Sarilumab in Patients With Glucocorticoid-Dependent Sarcoidosis

Study Overview
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Brief Summary
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The purpose of this study is to compare the effectiveness and the safety of sarilumab in patients with glucocorticoid-dependent sarcoidosis.

Detailed Description
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The purpose of this study is to compare the effectivness and the safety of sarilumab in patients with glucocorticoid-dependent sarcoidosis. To demonstrate that sarilumab treatment will be effective for inducing and maintaining glucocorticoid-free remission in male or female patients with biopsy proven active, glucocorticoid-dependent sarcoidosis affecting the lungs, lymph nodes, liver, kidneys, spleen, bone, soft tissues, skin, and/or eyes.

Official Title
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A Phase II, Single-Site, Double-Blind, Placebo-Controlled Randomized Withdrawal Study Assessing the Efficacy and Safety of Sarilumab in Patients With Glucocorticoid-Dependent Sarcoidosis

Conditions
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Sarcoidosis

Intervention / Treatment
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* Drug: Sarilumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy proven non-caseating granulomas consistent with sarcoidosis negative infectious studies including AFB and fungal stains, and with compatible clinical and/or radiographic manifestations of sarcoidosis. Involvement of the lungs (stage II or III pulmonary sarcoidosis), lymph nodes, liver, kidneys, spleen, bone, soft tissues, skin, and/or eyes. At least one active manifestation, defined by the need for ongoing glucocorticoid treatment to control a sign or symptom of sarcoidosis, which requires treatment with prednisone (or equivalent corticosteroid) ≥ 10 mg and ≤ 60 mg daily (i.e. glucocorticoid dependence), with stable dosing for ≥ 28 days prior to baseline. patients taking a glucocorticoid other than prednisone, will be changed to prednisone at the equivalent dose and take this daily for ≥ 14 days prior to baseline. DMARDs including methotrexate, leflunomide, azathioprine, mycophenolate mofetil, and/or anti-malarials (i.e. hydroxychloroquine) permitted must be stable for ≥ 28 days prior to baseline and remain stable during follow-up. Exclusion Criteria: Stage IV pulmonary sarcoidosis. Central nervous system sarcoidosis. Cardiac sarcoidosis. Prior treatment with an anti-IL-6 therapy. Treatment with a biologic agent including rituximab, belimumab, TNF inhibitors, abatacept, or IL-17 inhibitors administered within 28 days prior to baseline (6 months for rituximab). Treatment with cyclophosphamide within 3 months prior to baseline. Treatment with prednisone < 10 mg or > 60 mg daily. Known hypersensitivity or allergy to the study drug. History of, or current, inflammatory or autoimmune disease other than sarcoidosis which would present a safety issue or confound interpretation of the data. Prior or current history of other significant concomitant illness that, according to the investigator's judgment, would adversely affect the patient's participation in the study. These include, but are not limited to, cardiovascular (including stage III or IV cardiac failure according to the New York Heart Association classification), neurological (including demyelinating disease), active infectious diseases, or history of diverticulitis or gastrointestinal perforation. Patients currently pregnant or breast-feeding. Women of childbearing potential (WOCBP) who are unwilling to utilize adequate contraception and unwilling to not become pregnant during the full course of the study (must be willing to be tested for pregnancy). Adequate contraceptive measures include oral contraceptives (continuous use, as per prescription, for 2 or more cycles prior to screening), intrauterine devices, contraceptive sponges, condoms or diaphragms plus foam, or jelly, or surgical procedures such as bilateral tubal ligation or vasectomy in partner. Administration of a live/attenuated vaccine within 30 days. Evidence of active tuberculosis, HIV, or hepatitis B or C infection. History of cancer other than non-melanoma skin cancer. Patients with any of the following laboratory abnormalities at the screening visit: hemoglobin <8.5 g/dL, white blood cells <3000/mm3, neutrophils <2000/mm3, platelet count <150,000 cells/mm3, aspartate aminotransferase (AST) or ALT >1.5 x ULN, and/or bilirubin (total) above the upper limit of normal (unless Gilbert's disease has been determined by genetic testing and documented). Presence of severe uncontrolled hypercholesterolemia (>350 mg/dL, 9.1 mmol/L) or hypertriglyceridemia (>500 mg/dL, 5.6 mmol/L) at screening or baseline. Patients with calculated creatinine clearance <30 mL/minute (using Cockroft-Gault formula). History of alcohol or drug abuse within 5 years prior to the screening visit. Participation in any clinical research study evaluating another investigational drug or therapy within 5 half-lives or 60 days of first investigational medicinal product (IMP) administration, whichever is longer. Any patient who has had surgery within 4 weeks prior to the screening visit or with planned surgery during the course of the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: All subjects will all receive sarilumab 200 mg subcutaneously every two weeks for the first 16 weeks of the study. At Week 16, those patients who were able to successfully taper off of prednisone will then be assigned randomly to receive either sarilumab 200 mg subcutaneously every two weeks (study drug) or placebo subcutaneously for an additional 12 weeks.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-Label Sarilumab (pre-randomization)<br>On entering the study, all participants receive open-label sarilumab every two weeks for 16 weeks. | Drug: Sarilumab<br>* Sarilumab 200 mg administered subcutaneously<br>* Other names: Kevzara;|
