Effect of dapagliflozin on the quality of life and exercise capacity of patients with amyloid transthyretin cardiac amyloidosis: a pilot, phase 2b study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Toscana Gabriele Monasterio

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

17 Nov 2023 → ongoing

Decision date (initial)

2023-06-23

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

to define the effect of dapagliflozin therapy on the exercise capacity of patients with ATTR-CA

Secondary objectives 4

1. to define the impact of dapagliflozin therapy on quality of life;
2. to define the impact of dapagliflozin therapy on NT-proBNP levels;
3. to define the impact of dapagliflozin therapy on the need for diuretic therapy;
4. establish the safety profile of dapagliflozin.

Conditions and MedDRA coding

ATTR Cardiac Amyloidosis

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Ability to understand and sign a written informed consent. The signature must be obtained before the start of the study procedures;
2. Age ≥18 and ≤90 years;
3. 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;
4. 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);
5. 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.

Exclusion criteria 27

1. 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;
2. Therapy with an SGLT2 inhibitor within 4 weeks prior to randomization or previous intolerance to an SGLT2 inhibitor;
3. Type 1 diabetes mellitus;
4. eGFR <25mL/min/1.73 m2 (CKD-EPI formula) at the time of screening;
5. Hypersensitivity to dapagliflozin or to any of the excipients listed in the Summary of Product Characteristics (SmPC);
6. 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;
7. 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;
8. Planned coronary revascularization, flutter ablation/atrial fibrillation and valve repair/replacement;
9. Stroke or transient ischemic attack within 12 weeks prior to enrollment;
10. 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);
11. Body mass index> 50 kg/m2;
12. Patient awaiting cardiac transplant, continuous intravenous infusion of an inotropic, carrier or awaiting ventricular assist device;
13. Valvular heart disease requiring a surgical or percutaneous intervention or surgery or percutaneous procedure for a valve disease during the previous 3 months;
14. Subject likely to die or undergo heart transplantation or implantation of a mechanical cardiac assist device within one year of screening;
15. Any etiological diagnosis other than ATTR-CA;
16. Enrollment in other interventional studies (drug or device) on ATTR amyloidosis;
17. Cardiomyopathy induced by uncontrolled tachycardia and / or tachyarrhythmia;
18. Symptomatic carotid stenosis, transient ischemic attack or stroke within 60 days;
19. Complex congenital heart disease;
20. Active endocarditis or constrictive pericarditis;
21. Severe liver disease (Child-Pugh class C);
22. Need for continuous home oxygen for severe lung disease;
23. Current alcohol and / or drug abuse;
24. Direct family member (e.g., spouse, parent/legal guardian, brother or child) involved in this study;
25. 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;
26. 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;
27. Failure to sign informed consent or inability to complete the procedures envisaged by the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Absolute change in 6 minute walking distance

Secondary endpoints 4

1. Proportion of patients experiencing a clinically significant increase in the Kansas City Cardiomyopathy Questionnaire overall summary score (≥5 points)
2. Proportion of patients with meaningful change in NT-proBNP (≥20% decrease);
3. Any decrease in diuretic dose;
4. Evaluate the safety profile of dapagliflozin, in terms of adverse events recorded, compared to the SOC.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione Toscana Gabriele Monasterio

Sponsor organisation

Fondazione Toscana Gabriele Monasterio

Address

Via Trieste 41

City

Pisa

Postcode

56126

Country

Italy

Scientific contact point

Organisation

Fondazione Toscana Gabriele Monasterio

Contact name

Stefania Biagini

Public contact point

Organisation

Fondazione Toscana Gabriele Monasterio

Contact name

Stefania Biagini

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications