Pulmonary Sarcoidosis
Conditions
Keywords
chronic pulmonary sarcoidosis
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
Interventions
DRUGCMK389
single i.v. dose every 4 weeks
DRUGPlacebo
single i.v. dose every 4 weeks
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Participants will be assigned to one of two treatment arms, either CMK389 or placebo.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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). |
| 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. |
| 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. |
Countries
Czechia, Denmark, Germany, Poland, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in 22 investigative sites in 6 countries.
Pre-assignment details
After obtaining signed informed consent, a screening epoch of 28 days was used to assess subject eligibility.
Participants by arm
| Arm | Count |
|---|---|
| CMK389 10 mg/kg i.v. CMK389 10 mg/kg i.v. every 4 weeks for a total of 4 doses | 31 |
| Placebo i.v. Placebo i.v. every 4 weeks for a total of 4 doses | 31 |
| Total | 62 |
Baseline characteristics
| Characteristic | CMK389 10 mg/kg i.v. | Placebo i.v. | Total |
|---|---|---|---|
| Age, Continuous | 51.5 years STANDARD_DEVIATION 8.69 | 50.7 years STANDARD_DEVIATION 9.36 | 51.1 years STANDARD_DEVIATION 8.96 |
| Race/Ethnicity, Customized Black Or African American | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 28 Participants | 28 Participants | 56 Participants |
| Sex: Female, Male Female | 7 Participants | 13 Participants | 20 Participants |
| Sex: Female, Male Male | 24 Participants | 18 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 31 | 0 / 62 |
| other Total, other adverse events | 21 / 31 | 19 / 31 | 40 / 62 |
| serious Total, serious adverse events | 2 / 31 | 0 / 31 | 2 / 62 |
Outcome results
Primary
Change in Percent Predicted FVC From Baseline to 16 Weeks of Treatment
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.
Time frame: Baseline, Week 16
Population: The Pharmacodynamic (PD) analysis set included all patients with available PD data and no protocol deviations with relevant impact on PD data. Data collected after a change of the steroid dose not based on the clinical status evaluation (CSE) algorithm were excluded from the analysis set if assessed as having a potentially relevant impact on PD data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CMK389 10 mg/kg i.v. | Change in Percent Predicted FVC From Baseline to 16 Weeks of Treatment | -0.48 Percent predicted | Standard Deviation 1.17 |
| Placebo i.v. | Change in Percent Predicted FVC From Baseline to 16 Weeks of Treatment | 1.02 Percent predicted | Standard Deviation 1.13 |
p-value: 0.180480% CI: [-3.56, 0.6]Bayesian analysis
Secondary
Change in 6-minute Walk Distance (6MWD) From Baseline to 16 Weeks of Treatment
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.
Time frame: Baseline, Week 16
Population: The PD analysis set included all patients with available PD data and no protocol deviations with relevant impact on PD data. Data collected after a change of the steroid dose not based on the CSE algorithm were excluded from the analysis set if assessed as having a potentially relevant impact on PD data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| CMK389 10 mg/kg i.v. | Change in 6-minute Walk Distance (6MWD) From Baseline to 16 Weeks of Treatment | 11.21 meters | Standard Error 9.47 |
| Placebo i.v. | Change in 6-minute Walk Distance (6MWD) From Baseline to 16 Weeks of Treatment | 10.50 meters | Standard Error 9.223 |
p-value: 0.47980% CI: [-16.35, 17.76]Mixed effects Model for Repeated Measure
Secondary
Change in Diffusion Capacity of the Lung for Carbon Monoxide (DLCO) From Baseline to 16 Weeks of Treatment
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.
Time frame: Baseline, Week 16
Population: The PD analysis set included all patients with available PD data and no protocol deviations with relevant impact on PD data. Data collected after a change of the steroid dose not based on the CSE algorithm were excluded from the analysis set if assessed as having a potentially relevant impact on PD data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| CMK389 10 mg/kg i.v. | Change in Diffusion Capacity of the Lung for Carbon Monoxide (DLCO) From Baseline to 16 Weeks of Treatment | -0.58 mL/min/mmHg | Standard Error 0.493 |
| Placebo i.v. | Change in Diffusion Capacity of the Lung for Carbon Monoxide (DLCO) From Baseline to 16 Weeks of Treatment | -0.40 mL/min/mmHg | Standard Error 0.448 |
p-value: 0.60880% CI: [-1.05, 0.68]Mixed effects Model for Repeated Measure
Secondary
Change in FEV1 From Baseline to 16 Weeks of Treatment
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.
