Repurposing Empagliflozin and Dapagliflozin for Paediatric Heart Failure: Translational Approach and Dose Rationale

NCT06012266 | Not Yet Recruiting Phase 2 DMC

• 2 other identifiers: 22HL332023-000441-16
• Study Type: interventional
• Target: 12
• Locations: 2 countries
• Sites: 3

Brief Summary

This study aims at exploring the use of Dapagliflozin and Empagliflozin in children and adolescents 6-18 years old with heart failure. These molecules are effective in reducing hospitalisations and mortality in adults with heart failure and are used in adolescents with type 2 diabetes mellitus, but little is known on children with heart failure. Particularly, the best dose to use in this population is currently unknown. This trial aims to:

1. 1.define a dose rationale for this indication and age group (pharmacokinetic study),
2. 2.assess and monitor safety,
3. 3.assess ease-of-swallow,
4. 4.explore middle-term (4-6 weeks) efficacy and efficacy markers.

Conditions

Heart Failure

Keywords

child

Outcome Measures

Primary Outcomes (3)

• Pharmacokinetics 1: Dapagliflozin, respectively Empagliflozin half-life

  This will be derived by pharmacokinetic analysis and modeling, basing on Dapagliflozin, respectively Empagliflozin, concentrations at the different time-points (5-6 samples \[according to weight\] at Visit 1, 1 opportunistic sample at Visits 2 and 3 for Drug A; 5-6 samples \[according to weight\] at Visit 3 and 1 opportunistic sample at Visit 4 for Drug B; the timing of the samples will be optimized with modeling \& simulation techniques).

  Visits 1-4 (Visit 1 = day 1, Visit 2 = week 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start)

• Pharmacokinetics 2: Dapagliflozin, respectively Empagliflozin Volume of distribution

  This will be derived by pharmacokinetic analysis and modeling, basing on Dapagliflozin, respectively Empagliflozin, concentrations at the different time-points (5-6 samples \[according to weight\] at Visit 1, 1 opportunistic sample at Visits 2 and 3 for Drug A; 5-6 samples \[according to weight\] at Visit 3 and 1 opportunistic sample at Visit 4 for Drug B; the timing of the samples will be optimized with modeling \& simulation techniques).

  Visits 1-4 (Visit 1 = day 1, Visit 2 = week 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start)

• Pharmacokinetics 3: Dapagliflozin, respectively Empagliflozin AUC

  This will be derived by pharmacokinetic analysis and modeling, basing on Dapagliflozin, respectively Empagliflozin, concentrations at the different time-points (5-6 samples \[according to weight\] at Visit 1, 1 opportunistic sample at Visits 2 and 3 for Drug A; 5-6 samples \[according to weight\] at Visit 3 and 1 opportunistic sample at Visit 4 for Drug B; the timing of the samples will be optimized with modeling \& simulation techniques).

  Visits 1-4 (Visit 1 = day 1, Visit 2 = week 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start)

Secondary Outcomes (10)

• Safety 1 - eGFR

  Visits 1-4 (Visit 1 = day 1, Visit 2 = week 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start)

• Safety 2 - Occurrence of hypoglycemia

  Visits 1-4 (Visit 1 = day 1, Visit 2 = week 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start)

• Safety 3 - Occurrence of ketoacidosis

  Visits 1-4 (Visit 1 = day 1, Visit 2 = week 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start)

• Ease-of-swallow

  Visit 1, Visit 3 (Visit 1 = day 1, Visit 3 = week 3 to 5 after study start)

• Efficacy and efficacy markers (exploratory) 1 - Heart failure severity class

  Visits 1, 3 and 4 (Visit 1 = day 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start)

Other Outcomes (6)

• Efficacy markers (exploratory), Mechanistic insights - 1: body weight (kg)

  Visit 1, Visit 4 (Visit 1 = day 1, Visit 4 = week 4 to 6 after study start)

• Efficacy markers (exploratory), Mechanistic insights - 2: heart rate (bpm)

  Visit 1, Visit 4 (Visit 1 = day 1, Visit 4 = week 4 to 6 after study start)

• Efficacy markers (exploratory), Mechanistic insights - 3: blood pressure (SBP/DBP, mmHg)

  Visit 1, Visit 4 (Visit 1 = day 1, Visit 4 = week 4 to 6 after study start)

Study Arms (2)

Group A: Dapagliflozin first, Empagliflozin second

ACTIVE COMPARATOR

Patients randomized to Group A will start with Dapagliflozin on Visit 1 and take Dapagliflozin once daily up to the day before Visit 3. On the day of Visit 3, they will switch to Empagliflozin once daily, to be continued up to the day preceding Visit 4.

