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1.
Respir Res ; 21(1): 7, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31906942

RESUMO

The approvals of nintedanib and pirfenidone changed the treatment paradigm in idiopathic pulmonary fibrosis (IPF), and increased our understanding of the underlying disease mechanisms. Nonetheless, many challenges and unmet needs remain in the management of patients with IPF and other progressive fibrosing interstitial lung diseases.This review describes how the nintedanib clinical programme has helped to address some of these challenges. Data from this programme have informed changes to the IPF diagnostic guidelines, the timing of treatment initiation, and the assessment of disease progression. The use of nintedanib to treat patients with advanced lung function impairment, concomitant emphysema, patients awaiting lung transplantation and patients with IPF and lung cancer is discussed. The long-term use of nintedanib and an up-to-date summary of nintedanib in clinical practice are discussed. Directions for future research, namely emerging therapeutic options, precision medicine and other progressive fibrosing interstitial lung diseases, are described.Further developments in these areas should continue to improve patient outcomes.

2.
BMC Pulm Med ; 20(1): 3, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31914963

RESUMO

BACKGROUND: The two 52-week INPULSIS trials investigated nintedanib versus placebo in patients with IPF, FVC ≥50% predicted and DLco 30-79% predicted. The 24-week INSTAGE trial investigated nintedanib plus sildenafil versus nintedanib alone in patients with IPF and DLco ≤35% predicted. We used data from INPULSIS and INSTAGE to compare the effects of nintedanib in patients with IPF with less versus more severe impairment in gas exchange at baseline. METHODS: Analyses were conducted in patients treated with nintedanib alone in the INPULSIS and INSTAGE trials and in patients treated with placebo in the INPULSIS trials. Outcomes included the rate of decline in FVC over 24 weeks, the proportions of patients who had a confirmed or suspected idiopathic acute exacerbation over 24 weeks, deaths over 24 weeks, and adverse events. Analyses were descriptive. RESULTS: In total, 638 and 136 patients received nintedanib alone in the INPULSIS and INSTAGE trials, respectively, and 423 patients received placebo in the INPULSIS trials. Rates of FVC decline were - 52.3 and - 66.7 mL/24 weeks in patients treated with nintedanib alone in INPULSIS and INSTAGE, respectively, and - 102.8 mL/24 weeks in patients treated with placebo in INPULSIS. Confirmed or suspected idiopathic acute exacerbations were reported in 0.6 and 3.7% of patients treated with nintedanib alone in INPULSIS and INSTAGE, respectively, and 2.1% of patients treated with placebo in INPULSIS. Deaths occurred in 2.0, 11.0 and 1.9% of patients in these groups, respectively. Diarrhoea adverse events were reported in 52.5 and 48.5% of patients treated with nintedanib alone in INPULSIS and INSTAGE, respectively, and 16.1% of patients treated with placebo in INPULSIS. CONCLUSIONS: Based on data from the INSTAGE and INPULSIS trials, nintedanib had a similar effect on FVC decline over 24 weeks, and a similar safety and tolerability profile, in patients with IPF and more versus less severe impairment in gas exchange. These data support the use of nintedanib in patients with IPF who have advanced disease. TRIAL REGISTRATION: INPULSIS (NCT01335464 and NCT01335477); INSTAGE (NCT02802345).