Time frame: Baseline, Week 16
Population: The PD analysis set included all patients with available PD data and no protocol deviations with relevant impact on PD data. Data collected after a change of the steroid dose not based on the CSE algorithm were excluded from the analysis set if assessed as having a potentially relevant impact on PD data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| CMK389 10 mg/kg i.v. | Change in FEV1 From Baseline to 16 Weeks of Treatment | -0.03 liters (L) | Standard Error 0.033 |
| Placebo i.v. | Change in FEV1 From Baseline to 16 Weeks of Treatment | 0.00 liters (L) | Standard Error 0.032 |
p-value: 0.78380% CI: [-0.09, 0.02]Mixed effects Model for Repeated Measure
Secondary
Number of Participants Who Deteriorate From Baseline to 16 Weeks of Treatment
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.
Time frame: Baseline, Week 16
Population: The PD analysis set included all patients with available PD data and no protocol deviations with relevant impact on PD data. Data collected after a change of the steroid dose not based on the CSE algorithm were excluded from the analysis set if assessed as having a potentially relevant impact on PD data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMK389 10 mg/kg i.v. | Number of Participants Who Deteriorate From Baseline to 16 Weeks of Treatment | 9 Participants |
| Placebo i.v. | Number of Participants Who Deteriorate From Baseline to 16 Weeks of Treatment | 10 Participants |
Secondary
Number of Participants Who Had an Increase in Steroid Usage From Baseline to 16 Weeks of Treatment
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).
Time frame: Baseline, Week 16
Population: The PD analysis set included all patients with available PD data and no protocol deviations with relevant impact on PD data. Data collected after a change of the steroid dose not based on the CSE algorithm were excluded from the analysis set if assessed as having a potentially relevant impact on PD data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CMK389 10 mg/kg i.v. | Number of Participants Who Had an Increase in Steroid Usage From Baseline to 16 Weeks of Treatment | 5 Participants |
| Placebo i.v. | Number of Participants Who Had an Increase in Steroid Usage From Baseline to 16 Weeks of Treatment | 4 Participants |
Secondary
Percent Change in [18F]-FDG-PET/CT (SUVmax and SUVmean) From Baseline to 16 Weeks of Treatment
\[18F\]-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.
Time frame: Baseline, Week 16
Population: The PD analysis set included all patients with available PD data and no protocol deviations with relevant impact on PD data. Data collected after a change of the steroid dose not based on the CSE algorithm were excluded from the analysis set if assessed as having a potentially relevant impact on PD data. This analysis included only participants with a baseline positron emission tomography (PET) signal in the corresponding region.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| CMK389 10 mg/kg i.v. | Percent Change in [18F]-FDG-PET/CT (SUVmax and SUVmean) From Baseline to 16 Weeks of Treatment | Extrathoracic SUVmean | -11.23 percent change from Baseline | Standard Error 13.02 |
| CMK389 10 mg/kg i.v. | Percent Change in [18F]-FDG-PET/CT (SUVmax and SUVmean) From Baseline to 16 Weeks of Treatment | Extrathoracic SUVmax | -12.89 percent change from Baseline | Standard Error 14.361 |
| CMK389 10 mg/kg i.v. | Percent Change in [18F]-FDG-PET/CT (SUVmax and SUVmean) From Baseline to 16 Weeks of Treatment | Lung Parenchyma SUVmean | -34.06 percent change from Baseline | Standard Error 28.626 |
