Nintedanib in children and adolescents with fibrosing interstitial lung diseases.

BACKGROUND: Childhood interstitial lung disease (ILD) comprises a spectrum of rare ILDs affecting infants, children and adolescents. Nintedanib is a licensed treatment for pulmonary fibrosis in adults. The primary objectives of the InPedILD trial were to determine the dose-exposure and safety of nintedanib in children and adolescents with fibrosing ILD. METHODS: Patients aged 6-17 years with fibrosing ILD on high-resolution computed tomography and clinically significant disease were randomised 2:1 to receive nintedanib or placebo for 24 weeks and then open-label nintedanib. Dosing was based on weight-dependent allometric scaling. Co-primary end-points were the area under the plasma concentration-time curve at steady state (AUCτ,ss) at weeks 2 and 26 and the proportion of patients with treatment-emergent adverse events at week 24. RESULTS: 26 patients received nintedanib and 13 patients received placebo. The geometric mean (geometric coefficient of variation) AUCτ,ss for nintedanib was 175 µg·h·L-1 (85.1%) in patients aged 6-11 years and 160 µg·h·L-1 (82.7%) in patients aged 12-17 years. In the double-blind period, adverse events were reported in 84.6% of patients in each treatment group. Two patients discontinued nintedanib due to adverse events. Diarrhoea was reported in 38.5% and 15.4% of the nintedanib and placebo groups, respectively. Adjusted mean±se changes in percentage predicted forced vital capacity at week 24 were 0.3±1.3% in the nintedanib group and -0.9±1.8% in the placebo group. CONCLUSIONS: In children and adolescents with fibrosing ILD, a weight-based dosing regimen resulted in exposure to nintedanib similar to adults and an acceptable safety profile. These data provide a scientific basis for the use of nintedanib in this patient population.

Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease.

BACKGROUND: Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis-related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of systemic sclerosis and ILD. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of nintedanib in patients with ILD associated with systemic sclerosis. Patients who had systemic sclerosis with an onset of the first non-Raynaud's symptom within the past 7 years and a high-resolution computed tomographic scan that showed fibrosis affecting at least 10% of the lungs were randomly assigned, in a 1:1 ratio, to receive 150 mg of nintedanib, administered orally twice daily, or placebo. The primary end point was the annual rate of decline in forced vital capacity (FVC), assessed over a 52-week period. Key secondary end points were absolute changes from baseline in the modified Rodnan skin score and in the total score on the St. George's Respiratory Questionnaire (SGRQ) at week 52. RESULTS: A total of 576 patients received at least one dose of nintedanib or placebo; 51.9% had diffuse cutaneous systemic sclerosis, and 48.4% were receiving mycophenolate at baseline. In the primary end-point analysis, the adjusted annual rate of change in FVC was -52.4 ml per year in the nintedanib group and -93.3 ml per year in the placebo group (difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P = 0.04). Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10. The change from baseline in the modified Rodnan skin score and the total score on the SGRQ at week 52 did not differ significantly between the trial groups, with differences of -0.21 (95% CI, -0.94 to 0.53; P = 0.58) and 1.69 (95% CI, -0.73 to 4.12 [not adjusted for multiple comparisons]), respectively. Diarrhea, the most common adverse event, was reported in 75.7% of the patients in the nintedanib group and in 31.6% of those in the placebo group. CONCLUSIONS: Among patients with ILD associated with systemic sclerosis, the annual rate of decline in FVC was lower with nintedanib than with placebo; no clinical benefit of nintedanib was observed for other manifestations of systemic sclerosis. The adverse-event profile of nintedanib observed in this trial was similar to that observed in patients with idiopathic pulmonary fibrosis; gastrointestinal adverse events, including diarrhea, were more common with nintedanib than with placebo. (Funded by Boehringer Ingelheim; SENSCIS ClinicalTrials.gov number, NCT02597933.).

Continued treatment with nintedanib in patients with systemic sclerosis-associated interstitial lung disease: data from SENSCIS-ON.

