Roflumilast In Patients Research Articles

52267 Effectiveness and safety of oral roflumilast in patients with hidradenitis suppurativa: A prospective single-center study

52267 Effectiveness and safety of oral roflumilast in patients with hidradenitis suppurativa: A prospective single-center study

A proof of concept phase II study with the PDE-4 inhibitor roflumilast in patients with mild cognitive impairment or mild Alzheimer’s disease dementia (ROMEMA): study protocol of a double-blind, randomized, placebo-controlled, between-subjects trial

BackgroundResearch into the neurobiological underpinnings of learning and memory has demonstrated the cognitive-enhancing effects associated with diverse classes of phosphodiesterase (PDE) inhibitors. Specific PDE inhibitors have been identified to improve neuronal communication through selective inhibition of PDE activity. Roflumilast, a PDE4 inhibitor, has demonstrated efficacy in enhancing episodic memory in healthy adults and elderly participants with pronounced memory impairment, indicative of amnestic mild cognitive impairment (aMCI). In alignment with these findings, the present protocol aims to provide a proof of concept phase II of the potential of roflumilast to aid patients diagnosed with (a)MCI or mild Alzheimer’s disease (AD) dementia.MethodsThe study will be conducted according to a double-blind, randomized placebo-controlled, between-subjects design. Participants with (a)MCI and mild AD dementia will be recruited through the Memory Clinic at the Maastricht University Medical Centre + (MUMC +) in Maastricht, the Netherlands, alongside outreach through regional hospitals, and social media. The study will have three arms: placebo, 50 μg roflumilast, and 100 μg roflumilast, with a treatment duration of 24 weeks. The primary outcome measure will focus on the assessment of episodic memory, as evaluated through participants’ performance on the 15-word Verbal Learning Task (VLT). Our secondary objectives are multifaceted, including an exploration of various cognitive domains. In addition, insights into the well-being and daily functioning of participants will be investigated through interviews with both the participants and their (informal) caregivers, we are interested in the well-being and daily functioning of the participants.DiscussionThe outcomes of the present study aim to elucidate the significance of the PDE4 inhibition mechanism as a prospective therapeutic target for enhancing cognitive function in individuals with (a)MCI and mild AD dementia. Identifying positive effects within these patient cohorts could extend the relevance of this treatment to encompass a broader spectrum of neurological disorders.Trial registrationThe Medical Ethics Committee of MUMC + granted ethics approval for the 4th version of the protocol on September 10th, 2020. The trial was registered at the European Drug Regulatory Affairs Clinical Trials (EudraCT) registered on the 19th of December 2019 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004959-36/NL) and ClinicalTrial.gov (NCT04658654, https://clinicaltrials.gov/study/NCT04658654?intr=roflumilast&cond=mci&rank=1) on the 8th of December 2020. The Central Committee on Research Involving Human Subjects (CCMO) granted approval on the 30th of September 2020.

504 - Investigator- and patient-rated local tolerability in phase 3 trials of topical roflumilast in patients with psoriasis, seborrheic dermatitis, and atopic dermatitis

Abstract Introduction Formulating a topical medication that does not irritate the skin is an important factor contributing to patient treatment adherence and satisfaction. Many topical prescription products use penetration enhancers (including propylene glycol, polyethylene glycol, and ethanol) to overcome barrier properties of the skin. However, these excipients may irritate the skin causing tolerability reactions such as burning and stinging, which can reduce patient treatment adherence. Topical roflumilast is a highly potent (Kd∼0.7 nM) phosphodiesterase 4 inhibitor formulated as a water-based cream or foam that does not contain penetration enhancers or fragrances. Objectives We present prospectively assessed investigator- and patient-rated local tolerability from Phase 3 trials of topical roflumilast for patients with psoriasis (DERMIS-1, DERMIS-2, ARRECTOR) seborrheic dermatitis (SD; STRATUM), and atopic dermatitis (AD; INTEGUMENT-1, INTEGUMENT-2). Methods Patients were randomized to apply topical roflumilast (DERMIS: 0.3% cream; ARRECTOR and STRATUM: 0.3% foam; INTEGUMENT: 0.15% cream) or vehicle once daily for 8 weeks (DERMIS, ARRECTOR, and STRATUM) or 4 weeks (INTEGUMENT). Investigators assessed local tolerability on an 8-point scale (0 [no evidence of irritation] to 7 [strong reaction spreading beyond application site]) in the clinic before investigational product (IP) application. Patients reported local tolerability on a 4-point scale (0 [none: no sensation] to 3 [severe: hot, tingling/stinging sensation that has caused definite discomfort]) in the clinic 10-15 minutes after IP application. Tolerability was also assessed by reviewing documented adverse events. Results As assessed by investigators, ≥96.5% of patients in the roflumilast-treated groups had no evidence of irritation at the application site across all trials at all timepoints. Patient-rated local tolerability was favorable and improved with treatment: across all trials, 1% of roflumilast-treated patients reported a score of 3 (severe; defined as a “hot tingling/stinging sensation that has caused definite discomfort”) after the first application (day 1) and <1% at each subsequent assessment. Rates of adverse events, including those at the application site, were low for all trials. Conclusions Roflumilast cream and foam formulations demonstrated favorable local tolerability based on investigator- and patient-rated assessments in patients with psoriasis, SD, and AD, including application to sensitive areas such as the face and intertriginous areas. ClinicalTrials.gov Identifiers: DERMIS-1: NCT04211363; DERMIS-2: NCT04211389; ARRECTOR: NCT05028582; STRATUM: NCT04973228; INTEGUMENT-1: NCT047​73587; INTEGUMENT-2: NCT04773600.

