Study of Efficacy, Safety and Tolerability of CMK389 in Patients With Chronic Pulmonary Sarcoidosis

Phase 2

Completed

• Conditions: Pulmonary Sarcoidosis
• Interventions: Drug: CMK389; Drug: Placebo

• Registration Number: NCT04064242
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

The purpose of this proof of concept study was to determine whether CMK389 displays the safety and efficacy profile to support further development in chronic pulmonary sarcoidosis.

Detailed Description

This was a subject and investigator blinded, randomized, placebo-controlled, parallel-group, repeat-dose, multicenter, non-confirmatory study of CMK389 in chronic pulmonary sarcoidosis. This study investigated the safety and efficacy of 10 mg/kg CMK389 administered intravenously (i.v.) every 4 weeks for a total of 4 doses, versus placebo

Study Timeline

• Study First Submitted: 2019-08-20
• Study First Submitted QC: 2019-08-20
• Study First Posted: 2019-08-21
• Study Start: 2020-09-23
• Primary Completion: 2023-09-19
• Study Completion: 2023-12-12
• Status Verified: 2024-09
• Results First Submitted: 2024-09-09
• Results First Submitted QC: 2024-09-09
• Last Update Submitted: 2024-09-09
• Results First Posted: 2024-10-02
• Last Update Posted: 2024-10-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 62

Inclusion Criteria

• Subjects must have a body mass index (BMI) at screening within the range of 18 - 46 kg/m2. BMI = Body weight (kg) / [Height (m)]2
• Biopsy proven pulmonary sarcoidosis diagnosed > 1 year prior to screening
• Scadding stage II, III or IV as determined by the most recent chest x-ray obtained within 12 months prior to screening or at screening (confirmed by the Investigator)
• HRCT extent of fibrosis <20% (confirmed by the central imaging reader) at screening
• Treatment with 5-15 mg/day prednisone (or prednisone oral equivalents) for ≥ 6 months prior to screening.
• Co-medication with methotrexate or azathioprine for ≥ 6 months prior to screening (Note: hydroxychloroquine is allowed as background therapy but not required)
• Able to perform reliable, reproducible pulmonary function test maneuvers per American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines

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Exclusion Criteria

• Diagnosis of significant pulmonary hypertension (WHO group 5) requiring pharmacological treatment
• Active cardiac sarcoidosis requiring treatment. Inactive cardiac sarcoidosis or stable cardiac sarcoidosis not requiring treatment are permissible.
• A known diagnosis of neurosarcoidosis
• Forced vital capacity (FVC) <50% of predicted at screening (central read)
• Modified British Medical Research Council (mMRC) dyspnea scale ≥ 3 at screening
• Concomitant treatment with leflunomide, cyclophosphamide, mycophenolate, infliximab, etanercept, adalimumab, golimumab, ustekinumab, roflumilast, pentoxifylline, and abatacept within 12 weeks of screening
• Prior treatment with rituximab, canakinumab, anakinra, and tocilizumab
• Current use of any inhaled substance, including but not limited to tobacco, marijuana products and use of electronic cigarette or vaping device, and excluding inhalers or nebulizers prescribed for pulmonary sarcoidosis
• Any conditions or significant medical problems which in the opinion of the investigator and in consultation with the sponsor, immunocompromises the patient and/or places the patient at unacceptable risk for immunomodulatory therapy
• Contraindication to FDG-PET scan investigations such as severe claustrophobia or uncontrolled diabetes
• History or current diagnosis of ECG abnormalities not due to Cardiac Sarcoidosis and indicating significant risk of safety for patients participating in the study
• A diagnosis of Lofgren's syndrome
• A history of pancreatitis

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CMK389	CMK389	CMK389 10 mg/kg i.v. every 4 weeks for a total of 4 doses
Placebo	Placebo	Placebo i.v. every 4 weeks for a total of 4 doses

Primary Outcome Measures

Name	Time	Method
Change in Percent Predicted FVC From Baseline to 16 Weeks of Treatment	Baseline, Week 16	To assess the effect of CMK389 compared to placebo after 16 weeks of treatment on spirometry (Forced Vital Capacity). Forced Vital Capacity (FVC) is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Percent predicted FVC is the percentage of the age, height and gender adjusted predicted value.