3.
N Engl J Med ; 381(18): 1718-1727, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31566307

RESUMO

BACKGROUND: Preclinical data have suggested that nintedanib, an intracellular inhibitor of tyrosine kinases, inhibits processes involved in the progression of lung fibrosis. Although the efficacy of nintedanib has been shown in idiopathic pulmonary fibrosis, its efficacy across a broad range of fibrosing lung diseases is unknown. METHODS: In this double-blind, placebo-controlled, phase 3 trial conducted in 15 countries, we randomly assigned patients with fibrosing lung disease affecting more than 10% of lung volume on high-resolution computed tomography (CT) to receive nintedanib at a dose of 150 mg twice daily or placebo. All the patients met criteria for progression of interstitial lung disease in the past 24 months despite treatment and had a forced vital capacity (FVC) of at least 45% of the predicted value and a diffusing capacity of the lung for carbon monoxide ranging from 30 to less than 80% of the predicted value. Randomization was stratified according to the fibrotic pattern (a pattern of usual interstitial pneumonia [UIP] or other fibrotic patterns) on high-resolution CT. The primary end point was the annual rate of decline in the FVC, as assessed over a 52-week period. The two primary populations for analysis were the overall population and patients with a UIP-like fibrotic pattern. RESULTS: A total of 663 patients were treated. In the overall population, the adjusted rate of decline in the FVC was -80.8 ml per year with nintedanib and -187.8 ml per year with placebo, for a between-group difference of 107.0 ml per year (95% confidence interval [CI], 65.4 to 148.5; P<0.001). In patients with a UIP-like fibrotic pattern, the adjusted rate of decline in the FVC was -82.9 ml per year with nintedanib and -211.1 ml per year with placebo, for a difference of 128.2 ml (95% CI, 70.8 to 185.6; P<0.001). Diarrhea was the most common adverse event, as reported in 66.9% and 23.9% of patients treated with nintedanib and placebo, respectively. Abnormalities on liver-function testing were more common in the nintedanib group than in the placebo group. CONCLUSIONS: In patients with progressive fibrosing interstitial lung diseases, the annual rate of decline in the FVC was significantly lower among patients who received nintedanib than among those who received placebo. Diarrhea was a common adverse event. (Funded by Boehringer Ingelheim; INBUILD ClinicalTrials.gov number, NCT02999178.).


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Diarreia/induzido quimicamente , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Fibrose Pulmonar Idiopática/fisiopatologia , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Capacidade Vital/efeitos dos fármacos
4.
J Bras Pneumol ; 45(5): e20180414, 2019 Sep 16.
Artigo em Português, Inglês | MEDLINE | ID: mdl-31531619

RESUMO

OBJECTIVE: Clinical trials have shown that nintedanib 150 mg twice daily (bid) reduces disease progression in patients with idiopathic pulmonary fibrosis (IPF), with an adverse event profile that is manageable for most patients. Prior to the approval of nintedanib as a treatment for IPF in Brazil, an expanded access program (EAP) was initiated to provide early access to treatment and to evaluate the safety and tolerability of nintedanib in this patient population. METHODS: Patients with a diagnosis of IPF within the previous five years, forced vital capacity (FVC) ≥ 50% predicted and diffusing capacity of the lungs for carbon monoxide (DLco) 30% to 79% predicted were eligible to participate in the EAP. Patients received nintedanib 150 mg bid open-label. Safety assessments included adverse events leading to permanent discontinuation of nintedanib and serious adverse events. RESULTS: The EAP involved 57 patients at eight centers. Most patients were male (77.2%) and white (87.7%). At baseline, mean (SD) age was 70.7 (7.5) years and FVC was 70.7 (12.5) % predicted. Mean (SD) exposure to nintedanib was 14.4 (6.2) months; maximum exposure was 22.0 months. The most frequently reported adverse events considered by the investigator to be related to nintedanib treatment were diarrhea (45 patients, 78.9%) and nausea (25 patients, 43.9%). Adverse events led to permanent discontinuation of nintedanib in 16 patients (28.1%). Sixteen patients (28.1%) had a serious adverse event. CONCLUSION: In the Brazilian EAP, nintedanib had an acceptable safety and tolerability profile in patients with IPF, consistent with data from clinical trials.

