In this randomized, controlled, phase 3 trial of tafamidis for transthyretin amyloid cardiomyopathy, tafamidis was associated with lower all-cause mortality and lower rates of cardiovascular-related ...hospitalizations and decline in functional capacity and quality of life.
Aims
Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR‐CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT). While ATTR‐ACT was not designed ...for a dose‐specific assessment, further analysis from ATTR‐ACT and its long‐term extension study (LTE) can guide determination of the optimal dose.
Methods and results
In ATTR‐ACT, patients were randomized (2:1:2) to tafamidis 80 mg, 20 mg, or placebo for 30 months. Patients completing ATTR‐ACT could enrol in the LTE (with placebo‐treated patients randomized to tafamidis 80 or 20 mg; 2:1) and all patients were subsequently switched to high‐dose tafamidis. All‐cause mortality was assessed in ATTR‐ACT combined with the LTE (median follow‐up 51 months). In ATTR‐ACT, the combination of all‐cause mortality and cardiovascular‐related hospitalizations over 30 months was significantly reduced with tafamidis 80 mg (P = 0.0030) and 20 mg (P = 0.0048) vs. placebo. All‐cause mortality vs. placebo was reduced with tafamidis 80 mg Cox hazards model (95% confidence interval): 0.690 (0.487–0.979), P = 0.0378 and 20 mg 0.715 (0.450–1.137), P = 0.1564. The mean (standard error) change in N‐terminal pro‐B‐type natriuretic peptide from baseline to Month 30 was −1170.51 (587.31) (P = 0.0468) with tafamidis 80 vs. 20 mg. In ATTR‐ACT combined with the LTE there was a significantly greater survival benefit with tafamidis 80 vs. 20 mg 0.700 (0.501–0.979), P = 0.0374. Incidence of adverse events in both tafamidis doses were comparable to placebo.
Conclusion
Tafamidis, both 80 and 20 mg, effectively reduced mortality and cardiovascular‐related hospitalizations in patients with ATTR‐CM. The longer‐term survival data and the lack of dose‐related safety concerns support tafamidis 80 mg as the optimal dose.
Clinical Trial Registration: ClinicalTrials.gov NCT01994889; NCT02791230.
Design of ATTR‐ACT and the LTE and reduction in all‐cause mortality with tafamidis 80 mg/61 mg compared with tafamidis 20 mg
Emerging evidence suggests that several factors can impact disease progression in transthyretin amyloid polyneuropathy (ATTR-PN). The present analysis used longitudinal data from Val30Met patients ...participating in the tafamidis (selective TTR stabilizer) clinical development program to evaluate the impact of baseline neurologic severity on disease progression in ATTR-PN.
A linear mixed-effects model for repeated measures (MMRM) was constructed using tafamidis and placebo data from the intent-to-treat Val30Met population of the original registration study as well as tafamidis data from the two consecutive open-label extension studies. The second extension study is ongoing, but a prospectively-planned interim analysis involving a cleaned and locked database was conducted (cut-off: December 31, 2014). Val30Met patients are presented by treatment groups as those who received tafamidis during the registration and open-label studies (T-T group), or who received placebo during the registration study and were switched to tafamidis in the open-label studies (P-T group). Neurologic functioning was assessed at baseline and subsequent visits using the Neuropathy Impairment Score-Lower Limbs (NIS-LL). The analysis focused on the disease trajectory over the first 18 months of treatment.
The T-T (n = 64) and P-T (n = 61) cohorts were predominantly Caucasian and presented with early-stage neurologic disease (mean standard deviation baseline NIS-LL values were 8.4 11.4 and 11.4 13.5, respectively). The MMRM analysis demonstrated that baseline severity is an independent significant predictor of disease progression in addition to the treatment effect: patients with a lower baseline NIS-LL showed less progression than those with a higher baseline NIS-LL (p < 0.0001). Neurologic progression in the T-T group was less than in the P-T group across all levels of baseline NIS-LL (p = 0.0088), and the degree of separation increased over the 18-month period. Similar results were seen with the NIS-LL muscle weakness subscale.
This analysis of patients with Val30Met ATTR-PN demonstrates that neurologic disease progression strongly depends on baseline neurologic severity and illustrates the disease-modifying effect of tafamidis relative to placebo across a range of baseline levels of neurologic severity and treatment durations. These data also underscore the benefit of early diagnosis and treatment with tafamidis in delaying disease progression in ATTR-PN.
NCT00409175 , NCT00791492 and NCT00925002 registered 08 December 2006, 14 November 2008 (retrospectively registered), and 19 June 2009, respectively.
