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Results of Macitentan in Japanese Patients With Chronic Thromboembolic Pulmonary Hypertension　- A Prospective, Multicenter, Open-Label, Single-Arm, Phase 3 Study.

ABSTRACT: Background: Macitentan, an endothelin-receptor antagonist, is approved in Japan for the treatment of pulmonary arterial hypertension (PAH). This study evaluated the use of macitentan for chronic thromboembolic pulmonary hypertension (CTEPH) in Japanese patients. Methods and Results: This open-label single-arm Phase 3 study evaluated the efficacy and safety of oral macitentan 10 mg (once daily) in Japanese CTEPH patients. The study was prematurely discontinued due to the sponsor's decision to not develop macitentan 10 mg further for the indication of CTEPH (unrelated to safety concerns). Of the 9 patients enrolled in the study, 4 completed 24 weeks of treatment. The mean (±SD) ratio of pulmonary vascular resistance (PVR) at Week 16 to baseline was 71.9±34.3%. The mean (±SD) decreases in PVR and the PVR index (PVRI) from baseline to Week 16 were 181.4±243.9 dyn·s/cm⁵ and 280.6±366.0 dyn·s·m²/cm⁵, respectively. The mean (±SD) increase in the 6-min walk distance from baseline to Week 24 was 44.3±46.8 m. All treatment-emergent adverse events (TEAEs) were mild or moderate in severity, except for 1 serious TEAE of angioplasty reported in 1/9 patients that was severe in intensity. Conclusions: Definite conclusions regarding the efficacy of macitentan 10 mg in Japanese patients with CTEPH cannot be drawn because of premature study discontinuation. No safety concerns were observed, and the safety profile was consistent with previously reported studies in CTEPH and PAH patients.

SUBMITTER: Sakurai S

PROVIDER: S-EPMC8258181 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objective To evaluate the efficacy and tolerability of single pulse transcranial magnetic stimulation (sTMS) for the preventive treatment of migraine. Background sTMS was originally developed for the acute treatment of migraine with aura. Open label experience has suggested a preventive benefit. The objective of this trial was to evaluate the efficacy and tolerability of sTMS for migraine prevention. Methods The eNeura SpringTMS Post-Market Observational U.S. Study of Migraine (ESPOUSE) Study was a multicenter, prospective, open label, observational study. From December 2014 to March 2016, patients with migraine (n = 263) were consented to complete a 1-month baseline headache diary followed by 3 months of treatment. The treatment protocol consisted of preventive (four pulses twice daily) and acute (three pulses repeated up to three times for each attack) treatment. Patients reported daily headache status, medication use, and device use with a monthly headache diary. The primary endpoint, mean reduction of headache days compared to baseline, was measured over the 28-day period during weeks 9 to 12. The primary endpoint was compared to a statistically-derived placebo estimate (performance goal). Secondary endpoints included: 50% responder rate, acute headache medication consumption, HIT-6, and mean reduction in total headache days from baseline of any intensity. Results Of a total of 263 consented subjects, 229 completed a baseline diary, and 220 were found to be eligible based on the number of headache days. The device was assigned to 217 subjects (Safety Data Set) and 132 were included in the intention to treat Full Analysis Set. For the primary endpoint, there was a -2.75 ± 0.40 mean reduction of headache days from baseline (9.06 days) compared to the performance goal (-0.63 days) ( p < 0.0001). The 50% responder rate of 46% (95% CI 37%, 56%) was also significantly higher ( p < 0.0001) than the performance goal (20%). There was a reduction of -2.93 (5.24) days of acute medication use, headache impact measured by HIT-6, -3.1 (6.4) ( p < 0.0001), and total headache days of any intensity -3.16 days (5.21) compared to the performance goal (-0.63 days) ( p < 0.0001). The most common adverse events were lightheadedness (3.7%), tingling (3.2%), and tinnitus (3.2%). There were no serious adverse events. Conclusions This open label study suggests that sTMS may be an effective, well-tolerated treatment option for migraine prevention. Trial registration number NCT02357381.