Differential response to roflumilast in patients with chronic obstructive pulmonary disease: real-world evidence.

Roflumilast is effective in reducing acute exacerbation in patients with chronic obstructive pulmonary disease (COPD) at high risk of severe exacerbation. Clinical traits related to the benefits of roflumilast need to be evaluated in patients with COPD. A longitudinal observational study in patients newly diagnosed with COPD was conducted using claims data from the Health Insurance Review and Assessment Service in South Korea from 2012-2020 after a 2-year washout period. The primary outcome was to estimate the ratio of hazard ratio (RHR) of roflumilast for moderate-to-severe exacerbation in prespecified subgroups. A time-dependent Cox regression model was used to estimate the hazard ratio (HR) for moderate-to-severe exacerbations. Among 823,862 patients with COPD, 0.6% used roflumilast. The adjusted HR of roflumilast for moderate-to-severe exacerbations was reduced when treated for ≥3 months (RHR =0.558). Interaction effects of the variables on the HR of roflumilast for moderate-to-severe exacerbation were identified. The adjusted HR of roflumilast for moderate-to-severe exacerbation was significantly reduced in several subgroups: older age (65 years > age ≥50 years, RHR =0.838; age ≥65 years, RHR =0.818), a higher Charlson comorbidity index (1, RHR =0.832; 2, RHR =0.798; ≥3, RHR =0.790), history of exacerbation (RHR =0.886), bronchiectasis (RHR =0.774), chronic bronchitis (RHR =0.793), inhaled therapy [mono-bronchodilator, RHR =0.824; inhaled corticosteroid (ICS)/long-acting beta-agonist (LABA), RHR =0.591; LABA/long-acting muscarinic antagonist (LAMA), RHR =0.822; ICS/LABA/LAMA, RHR =0.570], methylxanthine (RHR =0.853), and statin (RHR =0.888). The benefit of roflumilast in moderate-to-severe exacerbations was estimated to be greater in specific subgroups of patients with COPD. Personalised approaches to roflumilast based on clinical phenotypes would be effective for COPD.

Investigator- and Patient-Rated Local Tolerability in Phase 3 Trials of Topical Roflumilast in Patients With Psoriasis, Seborrheic Dermatitis, and Atopic Dermatitis

Investigator- and patient-rated local tolerability in phase 3 trials of topical roflumilast in patients with psoriasis, seborrheic dermatitis, and atopic dermatitis
 