5.
Respir Med ; 156: 20-25, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31404749

RESUMO

BACKGROUND: We explored the impact of FVC decline on subsequent FVC decline and mortality in the INPULSIS trials of nintedanib in patients with IPF and their open-label extension, INPULSIS-ON. METHODS: Changes in FVC and mortality between weeks 24 and 52 of the INPULSIS trials were assessed in patients with an increase/no decline in FVC % predicted and with declines in FVC <10% and ≥10% predicted from baseline to week 24. Changes in FVC and mortality in the first year of INPULSIS-ON were assessed in patients treated with nintedanib in the preceding INPULSIS trial who did and did not have a decline in FVC ≥10% predicted at week 52. RESULTS: The proportion of placebo-treated patients with decline in FVC ≥10% predicted between weeks 24 and 52 of INPULSIS was similar in patients with increase/no decline in FVC and with decline in FVC ≥10% predicted between baseline and week 24 (20.5% and 18.9%, respectively). Mortality between weeks 24 and 52 of INPULSIS was higher in patients with FVC decline ≥10% predicted than <10% predicted between baseline and week 24 (13.2% vs 3.8%). Among nintedanib-treated patients in INPULSIS who had decline in FVC ≥10% versus <10% predicted at week 52, 34.0% versus 21.4%, respectively, had decline in FVC ≥10% predicted in the first year of INPULSIS-ON. Mortality in the first year of INPULSIS-ON was 21.3% vs 5.7% in these groups, respectively. CONCLUSIONS: Decline in FVC did not predict FVC decline but was associated with mortality in patients with IPF.

6.
Am J Respir Crit Care Med ; 200(12): 1505-1512, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31365829

RESUMO

Rationale: In the INSTAGE trial in patients with idiopathic pulmonary fibrosis (IPF) and severely impaired gas exchange, nintedanib plus sildenafil was associated with numerical benefits on St. George's Respiratory Questionnaire (SGRQ) total score, brain natriuretic peptide (BNP), and FVC decline versus nintedanib alone. Exploratory analyses of the STEP-IPF (Sildenafil Trial of Exercise Performance in IPF) trial suggested that sildenafil may have a greater effect on SGRQ score in patients with IPF who have right heart dysfunction (RHD).Objectives: Assess whether RHD influenced the effects of nintedanib plus sildenafil versus nintedanib alone in the INSTAGE trial.Methods: Subgroup analyses of patients with (n = 117) versus those without (n = 156) echocardiographic signs of RHD at baseline.Measurements and Main Results: There was no heterogeneity between subgroups by presence of RHD in the effect of nintedanib plus sildenafil versus nintedanib alone on change in SGRQ total score at Week 12 (P = 0.74) or Week 24 (P = 0.90), or change in FVC at Week 12 (P = 0.58) or Week 24 (P = 0.55). In both subgroups, nintedanib plus sildenafil had a numerically greater effect on reducing FVC decline versus nintedanib alone. Between-group differences in change in BNP at Week 24 were -119.9 ng/L (95% confidence interval = -171.3 to -68.5) and -3.6 ng/L (95% confidence interval = -47.2 to 40.0) in patients with and without signs of RHD at baseline, respectively (P < 0.01).Conclusions: In the INSTAGE trial, there were no significant differences in the effects of nintedanib plus sildenafil versus nintedanib alone on changes in SGRQ and FVC between patients with or without echocardiographic signs of RHD at baseline. The benefit of combination therapy on stabilizing BNP was more pronounced in patients with RHD at baseline.Clinical trial registered with www.clinicaltrials.gov (NCT02802345).

7.
Curr Med Res Opin ; 35(11): 2015-2024, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31328965

RESUMO

Objective: Some patients with interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF) develop a progressive fibrosing phenotype. We investigated the diagnosis and management of non-IPF ILDs using data from a survey of physicians and from US insurance claims. Methods: Pulmonologists, rheumatologists and internists in France, Germany, Italy, Japan, Spain, UK and US who had managed ≥10 patients with non-IPF ILDs in the past year, including those with progressive fibrosing ILDs, completed an online survey. Data on US insurance and prescription claims were obtained from a repository that aggregates data on claims routed from providers or pharmacies to payers. Results: In May-June 2017, 243 pulmonologists, 203 rheumatologists and 40 internists completed an online survey. Respondents estimated that 18-32% of patients diagnosed with non-IPF ILDs develop progressive fibrosis and that time from symptom onset to death in these patients was 61-80 months. Drug treatment was given to 50-75% of patients with non-IPF progressive fibrosing ILDs. Reasons for patients not being treated included that physicians considered patients to have mild or slowly progressing disease, or did not believe that available treatments are effective or well tolerated. Corticosteroids were the preferred first-line treatment for all types of non-IPF ILD. There was considerable heterogeneity in preferences for second- and third-line treatments. US insurance claims data from 3823 patients indicated that, in 2016, 50-75% of patients with ILDs received drug treatment (mostly corticosteroids) for their ILD. Conclusions: Physicians estimate that 18-32% of patients diagnosed with non-IPF ILDs develop a progressive fibrosing phenotype and that these patients experience significant delays in the diagnosis of ILD and the detection of progressive fibrosis. Between 25% and 50% of patients with progressive fibrosing ILDs do not receive drug therapy. There is an unmet need for effective and well tolerated treatments for progressive fibrosing ILDs.

