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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.
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| CMK389 | Experimental | CMK389 10 mg/kg i.v. every 4 weeks for a total of 4 doses |
|
| Placebo | Placebo Comparator | Placebo i.v. every 4 weeks for a total of 4 doses |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| CMK389 | Drug | single i.v. dose every 4 weeks |
| |
| Placebo |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline, Week 16 |
| Measure | Description | Time Frame |
|---|---|---|
| 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). |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Novartis Investigative Site | Birmingham | Alabama | 35294-3300 | United States | ||
| Univ of Florida College of Medicine x |
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| Label | URL |
|---|---|
| A Plain Language Trial Summary is available on www.novctrd.com | View source |
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Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.
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After obtaining signed informed consent, a screening epoch of 28 days was used to assess subject eligibility.
Participants took part in 22 investigative sites in 6 countries.
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| ID | Title | Description |
|---|---|---|
| FG000 | CMK389 10 mg/kg i.v. | CMK389 10 mg/kg i.v. every 4 weeks for a total of 4 doses |
| FG001 | Placebo i.v. | Placebo i.v. every 4 weeks for a total of 4 doses |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jun 23, 2022 | Sep 9, 2024 |
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Participants will be assigned to one of two treatment arms, either CMK389 or placebo.
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| Drug |
single i.v. dose every 4 weeks |
|
| Baseline, Week 16 |
| 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. | Baseline, Week 16 |
| 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. | Baseline, Week 16 |
| 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. | Post 1 hour: Day 1, Day 29, Day 57, Day 85 |
| 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. | Pre-dose: Day 1, Day 29, Day 57, Day 85 |
| 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. | Baseline, Week 16 |
| 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. | Baseline, Week 16 |
| 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. | Baseline, Week 16 |
| Gainesville |
| Florida |
| 32610 |
| United States |
| University of Kansas Medical Center | Kansas City | Kansas | 66160-7330 | United States |
| John Hopkins Asthma And Alrgy Cntr | Baltimore | Maryland | 21224 | United States |
| Icahn School Of Med At Mount Sinai . | New York | New York | 10029 | United States |
| East Carolina University . | Greenville | North Carolina | 27858 | United States |
| University of Pittsburgh Medical Center | Pittsburgh | Pennsylvania | 15213 | United States |
| Novartis Investigative Site | Brno | 625 00 | Czechia |
| Novartis Investigative Site | Olomouc | 779 00 | Czechia |
| Novartis Investigative Site | Aarhus N | 8200 | Denmark |
| Novartis Investigative Site | Hellerup | 2900 | Denmark |
| Novartis Investigative Site | Odense C | DK 5000 | Denmark |
| Novartis Investigative Site | Heidelberg | Baden-Wurttemberg | 69126 | Germany |
| Novartis Investigative Site | Essen | 45147 | Germany |
| Novartis Investigative Site | Frankfurt | 60596 | Germany |
| Novartis Investigative Site | Hamburg | 20246 | Germany |
| Novartis Investigative Site | Hanover | 30625 | Germany |
| Novartis Investigative Site | Bialystok | 15-044 | Poland |
| Novartis Investigative Site | Lodz | 90 153 | Poland |
| Novartis Investigative Site | Warsaw | 01-138 | Poland |
| Novartis Investigative Site | Edinburgh | EH1 1BE | United Kingdom |
| Novartis Investigative Site | London | SW3 6PH | United Kingdom |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | CMK389 10 mg/kg i.v. | CMK389 10 mg/kg i.v. every 4 weeks for a total of 4 doses |
| BG001 | Placebo i.v. | Placebo i.v. every 4 weeks for a total of 4 doses |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Mean | Standard Deviation | Percent predicted | Baseline, Week 16 |
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| 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). | 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. | Posted | Count of Participants | Participants | Baseline, Week 16 |
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| 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. | 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. | Posted | Count of Participants | Participants | Baseline, Week 16 |
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| 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. | 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. | Posted | Least Squares Mean | Standard Error | percent change from Baseline | Baseline, Week 16 |
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| 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. | 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. | Posted | Median | Full Range | ng/mL | Post 1 hour: Day 1, Day 29, Day 57, Day 85 |
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| 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. | 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. | Posted | Median | Full Range | ng/mL | Pre-dose: Day 1, Day 29, Day 57, Day 85 |
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| 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. | 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. | Posted | Least Squares Mean | Standard Error | liters (L) | Baseline, Week 16 |
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| 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. | 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. | Posted | Least Squares Mean | Standard Error | mL/min/mmHg | Baseline, Week 16 |
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| 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. | 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. | Posted | Least Squares Mean | Standard Error | meters | Baseline, Week 16 |
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Adverse events were reported from first dose of study treatment until end of study treatment plus follow up period, up to a maximum duration of approximately 197 days..