 Christopher G. Bunick1 on behalf of the authors
 
 INTRODUCTION: Formulating a topical medication that does not irritate the skin is an important factor contributing to patient treatment adherence and satisfaction. Many topical prescription products use penetration enhancers (including propylene glycol, polyethylene glycol, and ethanol) to overcome barrier properties of the skin. However, these excipients may irritate the skin causing tolerability reactions such as burning and stinging, which can reduce patient treatment adherence. Topical roflumilast is a highly potent (Kd~0.7 nM) phosphodiesterase 4 inhibitor formulated as a water-based cream or foam that does not contain penetration enhancers or fragrances. We present prospectively assessed investigator- and patient-rated local tolerability from Phase 3 trials of topical roflumilast for patients with psoriasis (DERMIS-1, DERMIS-2, ARRECTOR) seborrheic dermatitis (SD; STRATUM), and atopic dermatitis (AD; INTEGUMENT-1, INTEGUMENT-2).
 METHODS: Patients were randomized to apply topical roflumilast (DERMIS: 0.3% cream; ARRECTOR and STRATUM: 0.3% foam; INTEGUMENT: 0.15% cream) or vehicle once daily for 8 weeks (DERMIS, ARRECTOR, and STRATUM) or 4 weeks (INTEGUMENT). Investigators assessed local tolerability on an 8-point scale (0 [no evidence of irritation] to 7 [strong reaction spreading beyond application site]) in the clinic before investigational product (IP) application. Patients reported local tolerability on a 4-point scale (0 [none: no sensation] to 3 [severe: hot, tingling/stinging sensation that has caused definite discomfort]) in the clinic 10-15 minutes after IP application. Tolerability was also assessed by reviewing documented adverse events.
 RESULTS: As assessed by investigators, ≥96.5% of patients in the roflumilast-treated groups had no evidence of irritation at the application site across all trials at all timepoints. Patient-rated local tolerability was favorable and improved with treatment: across all trials, 1% of roflumilast-treated patients reported a score of 3 (severe; defined as a “hot tingling/stinging sensation that has caused definite discomfort”) after the first application (day 1) and <1% at each subsequent assessment. Rates of adverse events, including those at the application site, were low for all trials and <0.5% of roflumilast-treated patients discontinued due to adverse events at the application site across all trials.
 CONCLUSION: Roflumilast cream and foam formulations demonstrated favorable local tolerability based on investigator- and patient-rated assessments in patients with psoriasis, SD, and AD, including application to sensitive areas such as the face and intertriginous areas.
 Sponsored by Arcutis Biotherapeutics, Inc.
 ClinicalTrials.gov Identifiers: DERMIS-1: NCT04211363; DERMIS-2: NCT04211389; ARRECTOR: NCT05028582; STRATUM: NCT04973228; INTEGUMENT-1: NCT04773587; INTEGUMENT-2: NCT04773600

Long-Term Safety of Roflumilast in Patients with Chronic Obstructive Pulmonary Disease, a Multinational Observational Database Cohort Study.

This study evaluated the long-term safety of roflumilast in patients with chronic obstructive pulmonary disease or chronic bronchitis using electronic healthcare databases from Germany, Norway, Sweden, and the United States (US). The study population consisted of patients aged ≥40 years who had been exposed to roflumilast and a matched cohort unexposed to roflumilast. The matching was based on sex, age, calendar year of cohort entry date (2010-2011, 2012, or 2013), and a propensity score that included variables such as demographics, markers of chronic obstructive pulmonary disease (COPD) severity and morbidity, and comorbidities. In comparison to the unexposed matched cohort (never use), three exposure definitions were used for the exposed matched cohort: ever use, use status (current, recent, past use), and cumulative duration of use. The main outcome was 5-year all-cause mortality. Cox regression models were used to estimate crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CI). 112,541 unexposed and 23,239 exposed patients across countries were included. Some variables remained unbalanced after matching, indicating higher COPD disease severity among the exposed patients. Adjusted HRs of 5-year all-cause mortality for "ever use" of roflumilast, compared to "never use", were 1.12 (95% CI, 1.08-1.17) in Germany, 1.00 (95% CI, 0.92-1.08) in Norway, 0.98 (95% CI, 0.92-1.04) in Sweden, and 1.16 (95% CI, 1.12-1.20) in the US. Compared to never users, there was a decrease in 5-year mortality risk observed among "current users" in Germany (HR: 0.93, 95% CI: 0.88-0.98), Norway (HR: 0.77, 95% CI: 0.67-0.87), and Sweden (HR: 0.80, 95% CI: 0.73-0.88). There was no observed increase in 5-year mortality risk with the use of roflumilast in Sweden or Norway. A small increase in 5-year mortality risk was observed in Germany and the US in the ever versus never comparison, likely due to residual confounding by indication.

Investigator- and Patient-Rated Local Tolerability in Phase 3 Trials of Topical Roflumilast in Patients With Psoriasis, Seborrheic Dermatitis, and Atopic Dermatitis

Investigator- and Patient-Rated Local Tolerability in Phase 3 Trials of Topical Roflumilast in Patients With Psoriasis, Seborrheic Dermatitis, and Atopic Dermatitis

Efficacy and safety of oral roflumilast for moderate-to-severe psoriasis-a randomized controlled trial (PSORRO).

