Study methodology and insights from the palovarotene clinical development program in fibrodysplasia ossificans progressiva.

BACKGROUND: The design of clinical trials in rare diseases is often complicated by a lack of real-world translational knowledge. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by skeletal malformations and progressive heterotopic ossification (HO). Palovarotene is a selective retinoic acid receptor gamma agonist. Here, we describe the methodology of three studies in the palovarotene clinical development program in FOP and discuss insights that could inform future research, including endpoint suitability and the impact of trial design. METHODS: PVO-1A-001 (NCT02322255) was a prospective, protocol-specified, longitudinal FOP natural history study (NHS). PVO-1A-201 (NCT02190747) was a randomized, double-blind, placebo-controlled phase II trial; PVO-1A-202 (NCT02279095) was its open-label extension. Trial designs, including treatment regimens and imaging assessments, were refined between PVO-1A-201 and PVO-|1A-202, and within PVO-1A-202, based on emerging data as the studies progressed. Palovarotene doses were administered using a flare-up treatment regimen (higher dose for 2/4 weeks, followed by lower dose for 4/≥8 weeks; from flare-up onset), with or without accompanying chronic (daily) treatment. Flare-up and disease progression outcomes were assessed, including incidence and volume of new HO during flare-ups and/or annually, as well as other clinical, patient-reported, and exploratory outcomes. Safety was monitored throughout all studies. RESULTS: Overall, 114 and 58 individuals with FOP were enrolled in the NHS and phase II trials, respectively. Results of the NHS and PVO-1A-201 were published in 2022; complete results of PVO-1A-202 will be publicly available in due course. Together the studies yielded important information on endpoint suitability, including that low-dose whole-body computed tomography was the optimum imaging modality for assessing HO progression annually and that long study durations are needed to detect substantial changes in functional and patient-reported outcomes. CONCLUSIONS: A flexible clinical development program is necessary for underexplored rare diseases to overcome the many challenges faced. Here, the NHS provided a longitudinal evaluation of FOP progression and interventional trials were based on emerging data. The studies described informed the design and endpoints implemented in the phase III MOVE trial (NCT03312634) and provide a foundation for future clinical trial development. TRIAL REGISTRATION: NCT02322255 (registered 23/12/2014); NCT02190747 (registered 15/07/2014); NCT02279095 (registered 30/10/2014).

A Pharmacokinetic, Safety, and Tolerability Trial of Palovarotene in Healthy Japanese and Non-Japanese Participants.

BACKGROUND AND OBJECTIVE: Palovarotene is an oral, selective retinoic acid receptor gamma agonist under investigation for fibrodysplasia ossificans progressiva (FOP). Palovarotene is primarily metabolized by cytochrome P450 (CYP) 3A4. Differences in CYP-mediated metabolism of CYP substrates have been observed between Japanese and non-Japanese individuals. This phase I trial (NCT04829786) compared the pharmacokinetic profile of palovarotene in healthy Japanese and non-Japanese participants and evaluated the safety of single doses. METHODS: Healthy Japanese and non-Japanese participants were matched individually (1:1) and randomized to receive a single oral dose of palovarotene 5 or 10 mg, followed by the alternate dose after a 5-day washout period. Maximum plasma drug concentration (Cmax) and area under the plasma concentration-time curve (AUC) were assessed. Estimates of the geometric mean difference between dose and Japanese and non-Japanese groups were calculated for natural log-transformed Cmax and AUC parameters. Adverse events (AEs), serious AEs, and treatment-emergent AEs were recorded. RESULTS: Eight pairs of matched non-Japanese and Japanese individuals and two unmatched Japanese individuals participated. Mean plasma concentration-time profiles were similar between the two cohorts at both dose levels, demonstrating that palovarotene absorption and elimination are similar irrespective of dose level. The pharmacokinetic parameters of palovarotene were similar between groups at both dose levels. Cmax and AUC values were dose-proportional between doses in each group. Palovarotene was well tolerated; there were no deaths or AEs leading to treatment discontinuation. CONCLUSIONS: Japanese and non-Japanese groups had similar pharmacokinetic profiles, indicating that palovarotene dose adjustments are not necessary for Japanese patients with FOP.

Palovarotene for Fibrodysplasia Ossificans Progressiva (FOP): Results of a Randomized, Placebo-Controlled, Double-Blind Phase 2 Trial.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by progressive heterotopic ossification (HO), often heralded by flare-ups, leading to reduced movement and life expectancy. This placebo-controlled, double-blind trial (NCT02190747) evaluated palovarotene, an orally bioavailable selective retinoic acid receptor gamma agonist, for prevention of HO in patients with FOP. Patients experiencing a flare-up were enrolled in two cohorts: (1) patients ≥15 years were randomized 3:1 to palovarotene 10/5 mg (weeks 1-2/3-6) or placebo; (2) patients ≥6 years were randomized 3:3:2 to palovarotene 10/5 mg, palovarotene 5/2.5 mg (weeks 1-2/3-6), or placebo. Cohort data were pooled. The primary endpoint was the proportion of responders (no/minimal new HO at flare-up body region by plain radiograph) at week 6. Change from baseline in HO volume and new HO incidence were assessed by computed tomography (CT) at week 12. Tissue edema was assessed by magnetic resonance imaging (MRI) or ultrasound. Forty patients (aged 7-53 years) were enrolled (placebo: n = 10; palovarotene 5/2.5 mg: n = 9; palovarotene 10/5 mg: n = 21). Disease history was similar between groups. In the per-protocol population, the proportion of responders at week 6 by plain radiograph was 100% with palovarotene 10/5 mg; 88.9% with palovarotene 5/2.5 mg; 88.9% with placebo (Cochran-Armitage trend test: p = 0.17). At week 12, the proportions were 95.0% with palovarotene 10/5 mg; 88.9% with palovarotene 5/2.5 mg; 77.8% with placebo (Cochran-Armitage trend test: p = 0.15). Week 12 least-squares mean (LSmean) new HO volume, assessed by CT, was 3.8 × 103  mm3 with palovarotene 10/5 mg; 1.3 × 103  mm3 with palovarotene 5/2.5 mg; 18.0 × 103  mm3 with placebo (pairwise tests versus placebo: p ≤ 0.12). Palovarotene was well-tolerated. No patients discontinued treatment or required dose reduction; one patient had dose interruption due to elevated lipase. Although these findings were not statistically significant, they support further evaluation of palovarotene for prevention of HO in FOP in larger studies. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Whole-body Computed Tomography Versus Dual Energy X­ray Absorptiometry for Assessing Heterotopic Ossification in Fibrodysplasia Ossificans Progressiva.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder that leads to heterotopic ossification (HO), resulting in progressive restriction of physical function. In this study, low-dose, whole-body computed tomography (WBCT) and dual energy X-ray absorptiometry (DXA) were evaluated to determine the preferred method for assessing total body burden of HO in patients with FOP. This was a non-interventional, two-part natural history study in patients with FOP (NCT02322255; date of registration: December 2014). In Part A (described here), WBCT and DXA scans were individually assessed for HO presence and severity across 15 anatomical regions. All images were independently reviewed by an expert imaging panel. Ten adult patients were enrolled across four sites. The sensitivity to HO presence and severity varied considerably between the two imaging modalities, with WBCT demonstrating HO in more body regions than DXA (76/138 [55%] versus 47/113 [42%]) evaluable regions). Inability to evaluate HO presence, due to overlapping body regions (positional ambiguity), occurred less frequently by WBCT than by DXA (mean number of non-evaluable regions per scan 1.2 [standard deviation: 1.5] versus 2.4 [1.4]). Based on the increased sensitivity and decreased positional ambiguity of low-dose WBCT versus DXA in measuring HO in patients with FOP, low-dose WBCT was chosen as the preferred imaging for measuring HO. Therefore, low-dose WBCT was carried forward to Part B of the natural history study, which evaluated disease progression over 36 months in a larger population of patients with FOP.

Patients with ACVR1R206H mutations have an increased prevalence of cardiac conduction abnormalities on electrocardiogram in a natural history study of Fibrodysplasia Ossificans Progressiva.

BACKGROUND: Genetic contributors to cardiac arrhythmias are often found in cardiovascular conduction pathways and ion channel proteins. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disease of massive heterotopic ossification caused by a highly recurrent R206H mutation in ACVR1/ALK2. This mutation causes abnormal activation of the bone morphogenetic protein (BMP) pathway in response to Activin A. Prior studies suggested increased risks of cardiopulmonary complications in FOP. We examined participants in a Natural History Study (NHS) of FOP (ClinicalTrials.gov #NCT02322255) to better understand their cardiovascular status. METHODS: The NHS is an ongoing 3 year international multi-center longitudinal study of 114 patients (ages 4-56 years) with genetically confirmed ACVR1/ALK2R206H FOP. Patients were clinically assessed at baseline and 12 months. Electrocardiograms (ECGs) were reviewed in a central ECG laboratory. Conduction abnormalities were compared against clinical data collected in the NHS, and echocardiograms collected from NHS and non-NHS patients. RESULTS: Conduction abnormalities were present in 45.3% of baseline ECGs, with the majority of abnormalities classified as nonspecific intraventricular conduction delay (37.7%). More specifically, 22.2% of patients > 18 years old had conduction abnormalities, which was significantly higher than a prior published study of a healthy population (5.9%; n = 3978) (p < 0.00001). Patients with FOP < 18 years old also had a high prevalence of conduction abnormalities (62.3%). The 12-month follow up data was similar to baseline results. Conduction abnormalities did not correlate with chest wall deformities, scoliosis, pulmonary function test results, or increased Cumulative Analog Joint Involvement Scale scores. Echocardiograms from 22 patients with FOP revealed 8 with structural cardiac abnormalities, only 1 of which correlated with a conduction abnormality. CONCLUSIONS: We found that patients with FOP may have subclinical conduction abnormalities manifesting on ECG, independent of heterotopic ossification. Although clinically significant heart disease is not typically associated with FOP, and the clinical implications for cardiovascular risk remain unclear, knowledge about ECG and echocardiogram changes is important for clinical care and research trials in patients with FOP. Further studies on how ACVR1/ALK2R206H affects cardiac health will help elucidate the underlying mechanism.

Natural history of fibrodysplasia ossificans progressiva: cross-sectional analysis of annotated baseline phenotypes.

BACKGROUND: Fibrodysplasia Ossificans Progressiva (FOP; OMIM#135100) is an ultra-rare, severely disabling genetic disease characterized by congenital malformation of the great toes and progressive heterotopic ossification (HO) in muscles, tendons, ligaments, fascia, and aponeuroses often preceded by painful, recurrent soft tissue swelling (flare-ups). The formation of HO leads to progressive disability, severe functional limitations in joint mobility, and to a shortened life-span. In this prospective natural history study, we describe the baseline, cross-sectional disease phenotype of 114 individuals with FOP. METHODS: All subjects underwent protocol-specified baseline assessments to determine their disease status. Cross-sectional analyses were performed using linear regression in which functional evaluations (Cumulative Analogue Joint Involvement Scale [CAJIS] and the FOP-Physical Function Questionnaire [FOP-PFQ]) and the burden of HO as measured by low-dose whole body CT (volume of HO and number of body regions with HO) were assessed. RESULTS: Findings from 114 subjects (age range 4 to 56 years) were evaluated. While subject age was significantly (p < 0.0001) correlated with increased CAJIS (r = 0.66) and FOP-PFQ scores (r = 0.41), the estimated mean increases per year (based on cross-sectional average changes over time) were small (0.47 units and 1.2%, respectively). There was also a significant (p < 0.0001) correlation between baseline age and HO volume (r = 0.56), with an estimated mean increase of 25,574 mm3/year. There were significant (p < 0.0001) correlations between the objective assessment of HO volume and clinical assessments of CAJIS (r = 0.57) and FOP-PFQ (r = 0.52). CONCLUSIONS: Based on the cross-sectional analysis of the baseline data, functional and physical disability as assessed by CAJIS and the FOP-PFQ increased over time. Although longitudinal data are not yet available, the cross-sectional analyses suggest that CAJIS and FOP-PFQ are not sensitive to detect substantial progression over a 1- to 2-year period. Future evaluation of longitudinal data will test this hypothesis. The statistically significant correlations between HO volume and the functional endpoints, and the estimated average annual increase in total HO volume, suggest that the formation of new HO will be measurable over the relative short-term course of a clinical trial, and represents an endpoint that is clinically meaningful to patients. TRIAL REGISTRATION: This study ( NCT02322255 ) was first posted on 23 December, 2014.

Correction to: Natural history of fibrodysplasia ossificans progressiva: cross-sectional analysis of annotated baseline phenotypes.

The original version of this article [1] unfortunately included an error to an author's name. Author Maja Di Rocco was erroneously presented as Maja DiRocco.The correct author name has been included in the author list of this Correction article and is already updated in the original article.

The FOP Connection Registry: Design of an international patient-sponsored registry for Fibrodysplasia Ossificans Progressiva.