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | CMK389 10 mg/kg i.v | CMK389 10 mg/kg i.v. every 4 weeks for a total of 4 doses | 0 | 31 | 2 | 31 | 21 | 31 |
| EG001 | Placebo i.v | Placebo i.v. every 4 weeks for a total of 4 doses | 0 | 31 | 0 | 31 | 19 | 31 |
| EG002 | Total | Total | 0 | 62 | 2 | 62 | 40 | 62 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Head injury | Injury, poisoning and procedural complications | MedDRA (22.0) | Systematic Assessment |
| |
| Squamous cell carcinoma of skin | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (22.0) | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | MedDRA (22.0) | Systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA (22.0) | Systematic Assessment |
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| Chest pain | General disorders | MedDRA (22.0) | Systematic Assessment |
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| Fatigue | General disorders | MedDRA (22.0) | Systematic Assessment |
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| COVID-19 | Infections and infestations | MedDRA (22.0) | Systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA (22.0) | Systematic Assessment |
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| Upper respiratory tract infection | Infections and infestations | MedDRA (22.0) | Systematic Assessment |
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| Urinary tract infection | Infections and infestations | MedDRA (22.0) | Systematic Assessment |
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| Ligament sprain | Injury, poisoning and procedural complications | MedDRA (22.0) | Systematic Assessment |
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| Blood alkaline phosphatase increased | Investigations | MedDRA (22.0) | Systematic Assessment |
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| Blood creatinine increased | Investigations | MedDRA (22.0) | Systematic Assessment |
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| Lipase increased | Investigations | MedDRA (22.0) | Systematic Assessment |
| |
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (22.0) | Systematic Assessment |
| |
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (22.0) | Systematic Assessment |
| |
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA (22.0) | Systematic Assessment |
| |
| Dizziness | Nervous system disorders | MedDRA (22.0) | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA (22.0) | Systematic Assessment |
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| Haematuria | Renal and urinary disorders | MedDRA (22.0) | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (22.0) | Systematic Assessment |
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| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA (22.0) | Systematic Assessment |
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| Pulmonary sarcoidosis | Respiratory, thoracic and mediastinal disorders | MedDRA (22.0) | Systematic Assessment |
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| Cutaneous sarcoidosis | Skin and subcutaneous tissue disorders | MedDRA (22.0) | Systematic Assessment |
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| Hypertension | Vascular disorders | MedDRA (22.0) | Systematic Assessment |
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The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Novartis Pharmaceuticals | + 1 862 778 8300 | novartis.email@novartis.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Feb 5, 2024 | Sep 9, 2024 | SAP_001.pdf |
| ID | Term |
|---|---|
| D017565 | Sarcoidosis, Pulmonary |
| ID | Term |
|---|---|
| D017563 | Lung Diseases, Interstitial |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D012507 | Sarcoidosis |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D006968 | Hypersensitivity, Delayed |
| D006967 | Hypersensitivity |
| D007154 | Immune System Diseases |
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| Unknown |
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