CLINICAL PHARMACOLOGY
Mechanism Of Action
Nintedanib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs). Nintedanib inhibits the following RTKs: platelet-derived growth factor receptor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-3, vascular endothelial growth factor receptor (VEGFR) 1-3, colony stimulating factor 1 receptor (CSF1R), and Fms-like tyrosine kinase-3 (FLT-3). These kinases except for FLT-3 have been implicated in pathogenesis of interstitial lung diseases (ILD). Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these kinases and blocks the intracellular signaling cascades, which have been demonstrated to be involved in the pathogenesis of fibrotic tissue remodeling in ILD. Nintedanib also inhibits the following nRTKs: Lck, Lyn and Src kinases. The contribution of FLT-3 and nRTK inhibition to nintedanib efficacy in ILD is unknown.
Pharmacodynamics
Cardiac Electrophysiology
In a study in renal cell cancer patients, QT/QTc measurements were recorded and showed that a single oral dose of 200 mg nintedanib as well as multiple oral doses of 200 mg nintedanib administered twice daily for 15 days did not prolong the QTcF interval.
Pharmacokinetics
The PK properties of nintedanib were similar in healthy volunteers, patients with IPF, patients with chronic fibrosing ILDs with a progressive phenotype, patients with SSc-ILD, and cancer patients. The PK of nintedanib is linear. Dose proportionality was shown by an increase of nintedanib exposure with increasing doses (dose range 50 to 450 mg once daily and 150 to 300 mg twice daily). Accumulation upon multiple administrations in patients with IPF was 1.76-fold for AUC. Steady-state plasma concentrations were achieved within one week of dosing. Nintedanib trough concentrations remained stable for more than one year. The inter-individual variability in the PK of nintedanib was moderate to high (coefficient of variation of standard PK parameters in the range of 30% to 70%), intra-individual variability low to moderate (coefficients of variation below 40%).
Absorption
Nintedanib reached maximum plasma concentrations approximately 2 to 4 hours after oral administration as a soft gelatin capsule under fed conditions. The absolute bioavailability of a 100 mg dose was 4.7% (90% CI:3.62 to 6.08) in healthy volunteers. Absorption and bioavailability are decreased by transporter effects and substantial first-pass metabolism.
After food intake, nintedanib exposure increased by approximately 20% compared to administration under fasted conditions (90% CI: 95.3% to 152.5%) and absorption was delayed (median tmax fasted: 2.00 hours; fed:3.98 hours), irrespective of the food type.
Distribution
Nintedanib follows bi-phasic disposition kinetics. After intravenous infusion, a high volume of distribution which was larger than total body volume (Vss: 1050 L) was observed.
The in vitro protein binding of nintedanib in human plasma was high, with a bound fraction of 97.8%. Serum albumin is considered to be the major binding protein. Nintedanib is preferentially distributed in plasma with a blood to plasma ratio of 0.87.
Elimination
The effective half-life of nintedanib in patients with IPF was 9.5 hours (gCV 31.9%). Total plasma clearance after intravenous infusion was high (CL: 1390 mL/min; gCV 28.8%). Urinary excretion of unchanged drug within 48 hours was about 0.05% of the dose after oral and about 1.4% of the dose after intravenous administration; the renal clearance was 20 mL/min.
Metabolism
The prevalent metabolic reaction for nintedanib is hydrolytic cleavage by esterases resulting in the free acid moiety BIBF 1202. BIBF 1202 is subsequently glucuronidated by UGT enzymes, namely UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10 to BIBF 1202 glucuronide. Only a minor extent of the biotransformation of nintedanib consisted of CYP pathways, with CYP3A4 being the predominant enzyme involved. The major CYP-dependent metabolite could not be detected in plasma in the human absorption, distribution, metabolism,and elimination study. In vitro, CYP-dependent metabolism accounted for about 5% compared to about 25% ester cleavage.
Excretion
The major route of elimination of drug-related radioactivity after oral administration of [14C] nintedanib was via fecal/biliary excretion (93.4% of dose), and the majority of OFEV was excreted as BIBF 1202. The contribution of renal excretion to the total clearance was low (0.65% of dose). The overall recovery was considered complete (above 90%) within 4 days after dosing.
Specific Populations
Age, Body Weight, And Sex
Based on population PK analysis, age and body weight were correlated with nintedanib exposure. However, the effects on exposure are not sufficient to warrant a dose adjustment. There was no influence of sex on the exposure of nintedanib.
