The Immunological Basis for Treatment Resistance to Anti-TNF Treatments

• ClinicalTrials.gov Identifier: NCT01971346
• Recruitment Status: Completed
• First Posted: October 29, 2013
• Results First Posted: January 9, 2019
• Last Update Posted: March 4, 2020
• Sponsor: University of Michigan
• Collaborator: Amgen
• Information provided by (Responsible Party): Johann E Gudjonsson MD, PhD, University of Michigan

Study Description

Brief Summary:

The purpose of this study is to determine the relationship between two types of cell signals, type I interferon (IFN) and tumor necrosis factor (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 or disease	Intervention/treatment	Phase
Psoriasis	Drug: etanercept	Phase 4

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Immunological Basis for Treatment Resistance to Anti-TNF Treatments
• Actual Study Start Date: March 13, 2014
• Actual Primary Completion Date: November 1, 2017
• Actual Study Completion Date: November 1, 2017

Arms and Interventions

Arm	Intervention/treatment
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

Outcome Measures

Primary Outcome Measures :

1. Change in Psoriasis Area and Severity Index (PASI) Score [ Time Frame: Baseline, 12 weeks ]
   A cumulative change in PASI score from baseline to week 12 will be calculated for each patient. The PASI is the industry standard to decrease/eliminate subjectivity in determining psoriasis severity. It is a quantitative rating scale for measuring the severity of psoriatic lesions based on area coverage and plaque appearance. The severity of plaque characteristics (erythema, thickness and scaling) for body regions (head, upper limbs, trunk and lower limbs) is combined with the degree of plaque involvement in each body region to determine a single PASI score in the range of 0 (no disease) and 72 (maximal disease).

Secondary Outcome Measures :

1. Tumor Necrosis Factor (TNF)-Alpha Signal Strength [ Time Frame: Baseline, Week 6, Week 12 ]
   Strength of TNF-alpha signatures will be measured in skin of study subjects at initiation, during and after treatment. The strength of these signals will be done using bioinformatic approach quantifying transcriptional signature of these cytokines. The strength of the cytokine signals will be treated as a response variable in a univariate repeated measure analysis of variance, with PASI response profile and time as covariates. PASI response profile will be categorized according to improvement in 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).
2. Interferon (IFN)-Alpha Signal Strength [ Time Frame: Baseline, Week 6, Week 12 ]
   Strength of IFN-alpha signatures will be measured in skin of study subjects at initiation, during and after treatment. The strength of these signals in skin will be done using bioinformatic approach quantifying transcriptional signature of these cytokines. The strength of the cytokine signals will be treated as a response variable in a univariate repeated measure analysis of variance, with PASI response profile and time as covariates. PASI response profile will be categorized according to improvement in 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).
3. Psoriasis Area and Severity Index (PASI) Response Profile [ Time Frame: 12 Weeks ]
   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).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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 oral psoralen with ultraviolet A (PUVA), oral retinoids, cyclosporine, alefacept, or any other systemic anti-psoriasis therapy within 28 days study drug initiation.
• Use of ulltraviolet B (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; congestive heart failure (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 blood pressure (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 [Nota Bene: 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.
• Diagnosis of multiple sclerosis in first degree family relationship (parent, sibling or child)

Contacts and Locations

Locations

United States, Michigan

University of Michigan Department of Dermatology

Ann Arbor, Michigan, United States, 48109

Sponsors and Collaborators

University of Michigan

Amgen

Investigators

• Principal Investigator: Johann Gudjonsson, MD PhD; University of Michigan

  Study Documents (Full-Text)

Documents provided by Johann E Gudjonsson MD, PhD, University of Michigan:

Study Protocol and Statistical Analysis Plan  [PDF] March 29, 2016

More Information

• Responsible Party: Johann E Gudjonsson MD, PhD, Assistant Professor of Dermatology, Medical School, University of Michigan
• ClinicalTrials.gov Identifier: NCT01971346
• Other Study ID Numbers: Derm 652
• First Posted: October 29, 2013
• Results First Posted: January 9, 2019
• Last Update Posted: March 4, 2020
• Last Verified: March 2020

Keywords provided by Johann E Gudjonsson MD, PhD, University of Michigan:

Psoriasis; ENBREL; etanercept; anti-TNF

Additional relevant MeSH terms:

Psoriasis; Skin Diseases, Papulosquamous; Skin Diseases; Etanercept; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Gastrointestinal Agents; Immunosuppressive Agents; Immunologic Factors