Sarilumab in Patients With Glucocorticoid-Dependent Sarcoidosis

Phase 2

Completed

Conditions: Sarcoidosis

Interventions: Drug: Sarilumab
Drug: Placebo

Registration Number: NCT04008069

Lead Sponsor: Stanford University

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

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 16

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Double-Blind Sarilumab (post-randomization)	Sarilumab	After completing the open-label period, participants are randomized in blinded fashion to receive sarilumab every two weeks for 12 weeks.
Double-Blind Placebo (post-randomization)	Placebo	After completing the open-label period, participants are randomized in blinded fashion to receive placebo every two weeks for 12 weeks.
Open-Label Sarilumab (pre-randomization)	Sarilumab	On entering the study, all participants receive open-label sarilumab every two weeks for 16 weeks.

Primary Outcome Measures

Name	Time	Method
Number of Participants Without Sarcoidosis Flare (Flare-Free Survival)	Week 16 to Week 28	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.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Physician Disease Activity Visual Analogue Scale (VAS)	Baseline, week 16, and week 28	Physician rates patient's disease on a 100 mm VAS. Score range: 0 to 100, higher scores correspond to worse disease state.
Number of Tender and Swollen Joints Per 68/66 Joint Evaluation	Baseline, week 16, and week 28	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
Sarcoidosis Activity and Severity Index for Cutaneous Sarcoidosis	Baseline, week 16, and week 28	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).
Change From Baseline in Serum Angiotensin Converting Enzyme	Baseline, week 16, and week 28	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.
Number of Participants With Serum Creatinine Outside Normal Range	Baseline, week 16, and week 28	Normal range as calculated by the local laboratory.
Change From Baseline in Forced Vital Capacity (FVC) Percent Predicted	Baseline and week 16	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.
Change in Size of Sarcoidosis Lesions	Baseline, week 16, and week 28
Change From Baseline in Hemoglobin-corrected Diffusing Capacity for Carbon Monoxide (DLCO) Percent Predicted	Baseline, and week 16	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.
Change in Pulmonary Function (FEV1) Percent Predicted	Baseline and week 16	FEV1 percent predicted is a normalized value of FEV1 calculated using the Knudson equation and based upon participant age, gender, and height.
Change From Baseline in Extrapulmonary Physician Organ Severity Tool (ePOST) Scale Score	Baseline, week 16, and week 28	Physician and patient assessments assessed using the extrapulmonary physician organ severity tool (ePOST). Score Description: 0: Not affected 1. Slight 2. Mild 3. Moderate 4. Moderate to severe 5. Severe 6. Very Severe 17 organ domains were rated and summed to create a total score (range 0-102, higher scores correspond with more severity).
Change From Baseline in Patient Disease Activity Visual Analogue Scale (VAS)	Baseline, week 16, and week 28	Patient rates their disease on a 100 mm VAS. Score range: 0 to 100, higher scores correspond to worse disease state.
Change From Baseline in FACIT-F Score (Fatigue Scale)	Baseline, week 16, and week 28	FACIT-F score Total score range: 0-52, lower scores correspond with more fatigue.
Change From Baseline in Serum C-Reactive Protein (CRP)	Baseline, week 16, and week 28	CRP is a protein made by the liver. The level of CRP increases when there's inflammation in the body.
Change in Prednisone Dose	Baseline, week 16, and week 28
Change From Baseline in Erythrocyte Sedimentation Rate (ESR)	Baseline, week 16, and week 28	ESR is the rate at which red blood cells in anticoagulated whole blood descend in a standardized tube over a period of one hour.
Number of Participants With Alanine Aminotransferase (ALT) Outside Normal Range	Baseline, week 16, and week 28	Normal range as calculated by the local laboratory.
Number of Participants With Urine Protein Outside Normal Range	Baseline, week 16, and week 28	Normal range as calculated by the local laboratory.
Number of Participants With Aspartate Aminotransferase (AST) Outside Normal Range	Baseline, week 16, and week 28	Normal range as calculated by the local laboratory.