Secondary Outcome Measures

Name	Time	Method
Number of Participants Who Had an Increase in Steroid Usage From Baseline to 16 Weeks of Treatment	Baseline, Week 16	The Clinical Status Evaluation (CSE) served as a safety evaluation and served to establish the patient's clinical status (Clinical Status Determination \[CSD\]). CSE was performed prior to the titration of steroids, and the CSD guided selection of the next dose of steroids. Participants with CSD of "improved" or "stable" decreased steroid dose by 1 step on the dosing scale. Participants with CSD of "deteriorating" were ineligible to continue the study (if found during the run-in epoch or at study Day 1); or they increased steroid dose by 1 step (if found during the treatment epoch).
Number of Participants Who Deteriorate From Baseline to 16 Weeks of Treatment	Baseline, Week 16	Composite index of pulmonary physiology (CIPP) and exercise capacity: a participant who deteriorated from baseline to each visit was defined as a patient with: relative reduction if FVC ≥ 10%, or relative reduction if FEV1 ≥ 10%, or relative reduction of DLCO ≥ 15%, or relative reduction of 6MWD ≥ 50 m.
Percent Change in [18F]-FDG-PET/CT (SUVmax and SUVmean) From Baseline to 16 Weeks of Treatment	Baseline, Week 16	\[18F\]-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) maximum standardized uptake value and mean standardized uptake value (SUVmax and SUVmean) imaging was used to assess potential anti-inflammatory effects by CMK389 on the sarcoidosis process. All participants underwent whole-body head to mid-thigh \[18F\]FDG-PET/CT imaging state-of-the-art, 3D PET/CT scanners with a reconstructed resolution of ≤5 mm.
The Observed Serum Concentration Following CMK389 Administration at End of Infusion	Post 1 hour: Day 1, Day 29, Day 57, Day 85	Pharmacokinetic parameters were directly derived from the PK concentration data using non-compartmental analysis.
Pre-dose Trough Concentration (Ctrough) of CMK389	Pre-dose: Day 1, Day 29, Day 57, Day 85	Pharmacokinetic parameters were directly derived from the PK concentration data using non-compartmental analysis. Ctrough is the observed plasma concentration that is just prior to the beginning of a dosing interval.
Change in FEV1 From Baseline to 16 Weeks of Treatment	Baseline, Week 16	FEV1 (forced expiratory volume in one second) is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation, measured through spirometry testing. The least-squares means for change from baseline in FEV1 to assess the effect of CMK389 compared to placebo after 16 weeks were obtained from a mixed effects model for repeated measures (MMRM). A positive change from baseline in pre-dose FEV1 is considered a favourable outcome.
Change in Diffusion Capacity of the Lung for Carbon Monoxide (DLCO) From Baseline to 16 Weeks of Treatment	Baseline, Week 16	DLCO is a measurement to assess the lungs' ability to transfer gas from inspired air to the bloodstream. The least squares means for change from baseline in DLCO to assess the effect of CMK389 compared to placebo after 16 weeks were obtained from a mixed effects model for repeated measures (MMRM). A positive change from baseline in DLCO is considered a favourable outcome.
Change in 6-minute Walk Distance (6MWD) From Baseline to 16 Weeks of Treatment	Baseline, Week 16	The 6MWD test is self-paced, with standardized instructions and encouragement being given as participants walk as far as possible over 6 minutes through a flat corridor. The final distance is recorded in meters. The least squares means for change from baseline in 6MWD to assess the effect of CMK389 compared to placebo after 16 weeks were obtained from a mixed effects model for repeated measures (MMRM). A positive change from baseline in 6MWD is considered a favourable outcome.

Trial Locations

Locations (7)

Novartis Investigative Site; 🇬🇧 London, United Kingdom

Univ of Florida College of Medicine x; 🇺🇸 Gainesville, Florida, United States

University of Kansas Medical Center; 🇺🇸 Kansas City, Kansas, United States

John Hopkins Asthma And Alrgy Cntr; 🇺🇸 Baltimore, Maryland, United States

Icahn School Of Med At Mount Sinai .; 🇺🇸 New York, New York, United States

East Carolina University .; 🇺🇸 Greenville, North Carolina, United States

University of Pittsburgh Medical Center; 🇺🇸 Pittsburgh, Pennsylvania, United States