OBJECTIVES: In the SENSCIS trial in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) versus placebo, with adverse events that were manageable for most patients. An open-label extension trial, SENSCIS-ON, is assessing safety and FVC decline during longer term nintedanib treatment. METHODS: Patients who completed the SENSCIS trial or a drug-drug interaction (DDI) study of nintedanib and oral contraceptive on treatment were eligible to enter SENSCIS-ON. Adverse events and changes in FVC over 52 weeks of SENSCIS-ON were assessed in patients who received nintedanib in SENSCIS and continued nintedanib in SENSCIS-ON ('continued nintedanib' group) and in patients who received placebo in SENSCIS and initiated nintedanib in SENSCIS-ON or who received nintedanib for ≤28 days in the DDI study ('initiated nintedanib' group). RESULTS: There were 197 patients in the continued nintedanib group and 247 in the initiated nintedanib group. Diarrhoea was reported in 68.0% and 68.8% of patients in these groups, respectively. Adverse events led to discontinuation of nintedanib in 4.6% and 21.5% of the continued nintedanib and initiated nintedanib groups, respectively. Mean (SE) changes in FVC from baseline to week 52 of SENSCIS-ON were -58.3 (15.5) mL in the continued nintedanib group and -44.0 (16.2) mL in the initiated nintedanib group. CONCLUSIONS: The safety profile of nintedanib over 52 weeks of SENSCIS-ON was consistent with that reported in SENSCIS. The change in FVC over 52 weeks of SENSCIS-ON was similar to that observed in the nintedanib group of SENSCIS.

Disease frequency, patient characteristics, comorbidity outcomes and immunosuppressive therapy in systemic sclerosis and systemic sclerosis-associated interstitial lung disease: a US cohort study.

OBJECTIVES: To investigate prevalence estimates and incidence rates (IRs) for SSc and SSc-associated interstitial lung disease (SSc-ILD) cohorts and describe patient characteristics, immunosuppressive therapy (IST) and comorbid outcomes among incident SSc and SSc-ILD cohorts. METHODS: Data were obtained from the US IBM MarketScan (2008-2017) claims database using algorithms developed with expert consultation. For the SSc cohort, newly diagnosed patients (aged ≥18 years) had one or more diagnostic claim for SSc. For the SSc-ILD cohort, patients had an additional ILD claim. Sensitivity analyses using two or more claims or alternative ILD diagnostic codes were also conducted. RESULTS: When requiring one or more diagnostic claim, the prevalence of SSc and SSc-ILD per 100 000 persons was 72.1 and 19.0. The IR for SSc and SSc-ILD per 100 000 person-years was 18.3 and 4.3. Sensitivity analyses requiring two or more claims yielded much lower prevalence (SSc: 41.5; SSc-ILD: 13.3) and IR (SSc: 8.8; SSc-ILD: 1.6) estimates. Patients with SSc-ILD were older, with increased comorbidities and diagnostic procedures at baseline. MTX and MMF were the most common ISTs; 12.7% of the SSc-ILD cohort received therapy at baseline vs 8.2% for SSc. A total of 42.5% and 45.0% of the SSc and SSc-ILD cohorts, respectively, started a stable IST regimen and 21.7% and 19.4% of these had an escalation. Skin disorders were the most common comorbid outcome in both cohorts during follow-up. CONCLUSIONS: SSc, with or without associated ILD, is a rare disease in the US. Newly diagnosed patients with SSc-ILD had received more IST and had more comorbidities compared with newly diagnosed SSc.

Nintedanib in patients with systemic sclerosis-associated interstitial lung disease: A Japanese population analysis of the SENSCIS trial.

OBJECTIVE: We examined the efficacy and safety of nintedanib in Japanese patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) in the global Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) trial. METHODS: Randomised patients received oral nintedanib 150 mg (N = 34) twice daily or placebo (N = 36) until the last patient reached 52 weeks of treatment (up to 100 weeks). Data were analysed using a subgroup analysis model with Japanese and non-Japanese patients as subgroup variables. RESULTS: In Japanese patients, the adjusted annual rate of forced vital capacity (FVC) decline over 52 weeks was -86.2 mL/year (nintedanib) and -90.9 mL/year (placebo); treatment difference, 4.67 mL/year (95% confidence interval, -103.28, 112.63). Treatment effect heterogeneity between Japanese and non-Japanese patients was not detected (treatment-by-visit-by-subgroup interaction; p = .49). FVC decline was smaller for nintedanib versus placebo through 100 weeks in Japanese patients. The most commonly reported adverse events with nintedanib were gastrointestinal and liver disorder events; most were mild-to-moderate in severity. CONCLUSION: In both Japanese and non-Japanese patients with SSc-ILD, nintedanib slowed the progression of ILD, with no heterogeneity detected between the subgroups. The safety profile for nintedanib in Japanese patients was similar to that observed in patients with idiopathic pulmonary fibrosis (ClinicalTrials.gov: NCT02597933).

Safety and tolerability of nintedanib in patients with systemic sclerosis-associated interstitial lung disease: data from the SENSCIS trial.