Project description:IntroductionIn SERAPHIN, a long-term, event-driven, double-blind randomised controlled trial in pulmonary arterial hypertension (PAH), macitentan 10 mg significantly reduced the risk of morbidity/mortality compared with placebo. Its open-label extension study (SERAPHIN OL) further assessed long-term safety and tolerability of macitentan 10 mg in PAH patients.MethodsPatients in SERAPHIN who completed the double-blind treatment period or experienced a morbidity event during the study could enter SERAPHIN OL. Patients received macitentan 10 mg once daily, and safety and survival were assessed until end of treatment (+ 28 days). Two overlapping sets were analysed for safety: (1) all patients in SERAPHIN OL (OL safety set); (2) patients randomised to macitentan 10 mg in SERAPHIN (long-term safety/survival set). Survival was evaluated as an exploratory endpoint in the latter set.ResultsOf 742 patients randomised in SERAPHIN, 550 (74.1%) entered SERAPHIN OL (OL safety set); 242 patients were randomised to macitentan 10 mg in SERAPHIN (long-term safety/survival set). Median (min, max) exposure to macitentan 10 mg was 40.1 (0.1, 130.5) months (2074.7 patient-years; OL safety set) and 54.7 (0.1, 141.3) months (1151.0 patient-years; long-term safety/survival set). Safety in both analysis sets was comparable to the known safety profile of macitentan. Kaplan-Meier survival estimates (95% CI) at 1, 5, 7 and 9 years were 95.0% (91.3, 97.1), 73.3% (66.6, 78.9), 62.6% (54.6, 69.6) and 52.7% (43.6, 61.0), respectively (long-term safety/survival set; median follow-up: 5.9 years).ConclusionsThis analysis provides the longest follow-up for safety and survival published to date for any PAH therapy. The safety profile of macitentan 10 mg over this extensive treatment period was in line with that observed in SERAPHIN. As the majority of patients were receiving other PAH therapy at macitentan initiation, our study provides additional insight into the long-term safety of macitentan, including as part of combination therapy.Trial registrationClinicalTrials.gov Identifiers: NCT00660179 and NCT00667823.

Project description:IntroductionThe efficacy of lowering intraocular pressure (IOP) and safety of switching to travoprost/timolol fixed combination ophthalmic solution (Duotrav(®), Alcon Laboratories, Inc., Fort Worth, TX, USA) in patients with primary open-angle glaucoma, normal tension glaucoma or ocular hypertension undergoing prostaglandin analog (PGA) monotherapy was investigated.MethodsPatients treated with travoprost, latanoprost, tafluprost, or bimatoprost for ≥3 months and requiring additional medication were switched to Duotrav without washout. Baseline IOP was calculated from measurements at two visits during PGA monotherapy. IOP reductions at 4, 8, and 12 weeks after switching to Duotrav and adverse events were assessed.ResultsOf 162 patients enrolled, 157 patients (96.9%) with ≥4 weeks of follow-up after switching to Duotrav were analyzed. The mean IOP decreased significantly (baseline = 16.3 ± 3.1 mmHg; 4 weeks = 14.6 ± 3.1 mmHg, 8 weeks = 14.7 ± 3.3 mmHg, 12 weeks = 14.6 ± 3.2 mmHg; all P < 0.0001). When study eyes were divided into three groups according to baseline IOP (≥19 mmHg: 33 eyes, 21.0%; ≥15 to <19 mmHg: 78 eyes, 49.7%; <15 mmHg: 46 eyes, 29.3%), all groups showed significant IOP reductions (P = 0.0324 ~ P < 0.0001) after switching to Duotrav. Twenty-seven of 166 patients (16.3%) in the safety analysis experienced adverse events and 26/166 patients (15.7%) experienced adverse events, for which a relationship to Duotrav could not be ruled out. Adverse events in five patients led to treatment discontinuation (eye pruritus; eye irritation; increased blood pressure and rash; increased blurred vision; deepening of the eyelid sulcus and blepharoptosis). Twelve weeks after treatment switching, eyelash changes, blepharal pigmentation and deepening of the eyelid sulcus occurred in 42 (26.8%), 29 (18.5%), and 13 (8.3%) cases, respectively, among 157 patients with follow-up. There was no significant worsening from baseline for superficial punctate keratopathy (SPK) or conjunctival hyperemia after switching (SPK score: baseline = 0.58 ± 1.31; 12 weeks = 0.92 ± 1.76, P = 0.1819; conjunctival hyperemia score: baseline = 0.41 ± 0.64; 12 weeks = 0.49 ± 0.63, P = 0.3774).ConclusionOur findings confirm that switching to Duotrav(®) in PGA monotherapy patients shows IOP-lowering effect with minimal safety concerns.FundingJapan Association of Health Service and Alcon Japan. Ltd.Trial registrationUMIN Clinical Trials Registry identifier, UMIN000007028.

Project description:Even though pulmonary arterial hypertension (PAH) remains an incurable disease, the combination of PAH-specific therapies allowed evolving from symptom-based strategies to others aiming to move patients to low-risk conditions. Endothelin-1 (ET-1) receptor antagonists emerged as specific-PAH drugs that can be used in combination with other specific therapies. This work aimed to perform a prospective clinical assessment of patients with PAH that switched from bosentan to macitentan (POTENT), due to inadequate response. POTENT is a prospective, open-label, single-arm, uncontrolled study including PAH patients from our ongoing SAUDIPH registry. It enrolled 50 PAH patients divided as follows: idiopathic/heritable pulmonary arterial hypertension (I/HPAH); n = 24; PAH associated with congenital heart disease, n = 19; PAH associated with connective tissue diseases, n = 5; and pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis (PVOD/PCH), n = 2. At baseline, most patients were in World Health Organization Functional Class (WHO FC) II/III (52.0%). After switching to macitentan, patients were more likely to be in WHO FC I/II (78%) and 22% of the overall cohort moved to a lower risk condition, with three low risk stratification parameters. Mean 6-min walking distance increased about 34 m after 12 months, with a significant mean change over time (12.63 ± 11.69 at month 3 vs. 40.75 ± 12.57 at month 12, p = 0.002). Most haemodynamic parameters decreased over time, with corresponding negative mean changes (p < 0.001). The safety of macitentan was confirmed by the absence of anaemia and liver injury; clinical worsening was observed only in a small group of patients. In general, macitentan might be a valid alternative to bosentan in PAH stable patients on combination therapy with insufficient clinical response, and presenting intermediate and high-risk parameters. We anticipate that studying this strategy in PAH subgroups would further clarify its potential and limitations.

Project description:ObjectiveThis study was conducted to evaluate the safety and efficacy of a new more thermostable Flolan (epoprostenol) solution prepared with the reformulated pH 12.0 diluent in Japanese patients with pulmonary arterial hypertension (PAH) receiving higher doses of Flolan than those typically administered in Western countries.MethodsThis open-label, single-arm study was conducted in 10 Japanese PAH patients. During the run-in period, patients were intravenously infused with Flolan (45 ng/kg/min or higher doses) solution prepared with the existing pH 10.5 diluent. The patients were then switched to a new more thermostable Flolan solution prepared with the reformulated pH 12.0 diluent and observed for a 4-week treatment period. As a primary endpoint, safety after switching to the new Flolan solution was evaluated. Secondary endpoints included hemodynamics and the necessity for dose adjustment of Flolan in these patients.ResultsAll 10 patients completed the study period. Observed adverse events were nausea and hepatic function abnormal in 1 patient each, and both events were mild. No patients required dose adjustment due to the change from baseline in mean pulmonary artery pressure (mPAP) measured 3 hrs after switching to Flolan solution prepared with the reformulated diluent. No major changes from baseline in mPAP, pulmonary vascular resistance, or right atrial pressure were observed at 24 hrs and at 4 weeks after switching to the Flolan solution prepared with pH 12.0 diluent. Although some patients showed increases in cardiac output (CO) from baseline at 24 hrs and 4 weeks, no patients required dose reduction as a result of an increase in CO.ConclusionNeither safety/efficacy concerns nor any dose adjustments of Flolan after switching to a more thermostable Flolan solution prepared with the reformulated pH 12.0 diluent could be required in Japanese patients with PAH receiving higher doses of Flolan.Trial registrationClinicalTrials.gov Identifier: NCT02705807.

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Results of Macitentan in Japanese Patients With Chronic Thromboembolic Pulmonary Hypertension　- A Prospective, Multicenter, Open-Label, Single-Arm, Phase 3 Study.

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Results of Macitentan in Japanese Patients With Chronic Thromboembolic Pulmonary Hypertension - A Prospective, Multicenter, Open-Label, Single-Arm, Phase 3 Study.

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OmicsDI is part of the ELIXIR infrastructure

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Results of Macitentan in Japanese Patients With Chronic Thromboembolic Pulmonary Hypertension　- A Prospective, Multicenter, Open-Label, Single-Arm, Phase 3 Study.