Idiopathic Pulmonary Fibrosis
Conditions
Keywords
Idiopathic Pulmonary Fibrosis
Brief summary
This trial is a multi-centre, open-label, single-arm phase 2 trial investigating the safety, efficacy and pharmacokinetics of C21 in subjects with idiopathic pulmonary fibrosis.
Interventions
DRUGC21
C21 100 mg BID (twice daily)
Sponsors
Orphan Reach Ltd.
Vicore Pharma AB
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written informed consent, consistent with ICH-GCP R2 and local laws, obtained before the initiation of any trial related procedure 2. A diagnosis of IPF within 5 years prior to Visit 1, as per either ATS/ERS/JRS/ATLAT/Fleischner guidelines 3. Age ≥40 years 4. Forced vital capacity (FVC) ≥60% predicted at Visit 1 (specifically for UK: FVC ≥80% predicted at Visit 1) 5. Forced expiratory volume in the first sec (FEV1)/FVC ratio ≥0.7 prebronchodilator at Visit 1 6. Oxygen saturation (SpO2) \>85% by pulse oximetry while breathing ambient air at rest at Visit 1 7. High-resolution computed tomography (HRCT) within 36 months prior to Visit 1 with central reading demonstrating either a or b, and c: a. A pattern consistent with usual interstitial pneumonitis (UIP) according to ATS/ERS/JRS/ALAT or Fleischner guidelines i. UIP ii. Probable UIP or b. A pattern indeterminate for UIP according to either ATS/ERS/JRS/ALAT or Fleischner guidelines and a historical biopsy consistent with IPF c. Extent of fibrosis \> extent of emphysema 8. Fully vaccinated against COVID-19 prior to screening (Visit 1). Subjects are considered fully vaccinated for COVID-19 ≥14 days after they have received vaccination dose(s) according to local label
Exclusion criteria
1. Previous use of antifibrotic treatment for an interstitial lung disease (e.g. nintedanib or pirfenidone) for \> 6 months 2. Smoking (including e-cigarettes) within 6 months prior to Visit 1 3. Body mass index (BMI) \>35 or \<18 4. IPF exacerbation within 3 months prior to Visit 1: * Acute worsening or development of dyspnoea typically \<1 month duration * Computed tomography with new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with usual interstitial pneumonia pattern (if no previous computed tomography is available, the qualifier new can be dropped) * Deterioration not fully explained by cardiac failure or fluid overload 5. Concurrent serious medical condition with special attention to cardiac or ophthalmic conditions (e.g. contraindications to cataract surgery) which in the opinion of the investigator makes the subject inappropriate for this trial 6. Malignancy within the past 5 years with the exception of in situ removal of basal cell carcinoma and cervical intraepithelial neoplasia grade I 7. Treatment with any of the medications listed below within 4 weeks prior to Visit 1: * Cytochrome p450 (CYP) 3A4 inducers (e.g. rifampicin, phenytoin, St. John's Wort) * CYP3A4 inhibitors (e.g. clarithromycin, ketoconazole, nefazodone, itraconazole, ritonavir) * Medicines that are substrates of CYP1A2, CYP3A4 or CYP2C9 with a narrow therapeutic range * Experimental drugs * Any systemic immunosuppressive therapies other than: * Inhaled corticosteroids which can be used throughout the trial period provided the dose is kept stable * Corticosteroids for the treatment of acute exacerbations * The continuation of stable doses of ≤15 mg daily doses of prednisolone 8. Treatment with any of the medications listed below within 2 weeks prior to Visit 1: * Proton pump inhibitors (PPI's) more than once daily * Histamine H2 receptor antagonists (H2RA's) * Sulphasalazine and rosuvastatin * High dose breast cancer resistance protein sensitive substrates (other than sulphasalazine or rosuvastatin) 9. Any of the following findings at Visit 1: * Prolonged QTcF (QT interval with Fridericia's correction) (\>450 ms), cardiac arrhythmias or any clinically significant abnormalities in the resting ECG, as judged by the Investigator * Positive results for hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCVAb) or human immunodeficiency virus 1+2 antigen/antibody (HIV 1+2 Ag/Ab) * Positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) 10. Inability to generate lung function data at Visit 1 meeting the minimum standards of the ATS/ERS 2005 guideline, as determined by central review 11. Clinically significant abnormal laboratory value at Visit 1 indicating a potential risk for the subject if enrolled in the trial as evaluated by the investigator 12. Pregnant or breast-feeding female subjects 13. Female subjects of childbearing potential not willing to use contraceptive methods 14. Male subjects not willing to use contraceptive methods 15. Subjects not willing to adhere to dietary restrictions during the trial period 16. Participation in any other interventional trial during the trial period 17. Subjects known or suspected of not being able to comply with this trial protocol (e.g. due to alcoholism, drug dependency or psychological disorder) 18. Discontinuation or change of previous antifibrotic treatment (e.g. nintedanib or pirfenidone) due to disease progression