8.
Respirology ; 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31329360

RESUMO

BACKGROUND AND OBJECTIVE: The efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis (IPF) were investigated in the placebo-controlled INPULSIS® trials. All patients who completed an INPULSIS® trial could receive open-label nintedanib in the extension trial INPULSIS®-ON. METHODS: We assessed the long-term efficacy and safety of nintedanib in patients of Asian race who were treated in INPULSIS®-ON. Analyses were descriptive. RESULTS: A total of 215 Asian patients were treated in INPULSIS®-ON, of whom 121 continued nintedanib in INPULSIS®-ON and 94 initiated nintedanib in INPULSIS®-ON having received placebo in an INPULSIS® trial. At baseline of INPULSIS®-ON, the mean (SD) age of Asian patients was 66.3 (7.5) years, 80.5% were males and mean (SD) forced vital capacity (FVC) was 78.9 (19.3) % predicted. Median total exposure to nintedanib in both INPULSIS® and INPULSIS®-ON was 42.2 months; maximum exposure was 64.1 months. In INPULSIS®, the annual rate (SE) of decline in FVC over 52 weeks in Asian patients was -124 (20) mL/year in the nintedanib group and -218 (24) mL/year in the placebo group. In INPULSIS®-ON, the annual rate (SE) of decline in FVC over 192 weeks in Asian patients was -127 (11) mL/year. Diarrhoea was reported in Asian patients at event rates of 58.8 and 82.5 events per 100 patient exposure-years in patients who continued and initiated nintedanib in INPULSIS®-ON, respectively. CONCLUSION: The effect of nintedanib on slowing disease progression in Asian patients with IPF is sustained over the long term. Long-term treatment with nintedanib has an acceptable safety and tolerability profile.

9.
BMJ Open Respir Res ; 6(1): e000397, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31179001

RESUMO

Introduction: Nintedanib slows disease progression in patients with idiopathic pulmonary fibrosis (IPF) by reducing the rate of decline in forced vital capacity, with an adverse event profile that is manageable for most patients. We used data from six clinical trials to characterise the safety and tolerability profile of nintedanib and to investigate its effects on survival. Methods: Data from patients treated with ≥1 dose of nintedanib 150 mg two times per day or placebo in the 52-week TOMORROW trial and/or its open-label extension; the two 52-week INPULSIS trials and/or their open-label extension, INPULSIS-ON; and a Phase IIIb trial with a placebo-controlled period of ≥6 months followed by open-label nintedanib were pooled. All adverse events, irrespective of causality, were included in descriptive analyses. Parametric survival distributions were fit to pooled Kaplan-Meier survival data from the trials and extrapolated to estimate long-term survival. Results: There were 1126 patients in the pooled nintedanib group and 565 patients in the pooled placebo group. The mean duration of nintedanib treatment was 28 months. No new safety signals were observed. Incidence rates of bleeding, liver enzyme elevations and cardiovascular events were consistent with those observed in the INPULSIS trials. Diarrhoea was reported at a lower event rate in the pooled nintedanib group than in nintedanib-treated patients in the INPULSIS trials (76.5 vs 112.6 events per 100 patient exposure-years) and infrequently led to permanent treatment discontinuation (3.6 events per 100 patient exposure-years). Based on the Weibull distribution, mean (95% CI) survival was estimated as 11.6 (9.6, 14.1) years in nintedanib-treated patients and 3.7 (2.5, 5.4) years in placebo-treated patients. Conclusions: Based on pooled data from six clinical trials, the adverse event profile of nintedanib was manageable for most patients. Exploratory analyses based on extrapolation of survival data suggest that nintedanib extends life expectancy in patients with IPF.

11.
Eur Respir Rev ; 28(151)2019 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-30814139

RESUMO

Patients with certain types of fibrosing interstitial lung disease (ILD) are at risk of developing a progressive phenotype characterised by self-sustaining fibrosis, decline in lung function, worsening quality of life, and early mortality. It has been proposed that such progressive fibrosing ILDs, which show commonalities in clinical behaviour and in the pathogenetic mechanisms that drive progressive fibrosis, may be "lumped" together for the purposes of clinical research and, potentially, for treatment. At present, no drugs are approved for the treatment of ILDs other than nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis. For other progressive fibrosing ILDs, the mainstay of drug therapy is immunosuppression. However, it is postulated that, once the response to lung injury in fibrosing ILDs has reached the stage at which fibrosis has become progressive and self-sustaining, targeted antifibrotic therapy would be required to slow disease progression. Nintedanib, an intracellular inhibitor of tyrosine kinases, has shown antifibrotic, anti-inflammatory and vascular remodelling effects in several non-clinical models of fibrosis, irrespective of the trigger for the injury. Ongoing clinical trials will provide insight into the role of antifibrotic treatment with nintedanib or pirfenidone in the management of fibrosing ILDs with a progressive phenotype.


Assuntos
Doenças Pulmonares Intersticiais , Pulmão , Fibrose Pulmonar , Progressão da Doença , Nível de Saúde , Humanos , Indóis/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/mortalidade , Doenças Pulmonares Intersticiais/patologia , Doenças Pulmonares Intersticiais/fisiopatologia , Fenótipo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/mortalidade , Fibrose Pulmonar/patologia , Fibrose Pulmonar/fisiopatologia , Piridonas/uso terapêutico , Qualidade de Vida , Fármacos do Sistema Respiratório/uso terapêutico , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento
12.
Lancet Respir Med ; 7(1): 60-68, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30224318

RESUMO

BACKGROUND: The efficacy and safety of nintedanib, an intracellular tyrosine kinase inhibitor, in patients with idiopathic pulmonary fibrosis were assessed in two phase 3, placebo-controlled INPULSIS trials. Patients who completed the 52-week treatment period in an INPULSIS trial could receive open-label nintedanib in the extension trial, INPULSIS-ON. We aimed to assess the long-term efficacy and safety of nintedanib in INPULSIS-ON. METHODS: Patients who completed the 52-week treatment period of INPULSIS, and the follow-up visit 4 weeks later, were eligible for INPULSIS-ON. The off-treatment period between INPULSIS and INPULSIS-ON could be 4-12 weeks. Patients receiving nintedanib 150 mg twice daily or placebo at the end of an INPULSIS trial received nintedanib 150 mg twice daily in INPULSIS-ON. Patients receiving nintedanib 100 mg twice daily or placebo at the end of an INPULSIS trial could receive nintedanib 100 mg twice daily or 150 mg twice daily in INPULSIS-ON. Spirometric tests were done at baseline, at weeks 2, 4, 6, 12, 24, 36, 48, and then every 16 weeks. The primary outcome of INPULSIS-ON was to characterise the long-term safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis, and this was analysed in patients who received at least one dose of nintedanib in INPULSIS-ON. This study is registered with ClinicalTrials.gov, number NCT01619085, and with EudraCT, number 2011-002766-21. FINDINGS: The first patient was enrolled into INPULSIS-ON in July 2, 2012. Of 807 patients who completed the INPULSIS trials, 734 (91%) were treated in INPULSIS-ON. 430 (59%) patients had received nintedanib in INPULSIS and continued nintedanib in INPULSIS-ON, and 304 (41%) had received placebo in INPULSIS and initiated nintedanib in INPULSIS-ON. Median exposure time for patients treated with nintedanib in both the INPULSIS and INPULSIS-ON trials was 44·7 months (range 11·9-68·3). The safety profile of nintedanib in INPULSIS-ON was consistent with that observed in INPULSIS. Diarrhoea was the most frequent adverse event in INPULSIS-ON (60·1 events per 100 patient exposure-years in patients who continued nintedanib, 71·2 events per 100 patient exposure-years in patients who initiated nintedanib). 20 (5%) of 430 patients who continued nintedanib and 31 (10%) of 304 patients who initiated nintedanib permanently discontinued nintedanib because of diarrhoea. The adverse event that most frequently led to permanent discontinuation of nintedanib was progression of idiopathic pulmonary fibrosis (51 [12%] patients continuing nintedanib and 43 [14%] patients initiating nintedanib). The event rate of bleeding was 8·4 events per 100 patient exposure-years in patients who continued nintedanib and 6·7 events per 100 patient exposure-years in patients who initiated nintedanib. The event rate of major adverse cardiovascular events was 3·6 events per 100 patient exposure-years in patients who continued nintedanib and 2·4 events per 100 patient exposure-years in patients who initiated nintedanib. The event rate of myocardial infarction using the broad scope (ie, all possible cases) was 1·3 events per 100 patient exposure-years in patients who continued nintedanib and 0·7 events per 100 patient exposure-years in patients who initiated nintedanib. INTERPRETATION: These findings suggest that nintedanib has a manageable safety and tolerability profile over long-term use, with no new safety signals. Patients with idiopathic pulmonary fibrosis could use nintedanib over the long-term to slow disease progression. FUNDING: Boehringer Ingelheim.


