Study of Efficacy, Safety and Tolerability of ACZ885 (Canakinumab) in Patients With Pulmonary Sarcoidosis

Study Overview
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Brief Summary
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The purpose of this study is to assess if ACZ885 will improve lung function in association with reduction of tissue inflammation in patients with chronic sarcoidosis.

Official Title
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A Multiple-dose, Subject and Investigator Blinded, Placebo-controlled, Parallel Design Study to Assess the Efficacy, Safety and Tolerability of ACZ885(Canakinumab) in Patients With Pulmonary Sarcoidosis

Conditions
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Pulmonary Sarcoidosis

Intervention / Treatment
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* Drug: ACZ885
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male and female subjects ages 18 to 80 years of age (both inclusive) Pulmonary sarcoidosis disease duration of ≥1 year Clinically active disease demonstrated either by a biopsy (any organ) or by bronchoalevolar lavage (lymphocytosis >15%, CD4+/CD8+ ration>3.5, CD103+/CD4+/CD4+ ratio <0.2). Patients must also have all of the following criteria: MMRC dyspnea scale ≥1 Threshold FVC 50 - 90% of predicted Evidence of parenchymal lung involvement by HRCT at screening or by historical radiological evidence (e.g. CT, MRI or x-ray) Key Exclusion Criteria: Treated pulmonary hypertension Previous exposure to concomitant treatment according to the following criteria: Prednisone >15 mg/day or changes in prednisone dose in the 8 weeks prior to screening More than one immune-modulator (i.e., methotrexate, azathioprine, leflunomide, hydroxychloroquine) or changes in their dosing levels within 12 weeks of randomization. Mycophenolate use within 12 weeks of randomization Prior treatment with any biologic drug targeting the immune system within 180 days of randomization or history of any previous use of rituximab History of bleeding disorder Forced vital capacity (FVC) <50% of predicted Extra-pulmonary sarcoidosis as primary treatment indication (e.g., involving brain, heart, eye and renal disease with significant hypercalcemia) Any conditions or significant medical problems which in the opinion of the investigator immune-compromise the patient and/or places the patient at unacceptable risk for immunomodulatory therapy, such as: Absolute neutrophil count (ANC) <LLN (1,500/μl) Thrombocytopenia CTCAE v4.03 Grade 1: Platelets <LLN (75.0 x 10exp9/L) Any active or recurrent bacterial, fungal (with exception of onychomycosis) or viral infection Presence of human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C infections based on screening lab results Presence of active or latent tuberculosis (Tb). If historical Tb result is available, Tb status needs to be confirmed pre-randomization as determined by screening laboratory measurements. Clinical evidence or history of multiple sclerosis or other demyelinating diseases, or Felty's syndrome Live vaccinations within 3 months prior to the start of the trial Current severe progressive or uncontrolled disease which in the judgment of the clinical investigator renders the patient unsuitable for the trial Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using methods of contraception defined in the protocol for 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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ACZ885<br>ACZ885 (300 mg/2 mL) will be administered subcutaneously to assigned study subjects once monthly for 6 months. | Drug: ACZ885<br>* ACZ885 will be administered subcutaneously to assigned study subjects once monthly for 6 months.<br>* Other names: Canakinumab;|
| Placebo Comparator: Placebo<br>Placebo (0 mg/2 mL) will be administered subcutaneously to assigned study subjects once monthly for 6 months. | Drug: Placebo<br>* Placebo will be administered subcutaneously to assigned study subjects once monthly for 6 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change Between Baseline and Week 24 in Pulmonary Function as Measured by Spirometry | To compare the effect of ACZ885 versus placebo in the change between baseline and week 24 in pulmonary function as measured by spirometry (Predicted Forced Vital Capacity). | Baseline, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change Between Baseline and Week 12 in Pulmonary Tissue Inflammation (Lung Parenchyma) as Measured by SUVmax[F-18]FDG-PET/CT | To determine the effect of ACZ885 on the change of pulmonary tissue inflammation as measured by SUVmax[F-18]FDG-PET/CT from baseline after 12 weeks of treatment compared to placebo. | Baseline, Week 12 | 
| Change Between Baseline and Week 12 in Nodular Uptake Regions as Measured by SUVmax[F-18]FDG-PET/CT | To determine the effect of ACZ885 on decreasing the maximum standardized uptake value (SUVmax) [F-18]FDG-PET in nodules (nodular uptake regions) after 12 weeks of treatment, compared to placebo. | Baseline, Week 12 | 
| Change Between Baseline and Week 12 in in the Extrathoracic Region as Measured by SUVmax[F-18]FDG-PET/CT | To determine the effect of ACZ885 on decreasing the maximum standardized uptake value (SUVmax) [F-18]FDG-PET in in the extrathoracic Region after 12 weeks of treatment, compared to placebo. | Baseline, Week 12 | 
| Change From Baseline in Other Parameters of Pulmonary Function Testing (FEV 1, 3, 6 Seconds and Predicted) | To determine the effect of ACZ885 versus placebo on other parameters of pulmonary function testing in patients with sarcoidosis at 24 weeks compared to baseline. Forced Expiratory Volume (FEV) in 1, 3, 6 seconds, predicted and forced expiratory flow 25-75%. Results expressed in change from baseline | Baseline, week 24 | 
| Change From Baseline in High Resolution Computed Tomography (HRCT) Scoring | To determine the effect of ACZ885 versus placebo on HRCT of patients with sarcoidosis at 24 weeks compared to initial HRCT scan as measured by side-by-side comparison by blinded reviewers and HRCT scoring. HRCT score : sum of total parameters scores, each measured in different lung zones (right upper lobe; left upper lobe; right middle lobe; right lower lobe; left lower lobe). The extent of the disease is assessed for each zone to the nearest 10% of parenchymal surface: 0 (no disease) to 10 (91-100% disease). | Baseline, Week 24 | 
| Change From Baseline Distance Walked as Assessed by the 6-minute Walk Test | To determine the effect of ACZ885 versus placebo on the 6-minute walk test distance of patients with sarcoidosis at 12 and 24 weeks compared to baseline | Baseline, Week 12, and Week 24 | 
| Change From Baseline of Additional [F-18]FDG-PET Outcomes | To determine the effect of ACZ885 on additional [F-18]FDG-PET outcomes after 12 weeks of treatment compared to placebo. SUVmean: Mean standard uptake value for activity in the focal region volume SUVpeak: Mean standardized uptake value of a sphere (a diamater of approximately 1.2cm - to produce a 1-cm3-volume spherical Region of Interest (ROI) that has the highest average SUV with the lesion volume | Baseline, Week 12 | 
| Change From Baseline in Other Parameters of Pulmonary Function Testing : Diffusion Capacity of Lung for CO | To determine the effect of ACZ885 versus placebo on other parameters of pulmonary function testing in patients with sarcoidosis at 24 weeks compared to baseline. | Baseline, week 24 | 
| Change From Baseline in Other Parameters of Pulmonary Function Testing : Percent Predicted DLco, FEV1/FVC, FEV3/FVC, Percent Predicted Forced Expiratory Flow (FEF) 25-75, RV/TLC (Residual Volume /Total Lung Capacity) | To determine the effect of ACZ885 versus placebo on other parameters of pulmonary function testing in patients with sarcoidosis at 24 weeks compared to baseline. Percent Predicted DLco (Diffusion Capacity of Lung for CO), FEV1/FVC, FEV3/FVC (forced expiratory volume in 1 or 3 seconds /forced vital capacity), percent Predicted FEF25-75, RV/TLC | Baseline, week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pulmonary sarcoidosis, sarcoidosis, canakinumab, autoimmune diseases, granulomas, inflammation, lung function testing, immunosuppressive agents, interleukin, interleukin-1Beta, [F-18]FDG-PET/CT, respiratory, pulmonary, steroids, corticosteroids, lung diseases