BACKGROUND: Transthyretin cardiomyopathy (TTR-CM) is a progressive, fatal disease caused by the accumulation of misfolded transthyretin (TTR) amyloid fibrils in the heart. Tafamidis is a kinetic ...stabilizer of TTR that inhibits misfolding and amyloid formation. METHODS: In this post hoc analysis, data from an observational study (Transthyretin Amyloidosis Cardiac Study; n = 29) were compared with an open-label study of tafamidis in patients with TTR-CM (Fx1B-201; n = 35). To ensure comparable baseline disease severity, patients with New York Heart Association (NYHA) functional classification ≥III were excluded in this time-to-mortality analysis. RESULTS: Patients with either wild-type or Val122Ile genotypes treated with tafamidis have a significantly longer time to death compared with untreated patients (P = .0004). Similar results were obtained when limiting the analysis to wild-type patients only, without restricting NYHA functional classification (P = .0262). CONCLUSIONS: These results support earlier conclusions suggesting that tafamidis slows disease progression compared with no treatment outside of standard of care and warrant further investigation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00694161.
Transthyretin amyloidosis is a rare, life-threatening disease resulting from aggregation and deposition of transthyretin amyloid fibrils in various tissues. There are 2 predominate phenotypic ...presentations of the disease: transthyretin familial amyloid polyneuropathy, which primarily affects the peripheral nerves, and transthyretin cardiomyopathy (TTR-CM), which primarily affects the heart. However, there is a wide overlap with symptoms at presentation and disease course being highly variable and influenced by the underlying transthyretin mutation, age of the affected individual, sex, and geographic location. Treatment of transthyretin amyloidosis is typically focused on symptom management. Although tafamidis has been shown to delay neurologic progression of transthyretin familial amyloid polyneuropathy, there are no approved pharmacologic therapies shown to improve survival in TTR-CM. The natural history of TTR-CM is poorly characterized, which presents difficulties for the design of large-scale trials for new treatments. This review provides a brief overview of TTR-CM and the challenges of identifying clinically meaningful end points and study parameters to determine the efficacy of treatments for rare diseases. The design and rationale behind the ongoing phase 3 ATTR-ACT study (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial), an international, multicenter, double-blind, placebo-controlled, randomized clinical trial, is also outlined. The ATTR-ACT study will provide important insight into the efficacy and safety of tafamidis for the treatment of TTR-CM.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01994889.
The purpose of this study was to evaluate the short- and long-term efficacy and safety of ziprasidone in children and adolescents with bipolar I disorder.
Subjects 10-17 years of age with a manic or ...mixed episode associated with bipolar I disorder participated in a 4 week, randomized, double-blind, placebo-controlled multicenter trial (RCT) followed by a 26 week open-label extension study (OLE). Subjects were randomized 2:1 to initially receive flexible-dose ziprasidone (40-160 mg/day, based on weight) or placebo. Primary outcome was the change in Young Mania Rating Scale (YMRS) scores from baseline. Safety assessments included weight and body mass index (BMI), adverse events (AEs), vital signs, laboratory measures, electrocardiograms, and movement disorder ratings.
In the RCT, 237 subjects were treated with ziprasidone (n=149; mean age, 13.6 years) or placebo (n=88; mean age, 13.7 years). The estimated least squares mean changes in YMRS total (intent-to-treat population) were -13.83 (ziprasidone) and -8.61 (placebo; p=0.0005) at RCT endpoint. The most common AEs in the ziprasidone group were sedation (32.9%), somnolence (24.8%), headache (22.1%), fatigue (15.4%), and nausea (14.1%). In the OLE, 162 subjects were enrolled, and the median duration of treatment was 98 days. The mean change in YMRS score from the end of the RCT to the end of the OLE (last observation carried forward) was -3.3 (95% confidence interval, -5.0 to -1.6). The most common AEs were sedation (26.5%), somnolence (23.5%), headache (22.2%), and insomnia (13.6%). For both the RCT and the OLE, no clinically significant mean changes in movement disorder scales, BMI z-scores, liver enzymes, or fasting lipids and glucose were observed. One subject on ziprasidone in the RCT and none during the OLE had Fridericia-corrected QT interval (QTcF) ≥ 460 ms.
These results demonstrate that ziprasidone is efficacious for treating children and adolescents with bipolar disorder. Ziprasidone was generally well tolerated with a neutral metabolic profile.
NCT00257166 and NCT00265330 at ClinicalTrials.gov.
The purpose of this study was to evaluate the short- and long-term efficacy, safety, and tolerability of ziprasidone in adolescents with schizophrenia.
Subjects ages 13-17 years with schizophrenia ...(American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. DSM-IV) were enrolled in a 6 week, randomized, double-blind, placebo-controlled multicenter trial (RCT) followed by a 26 week open-label extension study (OLE). Subjects were randomized in a 2:1 ratio to flexible-dose oral ziprasidone (40-160 mg/day, based on weight) or placebo. Primary end-point was change from baseline in Brief Psychiatric Rating Scale-Anchored (BPRS-A) total score. Safety assessments included adverse events, vital signs, laboratory measures, electrocardiograms, weight and body mass index, and movement disorder ratings.