Renal Impairment
Based on a population PK analysis of data from 933 patients with IPF, exposure to nintedanib was not influenced by mild (CrCl: 60 to 90 mL/min; n=399) or moderate (CrCl: 30 to 60 mL/min; n=116) renal impairment. Data in severe renal impairment (CrCl below 30 mL/min) was limited.
Hepatic Impairment
A dedicated single-dose phase I pharmacokinetics study of OFEV compared 8 subjects with mild hepatic impairment (Child Pugh A) and 8 subjects with moderate hepatic impairment (Child Pugh B) to 17 subjects with normal hepatic function. In subjects with mild hepatic impairment, the mean exposure to nintedanib was 2.4-fold higher based on Cmax (90% CI: 1.6 to 3.6) and 2.2-fold higher based on AUC0-inf (90% CI: 1.4 to 3.5). In subjects with moderate hepatic impairment, exposure was 6.9-fold higher based on Cmax (90% CI: 4.4 to 11.0) and 7.6-fold higher based on AUC0-inf (90% CI: 5.1 to 11.3). Subjects with severe hepatic impairment (Child Pugh C) have not been studied.
Smokers
In the population PK analysis, the exposure of nintedanib was 21% lower in current smokers compared to ex- and never-smokers. The effect is not sufficient to warrant a dose adjustment.
Drug Interaction Studies
Potential For Nintedanib To Affect Other Drugs
Effect of nintedanib coadministration on pirfenidone AUC and Cmax was evaluated in a multiple-dose study. Nintedanib did not have an effect on the exposure of pirfenidone.
In in vitro studies, nintedanib was shown not to be an inhibitor of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2, or MRP-2. In vitro studies also showed that nintedanib has weak inhibitory potential on OCT-1, BCRP, and P-gp; these findings are considered to be of low clinical relevance. Nintedanib and its metabolites, BIBF 1202 and BIBF 1202 glucuronide, did not inhibit or induce CYP enzymes in vitro.
Potential For Other Drugs To Affect Nintedanib
Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4. Coadministration with the P-gp and CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib 1.61-fold based on AUC and 1.83-fold based on Cmax in a dedicated drug-drug interaction study. In a drug-drug interaction study with the P-gp and CYP3A4 inducer, rifampicin, exposure to nintedanib decreased to 50.3% based on AUC and to 60.3% based on Cmax upon coadministration with rifampicin compared to administration of nintedanib alone.
Effect of pirfenidone coadministration on nintedanib AUC and Cmax was evaluated in a multiple-dose drug-drug interaction study. Pirfenidone did not have an effect on the exposure of nintedanib. Concomitant treatment with nintedanib and pirfenidone was also investigated in a separate trial, which was an exploratory open-label, randomized (1:1) trial of nintedanib 150 mg twice daily with add-on pirfenidone (titrated to 801 mg three times a day) compared to nintedanib 150 mg twice daily alone in 105 randomized patients for 12 weeks. Similar nintedanib trough plasma concentrations were observed when comparing patients receiving nintedanib alone with patients receiving nintedanib with add-on pirfenidone.
Healthy volunteers received a single dose of 150 mg nintedanib before and after multiple dosing of 125 mg bosentan twice daily at steady state. Coadministration of nintedanib with bosentan did not alter the pharmacokinetics of nintedanib.
Nintedanib displays a pH-dependent solubility profile with increased solubility at acidic pH less than 3. However, in the clinical trials, coadministration with proton pump inhibitors or histamine H2 antagonists did not influence the exposure (trough concentrations) of nintedanib.
In in vitro studies, nintedanib was shown not to be a substrate of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2, MRP-2, or BCRP. In vitro studies also showed that nintedanib was a substrate of OCT-1; these findings are considered to be of low clinical relevance.
Clinical Studies
Idiopathic Pulmonary Fibrosis
The clinical efficacy of OFEV has been studied in 1231 patients with IPF in one phase 2 (Study 1 [NCT00514683]) and two phase 3 studies (Study 2 [NCT01335464] and Study 3 [NCT01335477]). These were randomized, double-blind, placebo-controlled studies comparing treatment with OFEV 150 mg twice daily to placebo for 52 weeks.