| CMK389 10 mg/kg i.v. | Percent Change in [18F]-FDG-PET/CT (SUVmax and SUVmean) From Baseline to 16 Weeks of Treatment | Lymph Nodes SUVmax | -23.40 percent change from Baseline | Standard Error 9.083 |
| CMK389 10 mg/kg i.v. | Percent Change in [18F]-FDG-PET/CT (SUVmax and SUVmean) From Baseline to 16 Weeks of Treatment | Lymph Nodes SUVmean | -30.83 percent change from Baseline | Standard Error 8.157 |
| CMK389 10 mg/kg i.v. | Percent Change in [18F]-FDG-PET/CT (SUVmax and SUVmean) From Baseline to 16 Weeks of Treatment | Lung Parenchyma SUVmax | -29.23 percent change from Baseline | Standard Error 31.128 |
| Placebo i.v. | Percent Change in [18F]-FDG-PET/CT (SUVmax and SUVmean) From Baseline to 16 Weeks of Treatment | Extrathoracic SUVmean | -23.99 percent change from Baseline | Standard Error 6.44 |
| Placebo i.v. | Percent Change in [18F]-FDG-PET/CT (SUVmax and SUVmean) From Baseline to 16 Weeks of Treatment | Extrathoracic SUVmax | -19.07 percent change from Baseline | Standard Error 6.908 |
| Placebo i.v. | Percent Change in [18F]-FDG-PET/CT (SUVmax and SUVmean) From Baseline to 16 Weeks of Treatment | Lymph Nodes SUVmean | -22.75 percent change from Baseline | Standard Error 9.101 |
| Placebo i.v. | Percent Change in [18F]-FDG-PET/CT (SUVmax and SUVmean) From Baseline to 16 Weeks of Treatment | Lung Parenchyma SUVmax | 26.78 percent change from Baseline | Standard Error 24.461 |
| Placebo i.v. | Percent Change in [18F]-FDG-PET/CT (SUVmax and SUVmean) From Baseline to 16 Weeks of Treatment | Lymph Nodes SUVmax | -16.48 percent change from Baseline | Standard Error 9.759 |
| Placebo i.v. | Percent Change in [18F]-FDG-PET/CT (SUVmax and SUVmean) From Baseline to 16 Weeks of Treatment | Lung Parenchyma SUVmean | 20.74 percent change from Baseline | Standard Error 22.443 |
Secondary
Pre-dose Trough Concentration (Ctrough) of CMK389
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.
Time frame: Pre-dose: Day 1, Day 29, Day 57, Day 85
Population: The PK analysis set included all patients with at least one available valid (i.e. not flagged for exclusion) PK concentration measurement, who received CMK389 and with no protocol deviations with relevant impact on PK data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| CMK389 10 mg/kg i.v. | Pre-dose Trough Concentration (Ctrough) of CMK389 | Day 1 | 0.00 ng/mL |
| CMK389 10 mg/kg i.v. | Pre-dose Trough Concentration (Ctrough) of CMK389 | Day 29 | 83500 ng/mL |
| CMK389 10 mg/kg i.v. | Pre-dose Trough Concentration (Ctrough) of CMK389 | Day 57 | 105000 ng/mL |
| CMK389 10 mg/kg i.v. | Pre-dose Trough Concentration (Ctrough) of CMK389 | Day 85 | 125000 ng/mL |
Secondary
The Observed Serum Concentration Following CMK389 Administration at End of Infusion
Pharmacokinetic parameters were directly derived from the PK concentration data using non-compartmental analysis.
Time frame: Post 1 hour: Day 1, Day 29, Day 57, Day 85
Population: The Pharmacokinetics (PK) analysis set included all patients with at least one available valid (i.e. not flagged for exclusion) PK concentration measurement, who received CMK389 and with no protocol deviations with relevant impact on PK data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| CMK389 10 mg/kg i.v. | The Observed Serum Concentration Following CMK389 Administration at End of Infusion | Day 57 | 571000 ng/mL |
| CMK389 10 mg/kg i.v. | The Observed Serum Concentration Following CMK389 Administration at End of Infusion | Day 85 | 541000 ng/mL |
| CMK389 10 mg/kg i.v. | The Observed Serum Concentration Following CMK389 Administration at End of Infusion | Day 1 | 453000 ng/mL |
| CMK389 10 mg/kg i.v. | The Observed Serum Concentration Following CMK389 Administration at End of Infusion | Day 29 | 533000 ng/mL |