The Fibrodysplasia Ossificans Progressiva (FOP) Connection Registry is an international, voluntary, observational study that directly captures demographic and disease information initially from patients with FOP (the patient portal) and in the near future from treating physicians (the physician portal) via a secure web-based tool. It was launched by the International FOP Association (IFOPA) with a guiding vision to develop and manage one unified, global, and coordinated Registry allowing the assembly of the most comprehensive data on FOP. This will ultimately facilitate greater access and sharing of patient data and enable better and faster development of therapies and tracking their long-term treatment effectiveness and safety. This report outlines the FOP Connection Registry's design and procedures for data collection and reporting, as well as the long-term sustainability of Registry. Patient-reported, aggregate data are summarized for the first 196 enrolled patients, representing participation from 42 countries and approximately 25% of the world's known FOP population. Fifty-seven percent of the current Registry participants are female with a mean age of 23.8years (median=21years, range=1, 76years). Among the Registry participants who provided their FOP type, 51% reported FOP Classic (R206H), 41% reported FOP Type Unknown, and 8% reported FOP Variant. Patients reported 5.4years (median=3.0years, range=0, 45.8years) as the mean age at which they noticed their first FOP symptoms and a mean age at final FOP diagnosis of 7.5years (median=5.0years, range=0.1, 48.4years). Information on the patients' diagnostic journeys in arriving at a correct diagnosis of FOP is also presented. These early patient-reported data suggest that the IFOPA's vision of one, unified, global, and coordinated approach to the FOP Connection Registry is well underway to being realized. In addition, the positive response from the FOP patient community to the initial launch of the Registry's patient portal has created a solid foundation upon which to build the largest international registry for monitoring the clinical progression of FOP among patients.

Clinical measures in transthyretin familial amyloid polyneuropathy.

INTRODUCTION: This observational, cross-sectional, single-center study aimed to identify instruments capable of measuring disease progression in transthyretin familial amyloid polyneuropathy (TTR-FAP). METHODS: The relationship between disease stage and Neuropathy Impairment Score-Lower Limbs (NIS-LL) and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score was assessed in 61 (stages 1-3) patients with TTR-FAP (V30M variant) and 16 healthy controls. Composite measures of large- and small-nerve fiber function, and modified body mass index (mBMI) were also assessed. RESULTS: Ordinal-based NIS-LL and Norfolk QOL-DN scores discriminated between disease stages (P < 0.0001 for NIS-LL and Norfolk QOL-DN). Longer disease duration correlated with worse NIS-LL and Norfolk QOL-DN. Karnofsky performance score declined progressively by disease stage. Composite measures of nerve fiber function differentiated stage 1 from stage 2 disease. The mBMI declined with advancing disease. CONCLUSIONS: NIS-LL, Norfolk QOL-DN score, composite endpoints of nerve fiber function, and mBMI are valid, reliable measures of TTR-FAP severity. Muscle Nerve 55: 323-332, 2017.

Tafamidis in transthyretin amyloid cardiomyopathy: effects on transthyretin stabilization and clinical outcomes.

BACKGROUND: Transthyretin (TTR) amyloidosis is a progressive systemic disorder caused by misfolded TTR monomers that cumulatively deposit in the heart and systemically as amyloid. METHODS AND RESULTS: This phase 2 open-label trial evaluated the stabilization of TTR tetramers using 20 mg of tafamidis daily at week 6 (primary end point), month 6, and month 12, as well as safety of tafamidis treatment and efficacy with respect to progression of TTR amyloid cardiomyopathy. Thirty-one wild-type patients (median age, 76.7 years; 93.5% men) with a median disease duration of 55.6 months and mild to moderate heart failure (96.8%; New York Heart Association, classes I-II) were enrolled. Thirty of 31 patients (96.8%) achieved TTR stabilization after 6 weeks and 25 of 28 patients (89.3%) after 12 months. After 12 months of treatment, 3 patients discontinued prematurely, 2 patients died, 7 patients were hospitalized because of cardiovascular events, 20 of 28 patients demonstrated preserved New York Heart Association classification status, but 15 of 31 (48.4%) patients had clinical progression (eg, admission for cardiac failure, atrial fibrillation, and syncope). N-terminal prohormone brain natriuretic peptide levels did not increase significantly over time, troponin I and troponin T increased moderately, and no consistent clinically relevant changes were seen in echocardiographic cardiac assessments. Tafamidis treatment was generally well tolerated although 7 of 31 patients had bouts of diarrhea. CONCLUSIONS: Tafamidis treatment effectively achieved and maintained TTR stabilization and was well tolerated. The absence of significant changes in most biochemical and echocardiographic parameters suggests that further evaluation of tafamidis in TTR amyloid cardiomyopathy is warranted. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00694161.

Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction.

OBJECTIVES: This study sought to determine the frequency of left ventricular amyloid in heart failure with preserved ejection fraction (HFpEF). BACKGROUND: Left ventricular amyloid deposition can cause diastolic dysfunction and HFpEF. METHODS: Autopsy of left ventricular specimens from patients with antemortem diagnosis of HFpEF without clinically apparent amyloid (n = 109) and from control subjects (n = 131) were screened with sulfated Alcian blue and subsequent Congo red staining with microdissection for mass spectrometry-based proteomics to determine amyloid type. Fibrosis was assessed with quantitative whole-field digital microscopy. RESULTS: The presence of wild-type transthyretin (wtTTR) amyloid was associated with age at death and male sex, but the age- and sex-adjusted prevalence of wtTTR amyloid was higher in HFpEF patients than in control subjects (odds ratio: 3.8, 95% confidence interval: 1.5 to 11.3; p = 0.03). Among HFpEF patients, moderate or severe interstitial wtTTR deposition, consistent with senile systemic amyloidosis as the primary etiology of HFpEF, was present in 5 (5%) patients (80% men), with mild interstitial and/or variable severity of intramural coronary vascular deposition in 13 (12%) patients. While, wtTTR deposition was often mild, adjusting for age and presence of HFpEF, wtTTR amyloid was associated with more fibrosis (p = 0.005) and lower age, sex, and body size-adjusted heart weight (p = 0.04). CONCLUSIONS: Given the age- and sex-independent association of HFpEF and wtTTR deposition and an emerging understanding of the pathophysiology of the amyloidoses, the current findings support further investigation of the role of wtTTR in the pathophysiology of HFpEF.

Norfolk QOL-DN: validation of a patient reported outcome measure in transthyretin familial amyloid polyneuropathy.

The Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire is an instrument to assess QOL in diabetic polyneuropathy. The objective of this observational, cross-sectional study in 61 patients with V30M transthyretin familial amyloid polyneuropathy (TTR-FAP) and 16 healthy volunteers was to validate the Norfolk QOL-DN for assessment of QOL in TTR-FAP. Comparisons were conducted to identify the best items to discriminate disease stages and assess which individual Norfolk domains (symptoms, large fiber, small fiber, autonomic, and activities of daily living) would be most affected by disease stage. Analysis of individual items revealed a significant pattern of discrimination among disease stages (p < 0.001). Total QOL scores increased (indicating worsening) with duration of symptoms, with a steeper increase observed earlier in the course of disease. Significant correlations were observed between each Norfolk domain and other measures of neurological function. Limitations include cross-sectional study design, low patient numbers in this rare disease, and the ordinal-based character of the metric used; future areas to explore include item response theory approaches such as Rasch analysis. These results suggest the Norfolk QOL-DN is a reliable indicator of the impact of disease severity on QOL in patients with TTR-FAP.

Effects of tafamidis on transthyretin stabilization and clinical outcomes in patients with non-Val30Met transthyretin amyloidosis.

This phase II, open-label, single-treatment arm study evaluated the pharmacodynamics, efficacy, and safety of tafamidis in patients with non-Val30Met transthyretin (TTR) amyloidosis. Twenty-one patients with eight different non-Val30Met mutations received 20 mg QD of tafamidis meglumine for 12 months. The primary outcome, TTR stabilization at Week 6, was achieved in 18 (94.7%) of 19 patients with evaluable data. TTR was stabilized in 100% of patients with non-missing data at Months 6 (n = 18) and 12 (n = 17). Exploratory efficacy measures demonstrated some worsening of neurological function. However, health-related quality of life, cardiac biomarker N-terminal pro-hormone brain natriuretic peptide, echocardiographic parameters, and modified body mass index did not demonstrate clinically relevant worsening during the 12 months of treatment. Tafamidis was well tolerated. In conclusion, our findings suggest that tafamidis 20 mg QD effectively stabilized TTR associated with several non-Val30Met variants.

Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy.