Planned interim analysis for the primary end-point in the RCT resulted in early termination of both studies because of futility. In the RCT, 283 subjects received ziprasidone (n=193) or placebo (n=90). In the intent-to-treat analysis population, the least squares mean (SE) BPRS-A score decrease from baseline at week 6 was not significantly different (p=0.15; -14.16 0.78 for ziprasidone and -12.35 1.05 for placebo). Per-protocol analysis was significant (p=0.02). In the OLE, 221 subjects entered the OLE and received ziprasidone for a median of 99 days. The mean (SD) change in BPRS-A score from end of RCT to end of OLE (last observation carried forward) was -6.9 (8.9). The most common treatment-emergent adverse events (≥ 10%) for all causalities during the RCT were somnolence and extrapyramidal disorders, and during OLE was somnolence only. No subjects had Fridericia's corrected QT (QTcF) ≥ 500 ms in the RCT or OLE phases. One completed suicide occurred during the OLE phase. For RCT and OLE, no clinically significant changes were reported in metabolic indices and laboratory measures.
Ziprasidone failed to separate from placebo in treatment of schizophrenia in adolescents. Ziprasidone was generally well tolerated with an overall neutral weight and metabolic profile.
NCT00257192 and NCT00265382 at ClinicalTrials.gov .
Aims
Transthyretin amyloid cardiomyopathy (ATTR‐CM) is a progressive, fatal disorder that remains underdiagnosed. The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT) was the first ...large clinical trial to include both wild‐type (ATTRwt) and hereditary (ATTRv) patients. A description of the natural history of ATTR‐CM, utilizing data from placebo‐treated patients in ATTR‐ACT, will provide a greater understanding of presentation and progression of ATTR‐CM and may aid in disease awareness, earlier diagnosis and treatment monitoring.
Methods and results
Changes in clinical endpoints (mortality, cardiovascular CV‐related hospitalizations, 6‐min walk test 6MWT distance and Kansas City Cardiomyopathy Questionnaire Overall Summary KCCQ‐OS score) from baseline to Month 30 in the 177 patients (134 ATTRwt, 43 ATTRv) who received placebo in ATTR‐ACT were assessed. ATTRwt patients tended to have less severe disease at baseline. Over the duration of ATTR‐ACT, there were 76 (42.9%) all‐cause deaths, and 107 (60.5%) patients had a CV‐related hospitalization. There was a lower proportion of all‐cause deaths in ATTRwt (49, 36.6%) than ATTRv (27, 62.8%). There was a similar, steady decline in mean (SD) 6MWT distance from baseline to Month 30 in ATTRwt (93.9 93.7 m) and ATTRv (89.1 107.2 m) patients. The decline in mean (SD) KCCQ‐OS score was less severe in ATTRwt (13.8 20.7) than ATTRv (21.0 26.4) patients.
Conclusions
Patients with ATTR‐CM experience a severe, progressive disease. In ATTR‐ACT, placebo‐treated patients with ATTRv, compared with ATTRwt, had more severe disease at baseline, and their disease progressed more rapidly as shown by mortality, hospitalizations and quality of life over time.
Abstract Background Ziprasidone, adjunctive to either lithium or valproate, has previously been shown to be associated with a significantly lower risk of relapse in bipolar disorder compared with ...lithium or valproate treatment alone. Methods This placebo-controlled outpatient trial with ziprasidone adjunctive to lithium or valproate or lithium and valproate alone, for subjects with a recent or current manic or mixed episode of bipolar I disorder, comprised a 2.5- to 4-month, open-label stabilization period, followed by a 6-month, double-blind maintenance period. These post hoc analyses characterize the relapse outcomes by dose, relapse types and timing as well as all-reason discontinuations during the maintenance period. Results Time to relapse and all-reason discontinuation were both statistically significant in favor of the ziprasidone 120 mg/day group compared with placebo ( p =0.004 and 0.001, respectively) during the 6-month double-blind period. There was no difference in time to relapse in the 80 and 160 mg/day dose groups compared with placebo ( p =0.16 and 0.40, respectively) and, likewise, for time to all-reason discontinuation ( p =0.20 for both doses). The majority of relapses in each group occurred prior to week 8, and most were depressive in nature. Limitations The primary study was not designed to compare relapse rates by dose groups. Conclusions These analyses confirm the effectiveness of ziprasidone (80–160 mg/day) in preventing relapses in subjects with bipolar disorder, with the 120 mg/day dosage appearing to have the highest relapse prevention rate.
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