Study 2 and Study 3 were identical in design. Study 1 was very similar in design. Patients were randomized in a 3:2 ratio (1:1 for Study 1) to either OFEV 150 mg or placebo twice daily for 52 weeks. Study 1 also included other treatment arms (50 mg daily, 50 mg twice daily, and 100 mg twice daily) that are not further discussed. The primary endpoint was the annual rate of decline in Forced Vital Capacity (FVC). Time to first acute IPF exacerbation was a key secondary endpoint in Study 2 and Study 3 and a secondary endpoint in Study 1. Change from baseline in FVC percent predicted and survival were additional secondary endpoints in all studies.
Patients were required to have a diagnosis of IPF (ATS/ERS/JRS/ALAT criteria) for less than 5 years. Diagnoses were centrally adjudicated based on radiologic and, if applicable, histopathologic confirmation. Patients were required to be greater than or equal to 40 years of age with an FVC greater than or equal to 50% of predicted and a carbon monoxide diffusing capacity (DLCO, corrected for hemoglobin) 30% to 79% of predicted. Patients with relevant airways obstruction (i.e., pre-bronchodilator FEV1/FVC less than 0.7) or, in the opinion of the investigator, likely to receive a lung transplant during the studies were excluded (being listed for lung transplant was acceptable for inclusion). Patients with greater than 1.5 times ULN of ALT, AST, or bilirubin, patients with a known risk or predisposition to bleeding, patients receiving a full dose of anticoagulation treatment, and patients with a recent history of myocardial infarction or stroke were excluded from the studies. Patients were also excluded if they received other investigational therapy, azathioprine, cyclophosphamide, or cyclosporine A within 8 weeks of entry into this trial, or n-acetyl cysteine and prednisone (greater than 15 mg/day or equivalent) within 2 weeks. The majority of patients were Caucasian (60%) or Asian (30%) and male (79%). Patients had a mean age of 67 years and a mean FVC percent predicted of 80%.
Annual Rate Of Decline In FVC
A statistically significant reduction in the annual rate of decline of FVC (in mL) was demonstrated in patients receiving OFEV compared to patients receiving placebo based on the random coefficient regression model, adjusted for gender, height, and age. The treatment effect on FVC was consistent in all 3 studies. See Table 3 for individual study results.
Table 3 Annual Rate of Decline in FVC (mL) in Study 1, Study 2, and Study 3a
| Study 1 | Study 2 | Study 3 |
OFEV 150 mg twice daily | Placebo | OFEV 150 mg twice daily | Placebo | OFEV 150 mg twice daily | Placebo |
Number of analyzed patients | 84 | 83 | 309 | 204 | 329 | 219 |
Ratea of decline over 52 weeks | -60 | -191 | -115 | -240 | -114 | -207 |
Comparison vs placebo Differenceb | 131 | 125 | 94 |
95% CI | (27, 235) | (78, 173) | (45, 143) |
aRandomized set in Study 1; treated set in Study 2 and Study 3 bEstimated based on a random coefficient regression model |
Figure 1 displays the change from baseline over time in both treatment groups for Study 2. When the mean observed FVC change from baseline was plotted over time, the curves diverged at all timepoints through Week 52. Similar plots were seen for Study 1 and Study 3.
Figure 1: Mean (SEM) Observed FVC Change from Baseline (mL) Over Time in Study 2
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bid = twice daily |
Change From Baseline In Percent Predicted Forced Vital Capacity
Figure 2 presents the cumulative distribution for all cut-offs for the change from baseline in FVC percent predicted at Week 52 for Study 2. For all categorical declines in lung function, the proportion of patients declining was lower on OFEV than on placebo. Study 3 showed similar results.
Figure 2: Cumulative Distribution of Patients by Change in Percent Predicted FVC from Baseline to Week 52 (Study 2).* The vertical lines indicate ≥0% decline or ≥10% decline.
 |
*Missing data for change from baseline at Week 52 in percent predicted FVC (due to death, lost to follow-up or censoring before 52 weeks) was imputed using the worst decline from baseline at Week 52 observed among all patients with available data, regardless of treatment. bid = twice daily |
Time To First Acute IPF Exacerbation
Acute IPF exacerbation was defined as unexplained worsening or development of dyspnea within 30 days, new diffuse pulmonary infiltrates on chest x-ray, and/or new high-resolution CT parenchymal abnormalities with no pneumothorax or pleural effusion, and exclusion of alternative causes. Acute IPF exacerbation was adjudicated in Study 2 and Study 3. In Study 1 (investigator-reported) and Study 3 (adjudicated), the risk of first acute IPF exacerbation over 52 weeks was significantly reduced in patients receiving OFEV compared to placebo (hazard ratio [HR]: 0.16, 95% CI: 0.04, 0.71) and (HR: 0.20, 95% CI: 0.07, 0.56), respectively. In Study 2 (adjudicated), there was no difference between the treatment groups (HR: 0.55, 95% CI: 0.20, 1.54).