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events Occurring Over the Trial Period | Trial period of 36 weeks | Number of participants with adverse events occurring over the trial period incl. number of participants with any TEAE, serious TEAEs, TEAEs leading to withdrawal from trial, TEAEs leading to discontinuation of treatment, treatment-related TEAEs leading to discontinuation of treatment, TEAEs leading to death, and serious treatment-related TEAEs. Adverse events were recorded from signing of informed consent until end of trial. Nature and frequency of adverse events are presented in details in the adverse events section. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Forced Vital Capacity (Imputed Data) | 12, 24, and 36 weeks | Mean changes in forced vital capacity (FVC) (mL) from baseline to week 12, week 24, and week 36 were calculated |
| Rate of Forced Vital Capacity Decline Over Time, FAS | 12, 24, and 36 weeks | Model-based mean (90% CI) FVC changes over 12, 24, and 36 weeks were normalized to change over 24 weeks. A piece-wise linear regression model with knots at weeks 6 and 24 and unstructured covariance matrix was fitted to change from baseline data. Knot selection was performed by visual inspection. The model based change over 12, 24, and 36 weeks was normalized to represent a change over 24 weeks. Rate of decline was computed as y(t) - y(0) = t\*Beta1 + max(0, t-6)\*Beta2 + max(0,t-24)\*Beta3, adjusted to show the decline per 24 weeks, where y is the value at the respective week and Beta is the model coefficient. No imputation of data was conducted. |
| Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Day 1 | Prior to dosing, 30 min post dose, 1 h post dose, 2 h post dose, 3 h post dose, and 4 h post dose on Day 1 | The plasma concentration of C21 (ng/mL) was calculated in a subset of subjects at specified timepoints post-dose. |
| Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 12 | Prior to dosing, 30 min post dose, 1 h post dose, 2 h post dose, 3 h post dose, and 4 h post dose at Week 12 | The plasma concentration of C21 (ng/mL) was calculated at specified timepoints post-dose after 12 weeks of dosing. |
| Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 24 | Prior to dosing, 30 min post dose, 1 h post dose, 2 h post dose, 3 h post dose, and 4 h post dose at Week 24 | The plasma concentration of C21 (ng/mL) was calculated at specified timepoints post-dose after 24 weeks of dosing. |
| Change From Baseline in Forced Vital Capacity (Non-imputed Data) | 12, 24, and 36 weeks | Mean changes in forced vital capacity (FVC) (mL) from baseline to week 12, week 24, and week 36 were calculated |
| Cmax in a Sub-set of Subjects | Prior to dosing, 30 min post dose, 1 h post dose, 2 h post dose, 3 h post dose, and 4 h post dose at Weeks 0, 12, 24, and 36 | The maximal plasma concentration (Cmax (ng/ml)) was calculated in a subset of subjects after 0, 12, 24, and 36 weeks of dosing |
| Tmax in a Sub-set of Subjects | Prior to dosing, 30 min post dose, 1 h post dose, 2 h post dose, 3 h post dose, and 4 h post dose at Weeks 0, 12, 24, and 36 | The time for the maximal plasma concentration (Tmax (h)) was calculated in a subset of subjects after 0, 12, 24, and 36 weeks of dosing |
| AUClast in a Sub-set of Subjects | Prior to dosing, 30 min post dose, 1 h post dose, 2 h post dose, 3 h post dose, and 4 h post dose at Weeks 0, 12, 24, and 36 | Area under the plasma concentration time curve to the last quantified concentration (AUClast) (h\*ng/mL) was calculated in a subset of subjects after 0, 12, 24, and 36 weeks of dosing |
| Accumulation Ratio AUC in a Sub-set of Subjects | Prior to dosing, 30 min post dose, 1 h post dose, 2 h post dose, 3 h post dose, and 4 h post dose at Weeks 0, 12, 24, and 36 | Accumulation ratio AUC was calculated in a subset of subjects after 0, 12, 24, and 36 weeks of dosing |
| Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 36 | Prior to dosing, 30 min post dose, 1 h post dose, 2 h post dose, 3 h post dose, and 4 h post dose at Week 36 | The plasma concentration of C21 (ng/mL) was calculated at specified timepoints post-dose after 36 weeks of dosing. |
Countries
India, Russia, Ukraine, United Kingdom
Participant flow
Pre-assignment details
52 participants were enrolled and received at least one dose of C21. 138 participants signed informed content and were screened, however, 86 of those were screening failures and thus not enrolled.