OBJECTIVES: To characterise the safety and tolerability of nintedanib and the dose adjustments used to manage adverse events in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). METHODS: In the SENSCIS trial, patients with SSc-ILD were randomised to receive nintedanib 150 mg two times per day or placebo. To manage adverse events, treatment could be interrupted or the dose reduced to 100 mg two times per day. We assessed adverse events and dose adjustments over 52 weeks. RESULTS: A total of 576 patients received nintedanib (n=288) or placebo (n=288). The most common adverse event was diarrhoea, reported in 75.7% of patients in the nintedanib group and 31.6% in the placebo group; diarrhoea led to permanent treatment discontinuation in 6.9% and 0.3% of patients in the nintedanib and placebo groups, respectively. In the nintedanib and placebo groups, respectively, 48.3% and 12.2% of patients had ≥1 dose reduction and/or treatment interruption, and adverse events led to permanent discontinuation of the trial drug in 16.0% and 8.7% of patients. The adverse events associated with nintedanib were similar across subgroups defined by age, sex, race and weight. The rate of decline in forced vital capacity in patients treated with nintedanib was similar irrespective of dose adjustments. CONCLUSIONS: The adverse event profile of nintedanib in patients with SSc-ILD is consistent with its established safety and tolerability profile in patients with idiopathic pulmonary fibrosis. Dose adjustment is important to minimise the impact of adverse events and help patients remain on therapy.

Design of a randomised, placebo-controlled clinical trial of nintedanib in patients with systemic sclerosis-associated interstitial lung disease (SENSCIS™).

OBJECTIVES: Nintedanib is a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis (IPF). The pathological pathways involved in fibrogenesis in IPF and interstitial lung disease associated with systemic sclerosis (SSc-ILD) show commonalities; both involve fibroblast activation, myofibroblast accumulation and deposition of extracellular matrix. The SENSCIS™ trial is a randomised, placebo-controlled Phase III trial that will evaluate the efficacy and safety of nintedanib in patients with SSc-ILD (NCT02597933). METHODS: Approximately 520 patients with SSc (based on 2013 American College of Rheumatology/European League Against Rheumatism criteria) and ILD (≥10% fibrosis of the lungs, confirmed by central assessment of chest high resolution computed tomography), forced vital capacity (FVC) ≥40% predicted and diffusing capacity for carbon monoxide of 30-89% predicted will be enrolled. Patients will be randomised (1:1) to nintedanib 150 mg twice daily or placebo, stratified by the presence of anti-topoisomerase I antibody. To reflect real-world management, patients receiving prednisone (≤10 mg/day) and/or a stable dose of mycophenolate or methotrexate, will be eligible. The primary endpoint is the annual rate of decline in FVC (mL/ year) assessed over 52 weeks. Patients will remain on blinded study treatment until the last patient completes 52 weeks of treatment or for a maximum of 100 weeks of treatment. Key secondary endpoints are absolute changes from baseline in modified Rodnan skin score and St George's Respiratory Questionnaire at week 52. RESULTS: Recruitment for the trial began in November 2015. CONCLUSIONS: This trial will assess the efficacy and safety of nintedanib in patients with SSc-ILD.

Randomised, double-blind, placebo-controlled crossover study to investigate different dosing regimens of olodaterol delivered via Respimat® in patients with moderate to severe persistent asthma.

BACKGROUND: A Phase II, multicentre, randomised, double-blind, placebo-controlled, crossover trial comparing the 24-h forced expiratory volume in 1 s (FEV1) time profile after 3 weeks' treatment with once-daily (QD) or twice-daily (BID) olodaterol (at the same total daily dose) versus placebo delivered via Respimat® in patients with moderate to severe asthma. METHODS: Patients were randomised to different sequences of olodaterol with 2-week washout, either as a total daily dose of 5 µg (5 µg QD [AM] or 2.5 µg BID) or placebo, or 10 µg (10 µg QD [AM] or 5 µg BID) or placebo. Primary end point was FEV1 area under the curve from 0 to 24 h (AUC0-24) response (defined as change from study baseline FEV1) after 3 weeks. Key secondary end points were FEV1 AUC0-12 and AUC12-24 responses. RESULTS: Two hundred and six patients received treatment. All olodaterol treatments demonstrated statistically significant improvements in FEV1 AUC0-24 response at 3 weeks versus placebo (p < 0.0001); adjusted mean treatment difference versus placebo was 0.191 L for olodaterol 2.5 µg BID (95 % confidence interval [CI] 0.152, 0.229), 0.150 L for 5 µg QD (95 % CI 0.111, 0.189), 0.228 L for 5 µg BID (95 % CI 0.190, 0.266) and 0.209 L for 10 µg QD (95 % CI 0.170, 0.247). These results were supported by the key secondary end points. Olodaterol 5 µg QD provided numerically lower mean values for 24-h bronchodilation than olodaterol 2.5 µg BID (p = 0.0465), with no statistically significant difference between treatment with olodaterol 10 µg QD and 5 µg BID. No relevant differences in morning and evening peak expiratory flow or Asthma Control Questionnaire scores at 3 weeks were observed between different doses and regimens. Adverse events were generally mild to moderate and comparable between groups. CONCLUSIONS: All doses and dose frequencies provided adequate 24-h bronchodilation superior to placebo. Based on the results of this study, it would be reasonable to include both posologies of 5 µg olodaterol daily (5 µg QD or 2.5 µg BID, both delivered in two puffs per dose from the Respimat® inhaler) in subsequent studies. Further studies are necessary to confirm the optimum dosing regimen in asthma. No safety concerns were identified. TRIAL REGISTRATION: ClinicalTrials.gov NCT01311661.