Survival
Survival was evaluated for OFEV compared to placebo in Study 2 and Study 3 as an exploratory analysis to support the primary endpoint (FVC). All-cause mortality was assessed over the study duration and available follow-up period, irrespective of cause of death and whether patients continued treatment. All-cause mortality did not show a statistically significant difference (See Figure 3).
Figure 3: Kaplan-Meier Estimates of All-Cause Mortality at Vital Status – End of Study: Study 2 and Study 3
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bid = twice daily |
Chronic Fibrosing Interstitial Lung Diseases With A Progressive Phenotype
The clinical efficacy of OFEV has been studied in patients with chronic fibrosing ILDs with a progressive phenotype in a randomized, double-blind, placebo-controlled phase 3 trial (Study 5 [NCT02999178]). A total of 663 patients were randomized in a 1:1 ratio to receive either OFEV 150 mg twice daily or matching placebo for at least 52 weeks. Randomization was stratified based on high resolution computed tomography (HRCT) fibrotic pattern as assessed by central readers: 412 patients with UIP-like HRCT pattern and 251 patients with other HRCT fibrotic patterns were randomized. There were 2 co-primary populations defined for the analyses in this trial: all patients (the overall population) and patients with HRCT with UIP-like HRCT fibrotic pattern.
The primary endpoint was the annual rate of decline in FVC (in mL) over 52 weeks. Other endpoints included time to first acute ILD exacerbation and time to death.
Patients with a clinical diagnosis of a chronic fibrosing ILD were selected if they had relevant fibrosis (greater than 10% fibrotic features) on HRCT and presented with clinical signs of progression (defined as FVC decline ≥10%, FVC decline ≥ 5% and <10% with worsening symptoms or imaging, or worsening symptoms and worsening imaging all in the 24 months prior to screening). Patients were required to have an FVC greater than or equal to 45% of predicted and a DLCO 30% to less than 80% of predicted. Patients were required to have progressed despite management deemed appropriate in clinical practice by investigators for the patient’s relevant ILD.
Patients with IPF, relevant airways obstruction (i.e., pre-bronchodilator FEV1/FVC less than 0.7), or significant pulmonary hypertension were excluded from the trial. Patients with greater than 1.5 times ULN of ALT, AST, or bilirubin, patients with a known risk or predisposition to bleeding, patients receiving a full dose of anticoagulation treatment, and patients with a recent history of myocardial infarction or stroke were excluded. Patients were also excluded if they received other investigational therapy, previous treatment with nintedanib or pirfenidone, azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, oral corticosteroids greater than 20 mg/day, or the combination of oral corticosteroids + azathioprine + n-acetylcysteine within 4 weeks of randomization, cyclophosphamide within 8 weeks prior to randomization, or rituximab within 6 months.
The majority of patients were Caucasian (74%) or Asian (25%). Patients were mostly male (54%) and had a mean age of 66 years and a mean FVC percent predicted of 69%, and 49% were never-smokers. The underlying clinical ILD diagnoses in groups represented in the trial were hypersensitivity pneumonitis (26%), autoimmune ILDs (26%), idiopathic nonspecific interstitial pneumonia (19%), unclassifiable idiopathic interstitial pneumonia (17%), and other ILDs (12%).
Annual Rate Of Decline In FVC
There was a statistically significant reduction in the annual rate of decline in FVC (in mL) over 52 weeks in patients receiving OFEV compared to patients receiving placebo. The annual rate of decline in FVC (in mL) over 52 weeks was significantly reduced by 107 mL in patients receiving OFEV compared to patients receiving placebo. Results in the subpopulations of patients with HRCT with UIP-like fibrotic pattern and patients with other fibrotic patterns (Other HRCT) are included with the overall population in Table 4.
