IL1-TRAP, Rilonacept, in Systemic Sclerosis

NCT01538719 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: H31332
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

Scleroderma,also known as systemic sclerosis (SSc), is a multisystem disease affecting skin and other tissues including joints, muscles, lungs, the gastrointestinal tract and kidneys and tissue fibrosis is widespread. SSc presents special problems for developing therapies due to the heterogeneous clinical presentation, the variability of disease progression and the difficulty quantifying the extent of disease. For most disease manifestations, treatment is primarily symptomatic and generally inadequate. This study will utilize a 4-gene biomarker of skin disease as the primary efficacy outcome in a short duration, placebo-controlled clinical trial of rilonacept, designed to provide preliminary data for a larger trial. These gene biomarkers should provide a strong surrogate for such trials in the future and, if IL-1 is indeed the cytokine leading to fibrosis in this disease, provide a highly significant start to finding a therapeutic for SSc that for the first time might dramatically affect fibrosis. A central hypothesis of this study is that IL-1 inhibition will downregulate the 4-gene biomarker over a relatively short period of time, much shorter than is historically thought necessary to see changes in the MRSS, a skin score measurement tool. Entry criteria will include the recent onset of diffuse cutaneous SSc as this is the population most likely to show progressive skin disease and also the population examined in previous studies showing correlations between MRSS and the 4-gene biomarker. Secondary outcomes will include other validated measures of SSc disease activity. MRSS and SSc health assessment questionnaire (SHAQ), will be followed during the trial. This study will also test the effect of rilonacept on global skin gene expression using microarray analyses of skin biopsies. In addition, serum biomarkers of SSc disease activity (COMP, THS-1 and IFI44) and a biomarker of inflammasome activation (CRP) will be tested before and after treatment.

Conditions

Scleroderma; Systemic Sclerosis; Diffuse Scleroderma; Diffuse Systemic Sclerosis

Outcome Measures

Primary Outcomes (1)

• Change in 2- Gene Biomarker

  To investigate the effect of rilonacept on 2-gene biomarker expression in skin after treatment with rilonacept compared to pre-treatment 2-gene biomarker expression. These were measured at visit 3 (Day 42) and visit 1 (Day 0). This was calculated using a previously validated equation (MRSS = -27.6844 + \[4.46(baseline THBS1)\] + \[5.31(ΔMS4A4A) + 4.96(ΔTHBS1)\]). In this equation the expression of two genes (THBS1 and MS4A4) in collected samples are measured via nanostring, and then the expression levels of each gene are inserted into the equation in order to obtain the 2- gene biomarker score. A high biomarker score is equivalent to a high skin score, suggesting a higher severity of the disease.

  Visit 3 (Day 42) - Visit 1 (Day 0)

Secondary Outcomes (1)

• Change in Modified Rodnan Skin Score

  Visit 3 (Day 42) - Visit 1 (Day 0)

Study Arms (2)

Placebo

PLACEBO COMPARATOR

2:1 randomization

Other: Placebo

Rilonacept

ACTIVE COMPARATOR

2:1 randomization

Drug: Rilonacept

Interventions

Rilonacept DRUG

Patients randomized to active study drug will receive Rilonacept 320 mg subcutaneously (SQ) on day 0 and 160 mg SQ each week for 5 additional weeks

Also known as: IL1-TRAP

Rilonacept

Placebo OTHER

Patients randomized to placebo will receive saline subcutaneously (SQ) on day 0 and each week for 5 additional weeks

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Must meet the American College of Rheumatology criteria for systemic sclerosis with diffuse cutaneous involvement and \< 24 months since the onset of the first SSc manifestation other than Raynaud's phenomenon; or has had an increase of MRSS by 5 in the last 6 months.
• Must have a MRSS of ≥ 15.
• Male or female patients ≥ 18 years of age.
• Able and willing to give written informed consent and comply with the requirements of the study protocol.

You may not qualify if:

• Treatment with any investigational agent within 4 weeks of screening or 5 half-lives of the investigational drug (whichever is longer).
• Ongoing use of high dose steroids (\> 10mg/day prednisone or equivalent) or unstable steroid dose in the past 4 weeks.
• Treatment with immunosuppressive (other than low dose steroids), cytotoxic or anti-fibrotic drug within 4 weeks of screening.
• The patient has positive viral hepatitis B, hepatitis C or HIV serologies on screening laboratories. (Patients with a positive hepatitis B surface antibody (HBsAb) test with a history of prior hepatitis B immunization are eligible as long as other criteria are met (i.e., negative tests for: hepatitis B surface antigen \[HBsAg\], hepatitis B core antibody \[HBcAb\], and hepatitis C virus antibody \[HCVAb\]).)
• Known active bacterial, viral fungal mycobacterial, or other infection (including tuberculosis or atypical mycobacterial disease, but excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with i.v. antibiotics within 4 weeks of screening.
• Patients must have a negative PPD tested within 6 months of the time of screening, or past positive PPD treated with appropriate antibiotic prophylaxis.
• Patients with a history of malignancy within the past 5 years.
• Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.
• Scleroderma renal crisis within 6 months or creatinine greater than 2.0
• Pregnancy (a negative pregnancy test will be performed for all women of childbearing potential on study day 0 and 42).
• Male and female patients of child-producing potential must agree to use effective contraception while enrolled on study and receiving the experimental drug, and for at least 3 months after the last treatment.
• Nursing mothers
• Gastrointestinal involvement requiring total parenteral nutrition or hospitalization within the past 3 months for pseudo-obstruction
• Moderately severe pulmonary disease with FVC \< 60%, or DLCO \< 50% predicted.
• Moderately severe cardiac disease with either a history of significant arrhythmia (not to include conduction delays other than trifascicular block, or PVCs or PACs \< 5/minute), clinically significant heart failure, or unstable angina.

Sponsors & Collaborators

• Boston University: lead
• Regeneron Pharmaceuticals: collaborator

Study Sites (1)

Boston University Medical Center

Boston, Massachusetts, 02118, United States

Location

Related Publications (1)

• Mantero JC, Kishore N, Ziemek J, Stifano G, Zammitti C, Khanna D, Gordon JK, Spiera R, Zhang Y, Simms RW, Lafyatis R. Randomised, double-blind, placebo-controlled trial of IL1-trap, rilonacept, in systemic sclerosis. A phase I/II biomarker trial. Clin Exp Rheumatol. 2018 Jul-Aug;36 Suppl 113(4):146-149. Epub 2018 Sep 30.

  PMID: 30277862 DERIVED

MeSH Terms

Conditions

Scleroderma, Diffuse; Scleroderma, Systemic

Interventions

rilonacept

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Skin Diseases

Results Point of Contact

• Title: Eric A Stratton, Sr. Clinical Research Manager
• Organization: Boston University School of Medicine

eas@bu.edu

6174142507

Study Officials

• Robert W Simms, MD

  Boston University Medical Center-Rheum/Arthritis Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: February 21, 2012
• First Posted: February 24, 2012
• Study Start: December 1, 2011
• Primary Completion: January 1, 2017
• Study Completion: August 11, 2017
• Last Updated: May 1, 2018
• Results First Posted: May 1, 2018

Record last verified: 2018-04

Locations

US (1)