Participants by arm
| Arm | Count |
|---|---|
| C21 100 mg BID, SAS Oral administration of 100 mg BID C21 (200 mg daily) Safety analysis set (SAS) | 52 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 6 |
| Overall Study | Death | 1 |
| Overall Study | FVC decline and FVCpp<60% | 2 |
| Overall Study | FVC decline, FVCpp<60% and worsening of respiratory symptoms | 1 |
| Overall Study | Withdrawal by Subject | 15 |
Baseline characteristics
| Characteristic | C21 100 mg BID, SAS |
|---|---|
| Age, Continuous | 67.3 Years STANDARD_DEVIATION 9.38 |
| Age of High-resolution computed tomography (HRCT) scan | 5.58 Months STANDARD_DEVIATION 8.72 |
| Body mass index | 24.57 kg/m^2 STANDARD_DEVIATION 4.119 |
| E-cigarettes and vapes status Current | 0 Participants |
| E-cigarettes and vapes status Former | 1 Participants |
| E-cigarettes and vapes status Missing | 0 Participants |
| E-cigarettes and vapes status Never | 51 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 52 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| FEV1 | 1.912 L STANDARD_DEVIATION 0.528 |
| FEV1/FVC | 0.804 ratio STANDARD_DEVIATION 0.067 |
| FEV1 (% predicted normal) | 77.51 Percentage of predicted normal FEV1 STANDARD_DEVIATION 14.687 |
| FVC | 2.387 L STANDARD_DEVIATION 0.667 |
| FVC (% predicted normal) | 75.46 Percentage of predicted normal FVC STANDARD_DEVIATION 13.662 |
| Height | 161.69 cm STANDARD_DEVIATION 8.723 |
| HRCT pattern (central reading) HRCT Feature most consistent with Non-IPF diagnosis | 0 Participants |
| HRCT pattern (central reading) Missing | 0 Participants |
| HRCT pattern (central reading) Probable UIP HRCT Pattern | 32 Participants |
| HRCT pattern (central reading) Typical usual interstitial pneumonitis (UIP) HRCT Pattern | 20 Participants |
| Oxygen saturation at screening | 95.3 Percentage of oxygen saturation STANDARD_DEVIATION 2.4 |
| Previous use of antifibrotics Nintedanib | 0 Participants |
| Previous use of antifibrotics Pirfenidone | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 38 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Region of Enrollment India | 38 participants |
| Region of Enrollment Russia | 3 participants |
| Region of Enrollment Ukraine | 4 participants |
| Region of Enrollment United Kingdom | 7 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 40 Participants |
| Smoking status Current | 0 Participants |
| Smoking status Former | 10 Participants |
| Smoking status Missing | 0 Participants |
| Smoking status Never | 42 Participants |
| Time since diagnosis of idiopathic pulmonary fibrosis | 1.01 Years STANDARD_DEVIATION 1.195 |
| Weight | 64.64 kg STANDARD_DEVIATION 14.178 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 52 |
| other Total, other adverse events | 35 / 52 |
| serious Total, serious adverse events | 5 / 52 |
Outcome results
Primary
Number of Participants With Adverse Events Occurring Over the Trial Period
Number of participants with adverse events occurring over the trial period incl. number of participants with any TEAE, serious TEAEs, TEAEs leading to withdrawal from trial, TEAEs leading to discontinuation of treatment, treatment-related TEAEs leading to discontinuation of treatment, TEAEs leading to death, and serious treatment-related TEAEs. Adverse events were recorded from signing of informed consent until end of trial. Nature and frequency of adverse events are presented in details in the adverse events section.
Time frame: Trial period of 36 weeks
Population: Safety analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| C21 100 mg BID, SAS | Number of Participants With Adverse Events Occurring Over the Trial Period | Total number of subjects with treatment-emergent adverse events (TEAEs) | 37 Participants |
| C21 100 mg BID, SAS | Number of Participants With Adverse Events Occurring Over the Trial Period | Total number of subjects with serious TEAEs | 5 Participants |
| C21 100 mg BID, SAS | Number of Participants With Adverse Events Occurring Over the Trial Period | Total number of subjects with TEAEs leading to withdrawal from study | 6 Participants |
| C21 100 mg BID, SAS | Number of Participants With Adverse Events Occurring Over the Trial Period | Total number of subjects with TEAEs leading to discontinuation of treatment | 12 Participants |
| C21 100 mg BID, SAS | Number of Participants With Adverse Events Occurring Over the Trial Period | Total number of subjects with treatment-related TEAEs leading to discontinuation of treatment | 3 Participants |
| C21 100 mg BID, SAS | Number of Participants With Adverse Events Occurring Over the Trial Period | Total number of subjects with TEAEs leading to death | 2 Participants |
| C21 100 mg BID, SAS | Number of Participants With Adverse Events Occurring Over the Trial Period | Total number of subjects with serious treatment-related TEAEs | 0 Participants |
Secondary
Accumulation Ratio AUC in a Sub-set of Subjects
Accumulation ratio AUC was calculated in a subset of subjects after 0, 12, 24, and 36 weeks of dosing
Time frame: Prior to dosing, 30 min post dose, 1 h post dose, 2 h post dose, 3 h post dose, and 4 h post dose at Weeks 0, 12, 24, and 36
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| C21 100 mg BID, SAS | Accumulation Ratio AUC in a Sub-set of Subjects | Week 12 | 0.84598 Ratio | Geometric Coefficient of Variation 120.5 |
| C21 100 mg BID, SAS | Accumulation Ratio AUC in a Sub-set of Subjects | Week 24 | 0.45256 Ratio | Geometric Coefficient of Variation 328.9 |
| C21 100 mg BID, SAS | Accumulation Ratio AUC in a Sub-set of Subjects | Week 36 | 0.73765 Ratio | Geometric Coefficient of Variation 67.9 |
Secondary
AUClast in a Sub-set of Subjects
Area under the plasma concentration time curve to the last quantified concentration (AUClast) (h\*ng/mL) was calculated in a subset of subjects after 0, 12, 24, and 36 weeks of dosing
Time frame: Prior to dosing, 30 min post dose, 1 h post dose, 2 h post dose, 3 h post dose, and 4 h post dose at Weeks 0, 12, 24, and 36
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| C21 100 mg BID, SAS | AUClast in a Sub-set of Subjects | Week 0 | 3018.151 h*ng/mL | Geometric Coefficient of Variation 60.5 |
| C21 100 mg BID, SAS | AUClast in a Sub-set of Subjects | Week 12 | 1704.924 h*ng/mL | Geometric Coefficient of Variation 126.6 |
| C21 100 mg BID, SAS | AUClast in a Sub-set of Subjects | Week 24 | 995.600 h*ng/mL | Geometric Coefficient of Variation 213.2 |
| C21 100 mg BID, SAS | AUClast in a Sub-set of Subjects | Week 36 | 1622.774 h*ng/mL | Geometric Coefficient of Variation 49.8 |
Secondary
Change From Baseline in Forced Vital Capacity (Imputed Data)
Mean changes in forced vital capacity (FVC) (mL) from baseline to week 12, week 24, and week 36 were calculated
Time frame: 12, 24, and 36 weeks
Population: Full analysis set with imputed data
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| C21 100 mg BID, SAS | Change From Baseline in Forced Vital Capacity (Imputed Data) | Week 12 | -57.6 mL |
| C21 100 mg BID, SAS | Change From Baseline in Forced Vital Capacity (Imputed Data) | Week 24 | -70.3 mL |
| C21 100 mg BID, SAS | Change From Baseline in Forced Vital Capacity (Imputed Data) | Week 36 | 9.4 mL |