Roflumilast is a targeted inhibitor of phosphodiesterase (PDE)-4 and has been approved for treatment of severe chronic obstructive pulmonary disease for more than a decade. Generic versions are available in the United States. PDE-4 is involved in the psoriasis pathogenesis, but the efficacy and safety of oral roflumilast in patients with psoriasis have not previously been studied. A company-independent, multicenter, randomized, double-blind, placebo-controlled trial (ClinicalTrials.govNCT04549870). Patients were randomized 1:1 to receive monotherapy with oral roflumilast 500μg once daily or placebo. At week 12, placebo patients were switched to open-label roflumilast through week 24. The primary endpoint was a 75% or greater reduction from baseline in the psoriasis area and severity index (PASI75) at week12. In all, 46 patients were randomized (roflumilast, n=23; placebo, n=23). At week 12, significantly more patients in the active arm achieved PASI75 (8 of 23 patients [35%]) vs. placebo (0 of 23 patients [0%], with a difference vs. placebo of 8 [35%] patients, 95% CI: 3 [13%]-13 [57%] patients) (p=0.014). At week 24, 15 (65%), 10 (44%), 5 (22%), and 2 (9%) of patients treated with roflumilast from week 0 had PASI50, PASI75, PASI90, and PASI100 responses (key secondary endpoints), respectively. The most prevalent, drug-related adverse events in both treatment groups were transient gastrointestinal symptoms, weight-loss, headache, and insomnia. A total of three patients (roflumilast n=2; placebo, n=1) discontinued therapy due to adverse events. Oral roflumilast was efficacious and safe in treating moderate-to-severe plaque psoriasis over 24 weeks. With generic versions available, this drug may represent an inexpensive and convenient alternative to established systemic psoriasis treatments. Financial support was received from Herlev and Gentofte Hospital, University of Copenhagen, and independent grants from private foundations in Denmark. No pharmaceutical company, including the market authorization holder of roflumilast, was involved in the study at any point.

PRS65 ADHERENCE AND PERSISTENCE TO ROFLUMILAST AMONG ADULT PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Roflumilast is a non-first-line medication for adults with Chronic Obstructive Pulmonary Disease (COPD) and is associated with multiple side effects, which can affect its long-term use. This study aims to describe the persistence and adherence of roflumilast in patients with COPD. A cohort of patients aged ≥40 years diagnosed with COPD who newly initiated roflumilast from March 2011 to September 2015, were identified from the Truven MarketScan database. We measured demographic and clinical characteristics in the 12-month period prior to first date of use, the index date. Adherence was measured using prescription days covered (PDC) ≥ 80% threshold over a 6-month period. We calculated persistence as the proportion of patients that did not discontinue roflumilast, defined as a gap of >30 days. A total of 9919 patients were included with a mean age of 67.7 years (±10.1) and 4972 (50.1%) were female. Inhaled corticosteroids (ICS) and long-acting beta agonists (LABA), single inhaler use or in combination, were frequently used, 7300 (73.6%) and 7073 (71.3%) respectively, in the baseline period. We also captured multiple COPD medication use prior to the index date. Accordingly, LABA and ICS 6903 (69.6%) were commonly prescribed followed by long acting muscarinic antagonists (LAMA) and ICS (5112, 51.5%). The overall PDC over a 6-month period was 69% with only 3104 (48.8%) patients being adherent (PDC≥ 80%). Over the same 6-month period, only 2581 (26.0%) were persistent. We also measured PDC over 3-month (81%) and 12-month (56%). In addition, persistence to roflumilast was 4899 (49.4%) and 1196 (12.1%) over a 3- and 12-month period respectively. A substantial number of adult patients with COPD have sub-optimal adherence and persistence to roflumilast. Reasons for low adherence or discontinuation such as prevalence of treatment-related adverse effects deserve further investigation.

