IRB Number: 14115
Institutional Review Board, Hospital for Special Surgery
December 15, 2014
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Jessica K. Gordon, MD
Research Hypothesis: This study will test safety of IL-1 inhibition by rilonacept in patients with diffuse cutaneous systemic sclerosis (SSc). This study will also test the hypothesis that IL-1 drives fibrosis in SSc, and that inhibition of IL-1 by rilonacept will downregulate expression of the 4-gene biomarker, a biomarker of skin disease in SSc, providing a proof-of-concept for a larger clinical trial of this agent in SSc.
1. To evaluate safety of rilonacept in patients with systemic sclerosis
2. To investigate the effect of rilonacept on 4-gene biomarker expression in skin after treatment with rilonacept compared to pre-treatment 4-gene biomarker expression
Study Drug: Rilonacept
Study Design: This will be as a 2:1 active treatment:placebo, blinded trial, evaluating the effect of short-term treatment with rilonacept on skin expression of the 4-gene biomarker surrogate for the modified Rodnan skin score (MRSS). Study patients will receive weekly treatments for 6 weeks, either rilanocept 320 mg loading dose at day 0 and then 160 mg for each of the 5 subsequent weekly
doses, or placebo. Skin biopsies will be taken to test for 4-gene biomarker expression at day 0 before treatment and one week after the final study drug dose. Sera will be taken to test for protein levels of secreted components of the 4-gene biomarker (cartilage oligomeric protein, thrombospondin-1, and interferon-induced protein 44) at day 0 before treatment and one week after the final study drug dose. Safety assessments will extend to 7 weeks after the final dose of study drug or placebo. Number of Subjects per Group: The study will recruit 24 patients with diffuse cutaneous SSc: 16 patients to receive rilonacept, 8 patients to receive placebo.
Study Duration: 12 weeks.
Patients must meet the following inclusion criteria to be eligible for study entry:
- Must meet the American College of Rheumatology criteria for systemic sclerosis with diffuse cutaneous involvement.
- Onset of the first SSc manifestation other than Raynaud’s phenomenon must be <24 months or first SSc manifestationan can be greater than 24 months if there is an increase in MRSS by 5 within the 6 month period preceding screening.
- 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
Patients will be excluded from the study based on the following criteria:
- 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/mintue), clinically significant heart failure, or unstable angina.
- Hemoglobin: < 8.5 gm/dL
- White blood count < 3,000/mm3 or total neutrophil count < 1,500
- Platelets: < 100,000/mm3
- AST or ALT >2.5 x Upper Limit of Normal.
- total bilirubin > 1.5 x upper limit of normal (ULN). Patients with Gilbert’s Disease may be included if their total bilirubin is ≤ 3.0 mg/dL.
- Patients should not have received any live vaccine within 30 days of trial entry
- Patients with a history of rilonacept allergy will be excluded.
- Patients who, in the opinion of the Investigator, have significant medical or psychosocial problems that warrant exclusion. Examples of significant problems include, but are not limited to:
- Other serious non-malignancy-associated medical conditions that may be expected to limit life expectancy or significantly increase the risk of SAEs. Any condition, psychiatric, substance abuse, or otherwise, that, in the opinion of the Investigator, would preclude informed consent, consistent follow-up, or compliance with any aspect of the study.
- Concomitant administration of other agents that block IL-1 or its receptors