Dose-finding evaluation of once-daily treatment with olodaterol, a novel long-acting ß2-agonist, in patients with asthma: results of a parallel-group study and a crossover study.

BACKGROUND: Olodaterol is a novel, inhaled long-acting ß2-agonist (LABA) with >24-hour duration of action investigated in asthma and chronic obstructive pulmonary disease. METHODS: Two multicentre studies examined the efficacy and safety of 4 weeks' once-daily (QD) olodaterol (2, 5, 10 and 20 µg, with background inhaled corticosteroids) in patients with asthma. One randomised, double-blind, parallel-group study (1222.6; 296 patients) administered treatment in the morning. Pulmonary function tests (PFTs) were performed pre-dose (trough) and ≤3 hours post-dose (weeks 1 and 2), and ≤6 hours post-dose after 4 weeks; primary end point was trough forced expiratory volume in 1 second (FEV1) response (change from baseline mean FEV1) after 4 weeks. A second randomised, double-blind, placebo- and active-controlled (formoterol 12 µg twice-daily) incomplete-block crossover study (1222.27; 198 patients) administered QD treatments in the evening. PFTs were performed over a 24-hour dosing interval after 4 weeks; primary end point was FEV1 area under the curve from 0-24 hours (AUC0-24) response (change from study baseline [mean FEV1] after 4 weeks). RESULTS: Study 1222.6 showed a statistically significant increase in trough FEV1 response with olodaterol 20 µg (0.147 L; 95 % confidence interval [CI]: 0.059, 0.234; p = 0.001) versus placebo, with more limited efficacy and no evidence of dose response compared to placebo across the other olodaterol doses (2, 5 and 10 µg). Study 1222.27 demonstrated increases in FEV1 AUC0-24 responses at 4 weeks with all active treatments (p < 0.0001); adjusted mean (95 % CI) differences from placebo were 0.140 (0.097, 0.182), 0.182 (0.140, 0.224), 0.205 (0.163, 0.248) and 0.229 (0.186, 0.272) L for olodaterol 2, 5, 10 and 20 µg, respectively, and 0.169 (0.126, 0.211) for formoterol, providing evidence of increased efficacy with higher olodaterol dose. Olodaterol was generally well tolerated, with a few events associated with known sympathomimetic effects, mainly with 20 µg. CONCLUSIONS: The LABA olodaterol has >24-hour duration of action. In patients with asthma, evidence of bronchodilator efficacy was demonstrated with statistically and clinically significant improvements in the primary end point of trough FEV1 response measured in clinics over placebo for the highest administered dose of 20 µg in Study 1222.6, and statistically and clinically significant improvements versus placebo in FEV1 AUC0-24 responses at 4 weeks for all doses tested in Study 1222.27, which also exhibited a dose response. Bronchodilator efficacy was seen over placebo for all olodaterol doses for morning and evening peak expiratory flow in both studies. All doses were well tolerated. TRIAL REGISTRATIONS: NCT00467740 (1222.6) and NCT01013753 (1222.27).

Estimating the effect of nintedanib on forced vital capacity in children and adolescents with fibrosing interstitial lung disease using a Bayesian dynamic borrowing approach.

BACKGROUND: The rarity of childhood interstitial lung disease (chILD) makes it challenging to conduct powered trials. In the InPedILD trial, among 39 children and adolescents with fibrosing ILD, there was a numerical benefit of nintedanib versus placebo on change in forced vital capacity (FVC) over 24 weeks (difference in mean change in FVC % predicted of 1.21 [95% confidence interval: -3.40, 5.81]). Nintedanib has shown a consistent effect on FVC across populations of adults with different diagnoses of fibrosing ILD. METHODS: In a Bayesian dynamic borrowing analysis, prespecified before data unblinding, we incorporated data on the effect of nintedanib in adults and the data from the InPedILD trial to estimate the effect of nintedanib on FVC in children and adolescents with fibrosing ILD. The data from adults were represented as a meta-analytic predictive (MAP) prior distribution with mean 1.69 (95% credible interval: 0.49, 3.08). The adult data were weighted according to expert judgment on their relevance to the efficacy of nintedanib in chILD, obtained in a formal elicitation exercise. RESULTS: Combined data from the MAP prior and InPedILD trial analyzed within the Bayesian framework resulted in a median difference between nintedanib and placebo in change in FVC % predicted at Week 24 of 1.63 (95% credible interval: -0.69, 3.40). The posterior probability for superiority of nintedanib versus placebo was 95.5%, reaching the predefined success criterion of at least 90%. CONCLUSION: These findings, together with the safety data from the InPedILD trial, support the use of nintedanib in children and adolescents with fibrosing ILDs.

Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial.

BACKGROUND: Some patients with severe asthma remain symptomatic and obstructed despite maximal recommended treatment. Tiotropium, a long-acting inhaled anticholinergic agent, might be an effective bronchodilator in such patients. OBJECTIVE: We sought to compare the efficacy and safety of 2 doses of tiotropium (5 and 10 µg daily) administered through the Respimat inhaler with placebo as add-on therapy in patients with uncontrolled severe asthma (Asthma Control Questionnaire score, ≥ 1.5; postbronchodilator FEV1, ≤ 80% of predicted value) despite maintenance treatment with at least a high-dose inhaled corticosteroid plus a long-acting ß2-agonist. METHODS: This was a randomized, double-blind, crossover study with three 8-week treatment periods. The primary end point was peak FEV1 at the end of each treatment period. RESULTS: Of 107 randomized patients (54% female patients; mean, 55 years of age; postbronchodilator FEV1, 65% of predicted value), 100 completed all periods. Peak FEV1 was significantly higher with 5 µg (difference, 139 mL; 95% CI, 96-181 mL) and 10 µg (difference, 170 mL; 95% CI, 128-213 mL) of tiotropium than with placebo (both P < .0001). There was no significant difference between the active doses. Trough FEV1 at the end of the dosing interval was higher with tiotropium (5 µg: 86 mL [95% CI, 41-132 mL]; 10 µg: 113 mL [95% CI, 67-159 mL]; both P < .0004). Daily home peak expiratory flow measurements were higher with both tiotropium doses. There were no significant differences in asthma-related health status or symptoms. Adverse events were balanced across groups except for dry mouth, which was more common on 10 µg of tiotropium. CONCLUSION: The addition of once-daily tiotropium to asthma treatment, including a high-dose inhaled corticosteroid plus a long-acting ß2-agonist, significantly improves lung function over 24 hours in patients with inadequately controlled, severe, persistent asthma.

An exploratory study investigating biomarkers associated with autoimmune pulmonary alveolar proteinosis (aPAP).

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare lung disorder involving production of autoantibodies against endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF). This study aimed to identify biomarkers that could be used to monitor for aPAP, particularly in patients treated with anti-GM-CSF antibodies. This was an exploratory, prospective, observational, single-center study. Pre-specified biomarkers were evaluated between baseline and Day 120 in serum/plasma, whole blood, sputum and exhaled breath condensate from patients with aPAP, healthy volunteers, and patients with chronic obstructive pulmonary disease (COPD) and asthma (not treated with anti-GM-CSF and with no evidence of aPAP). Pulmonary function tests were also performed. Overall, 144 individuals were enrolled (aPAP: n = 34, healthy volunteers: n = 24, COPD: n = 40 and asthma: n = 46). Plasma GM-CSF levels were lower, and Krebs von den Lungen 6 and GM-CSF autoantibody ranges were higher, in patients with aPAP compared with other populations. Surfactant proteins-A and -D, lactate dehydrogenase and carcinoembryonic antigen ranges partially or completely overlapped across populations. Most plasma biomarkers showed high sensitivity and specificity for detection of aPAP; GM-CSF and GM-CSF autoantibody concentrations demonstrated equivalent sensitivity for differentiating aPAP. In addition to characteristic GM-CSF autoantibodies, assessment of plasma GM-CSF may identify individuals at risk of developing aPAP.Trial registration: EudraCT, 2012-003475-19. Registered 23 July 2012- https://eudract.ema.europa.eu/ .

A Drug-Drug Interaction Study to Investigate the Effect of Nintedanib on the Pharmacokinetics of Microgynon (Ethinylestradiol and Levonorgestrel) in Female Patients with Systemic Sclerosis-Associated Interstitial Lung Disease.

BACKGROUND AND OBJECTIVES: Nintedanib is a tyrosine kinase inhibitor approved for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD), idiopathic pulmonary fibrosis, and other chronic fibrosing ILDs with a progressive phenotype. As nintedanib may cause foetal harm, patients taking nintedanib should avoid pregnancy. The objective of this study was to investigate the effect of nintedanib co-administration on the pharmacokinetics of Microgynon (ethinylestradiol and levonorgestrel) in female patients with SSc-ILD. METHODS: This was an open-label, two-period, fixed-sequence, drug-drug interaction study. Female patients with SSc and ≥ 10% extent of fibrotic ILD on a high-resolution computed tomography scan were eligible to participate. In Period 1, patients received one Microgynon tablet (ethinylestradiol 30 µg and levonorgestrel 150 µg) ≥ 3 days before the first administration of nintedanib in Period 2. In Period 2, patients received one Microgynon tablet following intake of nintedanib 150 mg twice daily for ≥ 10 consecutive days. The primary pharmacokinetic endpoints were the areas under the plasma concentration-time curve of ethinylestradiol and levonorgestrel over the time interval from 0 to the last quantifiable data point (AUC0-tz) and the maximum measured concentrations of ethinylestradiol and levonorgestrel in plasma (Cmax). The secondary pharmacokinetic endpoint was the area under the plasma concentration-time curve of ethinylestradiol and levonorgestrel over the time interval from 0 extrapolated to infinity (AUC0-∞). The relative exposures of ethinylestradiol and levonorgestrel when administered alone and in combination with nintedanib were assessed using an ANOVA model. RESULTS: Seventeen patients were treated. Pharmacokinetic data from 15 patients were analysed. Plasma concentration-time profiles of ethinylestradiol and levonorgestrel were similar following administration of Microgynon before and after administration of nintedanib for ≥ 10 consecutive days. Adjusted geometric mean (gMean) ratios [90% confidence intervals (CIs)] for AUC0‒tz (101.4% [92.8, 110.7]) and AUC0‒∞ (101.2% [94.0, 109.1]) indicated that there was no difference in total ethinylestradiol exposure when Microgynon was administered before or after administration of nintedanib. The adjusted gMean ratio for Cmax of ethinylestradiol (116.7% [90% CI 107.6, 126.5]) indicated an increase in peak exposure in the presence of nintedanib. Adjusted gMean ratios [90% CIs] for AUC0-tz (96.4% [91.5, 101.6]) and Cmax (100.9% [89.9, 113.2]) indicated that there was no difference in total or peak levonorgestrel exposure when Microgynon was administered before or after administration of nintedanib. The adjusted gMean ratio for AUC0‒∞ of levonorgestrel indicated a decrease in total exposure in the presence of nintedanib (88.1% [90% CI 80.0, 97.0]). CONCLUSION: Pharmacokinetic data indicate that there is no relevant effect of nintedanib on plasma exposure to ethinylestradiol and levonorgestrel in female patients with SSc-ILD. TRIAL REGISTRATION: Clinicaltrials.gov NCT03675581.

Nintedanib in Patients With Systemic Sclerosis-Associated Interstitial Lung Disease: Subgroup Analyses by Autoantibody Status and Modified Rodnan Skin Thickness Score.

OBJECTIVE: Using data from the SENSCIS trial, these analyses were undertaken to assess the effects of nintedanib versus placebo in subgroups of patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), based on characteristics previously identified as being associated with the progression of SSc-ILD. METHODS: Patients with SSc-ILD were randomized to receive either nintedanib or placebo, stratified by anti-topoisomerase I antibody (ATA) status. We assessed the rate of decline in forced vital capacity (FVC) (expressed in ml/year) over 52 weeks in subgroups based on baseline ATA status, modified Rodnan skin thickness score (MRSS) (<18 versus ≥18), and SSc subtype (limited cutaneous SSc [lcSSc] versus diffuse cutaneous SSc [dcSSc]). RESULTS: At baseline, 60.8% of 576 patients who received treatment with either nintedanib or placebo were positive for ATA, 51.9% had dcSSc, and 77.5% of 574 patients with MRSS data available had an MRSS of <18. The effect of nintedanib versus placebo on reducing the rate of decline in FVC (ml/year) was numerically more pronounced in ATA-negative patients compared to ATA-positive patients (adjusted difference in the rate of FVC decline, 57.2 ml/year [95% confidence interval (95% CI) -3.5, 118.0] versus 29.9 ml/year [95% CI -19.1, 78.8]), in patients with a baseline MRSS ≥18 compared to those with a baseline MRSS of <18 (adjusted difference in the rate of FVC decline, 88.7 ml/year [95% CI 7.7, 169.8] versus 26.4 ml/year [95% CI -16.8, 69.6]), and in patients with dcSSc compared to those with lcSSc (adjusted difference in the rate of FVC decline, 56.6 ml/year [95% CI 3.2, 110.0] versus 25.3 ml/year [95% CI -28.9, 79.6]). However, all exploratory interaction P values were nonsignificant (all P > 0.05), indicating that there was no heterogeneity in the effect of nintedanib versus placebo between these subgroups of patients. CONCLUSION: In patients with SSc-ILD, reduction in the annual rate of decline in FVC among patients receiving nintedanib compared to those receiving placebo was not found to be heterogenous across subgroups based on ATA status, MRSS, or SSc subtype.