Table 4 Annual Rate of Decline in FVC (mL) in Study 5
| Overall | UIP-like Subpopulation | Other HRCT Subpopulation |
OFEV | Placebo | OFEV | Placebo | OFEV | Placebo |
Number of analyzed patients | 331 | 331 | 206 | 206 | 125 | 125 |
Adjusted annual rate of decline over 52 weeks | -81 | -188 | -83 | -211 | -79 | -154 |
Comparison vs placebo differencea | 107 | 128 | 75* |
95% CI | (65, 148) | (71, 186) | (16, 135)* |
*Comparison based on the Other HRCT subpopulation was not included in the multiple testing procedure. Values shown here are for descriptive purposes. aBased on a random coefficient regression model with fixed categorical effects of treatment, HRCT pattern, fixed continuous effects of time, baseline FVC (mL), and including treatment by time and baseline by time interactions |
A post-hoc exploratory analysis by ILD diagnosis was performed and is shown in Figure 4. Treatment response across ILD diagnoses was consistent for FVC.
Figure 4: Annual Rate of Decline in FVC (mL) over 52 Weeks based on Underlying ILD Diagnosis in Study 5*
 |
ILD = interstitial lung disease; Autoimmune ILDs: includes rheumatoid arthritis-associated ILD, mixed connective tissue disease, systemic sclerosis-associated ILD, and other terms; Other ILDs: includes fibrosing ILDs not categorized under autoimmune ILDs, hypersensitivity pneumonitis, idiopathic nonspecific interstitial pneumonia, or unclassifiable idiopathic interstitial pneumonia. The three most common ILDs in this category are exposure-related ILD, sarcoidosis, and pleuro-parenchymal fibroelastosis. *These results are from a post-hoc exploratory analysis. Values shown here are for descriptive purposes. |
Figure 5 shows the change in FVC from baseline over time in the treatment groups. When the mean observed FVC change from baseline was plotted over time, the curves diverged at all timepoints through Week 52.
Figure 5: Mean (SEM) Observed FVC Change from Baseline (mL) Over 52 Weeks in Study 5
 |
bid = twice daily |
Percent Change From Baseline In Forced Vital Capacity
Figure 6 presents the percent change from baseline in FVC in mL at Week 52 for Study 5. For the majority of patients, the decline in lung function was less on OFEV than on placebo.
Figure 6: Histogram of the Percent Change in FVC (mL) from Baseline to Week 52 According to Treatment and Percent Increments or Decrements of 5 (Study 5)a
 |
a Patients classified as having missing FVC data at Week 52 are those with no FVC assessment between Day 310 and Day 373. bid = twice daily |
Time To First Acute ILD Exacerbation
Acute ILD exacerbation was defined as unexplained worsening or development of dyspnea within 30 days, new diffuse pulmonary infiltrates on chest x-ray, and/or new HRCT parenchymal abnormalities with no pneumothorax or pleural effusion, and exclusion of alternative causes. Acute ILD exacerbations were not adjudicated.
The risk of first acute ILD exacerbation did not show a statistically significant difference between the OFEV group compared to placebo (52 week treatment period: HR 0.72, (95% CI: 0.38, 1.37); whole trial: HR 0.63 (95% CI: 0.37, 1.07)).
Survival
Survival was evaluated for OFEV compared to placebo in Study 5 to support the primary endpoint (FVC). All-cause mortality was assessed over the study duration and available follow-up period, irrespective of cause of death and whether patients continued treatment. All-cause mortality did not show a statistically significant difference (52 week treatment period: HR 0.94 (95% CI: 0.47, 1.86); whole trial: HR 0.78 (95% CI: 0.50, 1.21)).
Systemic Sclerosis-Associated Interstitial Lung Disease
The clinical efficacy of nintedanib has been studied in patients with SSc-ILD in a randomized, double-blind, placebo-controlled phase 3 trial (Study 4 [NCT02597933]). A total of 580 patients were randomized in a 1:1 ratio to receive either OFEV 150 mg twice daily or matching placebo for at least 52 weeks, of which 576 patients were treated. Randomization was stratified by anti-topoisomerase antibody (ATA) status. Individual patients remained on blinded trial treatment for up to 100 weeks. The primary endpoint was the annual rate of decline in FVC over 52 weeks. The absolute change from baseline in the modified Rodnan skin score (mRSS) at Week 52 was a key secondary endpoint. Mortality over the whole trial was an additional secondary endpoint.