Tafamidis, a transthyretin (TTR) kinetic stabilizer, delayed neuropathic progression in patients with Val30Met TTR familial amyloid polyneuropathy (TTR-FAP) in an 18-month randomized controlled trial (study Fx-005). This 12-month, open-label extension study evaluated the long-term safety, tolerability, and efficacy of tafamidis 20 mg once daily in 86 patients who earlier received blinded treatment with tafamidis or placebo. Efficacy measures included the Neuropathy Impairment Score in the Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy total quality of life (TQOL) score, and changes in neurologic function and nutritional status. We quantified the monthly rates of change in efficacy measures, and TTR stabilization, and monitored adverse events (AEs). Patients who continued on tafamidis had stable rates of change in NIS-LL (from 0.08 to 0.11/month; p = 0.60) and TQOL (from -0.03 to 0.25; p = 0.16). In patients switched from placebo, the monthly rate of change in NIS-LL declined (from 0.34 to 0.16/month; p = 0.01), as did TQOL score (from 0.61 to -0.16; p < 0.001). Patients treated with tafamidis for 30 months had 55.9 % greater preservation of neurologic function as measured by the NIS-LL than patients in whom tafamidis was initiated later. Plasma TTR was stabilized in 94.1 % of patients treated with tafamidis for 30 months. AEs were similar between groups; no patients discontinued because of an AE. Long-term tafamidis was well tolerated, with the reduced rate of neurologic deterioration sustained over 30 months. Tafamidis also slowed neurologic impairment in patients previously given placebo, but treatment benefits were greater when tafamidis was begun earlier.

The Transthyretin Amyloidosis Outcomes Survey (THAOS) registry: design and methodology.

UNLABELLED: Abstract Background: Transthyretin (TTR) amyloidosis - the most common type of hereditary amyloidosis - also has an acquired form and is observed in geographically dispersed populations. TTR amyloidosis is marked by considerable clinical heterogeneity, and the main phenotypes are neurologic and cardiovascular. METHODS: THAOS is an international, noninterventional, longitudinal, observational registry designed to evaluate overall survival in patients, better understand genotype-phenotype relationships and the natural history of TTR amyloidosis, and evaluate the effects of liver transplantation and other treatments on disease progression in TTR amyloidosis. All individuals with a confirmed TTR mutation with or without a diagnosis of TTR amyloidosis and patients with wild-type TTR amyloidosis are eligible to be enrolled in the registry. PURPOSE: To describe the design and methodology of the recently established registry. Procedures for data collection are outlined and a minimum set of assessments for the standard evaluation of all subjects with TTR amyloidosis is described. Demographic information, TTR genotype, medical history, family history of the disease, and transplant history are assessed at baseline. On return visits, signs and symptoms of the disease are evaluated, general examinations are conducted, and laboratory data, measures of neurologic and cardiovascular function, and quality of life are assessed according to the standard of care for patients. Visits on at least a biannual basis are recommended. The registry will remain open for a period of at least 10 years. RESULTS: The initial experience suggests that the registry is characterized by a comprehensive set of data elements which can be completed by providers from the various clinical backgrounds who administer care to individuals with TTR amyloidosis. CONCLUSION: As of September 2011, 30 centers in 15 of the 19 countries participating in the THAOS registry have enrolled 975 patients. Such data provide a representative sample of the global TTR amyloidosis patient population, including asymptomatic TTR variant carriers, which can inform the natural history of the disease and offer the potential to evaluate novel therapeutic modalities in diverse patient subpopulations.

Prospective evaluation of the morbidity and mortality of wild-type and V122I mutant transthyretin amyloid cardiomyopathy: the Transthyretin Amyloidosis Cardiac Study (TRACS).

BACKGROUND: TRACS sought to describe the clinical outcomes and disease progression of transthyretin (TTR) cardiac amyloidosis (ATTR) in an observational study. Clinical course is largely determined by disease type with ATTR categorized as wild-type (ATTRwt) or genetic-variant protein (ATTRm). Prospective data are lacking in the most common TTR mutation, V122I, present in approximately 3.5% of African Americans. METHODS: Patients with ATTRwt (n = 18) and V122I ATTRm (n = 11) were longitudinally assessed every 6 months for up to 2 years by functional class assessments, biochemical markers, and echocardiography. RESULTS: At baseline, no differences in clinical characteristics, biomarkers, or echocardiographic parameters were noted between patients with ATTRwt and patients with ATTRm. After 15.5 ± 8 months, there were 11 deaths and 1 cardiac transplant, with higher mortality (73% vs 22%, P = .03) and cardiovascular hospitalization (64% vs 28%, P = .02) among patients with ATTRm. The median survival from diagnosis was 25.6 months for ATTRm vs 43.0 months for ATTRwt (P = .04). Univariate predictors of mortality included disease duration, heart rate ≥ 70 beats/min, baseline stroke volume, left ventricular ejection fraction <50%, and ATTRm status. For each 6-month increment, the mean 6-minute walk distance declined by 25.8 m, N-terminal pro b-type natriuretic peptide increased by 1,816 pg/mL, and left ventricular ejection fraction fell by 3.2%, for the entire cohort. CONCLUSIONS: In this prospective study, disease progression, morbidity, and mortality were observed in ATTR cardiomyopathy, particularly due to V122I, over a short duration. Given the prevalence of this mutation, further study of V122I in at-risk African American patients is warranted.

Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial.

OBJECTIVES: To evaluate the efficacy and safety of 18 months of tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP). METHODS: In this randomized, double-blind trial, patients received tafamidis 20 mg QD or placebo. Coprimary endpoints were the Neuropathy Impairment Score-Lower Limbs (NIS-LL) responder analysis (<2-point worsening) and treatment-group difference in the mean change from baseline in Norfolk Quality of Life-Diabetic Neuropathy total score (TQOL) in the intent-to-treat (ITT) population (n = 125). These endpoints were also evaluated in the efficacy-evaluable (EE; n = 87) population. Secondary endpoints, including changes in neurologic function, nutritional status, and TTR stabilization, were analyzed in the ITT population. RESULTS: There was a higher-than-anticipated liver transplantation dropout rate. No differences were observed between the tafamidis and placebo groups for the coprimary endpoints, NIS-LL responder analysis (45.3% vs 29.5% responders; p = 0.068) and change in TQOL (2.0 vs 7.2; p = 0.116) in the ITT population. In the EE population, significantly more tafamidis patients than placebo patients were NIS-LL responders (60.0% vs 38.1%; p = 0.041), and tafamidis patients had better-preserved TQOL (0.1 vs 8.9; p = 0.045). Significant differences in most secondary endpoints favored tafamidis. TTR was stabilized in 98% of tafamidis and 0% of placebo patients (p < 0.0001). Adverse events were similar between groups. CONCLUSIONS: Although the coprimary endpoints were not met in the ITT population, tafamidis was associated with no trend toward more NIS-LL responders and a significant reduction in worsening of most neurologic variables, supporting the hypothesis that preventing TTR dissociation can delay peripheral neurologic impairment. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that 20 mg tafamidis QD was associated with no difference in clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the Norfolk QOL-DN score. Secondary outcomes demonstrated a significant delay in peripheral neurologic impairment with tafamidis, which was well tolerated over 18 months.

Pressure-volume relationships in patients with transthyretin (ATTR) cardiac amyloidosis secondary to V122I mutations and wild-type transthyretin: Transthyretin Cardiac Amyloid Study (TRACS).

BACKGROUND: ATTR cardiac amyloidosis can result from a mutated variant of transthyretin (eg, V122I) or wild-type variant (ATTRwt). We evaluated pressure-volume (PV) indices at baseline and over time to further characterize abnormal pump function in these subjects. METHODS AND RESULTS: Twenty-nine subjects (18 with ATTRwt and 11 with ATTRm (V122I) had 2-dimensional echocardiograms with complete Doppler measures at baseline and every 6 months for up to 2 years. PV indices were derived from echocardiographic measures of ventricular volume coupled with sphygmomanometer-measured pressure and Doppler estimates of filling pressure. The end-systolic and end-diastolic PV relations and the area between them as a function of end-diastolic pressure, the isovolumic PV area (PVA(iso)), were calculated. Clinical, demographic, and PV indices were compared between V122I and ATTRwt subjects and between survivors and nonsurvivors at baseline and over time. Cox proportional hazards model identified correlates for mortality. Stroke volume decline was associated with alterations in ventricular-vascular coupling and a decrease in ventricular capacitance with significant decrement in ejection fraction (56±12% to 48±14%, P=0.0001) over 18 months. PVA(iso) was lower in V122I subjects compared with wild-type at baseline and declined over time. Twelve (41%) subjects died or underwent a cardiac transplant after a mean follow-up of 478 days (range, 31 to 807). Multivariable survival analysis demonstrated that initial ejection fraction (a measure of ventricular-vascular coupling) <50% was associated with increased mortality (hazard ratio, 6.6; 95% confidence interval, 1.1 to 40.3). CONCLUSIONS: In ATTR cardiac amyloidosis secondary to a V122I mutation and wild-type transthyretin, PV analysis reveals alterations that are associated with reductions in the ability of the ventricle to perform work and, ultimately, with reduced survival in these subjects.

Arrhythmias in patients with chronic obstructive pulmonary disease (COPD): occurrence frequency and the effect of treatment with the inhaled long-acting beta2-agonists arformoterol and salmeterol.

