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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02888080

Enrollment

Registered

2016-09-02

Start date

2016-12-19

Completion date

2019-03-04

Last updated

2021-10-04

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pulmonary Sarcoidosis

Keywords

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

Brief summary

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.

Interventions

DRUGACZ885

ACZ885 will be administered subcutaneously to assigned study subjects once monthly for 6 months.

DRUGPlacebo

Placebo will be administered subcutaneously to assigned study subjects once monthly for 6 months.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

Healthy volunteers

Inclusion criteria

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: 1. MMRC dyspnea scale ≥1 2. Threshold FVC 50 - 90% of predicted 3. 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: 1. Prednisone \>15 mg/day or changes in prednisone dose in the 8 weeks prior to screening 2. More than one immune-modulator (i.e., methotrexate, azathioprine, leflunomide, hydroxychloroquine) or changes in their dosing levels within 12 weeks of randomization. 3. 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: 1. Absolute neutrophil count (ANC) \<LLN (1,500/μl) 2. Thrombocytopenia CTCAE v4.03 Grade 1: Platelets \<LLN (75.0 x 10exp9/L) 3. Any active or recurrent bacterial, fungal (with exception of onychomycosis) or viral infection 4. Presence of human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C infections based on screening lab results 5. 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. 6. 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.

Design outcomes

Primary

Measure	Time frame	Description
Change Between Baseline and Week 24 in Pulmonary Function as Measured by Spirometry	Baseline, Week 24	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).

Secondary

Measure	Time frame	Description
Change Between Baseline and Week 12 in Nodular Uptake Regions as Measured by SUVmax[F-18]FDG-PET/CT	Baseline, Week 12	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.
Change Between Baseline and Week 12 in in the Extrathoracic Region as Measured by SUVmax[F-18]FDG-PET/CT	Baseline, Week 12	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.
Change From Baseline in Other Parameters of Pulmonary Function Testing (FEV 1, 3, 6 Seconds and Predicted)	Baseline, week 24	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
Change From Baseline in High Resolution Computed Tomography (HRCT) Scoring	Baseline, Week 24	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).
Change Between Baseline and Week 12 in Pulmonary Tissue Inflammation (Lung Parenchyma) as Measured by SUVmax[F-18]FDG-PET/CT	Baseline, Week 12	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.
Change From Baseline of Additional [F-18]FDG-PET Outcomes	Baseline, Week 12	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
Change From Baseline in Other Parameters of Pulmonary Function Testing : Diffusion Capacity of Lung for CO	Baseline, week 24	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.
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)	Baseline, week 24	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
Change From Baseline Distance Walked as Assessed by the 6-minute Walk Test	Baseline, Week 12, and Week 24	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

Countries

Germany, Netherlands, United States

Participant flow

Pre-assignment details

Safety Analysis set : 20 patients ACZ885 and 20 patients Placebo PK Analysis set : 20 patients ACZ885 PD Analysis set : 20 patients CAZ885 and 20 patients placebo

Participants by arm

Arm	Count
ACZ885 ACZ885 (300 mg s.c. once monthly for 6 months)	20
Placebo Placebo (s.c. once monthly for 6 months)	20
Total	40

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	0	1
Overall Study	Lack of Efficacy	0	1
Overall Study	New Therapy for study indication	1	0
Overall Study	Subject / Guardian decision	1	3

Baseline characteristics

Characteristic	ACZ885	Placebo	Total
Age, Continuous	51.9 years STANDARD_DEVIATION 8.45	48.1 years STANDARD_DEVIATION 9.94	50.0 years STANDARD_DEVIATION 9.3
Race/Ethnicity, Customized Asian	0 Participants	2 Participants	2 Participants
Race/Ethnicity, Customized Black or African American	2 Participants	1 Participants	3 Participants
Race/Ethnicity, Customized Other	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized White	18 Participants	16 Participants	34 Participants
Sex: Female, Male Female	8 Participants	4 Participants	12 Participants
Sex: Female, Male Male	12 Participants	16 Participants	28 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 20	0 / 20
other Total, other adverse events	15 / 20	14 / 20
serious Total, serious adverse events	3 / 20	4 / 20

Outcome results

Primary

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).

Time frame: Baseline, Week 24