Efficacy and safety of nintedanib in Asian patients with systemic sclerosis-associated interstitial lung disease: Subgroup analysis of the SENSCIS trial.

BACKGROUND AND OBJECTIVE: In the SENSCIS trial in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) (mL/year) over 52 weeks by 44% in comparison with placebo, with manageable adverse events in most patients. We analyzed the efficacy and safety of nintedanib in patients of Asian race. METHODS: Patients with SSc-ILD were randomized to receive nintedanib or placebo. The outcomes over 52 weeks were analyzed in Asian versus non-Asian patients. RESULTS: Of the 288 patients in each treatment group, 62 (21.5%) in the nintedanib group and 81 (28.1%) in the placebo group were Asian; 90.2% of the Asian patients were enrolled in Asian countries. In the placebo group, the rate of FVC decline over 52 weeks was consistent between Asian and non-Asian patients (-99.9 and -90.6 mL/year, respectively). The effect of nintedanib on reducing the rate of FVC decline over 52 weeks was consistent between Asian (difference, 44.3 mL/year [95% CI: -32.8, 121.4]) and non-Asian patients (difference, 39.0 mL/year [95% CI: -5.1, 83.1]) (treatment-by-time-by-subgroup interaction, p = 0.91). Diarrhea was the most frequent adverse event and was reported in similar proportions of Asian and non-Asian patients in the nintedanib group (80.6% and 74.3%, respectively) and placebo group (28.4% and 32.9%, respectively). CONCLUSIONS: In patients with SSc-ILD, nintedanib had a consistent benefit on slowing the progression of SSc-ILD in Asian and non-Asian patients, with a similar adverse event profile. TRIAL REGISTRATION: ClinicalTrials.gov NCT02597933.

Efficacy and safety of nintedanib in patients with systemic sclerosis-associated interstitial lung disease treated with mycophenolate: a subgroup analysis of the SENSCIS trial.

BACKGROUND: In the Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) trial, nintedanib reduced the rate of decline in forced vital capacity (FVC) in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). Patients on stable treatment with mycophenolate for at least 6 months before randomisation could participate. The aim of this subgroup analysis was to examine the efficacy and safety of nintedanib by mycophenolate use at baseline. METHODS: The SENSCIS trial was a randomised, double-blind, placebo-controlled trial, in which patients with SSc-ILD were randomly assigned (1:1) to receive 150 mg of oral nintedanib twice daily or placebo for at least 52 weeks. In a prespecified subgroup analysis, we analysed the primary endpoint of rate of decline in FVC over 52 weeks by mycophenolate use at baseline. In a post-hoc analysis, we analysed the proportion of patients with an absolute decrease in FVC of at least 3·3% predicted at week 52 (proposed minimal clinically important difference estimate for worsening of FVC in patients with SSc-ILD) in subgroups by mycophenolate use at baseline. Adverse events were reported in subgroups by mycophenolate use at baseline. Analyses were done in all participants who received at least one dose of study drug. We analysed the annual rate of decline in FVC using a random coefficient regression model (with random slopes and intercepts) including anti-topoisomerase I antibody status, age, height, sex, and baseline FVC as covariates and terms for baseline-by-time, treatment-by-subgroup, and treatment-by-subgroup-by-time interactions. SENSCIS is registered with ClinicalTrials.gov, NCT02597933, and is now complete. FINDINGS: Between Nov 30, 2015, and Oct 31, 2017, 819 participants were screened and 576 were enrolled, randomly assigned to, and treated with nintedanib (n=288) or placebo (n=288). 139 (48%) of 288 in the nintedanib group and 140 (49%) of 288 in the placebo group were taking mycophenolate at baseline. In patients taking mycophenolate at baseline, the adjusted mean annual rate of decline in FVC was -40·2 mL per year (SE 19·8) with nintedanib and -66·5 mL per year (19·3) with placebo (difference: 26·3 mL per year [95% CI -27·9 to 80·6]). In patients not taking mycophenolate at baseline, the adjusted mean annual rate of decline in FVC was -63·9 mL per year (SE 19·3) with nintedanib and -119·3 mL per year (19·0) with placebo (difference: 55·4 mL per year [95% CI 2·3 to 108·5]). We found no heterogeneity in the effect of nintedanib versus placebo on the annual rate of decline in FVC between the subgroups by mycophenolate use (p value for interaction=0·45). In a post-hoc analysis, the proportion of patients with an absolute decrease in FVC of at least 3·3% predicted was lower with nintedanib than with placebo in both patients taking mycophenolate (40 [29%] of 138 vs 56 [40%] of 140; odds ratio 0·61 [0·37 to 1·01]) and those not taking mycophenolate (59 [40%] of 149 vs 70 [47%] of 148; 0·73 [0·46 to 1·16]) at baseline. The adverse event profile of nintedanib was similar between the subgroups. Diarrhoea, the most common adverse event, was reported in 106 (76%) of 139 patients in the nintedanib group and 48 (34%) of 140 in the placebo group among those taking mycophenolate at baseline, and in 112 (75%) of 149 in the nintedanib group and 43 (29%) of 148 in the placebo group among those not taking mycophenolate at baseline. Over the entire trial period, 19 patients died (ten in the nintedanib group and nine in the placebo group). One death in the nintedanib group was considered to be related to study drug. INTERPRETATION: Nintedanib reduced the progression of interstitial lung disease both in patients with SSc-ILD who were and were not using mycophenolate at baseline, with no heterogeneity in its treatment effect detected between the subgroups. The adverse event profile of nintedanib was similar in the subgroups by mycophenolate use. Our findings suggest that the combination of mycophenolate and nintedanib offers a safe treatment option for patients with SSc-ILD. More data are needed on the benefits of initial combination therapy versus a sequential approach to treatment of SSc-ILD. FUNDING: Boehringer Ingelheim.

Collaboration between patient organisations and a clinical research sponsor in a rare disease condition: learnings from a community advisory board and best practice for future collaborations.

Introduction Transparent collaborations between patient organisations (POs) and clinical research sponsors (CRS) can identify and address the unmet needs of patients and caregivers. These insights can improve clinical trial participant experience and delivery of medical innovations necessary to advance health outcomes and standards of care. We share our experiences from such a collaboration undertaken surrounding the SENSCIS® clinical trial (NCT02597933), and discuss its impact during, and legacy beyond, the trial.Summary We describe the establishment of a community advisory board (CAB): a transparent, multiyear collaboration between the scleroderma patient community and a CRS. We present shared learnings from the collaboration, which is split into three main areas: (1) the implementation and conduct of the clinical trial; (2) analysis and dissemination of the results; and (3) aspects of the collaboration not related to the trial.1. The scleroderma CAB reviewed and provided advice on trial conduct and reporting. This led to the improvement and optimisation of trial procedures; meaningful, patient-focused adaptations were made to address challenges relevant to scleroderma-associated interstitial lung disease patients.2. To ensure that results of the trial were accessible to lay audiences and patients, written lay summaries were developed by the trial sponsor with valuable input from the CAB to ensure that language and figures were understandable.3. The CAB and the CRS also collaborated to co-develop opening tools for medication blister packs and bottles. In addition, to raise disease awareness among physicians, patients and caregivers, educational materials to improve diagnosis and management of scleroderma were co-created and delivered by the CAB and CRS.Conclusions This collaboration between POs and a CRS, in a rare disease condition, led to meaningful improvements in patient safety, comfort and self-management and addressed information needs. This collaboration may serve as a template of best practice for future collaborations between POs, research sponsors and other healthcare stakeholders.

Rationale for the evaluation of nintedanib as a treatment for systemic sclerosis-associated interstitial lung disease.

Interstitial lung disease is a common manifestation of systemic sclerosis. Systemic sclerosis-associated interstitial lung disease is characterized by progressive pulmonary fibrosis and a reduction in pulmonary function. Effective treatments for systemic sclerosis-associated interstitial lung disease are lacking. In addition to clinical similarities, systemic sclerosis-associated interstitial lung disease shows similarities to idiopathic pulmonary fibrosis in the pathophysiology of the underlying fibrotic processes. Idiopathic pulmonary fibrosis and systemic sclerosis-associated interstitial lung disease culminate in a self-sustaining pathway of pulmonary fibrosis in which fibroblasts are activated, myofibroblasts accumulate, and the excessive extracellular matrix is deposited. Nintedanib is a tyrosine kinase inhibitor that has been approved for the treatment of idiopathic pulmonary fibrosis. In patients with idiopathic pulmonary fibrosis, nintedanib slows disease progression by decreasing the rate of lung function decline. In this review, we summarize the antifibrotic, anti-inflammatory, and attenuated vascular remodeling effects of nintedanib demonstrated in in vitro studies and in animal models of aspects of systemic sclerosis. Nintedanib interferes at multiple critical steps in the pathobiology of systemic sclerosis-associated interstitial lung disease, providing a convincing rationale for its investigation as a potential therapy. Finally, we summarize the design of the randomized placebo-controlled SENSCIS® trial that is evaluating the efficacy and safety of nintedanib in patients with systemic sclerosis-associated interstitial lung disease.