Beta-adrenergic stimulation may increase heart rate and the potential for cardiac arrhythmias. The effect of inhaled long-acting beta2-agonists (LABAs) on these outcomes was evaluated in patients with chronic obstructive pulmonary disease (COPD) in 2 double-blind randomized clinical trials. The pretreatment arrhythmia occurrence frequency in these patients was also described. In this analysis, 24-hour Holter monitoring data were pooled from 2 identically designed Phase III trials. Patients were randomized to LABA treatment or placebo for 12 weeks: a) nebulized arformoterol 15 microg BID, b) 25 microg BID, or c) 50 microg QD; d) salmeterol metered dose inhaler 42 microg BID; or e) placebo. The 24-hour Holter monitoring was performed pretreatment and at Weeks 0 (first day of dosing), 6, and 12. We assessed the proportion of patients with each of 4 arrhythmias: atrial tachycardia, atrial fibrillation/flutter, and "nonsustained"; (4-10 beats) and "sustained"; (>10 beats) ventricular tachycardia. There were 5226 Holter recordings in 1429 treated patients. At baseline, there was a low frequency of occurrence of atrial fibrillation/flutter (0.1%), nonsustained ventricular tachycardia (3.1%), and >10 beat ventricular tachycardia (0.3%). Atrial tachycardia occurred frequently (41.8%). The proportion of patients with treatment-emergent atrial tachycardia ranged from 27% to 32% and was non-significantly higher, by approximately 2%-5% (p = 0.70), in the LABA groups compared with the placebo group. The rates of the other more serious arrhythmias did not increase with LABA treatment and were similar to placebo. All treatment groups (LABA and placebo) had consistent small decreases from baseline in mean 24-hour and maximum hourly heart rate. In conclusion, in this large cohort of COPD patients with no or stable cardiac comorbidities, a high proportion ( approximately 40%) of patients were observed to have atrial tachycardia before treatment, which increased by 2%-5% with LABA treatment. More serious arrhythmias were infrequent and did not increase with inhaled LABA therapy. LABA administration did not increase mean heart rate.

Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: results from a 2-part, phase II, multicenter, randomized, placebo- and active-controlled trial.

BACKGROUND: Platelet-initiated acute thrombosis and coronary embolization are fundamental in the pathophysiology of complications during percutaneous coronary intervention (PCI). Cangrelor (formerly AR-C69931MX) is a novel, rapidly acting, intravenous, specific antagonist of platelet aggregation via binding to the adenosine diphosphate (ADP) P2Y12 receptor subtype. The primary aims of this study were to assess the initial safety and pharmacodynamics of cangrelor in patients undergoing PCI. METHODS: In part 1, patients undergoing PCI were randomized to an 18- to 24-hour of either placebo, 1-, 2-, or 4-microg/kg per minute cangrelor in addition to aspirin and heparin beginning before PCI. In part 2, patients were randomized to receive either cangrelor (4 microg/kg per minute) or abciximab before PCI. The primary end point was the composite incidence of major and minor bleeding through 7 days. Secondary end points included the occurrence of major adverse coronary events (death, MI, and unplanned repeat coronary intervention) through 30 days plus ex vivo platelet aggregation and bleeding times. RESULTS: Two hundred patients (3 dosage groups and placebo) were studied in part 1, and 199 additional patients were then randomized in the second part, comparing 1 dose of cangrelor and abciximab. Combined major and minor bleeding occurred in 13% of those receiving cangrelor and in 8% in those randomized to placebo (P = non significant [NS]) during part 1 and in 7% receiving cangrelor compared with 10% randomized to abciximab (P = NS), during part 2. The 30-day composite incidence of adverse cardiac events was similar between those receiving cangrelor and those receiving abciximab during part 2 (7.6% vs 5.3%, respectively, P = NS). Mean inhibition of ex vivo platelet aggregation in response to 3 micromol/L ADP at steady state was 100% for both cangrelor 4 microg/kg per minute and abciximab groups in part 2. After termination of infusion, platelet aggregation returned to baseline response more rapidly with cangrelor compared with abciximab. There was a trend toward longer bleeding time prolongation and lower platelet count with abciximab compared with cangrelor. CONCLUSIONS: This initial experience with intravenous cangrelor during PCI suggests an acceptable risk of bleeding and adverse cardiac events while achieving rapid, reversible inhibition of platelet aggregation via competitive binding to the ADP P2Y12 platelet receptor with less prolongation of bleeding time then the glycoprotein IIb/IIIa receptor antagonist abciximab.