Secondary
Change From Baseline in Forced Vital Capacity (Non-imputed Data)
Mean changes in forced vital capacity (FVC) (mL) from baseline to week 12, week 24, and week 36 were calculated
Time frame: 12, 24, and 36 weeks
Population: Participants in the Full analysis set (FAS) with a measurement.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| C21 100 mg BID, SAS | Change From Baseline in Forced Vital Capacity (Non-imputed Data) | Week 12 | -4.9 mL |
| C21 100 mg BID, SAS | Change From Baseline in Forced Vital Capacity (Non-imputed Data) | Week 24 | 16.0 mL |
| C21 100 mg BID, SAS | Change From Baseline in Forced Vital Capacity (Non-imputed Data) | Week 36 | 216.0 mL |
Secondary
Cmax in a Sub-set of Subjects
The maximal plasma concentration (Cmax (ng/ml)) was calculated in a subset of subjects after 0, 12, 24, and 36 weeks of dosing
Time frame: Prior to dosing, 30 min post dose, 1 h post dose, 2 h post dose, 3 h post dose, and 4 h post dose at Weeks 0, 12, 24, and 36
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| C21 100 mg BID, SAS | Cmax in a Sub-set of Subjects | 0 Weeks | 1852.13 ng/mL | Geometric Coefficient of Variation 80.1 |
| C21 100 mg BID, SAS | Cmax in a Sub-set of Subjects | 12 Weeks | 954.29 ng/mL | Geometric Coefficient of Variation 127.9 |
| C21 100 mg BID, SAS | Cmax in a Sub-set of Subjects | 24 Weeks | 524.79 ng/mL | Geometric Coefficient of Variation 281.6 |
| C21 100 mg BID, SAS | Cmax in a Sub-set of Subjects | 36 Weeks | 961.86 ng/mL | Geometric Coefficient of Variation 73.3 |
Secondary
Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Day 1
The plasma concentration of C21 (ng/mL) was calculated in a subset of subjects at specified timepoints post-dose.
Time frame: Prior to dosing, 30 min post dose, 1 h post dose, 2 h post dose, 3 h post dose, and 4 h post dose on Day 1
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Day 1 | Prior to dosing | 5.00 ng/mL | Standard Deviation 0 |
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Day 1 | 30 min post dose | 1622.0 ng/mL | Standard Deviation 1453.64 |
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Day 1 | 1 h post dose | 1788.11 ng/mL | Standard Deviation 1112.48 |
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Day 1 | 2 h post dose | 864.46 ng/mL | Standard Deviation 1062.15 |
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Day 1 | 3 h post dose | 322.19 ng/mL | Standard Deviation 407.29 |
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Day 1 | 4 h post dose | 282.82 ng/mL | Standard Deviation 379.31 |
Secondary
Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 12
The plasma concentration of C21 (ng/mL) was calculated at specified timepoints post-dose after 12 weeks of dosing.
Time frame: Prior to dosing, 30 min post dose, 1 h post dose, 2 h post dose, 3 h post dose, and 4 h post dose at Week 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 12 | Prior to dosing | 27.13 ng/mL | Standard Deviation 62.58 |
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 12 | 30 min post dose | 974.28 ng/mL | Standard Deviation 1028.9 |
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 12 | 1 h post dose | 1044.02 ng/mL | Standard Deviation 1128.3 |
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 12 | 2 h post dose | 794.02 ng/mL | Standard Deviation 774.34 |
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 12 | 3 h post dose | 491.25 ng/mL | Standard Deviation 820.36 |
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 12 | 4 h post dose | 101.50 ng/mL | Standard Deviation 113.96 |
Secondary
Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 24
The plasma concentration of C21 (ng/mL) was calculated at specified timepoints post-dose after 24 weeks of dosing.
