CardioPROTECTion With Dapagliflozin in Breast Cancer Patients Treated With AnthrAcycline - PROTECTAA TRIAL (PROTECTAA)

A Multicentre, Randomised, Double-blind, Placebo-controlled Phase III Study, Evaluating the Effect of Dapagliflozin on Prevention of Cardiotoxicity in Breast Cancer Patients Undergoing Anthracycline-based Chemotherapy

The purpose of this study is to evaluate the effect of dapagliflozin on the incidence of cancer therapeutics-related cardiac dysfunction in patients with breast cancer receiving anthracycline treatment.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Breast Cancer
• Intervention / Treatment: Drug: Dapagliflozin; Drug: Placebo

Detailed Description

This is a multicentre, randomised, double-blind, placebo-controlled phase III study, evaluating the effect of dapagliflozin versus placebo on prevention of cardiotoxicity in breast cancer patients undergoing anthracycline-based chemotherapy.

• Study Type: Interventional
• Enrollment (Estimated): 188
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Bartosz Krakowiak, PhD, MD; Phone Number: +48 261 660 234; Email: bkrakowiak@4wsk.pl

Study Locations

• Poland
  • Dolnośląskie
    • Wrocław, Dolnośląskie, Poland, 50-981
      • Recruiting
      • 4th Military Clinical Hospital with Polyclinic
      • Contact: Bartosz Krakowiak, PhD, MD; Phone Number: +48 261 660 234; Email: bkrakowiak@4wsk.pl
    • Wrocław, Dolnośląskie, Poland, 53-413
      • Recruiting
      • Lower Silesian Centre for Oncology, Lung Diseases and Hematology
      • Contact: Rafał Matkowski, PhD, MD
  • Mazowieckie
    • Warsaw, Mazowieckie, Poland, 04-141
      • Not yet recruiting
      • Military Medical Institute
      • Contact: Paweł Krzesiński, PhD, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age > 18 years and < 80 years.
• Diagnosis of invasive breast cancer [stage I-III] and planned anthracycline treatment within 60 days.
• Signed Informed Consent to participate in the study.

Exclusion Criteria:

• Urinary tract infection with the need for treatment with an antibiotic 48 hours before the scheduled start of anthracycline treatment.
• Recognised heart failure or symptoms which, in the opinion of the investigator may be a symptom of undiagnosed heart failure.
• Left ventricular ejection fraction < 50% at the time of the screening.
• Severe valvular heart disease.
• A history of clinically significant arrhythmia, including atrial fibrillation regardless of type (at discretion of the investigator).
• A history of stroke.
• Cardiomyopathy: congenital, post-inflammatory, toxic, infiltrative (e.g. amyloidosis, sarcoidosis, haemochromatosis), postnatal or hypertrophic.
• Pulmonary hypertension.
• Uncontrolled arterial pressure or systolic pressure < 80 mmHg at screening (at the discretion of the investigator).
• BMI > 40 kg/m2.
• Diagnosed type 1 or type 2 diabetes or fasting glucose ≥ 126 mg/dl or HbA1C ≥ 6,5% (48 mmol/mol).
• Pregnancy or breastfeeding.
• Lack of compliance to use highly effective method of birth control.
• Expected or possible treatment with epirubicin or liposomal doxorubicin within 12 months.
• Taking another study drug or drugs from the group of SGLT2 inhibitors up to 6 months before the screening visit.
• Taking semaglutide, liraglutide and metformin during the 30 days preceding the screening visit.
• eGFR < 25 ml/min/1.73m2 according to CKD EPI.
• Life expectancy < 12 months or cancer disease stage IV according to the TNM classification.
• Alanine transaminase or aspartate transaminase levels above 2.5 times the local norm.
• Anemia with Hemoglobin < 9 g/dl.
• Kidney failure > G2 (according to KDIGO classification).
• Liver disorders, Child-Pugh score > 4.
• Known, active infections with HIV, HBV, HCV, tuberculosis.
• Any other condition which, in the opinion of the investigator, makes it impossible to fulfill the requirements for participation in this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dapagliflozin; Dapagliflozin 10 mg tablet orally once daily for 12 months	Drug: Dapagliflozin; 10 mg tablet q.d; Other Names: Forxiga; Farxiga
Placebo Comparator: Placebo; Placebo tablet matching dapagliflozin orally once daily for 12 months	Drug: Placebo; tablet matching dapagliflozin 10 mg q.d