Assessment of Early Outcomes of Roflumilast in Patients With Non Cystic Fibrosis Bronchiectasis

Assessment of Early Outcomes of Roflumilast in Patients With Non Cystic Fibrosis Bronchiectasis

Roflumilast in patients with advanced chronic obstructive pulmonary disease: towards a better-targeted use

ABSTRACTIntroduction: For patients with chronic obstructive pulmonary disease (COPD), one of the main goals in its management is to reduce the number of disease exacerbations. Roflumilast is an anti-inflammatory compound used in patients with advanced COPD and chronic bronchitis in order to fulfill this objective. However, this is not always easily achieved due to the heterogeneity of the population. Clinical trial data can allow more in-depth analysis in order to identify predictors for maximal efficacy in different patient populations.Areas covered: A post hoc pooled data analysis derived from two large-scale randomized controlled trials helped to better define the disease subsets in which roflumilast would exert the maximal therapeutic effect. These are represented by patients with prior hospitalizations for COPD exacerbations and by patients with higher values for eosinophil blood count. This analysis is the focus of our key paper evaluation.Expert opinion: This pooled data analysis suggests that a phenotype/endotype guided therapy has the potential to be impactful on overall survival by reducing the number of exacerbations and increase the life span of patients.

Risk factors for the discontinuation of roflumilast in patients with chronic obstructive pulmonary disease.

IntroductionRoflumilast is a phosphodiesterase-4 inhibitor, which can decrease exacerbation in patients with chronic obstructive pulmonary disease (COPD). However, adverse effects are a major barrier to medication use, and little is known regarding the risk factors for discontinuation of roflumilast in COPD patients.MethodA search of the clinical databases identified all patients who were prescribed roflumilast between December 2012 and April 2015 in the four hospitals of The Catholic University of Korea, Korea. The study subjects were limited to patients who had taken 500 μg of roflumilast. We studied the factors associated with drug discontinuation and drug adverse events by univariate and multivariate analyses.ResultsAmong 154 eligible patients, 54 (35.1%) discontinued their roflumilast prescription. Most patients were elderly, male, current or former smokers, and had moderate-to-severe airflow limitation. Low–body mass index (BMI) patients were more likely to undergo drug discontinuation (1-unit decrease in BMI: odds ratio [OR] =1.165, p=0.006; BMI <23 kg/m2: OR =2.960, p=0.004). Fifty-five patients (35.7%) had adverse events. Loss of appetite, diarrhea, nausea, headache, and weight loss were the most frequent adverse events. Low-BMI patients were more likely to experience adverse events (1-unit decrease in BMI: OR =1.151, p=0.010; BMI <23 kg/m2: OR =2.644, p=0.009).ConclusionsThe patient discontinuation and adverse events rates in this study were higher than in previous randomized controlled studies. Discontinuation of roflumilast in ethnic Koreans is more likely to occur in low-BMI patients. In a clinical setting, low-BMI patients can more easily discontinue roflumilast; clinicians should, therefore, provide greater care for these patients.

An experience of therapy of patients with chronic obstructive pulmonary disease and metabolic syndrome with selective phosphodiesterase-4 inhibitor roflumilast

The aim of this study was to evaluate clinical efficacy and safety of selective phosphodiesterase"4 inhibitor roflumilast in patients with COPD and metabolic syndrome.Methods. In this prospective study, patients with stage III – IV COPD, frequent exacerbation phenotype (≥ 2 per a year) and metabolic syndrome (n = 42) were treated with roflumilast (Daxas) 500 mg q.d. additionally to the basic therapy for 12 months. Clinical investigation, mMRC scale and CAT questionnaire, pulse oxymetry, spirometry, 6"min walking test, measurement of glucose, lipids and C"reactive protein in blood were used in all patients.Results. Exacerbation rate decreased in patients with COPD treated with roflumilast. FEV1 and quality of life improved in patients treated with roflumilast. Therapy with roflumilast was associated with statistically significant reduction in the waist circumference without significant change in the body weight, waist"to"hip ratio or body mass index.Conclusion. Therapy with roflumilast was associated with improvement in clinical, laboratory and functional parameters and reduction in exacerbation rate in patients with COPD and metabolic syndrome.