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Idoso , Progressão da Doença , Feminino , Seguimentos , Humanos , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos
13.
J. bras. pneumol ; 45(5): e20180414, 2019. tab, graf
Artigo em Português | LILACS-Express | ID: biblio-1040274

RESUMO

RESUMO Objetivo Ensaios clínicos mostraram que 150 mg de Nintedanibe duas vezes ao dia reduzem a progressão da doença em pacientes com Fibrose Pulmonar Idiopática (FPI), com um perfil de efeitos adversos que é controlável para a maioria dos pacientes. Antes da aprovação do Nintedanibe como tratamento para a FPI no Brasil, um Programa de Acesso Expandido (PEA) foi iniciado para fornecer acesso precoce ao tratamento e avaliar a segurança e a tolerância do Nintedanibe para este grupo de pacientes. Métodos Foram elegíveis para participar da PEA pacientes com diagnóstico de FPI nos últimos 5 anos, com capacidade vital forçada (CVF) ≥ 50% do previsto e capacidade de difusão dos pulmões para monóxido de carbono (DLco) 30%-79% do previsto. Os pacientes receberam Nintedanibe 150 mg, 2 vezes ao dia (bid). As avaliações de segurança incluíram eventos adversos que levaram à suspensão permanente do Nintedanibe e eventos adversos graves. Resultados O PEA envolveu 57 pacientes em 8 centros. A maioria dos pacientes era do sexo masculino (77,2%) e brancos (87,7%). No início do estudo, a média de idade foi de 70,7 (7,5) anos e a CVF foi de 70,7 (12,5%) do previsto. A média de exposição ao Nintedanibe foi de 14,4 (6,2) meses; a exposição máxima foi de 22,0 meses. Os eventos adversos frequentemente relatados pelo pesquisador como relacionados ao tratamento com Nintedanibe foram diarreia (45 pacientes, 78,9%) e náusea (25 pacientes, 43,9%). Os eventos adversos levaram à suspensão permanente do Nintedanibe em 16 pacientes (28,1%) que passaram por um evento adverso grave. Conclusões No PEA brasileiro, o Nintedanibe apresentou um perfil aceitável de segurança e tolerância em pacientes com FPI, condizendo com dados de ensaios clínicos.


