Evaluation of Dapagliflozin on Exercise Capacity in Patients with Amyloid Transthyretin Cardiac Amyloidosis: A Phase 2b Pilot Study

Trial ID: 2023-504041-31-00
Protocol: DAMI
Sponsor: Fondazione Toscana Gabriele Monasterio

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Diseases & Conditions

Cardiac amyloidosis Acquired ATTR amyloidosis

Objectives

The primary objective of this study is to define the effect of **dapagliflozin** therapy on the exercise capacity of patients with ATTR Cardiac Amyloidosis (ATTR-CA). Evaluating exercise capacity is clinically relevant as it directly impacts the functional status and quality of life in patients with ATTR-CA, a condition characterized by the deposition of amyloid fibrils in the heart, leading to restrictive cardiomyopathy and heart failure symptoms.

Secondary objectives include:

Defining the impact of dapagliflozin therapy on quality of life, which is crucial for understanding the broader benefits of treatment beyond physiological measures.
Assessing the effect on NT-proBNP levels, a biomarker of cardiac stress, which can provide insights into the treatment's impact on cardiac function.
Evaluating the need for diuretic therapy, which may indicate changes in fluid management and heart failure symptoms.
Establishing the safety profile of dapagliflozin, ensuring that the benefits of therapy outweigh any potential risks.

Participants

The clinical trial focuses on patients diagnosed with **ATTR Cardiac Amyloidosis** (ATTR-CA), aiming to evaluate the impact of dapagliflozin therapy on their exercise capacity. The study population includes both male and female participants, aged between 18 and 90 years, who have an established diagnosis of either wild-type or variant ATTR-CA. Participants are required to have a history of heart failure, evidenced by at least one previous hospitalization or clinical signs of heart failure. The trial includes individuals who are on stable cardiovascular therapies, excluding diuretics, for at least two weeks prior to screening. The sponsor has not provided the total number of participants involved in the study. The trial population selection considers vulnerable groups, ensuring a comprehensive understanding of the therapy's effects across diverse demographics. Lifestyle factors such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the effect of **dapagliflozin** on the exercise capacity and quality of life in patients with ATTR Cardiac Amyloidosis. This is a pilot, phase 2b study, characterized by a randomized, double-blind, controlled trial design. The trial is expected to commence recruitment on June 1, 2023, and conclude by June 1, 2025. Participants will be administered Forxiga 10 mg film-coated tablets orally, with a maximum daily dose of 10 mg and a total treatment period of up to 3 months.

The study will involve several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of ATTR Cardiac Amyloidosis, and history of heart failure. Participants must be between 18 and 90 years old and have a confirmed diagnosis of wild-type or variant ATTR-CA. Following the screening, participants will undergo regular follow-up visits to monitor their response to the treatment and assess primary and secondary endpoints. The primary endpoint is the absolute change in the 6-minute walking distance, while secondary endpoints include changes in the Kansas City Cardiomyopathy Questionnaire score, NT-proBNP levels, diuretic dose adjustments, and the safety profile of dapagliflozin.

The expected duration of participant involvement is approximately 3 months, aligning with the maximum treatment period. Conditions that may lead to early termination from the study include significant adverse events or failure to adhere to the study protocol. The end-of-study visit will involve a comprehensive evaluation of the participant's health status and the collection of final data to assess the overall impact of the treatment. This trial aims to provide valuable insights into the therapeutic potential of dapagliflozin for patients with ATTR Cardiac Amyloidosis.

Treatment

The clinical trial involves the administration of **dapagliflozin**, marketed under the name Forxiga, as the experimental medication. Forxiga is formulated as **film-coated tablets** containing 10 mg of dapagliflozin, a chemical substance. The tablets are intended for **oral use**. The maximum daily dose is 10 mg, with a total maximum dose of 900 mg over the course of the study. The treatment period is limited to a maximum of 3 months. Dapagliflozin is classified under the ATC code A10BK01 and is not designated as an orphan drug. The pharmaceutical form and dosage are consistent with the standard marketing authorization provided by AstraZeneca AB in the European Union.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the effects of dapagliflozin on patients with amyloid transthyretin cardiac amyloidosis. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to assess the impact of dapagliflozin on the exercise capacity and quality of life of the participants.

Efficacy

Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoint is the absolute change in the 6-minute walking distance, which will be used to evaluate the effect of **dapagliflozin** on exercise capacity in patients with amyloid transthyretin cardiac amyloidosis (ATTR-CA). This measurement will provide a quantitative assessment of the improvement in physical endurance and functional capacity.