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary efficacy composite endpoint (cancer therapeutics related cardiac dysfunction) at 12 months.	Incidence of cancer therapeutics related cardiac dysfunction defined as: the appearance of heart failure symptoms (NYHA class I-IV) due to an impairment of heart function or structure within 12 months; or; asymptomatic decrease in left ventricular ejection fraction > 10% after 12 months; or; asymptomatic decrease in left ventricular ejection fraction < 10% but up to 40-49% after 12 months; or; asymptomatic decrease in global left ventricular longitudinal strain >15% after 12 months; or; asymptomatic increase in biomarkers (troponin I > upper reference limit (99th centile) and increase of at least 30% from pre-treatment concentration or NTproBNP > 125 pg/ml and increase of at least 30% from baseline) after 12 months.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary efficacy composite endpoint (cancer therapeutics related cardiac dysfunction) at 6 months.	Incidence of cancer therapeutics related cardiac dysfunction defined as: emergence of heart failure symptoms (NYHA class I-IV) due to impaired cardiac function or structure at 6 months; or; decrease LVEF > 10% after 6 months; or; decrease LVEF < 10% but to a value of 40-49% after 6 months; or; a decrease in global longitudinal strain of > 15% after 6 months; or; asymptomatic increase in biomarkers (troponin I > upper reference limit (99th centile) and an increase of at least 30% from pre-treatment concentration or NTproBNP >125pg/ml and an increase of at least 30% from baseline) after 6 months.	6 months
Change in left ventricular ejection fraction at 6 and 12 months.	Assessed by transthoracic echocardiography.	6 and 12 months
Change in left ventricular diastolic function at 6 and 12 months.	Assessed as the ratio of E/E', i.e. maximum mitral annular inflow velocity during the rapid ventricular filling phase, to maximum mitral annular motion velocity by tissue Doppler during the rapid ventricular filling phase.	6 and 12 months
Change in Troponin I after 6 and 12 months.	Secondary.	6 and 12 months
Change in NTproBNP levels at 6 and 12 months.	Secondary.	6 and 12 months
Quality of life at 6 and 12 months assessed using the five-dimensional EQ-5D questionnaire.	The EQ-5D questionnaire consists of two parts: descriptive one, which measures five dimensions of health (mobility, self care, usual activities, pain & discomfort, anxiety & depression) and EQ Visual Analogue Scale numbered from 0 to 100, where higher value indicate better self-reported health.	6 and 12 months
Occurrence of death from any cause.	Secondary safety endpoint.	13 months (additional 1 month of safety follow-up after end of treatment).
Composite endpoint of cardiovascular events.	Secondary safety endpoint. Occurrence of death from cardiovascular causes, nonfatal myocardial infarction, non-fatal stroke.	13 months (additional 1 month of safety follow-up after end of treatment).
Occurrence of death from any cardiovascular reasons.	Secondary safety endpoint.	13 months (additional 1 month of safety follow-up after end of treatment).
Occurrence of non-fatal myocardial infarction.	Secondary safety endpoint.	13 months (additional 1 month of safety follow-up after end of treatment).
Occurrence of non-fatal stroke.	Secondary safety endpoint.	13 months (additional 1 month of safety follow-up after end of treatment).
Occurrence of hypoglycaemia.	Secondary safety endpoint. Hypoglycaemia is defined as serum glucose level 3 mmol/l (<54 mg/dl) with coexisting related clinical symptoms.	13 months (additional 1 month of safety follow-up after end of treatment).
Occurrence of ionic disorders.	Secondary safety endpoint, defined as occurrence of: Sodium plasma level of >150 mmol/L; Potassium plasma level of >6.0 mmol/L	13 months (additional 1 month of safety follow-up after end of treatment).
Occurrence of renal failure.	Secondary safety endpoint. Defined as: sustained (i.e. >28 days) decline in eGFR ≥50% AND/OR; reaching end stage renal disease defined as:sustained (i.e. >28 days) eGFR <15 mL/min/1.73 m2chronic dialysis treatmentreceiving a renal transplant AND/OR; renal death	13 months (additional 1 month of safety follow-up after end of treatment).
Occurrence of hypersensitivity to investigated drug.	Secondary safety endpoint. Any unexpected adverse drug reaction (UADR).	13 months (additional 1 month of safety follow-up after end of treatment).
Occurrence of allergic reactions.	Secondary safety endpoint. Any hypersensitivity reaction with proven immunological pathomechanism (types I-IV according to Coombs and Gell).	13 months (additional 1 month of safety follow-up after end of treatment).
Occurrence of infection.	Secondary safety endpoint. Any symptomatic infection (viral, bacterial or fungal).	13 months (additional 1 month of safety follow-up after end of treatment).

Collaborators and Investigators

• Sponsor: 4th Military Clinical Hospital with Polyclinic, Poland
• Investigators: Principal Investigator: Waldemar Banasiak, PhD, MD, 4th Military Clinical Hospital with Polyclinic

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: October 9, 2023
• First Submitted That Met QC Criteria: March 8, 2024
• First Posted (Actual): March 12, 2024

Study Record Updates

• Last Update Posted (Actual): April 25, 2024
• Last Update Submitted That Met QC Criteria: April 24, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: breast cancer; heart failure; ejection fraction; anthracyclines
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Heart Failure; Breast Neoplasms; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: 2022/ABM/01/00039; 2023-506631-15-00 (Other Identifier: EUCT)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No