ABSTRACT Objective Clinical trials have shown that nintedanib 150 mg twice daily (bid) reduces disease progression in patients with idiopathic pulmonary fibrosis (IPF), with an adverse event profile that is manageable for most patients. Prior to the approval of nintedanib as a treatment for IPF in Brazil, an expanded access program (EAP) was initiated to provide early access to treatment and to evaluate the safety and tolerability of nintedanib in this patient population. Methods Patients with a diagnosis of IPF within the previous five years, forced vital capacity (FVC) ≥ 50% predicted and diffusing capacity of the lungs for carbon monoxide (DLco) 30% to 79% predicted were eligible to participate in the EAP. Patients received nintedanib 150 mg bid open-label. Safety assessments included adverse events leading to permanent discontinuation of nintedanib and serious adverse events. Results The EAP involved 57 patients at eight centers. Most patients were male (77.2%) and white (87.7%). At baseline, mean (SD) age was 70.7 (7.5) years and FVC was 70.7 (12.5) % predicted. Mean (SD) exposure to nintedanib was 14.4 (6.2) months; maximum exposure was 22.0 months. The most frequently reported adverse events considered by the investigator to be related to nintedanib treatment were diarrhea (45 patients, 78.9%) and nausea (25 patients, 43.9%). Adverse events led to permanent discontinuation of nintedanib in 16 patients (28.1%). Sixteen patients (28.1%) had a serious adverse event. Conclusion In the Brazilian EAP, nintedanib had an acceptable safety and tolerability profile in patients with IPF, consistent with data from clinical trials.

14.
N Engl J Med ; 379(18): 1722-1731, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30220235

RESUMO

BACKGROUND: Nintedanib is an approved treatment for idiopathic pulmonary fibrosis (IPF). A subgroup analysis of a previously published trial suggested that sildenafil may provide benefits regarding oxygenation, gas exchange as measured by the diffusion capacity of the lungs for carbon monoxide (DlCO), symptoms, and quality of life in patients with IPF and severely decreased DlCO. That idea was tested in this trial. METHODS: We randomly assigned, in a 1:1 ratio, patients with IPF and a DlCO of 35% or less of the predicted value to receive nintedanib at a dose of 150 mg twice daily plus sildenafil at a dose of 20 mg three times daily (nintedanib-plus-sildenafil group) or nintedanib at a dose of 150 mg twice daily plus placebo three times daily (nintedanib group) for 24 weeks. The primary end point was the change from baseline in the total score on the St. George's Respiratory Questionnaire (SGRQ) at week 12 (the total score ranges from 0 to 100, with higher scores indicating worse health-related quality of life). Secondary end points included measures of dyspnea and safety. RESULTS: A total of 274 patients underwent randomization. There was no significant difference in the adjusted mean change from baseline in the SGRQ total score at week 12 between the nintedanib-plus-sildenafil group and the nintedanib group (-1.28 points and -0.77 points, respectively; P=0.72). A benefit from sildenafil treatment was not observed with regard to dyspnea as measured with the use of the University of California, San Diego, Shortness of Breath Questionnaire. No new safety signals were observed, as compared with previous trials. CONCLUSIONS: In patients with IPF and a DlCO of 35% or less of the predicted value, nintedanib plus sildenafil did not provide a significant benefit as compared with nintedanib alone. No new safety signals were identified with either treatment regimen in this population of patients. (Funded by Boehringer Ingelheim; INSTAGE ClinicalTrials.gov number, NCT02802345 .).


Assuntos
Inibidores Enzimáticos/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/uso terapêutico , Inibidores da Fosfodiesterase 5/uso terapêutico , Citrato de Sildenafila/uso terapêutico , Adulto , Idoso , Método Duplo-Cego , Quimioterapia Combinada , Dispneia/tratamento farmacológico , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Fibrose Pulmonar Idiopática/mortalidade , Fibrose Pulmonar Idiopática/fisiopatologia , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Inibidores da Fosfodiesterase 5/efeitos adversos , Proteínas Tirosina Quinases/antagonistas & inibidores , Troca Gasosa Pulmonar/efeitos dos fármacos , Qualidade de Vida , Citrato de Sildenafila/efeitos adversos , Resultado do Tratamento
16.
Thorax ; 73(6): 581-583, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-28993537

RESUMO

The TOMORROW trial of nintedanib comprised a randomised, placebo-controlled, 52-week period followed by a further blinded treatment period and an open-label extension. We assessed outcomes across these periods in patients randomised to nintedanib 150 mg twice daily or placebo at the start of TOMORROW. The annual rate of decline in FVC was -125.4 mL/year (95% CI -168.1 to -82.7) in the nintedanib group and -189.7 mL/year (95% CI -229.8 to -149.6) in the comparator group. The adverse event profile of nintedanib remained consistent throughout the studies. These results support a benefit of nintedanib on slowing progression of idiopathic pulmonary fibrosis beyond 52 weeks.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/uso terapêutico , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Resultado do Tratamento
17.
Am J Respir Crit Care Med ; 197(3): 356-363, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28889759