Patients were diagnosed with SSc-ILD based upon the 2013 American College of Rheumatology / European League Against Rheumatism classification criteria for SSc with onset of disease (first non-Raynaud symptom) of less than 7 years and greater than or equal to 10% fibrosis on a chest high resolution computed tomography (HRCT) scan conducted within the previous 12 months. Patients were required to have an FVC greater than or equal to 40% of predicted and a DLCO 30-89% of predicted. Patients with relevant airways obstruction (i.e., pre-bronchodilator FEV1/FVC less than 0.7) or previous or planned hematopoietic stem cell transplant were excluded from the trial. Patients with greater than 1.5 times ULN of ALT, AST, or bilirubin, patients with a known risk or predisposition to bleeding, patients receiving a full dose of anticoagulation treatment, and patients with a recent history of myocardial infarction or stroke were excluded from the study. Patients were excluded if they had significant pulmonary hypertension, more than three digital fingertip ulcers, a history of severe digital necrosis requiring hospitalization, or a history of scleroderma renal crisis. Patients were also excluded if they received other investigational therapy, previous treatment with nintedanib or pirfenidone, azathioprine within 8 weeks prior to randomization, or cyclophosphamide or cyclosporine A within 6 months prior to randomization.
The majority of patients were female (75%). Patients were mostly Caucasian (67%), Asian (25%), or Black (6%). The mean age was 54 years. Overall, 52% of patients had diffuse cutaneous systemic sclerosis (SSc) and 48% had limited cutaneous SSc. The mean time since first onset of a non-Raynaud symptom was 3.49 years. At baseline, 49% of patients were on stable therapy with mycophenolate.
Annual Rate Of Decline In FVC
The annual rate of decline of FVC (in mL) over 52 weeks was significantly reduced by 41 mL in patients receiving OFEV compared to patients receiving placebo, corresponding to a relative treatment effect of 44%. See Table 5.
Table 5 Annual Rate of Decline in FVC (mL) in Study 4
| OFEV 150 mg twice daily | Placebo |
Number of analyzed patients | 287 | 288 |
Adjusted rate of decline over 52 weeks | -52 | -93 |
Comparison vs placebo Differencea | 41 |
95% CI | (3, 79) |
aBased on a random coefficient regression model, adjusted for gender, height, age, ATA status, FVC at baseline, FVC at baseline-by-time |
Figure 7 displays the change from baseline over time in both treatment groups. When the mean observed FVC change from baseline was plotted over time, the curves diverged at all timepoints through Week 52. Separation of the mean values is seen after 12 weeks of treatment.
Figure 7: Mean (SEM) Observed FVC Change from Baseline (mL) Over Time in Study 4
 |
bid = twice daily |
In two pre-specified subgroup efficacy analyses, the mean treatment difference in FVC decline at 52 weeks in patients were examined by region and mycophenolate use (Figure 8).
Figure 8: Subgroup Analyses of the Mean Treatment Difference in FVC (mL) Decline at Week 52 by Region and Mycophenolate Use (Study 4)
Percent Change From Baseline In Forced Vital Capacity
Figure 9 presents the percent change from baseline in FVC in mL at Week 52 for Study 4. For the majority of patients, the decline in lung function was less on OFEV than on placebo.
Figure 9: Histogram of the Percent Change in FVC (mL) from Baseline to Week 52 According to Treatment and Percent Increments or Decrements of 5 (Study 4)a
 |
a Patients classified as having missing FVC data at Week 52 are those with no FVC assessment between Day 310 and Day 373. bid = twice daily |
Modified Rodnan Skin Score
No benefit in mRSS was observed in patients receiving OFEV. The adjusted mean absolute change from baseline in mRSS at Week 52 was comparable between the OFEV group (-2.17 (95% CI: -2.69, -1.65)) and the placebo group (-1.96 (95% CI: -2.48, -1.45)). The adjusted mean difference between the treatment groups was -0.21 (95% CI: -0.94, 0.53).
Survival
No difference in survival was observed in an exploratory analysis of mortality over the whole trial (OFEV: n=10 (3.5%) vs. placebo: n=9 (3.1%)). The analysis of time to death over the whole trial resulted in a HR of 1.16 (95% CI: 0.47, 2.84).