Secondary endpoints include several parameters: the proportion of patients experiencing a clinically significant increase in the Kansas City Cardiomyopathy Questionnaire overall summary score (defined as an increase of ≥5 points), the proportion of patients with a meaningful change in NT-proBNP levels (defined as a ≥20% decrease), and any decrease in diuretic dose. Additionally, the safety profile of **dapagliflozin** will be evaluated by recording adverse events compared to the standard of care (SOC). These secondary endpoints will provide a comprehensive evaluation of the therapeutic benefits and safety of the treatment.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Ability to understand and sign a written informed consent. The signature must be obtained before the start of the study procedures;
Age ≥18 and ≤90 years;
An established diagnosis of wild-type or variant ATTR-CA (confirmed by genotyping) based on (1) endomyocardial biopsy or (2) positive 99mTc-pyrophosphate or bisphosphonate scintigraphy (Perugini score 2-3), combined with the absence of a monoclonal component (based on both serum and / or urine immunofixation electrophoresis, and on the analysis of free light chains in serum); Subjects with concomitant monoclonal gammopathy of undetermined significance may require confirmation of the diagnosis of ATTR-CA by endomyocardial biopsy with mass spectrometric analysis. The correctness of the diagnosis of ATTR-CA will be confirmed by reviewing the data used to establish the diagnosis;
History of heart failure from at least one previous hospitalization for heart failure or clinical evidence of heart failure without prior hospitalization for heart failure manifested by signs or symptoms of volume overload or elevated intracardiac pressures (e.g., elevated jugular venous pressure, shortness of breath or signs of pulmonary congestion on x-ray or auscultation or peripheral edema);
Individuals taking cardiovascular therapies, with the exception of diuretic dosage, should take stable doses (defined as no more than a 50% dose adjustment and no changes in medication taken) for at least 2 weeks prior to screening.

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Exclusion Criteria

Clinically unstable at randomization, as defined by administering any IV treatment within 24 hours prior to randomization and/or systolic blood pressure (SBP) <100 mmHg or symptomatic hypotension;
Therapy with an SGLT2 inhibitor within 4 weeks prior to randomization or previous intolerance to an SGLT2 inhibitor;
Type 1 diabetes mellitus;
eGFR <25mL/min/1.73 m2 (CKD-EPI formula) at the time of screening;
Hypersensitivity to dapagliflozin or to any of the excipients listed in the Summary of Product Characteristics (SmPC);
Systolic blood pressure <95 mmHg, ≥160 mmHg (if not being treated with ≥3 blood pressure lowering drugs) or ≥180 mmHg (regardless of treatment) on 2 consecutive measurements at 5-minute intervals at the time of screening;
Myocardial infarction, unstable angina, coronary revascularization (percutaneous coronary intervention or coronary artery bypass graft), flutter ablation/atrial fibrillation, valve repair/replacement within 12 weeks prior to enrollment;
Planned coronary revascularization, flutter ablation/atrial fibrillation and valve repair/replacement;
Stroke or transient ischemic attack within 12 weeks prior to enrollment;
Likely alternative or concomitant diagnoses which, in the investigator's judgment, could explain the patient's symptoms and signs of heart failure (e.g., anemia, hypothyroidism);
Body mass index> 50 kg/m2;
Patient awaiting cardiac transplant, continuous intravenous infusion of an inotropic, carrier or awaiting ventricular assist device;
Valvular heart disease requiring a surgical or percutaneous intervention or surgery or percutaneous procedure for a valve disease during the previous 3 months;
Subject likely to die or undergo heart transplantation or implantation of a mechanical cardiac assist device within one year of screening;
Any etiological diagnosis other than ATTR-CA;
Enrollment in other interventional studies (drug or device) on ATTR amyloidosis;
Cardiomyopathy induced by uncontrolled tachycardia and / or tachyarrhythmia;
Symptomatic carotid stenosis, transient ischemic attack or stroke within 60 days;
Complex congenital heart disease;
Active endocarditis or constrictive pericarditis;
Severe liver disease (Child-Pugh class C);
Need for continuous home oxygen for severe lung disease;
Current alcohol and / or drug abuse;
Direct family member (e.g., spouse, parent/legal guardian, brother or child) involved in this study;
State of pregnancy and lactation, sexually active fertile women in the absence of highly effective methods of contraception, with low dependence on the user, from screening to a menstrual cycle after the last dose of the drug under study, which include: i. Abstinence; ii. Sexual intercourse only with people of the same sex; iii. Monogamous relationship with vasectomized partner; iv. Intrauterine device; v. Combined hormonal contraception containing estrogen and progestogen associated with the inhibition of ovulation (oral, intravaginal, transdermal); you. Hormonal contraception based on progestins only associated with the inhibition of ovulation (oral, injectable, implantable); vii. Hormone-releasing intrauterine system. The highly effective contraceptive measures mentioned above are not intended for surgically sterile patients (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or postmenopausal patients defined as 12 months of spontaneous amenorrhea without a different clinical cause and high levels of FSH in the expected postmenopausal interval. For patients who practice true abstinence or who have only same-sex partners, the use of contraception is not necessary, provided that this is in line with their preferred and usual lifestyle. Periodic abstinence (e.g., calendar method, ovulation, symptothermal or post-ovulation method) and interrupted coitus are not acceptable methods of contraception. In the event that this patient ceases to practice abstinence, he must use the contraceptive methods as described above. The status of pregnancy in women of childbearing potential will be verified by a blood test of human chorionic gonadotropin at the time of screening and repeated at the end of the study;
Participation in a study in which an investigational drug was administered within 30 days of screening or 5 half-lives of the study drug, whichever is longer;
Failure to sign informed consent or inability to complete the procedures envisaged by the study.