| Experimental: Double-Blind Sarilumab (post-randomization)<br>After completing the open-label period, participants are randomized in blinded fashion to receive sarilumab every two weeks for 12 weeks. | Drug: Sarilumab<br>* Sarilumab 200 mg administered subcutaneously<br>* Other names: Kevzara;|
| Placebo Comparator: Double-Blind Placebo (post-randomization)<br>After completing the open-label period, participants are randomized in blinded fashion to receive placebo every two weeks for 12 weeks. | Drug: Placebo<br>* Placebo administered subcutaneously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Without Sarcoidosis Flare (Flare-Free Survival) | The primary outcome was flare-free survival of sarilumab-treated patients compared to placebo-treated controls. Patients will be considered to have flared if they receive rescue medication including increased glucocorticoids, or if they discontinue the study treatment in order to start a different therapy. | Week 16 to Week 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Forced Vital Capacity (FVC) Percent Predicted | FVC is a pulmonary function test, and is defined as the volume of air that can forcibly be blown out after taking a full breath. FVC% predicted is defined as FVC% of the patient divided by the average FVC% in the population for any person of similar age, sex and body composition. | Baseline and week 16 | 
| Change From Baseline in Hemoglobin-corrected Diffusing Capacity for Carbon Monoxide (DLCO) Percent Predicted | DLCO is a pulmonary function test, and measures the partial pressure difference between inspired and expired carbon monoxide. DLCO% predicted is defined as DLCO% of the patient divided by the average DLCO% in the population for any person of similar age, sex and body composition. | Baseline, and week 16 | 
| Change in Pulmonary Function (FEV1) Percent Predicted | FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height. | Baseline and week 16 | 
| Change From Baseline in Extrapulmonary Physician Organ Severity Tool (ePOST) Scale Score | Physician and patient assessments assessed using the extrapulmonary physician organ severity tool (ePOST). Score Description: 0: Not affected Slight Mild Moderate Moderate to severe Severe Very Severe 17 organ domains were rated and summed to create a total score (range 0-102, higher scores correspond with more severity). | Baseline, week 16, and week 28 | 
| Change From Baseline in Physician Disease Activity Visual Analogue Scale (VAS) | Physician rates patient's disease on a 100 mm VAS. Score range: 0 to 100, higher scores correspond to worse disease state. | Baseline, week 16, and week 28 | 
| Change From Baseline in Patient Disease Activity Visual Analogue Scale (VAS) | Patient rates their disease on a 100 mm VAS. Score range: 0 to 100, higher scores correspond to worse disease state. | Baseline, week 16, and week 28 | 
| Change From Baseline in FACIT-F Score (Fatigue Scale) | FACIT-F score Total score range: 0-52, lower scores correspond with more fatigue. | Baseline, week 16, and week 28 | 
| Number of Tender and Swollen Joints Per 68/66 Joint Evaluation | The 66/68 Joint Count evaluates 68 joints for tenderness and pain with movement and 66 joints for swelling (hip joints can be evaluated for tenderness only, not for swelling. Joint evaluation score: 0: Absent 1: Present 9: Not applicable | Baseline, week 16, and week 28 | 
| Sarcoidosis Activity and Severity Index for Cutaneous Sarcoidosis | Sarcoidosis Activity and Severity Index evaluates 7 parameters on a 0 to 4 scale, summed for an overall scale score of 0 to 28 (higher values indicate higher activity/severity). | Baseline, week 16, and week 28 | 
| Change in Size of Sarcoidosis Lesions |  | Baseline, week 16, and week 28 | 
| Change From Baseline in Serum Angiotensin Converting Enzyme | ACE is a serum marker that is increased in sarcoidosis. ACE is produced by epithelioid cells that are derived from recently-activated macrophages in granulomas; thus, ACE is an appropriate representative of whole-body granuloma. | Baseline, week 16, and week 28 | 
| Change From Baseline in Serum C-Reactive Protein (CRP) | CRP is a protein made by the liver. The level of CRP increases when there's inflammation in the body. | Baseline, week 16, and week 28 | 
| Change From Baseline in Erythrocyte Sedimentation Rate (ESR) | ESR is the rate at which red blood cells in anticoagulated whole blood descend in a standardized tube over a period of one hour. | Baseline, week 16, and week 28 | 
| Change in Prednisone Dose |  | Baseline, week 16, and week 28 | 
| Number of Participants With Alanine Aminotransferase (ALT) Outside Normal Range | Normal range as calculated by the local laboratory. | Baseline, week 16, and week 28 | 
| Number of Participants With Aspartate Aminotransferase (AST) Outside Normal Range | Normal range as calculated by the local laboratory. | Baseline, week 16, and week 28 | 
| Number of Participants With Serum Creatinine Outside Normal Range | Normal range as calculated by the local laboratory. | Baseline, week 16, and week 28 | 
| Number of Participants With Urine Protein Outside Normal Range | Normal range as calculated by the local laboratory. | Baseline, week 16, and week 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glucocorticoid-dependent