RESUMO

RATIONALE: Nintedanib and pirfenidone slow the progression of idiopathic pulmonary fibrosis (IPF), but the disease continues to progress. More data are needed on the safety and efficacy of combination therapy with nintedanib and add-on pirfenidone. OBJECTIVES: To investigate safety, tolerability, and pharmacokinetic and exploratory efficacy endpoints in patients treated with nintedanib and add-on pirfenidone versus nintedanib alone. METHODS: Patients with IPF and FVC greater than or equal to 50% predicted at screening who completed a 4- to 5-week run-in with nintedanib 150 mg twice daily without dose reduction or treatment interruption were randomized to receive nintedanib 150 mg twice daily with add-on pirfenidone (titrated to 801 mg three times daily) or nintedanib 150 mg twice daily alone in an open-label manner for 12 weeks. The primary endpoint was the percentage of patients with on-treatment gastrointestinal adverse events from baseline to Week 12. Analyses were descriptive and exploratory. MEASUREMENTS AND MAIN RESULTS: On-treatment gastrointestinal adverse events were reported in 37 of 53 patients (69.8%) treated with nintedanib with add-on pirfenidone and 27 of 51 patients (52.9%) treated with nintedanib alone. Predose plasma trough concentrations of nintedanib were similar when it was administered alone or with add-on pirfenidone. Mean (SE) changes from baseline in FVC at Week 12 were -13.3 (17.4) ml and -40.9 (31.4) ml in patients treated with nintedanib with add-on pirfenidone (n = 48) and nintedanib alone (n = 44), respectively. CONCLUSIONS: Nintedanib with add-on pirfenidone had a manageable safety and tolerability profile in patients with IPF, in line with the adverse event profiles of each drug. These data support further research into combination regimens in the treatment of IPF. Clinical trial registered with www.clinicaltrials.gov (NCT02579603).


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/uso terapêutico , Piridonas/uso terapêutico , Idoso , Progressão da Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/mortalidade , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Medição de Risco , Índice de Gravidade de Doença , Taxa de Sobrevida , Resultado do Tratamento
18.
Respir Res ; 16: 116, 2015 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-26400368

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterised by dyspnea and loss of lung function. METHODS: Using pooled data from the replicate, randomized, 52-week, placebo-controlled INPULSIS(®) trials, we characterized the safety and tolerability of nintedanib 150 mg twice daily in patients with IPF and described how adverse events were managed during these trials. RESULTS: One thousand and sixty- one patients were treated (nintedanib 638; placebo 423). Higher proportions of patients in the nintedanib group than the placebo group had ≥ 1 dose reduction to 100 mg bid (27.9% versus 3.8%) or treatment interruption (23.7% versus 9.9%). Adverse events led to permanent treatment discontinuation in 19.3% and 13.0% of patients in the nintedanib and placebo groups, respectively. Diarrhea was the most frequent adverse event, reported in 62.4% of patients in the nintedanib group versus 18.4% in the placebo group; however, only 4.4% of nintedanib-treated patients discontinued trial medication prematurely due to diarrhea. Monitoring of liver enzymes before and periodically during nintedanib treatment was recommended so that liver enzyme elevations could be managed through dose reduction or treatment interruption. CONCLUSION: Nintedanib had a manageable safety and tolerability profile in patients with IPF. Recommendations for adverse event management minimized permanent treatment discontinuations in the INPULSIS(®) trials. TRIAL REGISTRATION: clinicaltrials.gov NCT01335464 and NCT01335477.


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/administração & dosagem , Pulmão/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Idoso , Ensaios Clínicos Fase III como Assunto , Diarreia/induzido quimicamente , Esquema de Medicação , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/enzimologia , Fibrose Pulmonar Idiopática/fisiopatologia , Indóis/efeitos adversos , Pulmão/enzimologia , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
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