Roflumilast for asthma: Efficacy findings in mechanism of action studies

BackgroundThe efficacy profile of roflumilast, a phosphodiesterase-4 inhibitor used for the treatment of chronic obstructive pulmonary disease (COPD), is well known. In asthma treatment, much less is understood about the role of roflumilast, particularly its mechanism of action and potential bronchodilatory effects. AimTo evaluate the therapeutic efficacy and mechanism of action of roflumilast in patients with asthma using data from eight placebo-controlled, double-blind phase I–III studies. MethodsThe studies were conducted at 14 sites in Europe, North America and South Africa from 1997 to 2005. The effect of treatment with 250 μg, 500 μg or 1000 μg roflumilast was compared with placebo in seven cross-over studies and one parallel-group study in 197 patients 18–70 years of age. Primary endpoints focused on the extent of the late allergic response after an allergen challenge, change in sputum cell eosinophil counts or exhaled nitric oxide (eNO), forced expiratory volume in 1 s (FEV1) and exercise-induced bronchoconstriction. Secondary endpoints included the extent of the early allergic response and measurements of tumour necrosis factor α (TNFα), sputum cells and inflammatory markers. ResultsRoflumilast attenuated allergen-induced bronchoconstriction (FEV1) in patients with asthma. Significant reductions in allergen-induced airway inflammation, including a reduction in both eosinophil and neutrophil counts were also observed and physiologic responses to allergen-induced challenge were confirmed by a significant reduction in TNFα. Side effects were similar to COPD, but did not include weight loss. ConclusionsThe results from these studies indicate that the anti-inflammatory effects of roflumilast observed in COPD are also seen in asthma and advance our understanding of its mechanism of action.All studies were funded by Takeda. Trial registration numbers available on ClinicalTrials.gov: NCT01365533.

Effect of a Dose-Escalation Regimen for Improving Adherence to Roflumilast in Patients with Chronic Obstructive Pulmonary Disease.

BackgroundThe adverse effects of the phosphodiesterase-4 inhibitor roflumilast, appear to be more frequent in clinical practice than what was observed in chronic obstructive pulmonary disease (COPD) clinical trials. Thus, we designed this study to determine whether adverse effects could be reduced by starting roflumilast at half the dose, and then increasing a few weeks later to 500 µg daily.MethodsWe retrospectively investigated 85 patients with COPD who had taken either 500 µg roflumilast, or a starting dose of 250 µg and then increased to 500 µg. We analyzed all adverse events and assessed differences between patients who continued taking the drug after dose escalation and those who had stopped.ResultsAdverse events were reported by 22 of the 85 patients (25.9%). The most common adverse event was diarrhea (10.6%). Of the 52 patients who had increased from a starting dose of 250 µg roflumilast to 500 µg, 43 (82.7%) successfully maintained the 500 µg roflumilast dose. No difference in factors likely to affect the risk of adverse effects, was detected between the dose-escalated and the discontinued groups. Of the 26 patients who started with the 500 µg roflumilast regimen, seven (26.9%) discontinued because of adverse effects. There was no statistically significant difference in discontinuation rate between the dose-escalated and the control groups (p=0.22).ConclusionEscalating the roflumilast dose may reduce treatment-related adverse effects and improve tolerance to the full dose. This study suggests that the dose-escalated regimen reduced the rate of discontinuation. However, longer-term and larger-scale studies are needed to support the full benefit of a dose escalation strategy.

Reduction in Systemic Inflammation by the PDE4 Inhibitor Roflumilast in Patients With COPD

Reduction in Systemic Inflammation by the PDE4 Inhibitor Roflumilast in Patients With COPD

Response to: Oba, Y. and Lone, N. (2013) Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.Ther Adv Respir Dis 7: 13–24.

Response to: Oba, Y. and Lone, N. (2013) Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.<i>Ther Adv Respir Dis</i> 7: 13–24.

Efficacy and safety of roflumilast in patients with stable chronic obstructive pulmonary disease: A meta-analysis

BackgroundCurrently, several large studies showed that roflumilast has been demonstrated efficacy during treatment chronic obstructive pulmonary disease (COPD) patients, but also caused some side effects. AimTo assess the efficacy and safety of roflumilast in COPD patients. MethodsA computerized search through electronic databases included PubMed, EMBASE, CINAHL, the Cochrane clinical trials database, Physiotherapy Evidence Database and ClinicalTrials.gov was performed to identify randomized controlled trials. The primary outcomes were trough forced expiratory volume in 1 s (FEV1) (reported pre-bronchodilator values) and exacerbation rate. Secondary outcomes included other spirometric parameters, health-related quality of life, the overall mortality rate and adverse events. Weighted mean differences (WMDs), relative risks (RRs) and 95% confidence intervals (CIs) were calculated and pooled using a random effects model. ResultsEleven trials involving 9675 patients met the inclusion criteria. Roflumilast significantly reduced the mean exacerbation rate (mild, moderate or severe) (WMD = −0.23; 95% CI = −0.33 to −0.13; p < 0.00001) and improved trough FEV1 (WMD = 53.52 ml; 95% CI = 42.49 to 64.55; p < 0.00001), and other post-bronchodilator spirometric parameters (e.g., forced vital capacity, etc.). Roflumilast did not improve St George's Respiratory Questionnaire total score (WMD = −0.70 units; 95% CI = −2.65 to 1.26; p = 0.49) and decrease the overall mortality rate (RR = 0.90; 95% CI = 0.63 to 1.29; p = 0.56). Roflumilast increased some adverse events including diarrhea, headache, nausea, weight loss, and insomnia. ConclusionsRoflumilast significantly reduces the mean exacerbation rate in COPD patients. Although there are insufficient clinical evidence on other clinical endpoints and high risk of some adverse events, roflumilast therapy may benefit COPD patients. Further studies are needed to pay more attention to the long-term efficacy and safety of roflumilast.

Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis

Roflumilast, a phosphodiesterase 4 inhibitor, has been shown to improve lung function and reduce exacerbation rates, but is associated with adverse events (AEs). The purpose of this study was to systematically review the clinical effectiveness and safety of roflumilast. A systematic search was made of MEDLINE, Cochrane trials database, DARE and CINAHL. Randomized, controlled trials of more than 12 weeks' duration comparing roflumilast with placebo were reviewed. Studies were pooled to yield relative risk (RR), incident rate difference or weighted mean differences with 95% confidence intervals (CIs). Eight trials (8698 patients) met the inclusion criteria. Roflumilast significantly reduced moderate to severe exacerbations (RR 0.85; 95% CI 0.80-0.91) compared with placebo, but not severe exacerbations (RR 0.83; 95% CI 0.68-1.01) or mortality (RR 0.90; 95% CI 0.63-1.28). Roflumilast significantly improved lung function relative to placebo, but not quality of life measures. AEs (RR 1.11; 95% CI 1.03-1.19) and discontinuations of treatment due to AEs (RR 1.63; 95% CI 1.45-1.84) were significantly more frequent with roflumilast than placebo. In the chronic obstructive pulmonary disease (COPD) Safety Pool (12,054 patients), the overall incidence of serious AEs did not differ between groups. However, atrial fibrillation (0.4% versus 0.2%; p = 0.02) and suicidality (0.08% versus 0%) were more frequent with roflumilast than placebo. The efficacy of roflumilast appears modest compared with other available therapies for COPD. Further studies are needed to investigate the risk-benefit ratio and long-term safety of roflumilast before its wider use.

PRS27 COUNTRY ADAPTATION OF A HEALTH ECONOMIC MODEL:THE CASE FOR ROFLUMILAST IN THE NETHERLANDS

BACKGROUND: The phosphodiesterase-4 enzyme (PDE4) inhibitor roflumilast is a new treatment that targets the underlying inflammation associated with COPD. When approved, roflumilast will be registered as an add-on to bronchodilator treatment in adult patients with severe COPD, with a history of frequent exacerbations. a health economic (HE) micro-simulation Markov model was used to support its submission in the United Kingdom (UK). Pharmaceutical companies can save significantly on the process of HE evidence development, if models can be adapted for use in more than one country. OBJECTIVES: To transfer an existing UK HE model to the The Netherlands in order to calculate the cost-effectiveness (CE) of roflumilast in patients with severe COPD from a societal perspective. METHODS: The model structure was adapted to include production loss using the friction cost method, and to separate heterogeneity from parameter uncertainty. All input parameters on health care use, costs, utilities, and COPD epidemiology were obtained from Dutch sources, except for the case-fatality rate of an exacerbation-related hospitalization. a direct comparison was made between a combination of a long-acting |32 agonist (LABA) plus roflumilast (ROFLU) and LABA alone. a second, indirect comparison was between LABA + ROFLU and LABA plus an inhaled corticosteroid (ICS). One-way and probabilistic sensitivity analyses were performed. RESULTS: From a societal perspective, the incremental CE ratio (ICER) for LABA + ROFLU compared with LABA alone, was €7900. The ICER of LABA + ROFLU versus LABA + ICS was €10,000. The probability that LABA + ROFLU was cost-effective when compared with LABA alone at a threshold of €20,000 versus LABA was 97%. Compared with LABA + ICS this probability was 68.3%. CONCLUSIONS: The original UK model was suitable for adaptation to the Dutch setting. The ICERs of roflumilast were below commonly referred threshold values of a QALY.