Sildenafil added to pirfenidone in patients with advanced idiopathic pulmonary fibrosis and risk of pulmonary hypertension: A Phase IIb, randomised, double-blind, placebo-controlled study – Rationale and study design

Behr, Jüergen; Nathan, Steven D.; Harari, Sergio; Wuyts, Wim; Kirchgaessler, Klaus-Uwe; Bengus, Monica; Gilberg, Frank; Wells, Athol U.

doi:10.1016/j.rmed.2018.03.019

Cited by 28 publications

(25 citation statements)

References 53 publications

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“…Pulmonary hypertension frequently complicates severe fibrosis and is associated with diminished survival in IPF patients [84,85]. Multiple clinical trials of monotherapies with PAH drugs targeting either pulmonary hypertension-IPF or IPF have yielded negative results [84][85][86][87][88]. However, a subgroup analysis of the STEP-IPF (Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis) trial of sildenafil, a phosphodiesterase-5 inhibitor, reported some positive secondary outcomes including improvements in oxygenation, DLCO and, especially, HRQL [86].…”

Section: Combination Therapiesmentioning

confidence: 99%

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The therapy of idiopathic pulmonary fibrosis: what is next?

et al. 2019

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Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease, characterised by progressive scarring of the lung and associated with a high burden of disease and early death. The pathophysiological understanding, clinical diagnostics and therapy of IPF have significantly evolved in recent years. While the recent introduction of the two antifibrotic drugs pirfenidone and nintedanib led to a significant reduction in lung function decline, there is still no cure for IPF; thus, new therapeutic approaches are needed. Currently, several clinical phase I–III trials are focusing on novel therapeutic targets. Furthermore, new approaches in nonpharmacological treatments in palliative care, pulmonary rehabilitation, lung transplantation, management of comorbidities and acute exacerbations aim to improve symptom control and quality of life. Here we summarise new therapeutic attempts and potential future approaches to treat this devastating disease.

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Section: Combination Therapiesmentioning

confidence: 99%

“…Subgroup analyses are still pending. An ongoing phase IIb trial (NCT02951429) currently examines the effect of combined sildenafil and pirfenidone therapy in patients with advanced IPF and risk of pulmonary hypertension [88].…”

Section: Combination Therapiesmentioning

confidence: 99%

The therapy of idiopathic pulmonary fibrosis: what is next?

et al. 2019

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“…However, Nawata et al [53] Table 2 and the results of the estimation are given in Table 3. The estimate of BP_medicine is 5.1 mmHg for Model 1 and the t-value is 34.82. Although the values are smaller (about half) those of the previous section, this means that the SBP of individuals with BP medicines are still higher than those without even when controlling for various individual factors.…”

Section: Regression Analysis Using Bp_medicine Dummymentioning

confidence: 98%

“…Double-blind RCT, where both participants and researchers are unaware as to who is receiving prescribed medicines, are usually used. Numerous studies on treatments for hypertension and related diseases have been conducted by double-blind RCT [21]- [34]. However, ethical problems with double-blind RCT have also been widely discussed [35]- [45].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Blood Pressure Control Medicines Using Health and Medical Checkup Data in Japan: Alternative Methods for Randomized Controlled Trials

Nawata¹,

Sekizawa²,

Kimura³

2018

Health

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Background: Many people take medicines to control high blood pressure (BP), or hypertension. Randomized clinical trials (RCT) are usually used for the evaluation of effects of medicines. However, RCT have some serious problems. Data and Methods: We evaluated the effects of BP medicines in Japan using a dataset containing 113,979 cases. We employed four statistical methods in the analysis. First, we simply compared the systolic blood pressure (SBP) of individuals with and without BP medicines. We then used a regression model with a dummy variable, representing taking medicines or not. We replaced the dummy variable by its expected value, and estimated the regression model again. Finally, we selected individuals who had both taken and not taken medicines at different times. The effect of sample selection was also considered in the estimation. Results: For the simple comparison, SBP with BP medicines was 11 mmHg higher than without medicines. In the next regression analysis, SBP with BP medicines was still 5 mmHg higher. When the dummy variable was replaced by its expected value, SBP with medicines decreased by 7 mmHg. For individuals taking medicines at some times and not at others, SBP decreased by 9 and 8 mmHg in models with and without a sample bias correction, respectively. Conclusion: The methods eliminated some problems of RCT and might be attractive. However, we obtained contradictory conclusions depending on the statistical methods employed, despite using the identical dataset. Statistical methods must be selected carefully to obtain a reliable evaluation. Limitations: The dataset was observatory, and the sample period was only 3 years.

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“…Despite INSTAGE being a negative study (6), this is not necessarily the end for sildenafil in IPF. A phase IIb study comparing the addition of sildenafil or placebo to pirfenidone in IPF patients is ongoing (11). This study will again target patients with advanced disease (D LCO ≤40% predicted), but will also specifically recruit patients who are at risk of pulmonary hypertension secondary to lung disease.…”

mentioning

confidence: 99%

Treatment of severe idiopathic pulmonary fibrosis—is sildenafil the next (in)stage?

Hayton¹,

Craig²,

Chaudhuri³

2019

J. Thorac. Dis.

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Sildenafil added to pirfenidone in patients with advanced idiopathic pulmonary fibrosis and risk of pulmonary hypertension: A Phase IIb, randomised, double-blind, placebo-controlled study – Rationale and study design

Abstract: Combination treatment with sildenafil and pirfenidone may warrant investigation of the treatment of patients with advanced IPF and pulmonary vascular involvement leading to PH.

Cited by 28 publications

References 53 publications

The therapy of idiopathic pulmonary fibrosis: what is next?

The therapy of idiopathic pulmonary fibrosis: what is next?

Evaluation of Blood Pressure Control Medicines Using Health and Medical Checkup Data in Japan: Alternative Methods for Randomized Controlled Trials

Treatment of severe idiopathic pulmonary fibrosis—is sildenafil the next (in)stage?

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