OverTTuRe (NCT06355934) is a retrospective, observational, longitudinal, multi‐country study that will extract de-identified secondary data from a broad spectrum of sources, including healthcare registries, electronic health records, chart reviews, disease registries, and insurance claims databases (Table 2). Enrichment of the data is planned by linking certain insurance claims databases, electronic health records, and disease registries to administrative databases.

The primary objectives are to describe contemporary clinical characteristics, treatment patterns, disease outcomes, and HRQoL in patients with ATTR amyloidosis and to quantify associated healthcare resource utilization (HCRU). The secondary objective is to describe the demographics, clinical characteristics, and HCRU of patients before diagnosis.

OverTTuRe aims to extract data for patients identified as having a diagnosis of ATTR amyloidosis with a pre-index lookback period of at least 12 months. The index date is defined as the earliest recorded date of an ATTR amyloidosis diagnosis or disease-specific therapy. To reduce the identification of patients with a false-positive test result, the current cohort identification algorithm has been iteratively refined, based on input from disease state experts and the use of proxy measures, to identify patients with ATTR amyloidosis and exclude those without such evidence. Inclusion and exclusion criteria for patients identified in clinical databases, chart reviews, and disease registries are presented in Table 3.

Cohorts will be segmented into phenotype and genotype subgroups, data permitting. The ATTR-CM phenotype will comprise patients with one or more ATTR amyloidosis diagnosis codes specifying ATTR-CM, one or more claims for tafamidis 61 mg, or one or more diagnosis codes for cardiac manifestations including (but not limited to) heart failure, cardiomyopathy, cardiac conduction disorder, arrhythmia, atrial fibrillation, aortic valve stenosis, and angina. The ATTR-PN phenotype will comprise patients with one or more ATTR amyloidosis diagnosis codes specifying ATTR-PN, or one or more claims for ATTR-specific therapies, or one or more diagnosis codes indicating neuropathy (mono-, poly-, or unknown) or other neurologic manifestations. Based on these rules, a mixed phenotype will comprise patients with ATTR-CM and ATTR-PN, and an unknown phenotype will comprise patients with neither ATTR-CM nor ATTR-PN. Cohorts will otherwise be segmented using the co-existence of cardiac- and neuropathy-related diagnoses as size estimations of the ATTR-CM, ATTR-PN, and mixed phenotype populations.

Data describing clinical characteristics, treatment patterns, disease outcomes, HCRU, and HRQoL will be collected from each country-specific data source where available. Patients will be observed from the start of the lookback period until exit from the database, death, or end of database period (whichever occurs first) (Fig. 1).

OverTTuRe study design. ATTR amyloid transthyretin, ATTR-CM ATTR amyloidosis with cardiomyopathy, ATTR-PN ATTR amyloidosis with polyneuropathy. aIndex date is the earliest recorded ATTR amyloidosis diagnosis or treatment (if ATTR-specific treatment has occurred earlier than the earliest diagnosis, then the earliest treatment date will be the index date). bExit from database, death, or end of the database period

Countries currently included in the OverTTuRe study are the United States, the United Kingdom, Japan, Sweden, Denmark, Spain, Canada, Germany, Italy, China, Portugal, and Brazil.

MaesTTRo (NCT06465810) is a prospective, observational, longitudinal, multi‐country study that will extract data from patient-reported outcome (PRO) questionnaires, electronic health records, and insurance claims (United States only).

The primary objectives are to describe the clinical characteristics and treatment patterns of patients with ATTR amyloidosis at baseline and longitudinally, and to assess the effectiveness of ATTR amyloidosis therapies on HRQoL, clinical outcomes, HCRU, and mortality. The secondary objectives are to compare the demographics and clinical characteristics of treated patients, and to conduct comparative effectiveness analyses of ATTR amyloidosis therapies. The exploratory objectives are to identify risk factors for ATTR amyloidosis disease progression and to describe HCRU and associated costs for patients with ATTR amyloidosis.

The MaesTTRo study enrollment will include a minimum of 1500 patients with ATTR-CM and a minimum of 100 patients with ATTRv-PN. Investigators at each site will enroll all consenting patients with a confirmed ATTR amyloidosis diagnosis who meet the eligibility criteria. Eligible patients aged ≥ 18 years of age with a confirmed diagnosis of ATTR amyloidosis (wild-type or hereditary genotype; PN, CM, or mixed phenotype), regardless of their ATTR amyloidosis therapy, will be included. Ineligible patients will be those with evidence of primary or secondary systemic amyloidosis, asymptomatic patients, or asymptomatic TTR mutation carriers (to exclude candidates for non-treatment), and patients participating in other interventional trials for ATTR amyloidosis.

Clinical characteristics, HCRU, and HRQoL data will be collected from electronic health records and PRO questionnaires every 6 (± 3) months and only during routine medical visits (Fig. 2). PRO questionnaires will include the 36-Item Short Form Health Survey version 2 (SF-36v2), the 35-item Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) instrument, and the 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ-23). Previous and current therapies for ATTR amyloidosis at the index date and during follow-up will be documented. Depending on the enrollment date, patients will be followed for 3–7 years from the index date or until the first occurrence of death, loss to follow-up, study withdrawal, or end of study. The countries to be included in the MaesTTRo study are the United States, the United Kingdom, Canada, Germany, Spain, and China.

MaesTTRo study design. ATTR amyloid transthyretin, eCRF electronic case report form, ePRO electronic patient-reported outcome, HCC healthcare cost, HCRU healthcare resource utilization, KCCQ-23 Kansas City Cardiomyopathy Questionnaire 23-item, Norfolk QOL-DN Norfolk Quality of Life-Diabetic Neuropathy, SF-36 36-item Short Form Health Survey. aHCRU up to 1 year before baseline. bFollow-up interval will be dependent on a patient’s routine medical visits. cCalculated using reported HCRU and available national costs

Descriptive statistics will be produced for all study measures for each country cohort. Categorial measures will be presented using frequency (number of patients [N]) and percentage (%), and continuous measures will be presented as the mean, standard deviation (SD), median, interquartile range (IQR), minimum, and maximum.

Stratification by clinical characteristics at index date, therapies, exposures, and other measures of interest will be conducted. Results across countries will be considered for meta-analysis contingent on the accrual of an adequate total cohort size. No formal sample size calculations will be performed. Missing values will not be imputed.

Comparative effectiveness analyses of ATTR amyloidosis therapies will be performed contingent upon a sufficient number of patients receiving a particular therapy. At which point, the possibility of performing sample size calculations will be revisited. Endpoints used to measure effectiveness in patients with ATTRv-PN will include survival, hospitalization, biomarker data (including neurofilament light chain levels), imaging results (including magnetic resonance neurography), HRQoL questionnaire answers, neuropathy impairment score, polyneuropathy disability scores, and familial amyloid polyneuropathy (Coutinho) scores. Endpoints used to measure effectiveness in patients with ATTR-CM will include B-type natriuretic peptide levels, echocardiography results, and 6-min walking test scores.

Both observational studies will adhere to ethical principles that are consistent with the 1964 Declaration of Helsinki and its later amendments, Good Clinical Practice (GCP) guidelines of the International Conference on Harmonization (ICH), Guidelines for Good Pharmacoepidemiology Practices (GPP), and applicable legislation on non-interventional and/or observational studies. The investigators will perform their duties in adherence with local regulations and guidelines governing medical practice and ethics. Local ethics approvals will be obtained for data use where necessary. Informed consent will be obtained from patients prior to enrollment in the prospective MaesTTRo study.