Time frame: Prior to dosing, 30 min post dose, 1 h post dose, 2 h post dose, 3 h post dose, and 4 h post dose at Week 24
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 24 | Prior to dosing | 20.14 ng/mL | Standard Deviation 28.608 |
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 24 | 30 min post dose | 615.53 ng/mL | Standard Deviation 792.908 |
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 24 | 1 h post dose | 898.61 ng/mL | Standard Deviation 779.723 |
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 24 | 2 h post dose | 404.80 ng/mL | Standard Deviation 296.002 |
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 24 | 3 h post dose | 151.30 ng/mL | Standard Deviation 125.292 |
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 24 | 4 h post dose | 115.93 ng/mL | Standard Deviation 151.833 |
Secondary
Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 36
The plasma concentration of C21 (ng/mL) was calculated at specified timepoints post-dose after 36 weeks of dosing.
Time frame: Prior to dosing, 30 min post dose, 1 h post dose, 2 h post dose, 3 h post dose, and 4 h post dose at Week 36
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 36 | Prior to dosing | 89.78 ng/mL | Standard Deviation 176.452 |
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 36 | 30 min post dose | 796.29 ng/mL | Standard Deviation 839.353 |
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 36 | 1 h post dose | 713.86 ng/mL | Standard Deviation 453.54 |
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 36 | 2 h post dose | 298.29 ng/mL | Standard Deviation 299.235 |
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 36 | 3 h post dose | 374.16 ng/mL | Standard Deviation 459.545 |
| C21 100 mg BID, SAS | Plasma Concentration of C21 Evaluated in a Sub-set of Subjects, Week 36 | 4 h post dose | 348.11 ng/mL | Standard Deviation 479.786 |
Secondary
Rate of Forced Vital Capacity Decline Over Time, FAS
Model-based mean (90% CI) FVC changes over 12, 24, and 36 weeks were normalized to change over 24 weeks. A piece-wise linear regression model with knots at weeks 6 and 24 and unstructured covariance matrix was fitted to change from baseline data. Knot selection was performed by visual inspection. The model based change over 12, 24, and 36 weeks was normalized to represent a change over 24 weeks. Rate of decline was computed as y(t) - y(0) = t\*Beta1 + max(0, t-6)\*Beta2 + max(0,t-24)\*Beta3, adjusted to show the decline per 24 weeks, where y is the value at the respective week and Beta is the model coefficient. No imputation of data was conducted.
Time frame: 12, 24, and 36 weeks
Population: Full analysis set
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| C21 100 mg BID, SAS | Rate of Forced Vital Capacity Decline Over Time, FAS | Week 12 | -8.2 mL |
| C21 100 mg BID, SAS | Rate of Forced Vital Capacity Decline Over Time, FAS | Week 24 | 36.4 mL |
| C21 100 mg BID, SAS | Rate of Forced Vital Capacity Decline Over Time, FAS | Week 36 | 108.9 mL |
Secondary
Tmax in a Sub-set of Subjects
The time for the maximal plasma concentration (Tmax (h)) was calculated in a subset of subjects after 0, 12, 24, and 36 weeks of dosing
Time frame: Prior to dosing, 30 min post dose, 1 h post dose, 2 h post dose, 3 h post dose, and 4 h post dose at Weeks 0, 12, 24, and 36
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| C21 100 mg BID, SAS | Tmax in a Sub-set of Subjects | Week 0 | 1.00 h |
| C21 100 mg BID, SAS | Tmax in a Sub-set of Subjects | Week 12 | 1.50 h |
| C21 100 mg BID, SAS | Tmax in a Sub-set of Subjects | Week 24 | 1.00 h |
| C21 100 mg BID, SAS | Tmax in a Sub-set of Subjects | Week 36 | 1.00 h |