-4075 ktkeeley@umich.edu
Contact: Jennifer Bell 734-936-4075 jennbell@umich.edu

Locations
United States, Michigan
University of Michigan Department of Dermatology Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Kathryn Keeley    734-936-4075    ktkeeley@umich.edu   
Sub-Investigator: Andrew Johnston, PhD         
Sub-Investigator: Michael Goldfarb, MD         
Sub-Investigator: Yolanda Helfrich, MD         
Sub-Investigator: Rob Egbers, MD         
Sub-Investigator: Jason Waldinger, MD         
Sub-Investigator: Conroy Chow, MD         
Sub-Investigator: Megan Iacco, MD         
Sub-Investigator: Jeffery Messenger, MD         
Sub-Investigator: Emily Smith, MD         
Sub-Investigator: Michael Kelly-Sell, MD         
Sub-Investigator: Heather Pontasch, MD         
Sponsors and Collaborators
University of Michigan
Amgen
Investigators
Principal Investigator: Johann Gudjonsson, MD PhD University of Michigan
  More Information

No publications provided

Responsible Party: Johann E Gudjonsson MD, PhD, Assistant Professor of Dermatology, Medical School, University of Michigan
ClinicalTrials.gov Identifier: NCT01971346     History of Changes
Other Study ID Numbers: Derm 652
Study First Received: October 23, 2013
Last Updated: September 5, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Michigan:
Psoriasis
ENBREL
etanercept
anti-TNF

Additional relevant MeSH terms:
Psoriasis
Skin Diseases, Papulosquamous
Skin Diseases
TNFR-Fc fusion protein
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Inflammatory Agents
Therapeutic Uses
Antirheumatic Agents
Gastrointestinal Agents
Immunologic Factors
Immunosuppressive Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on October 19, 2014