Drug: Dapagliflozin tablet; Drug: Empagliflozin Tablets

Group B: Empagliflozin first, Dapagliflozin second

ACTIVE COMPARATOR

Patients randomized to Group B will start with Empagliflozin on Visit 1 and take Empagliflozin once daily up to the day before Visit 3. On the day of Visit 3, they will switch to Dapagliflozin once daily, to be continued up to the day preceding Visit 4.

Drug: Dapagliflozin tablet; Drug: Empagliflozin Tablets

Interventions

Dapagliflozin tablet DRUG

Patients randomized to Group A will start with Dapagliflozin on Visit 1 and take Dapagliflozin once daily up to the day before Visit 3. Patients randomized to Group B will start Dapagliflozin once daily on the day of Visit 3, to be continued up to the day preceding Visit 4. Dose: * participants ≤12 year old: 5mg once daily p.o. (commercially available tablet) * participants \>12 year old: 10mg once daily p.o. (commercially available tablet)

Group A: Dapagliflozin first, Empagliflozin second; Group B: Empagliflozin first, Dapagliflozin second

Empagliflozin Tablets DRUG

Patients randomized to Group A will start with Empagliflozin on Visit 1 and take Empagliflozin once daily up to the day before Visit 3. Patients randomized to Group B will start Empagliflozin once daily on the day of Visit 3, to be continued up to the day preceding Visit 4. Dose: Empagliflozin 10mg once daily p.o. (commercially available tablet)

Group A: Dapagliflozin first, Empagliflozin second; Group B: Empagliflozin first, Dapagliflozin second

Eligibility Criteria

• Age: 6 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Currently on heart failure medication (any drug or any combination).
• Patients should potentially benefit from adding a SGLT2i (as judged by the treating physician and the local PI or Co-PI).
• Patients need to be on stable medical treatment, defined as no new heart failure drug started over the preceding 2 weeks and no major drug dose modification (apart minor adaptations, like weight adaptations, rounding or formulation changes) during the 2 weeks prior to enrolment.
• Adolescents, respectively parents or caregivers of children, capable of giving informed consent.

You may not qualify if:

• Inability to understand and go through the informed consent procedure.
• Inability to receive medications per os or through a nasogastric tube.
• Type 1 Diabetes mellitus or any underlying metabolic disease associated with hypoglycaemias.
• Body weight \<13kg.
• Current smokers (defined as \>1 cigarette/week).
• Use of any other nicotine-delivering product (e.g. nicotine patches).
• Any known illicit drug abuse.
• Active chronic HBV, HCV or HIV.
• Any major surgery within 4 weeks of first dose administration.
• Blood transfusion recipient within 4 weeks of dose administration.
• eGFR =\<45mL/min/1.73m2 (simplified Schwartz formula).
• K+ \>6.5mmol/L.
• Blood glucose \<4mmol/L.
• Sustained or symptomatic arrhythmia insufficiently controlled with drug and/or device therapy.
• Cardio-surgical procedure within the 2 months prior to Visit 1, or interventional cardiac catheterization within 2 weeks prior to Visit 1, or the patient is planned to undergo cardiac surgery or an interventional cardiac catheterization during the study period (i.e. in the 6 weeks following Visit 1).

Sponsors & Collaborators

• Centre Hospitalier Universitaire Vaudois: lead
• Great Ormond Street Hospital for Children NHS Foundation Trust: collaborator
• University College, London: collaborator

Study Sites (3)

Centre Hospitalier Universitaire Vaudois (CHUV)

Lausanne, Canton of Vaud, 1011, Switzerland

Location

University College London

London, Greater London, WC1H 9JP, United Kingdom

Location

Great Ormond Street Hospital NHS Foundation Trust

London, Greater London, WC1N 3JH, United Kingdom

Location

Related Publications (18)

• Das BB. Current State of Pediatric Heart Failure. Children (Basel). 2018 Jun 28;5(7):88. doi: 10.3390/children5070088.

  PMID: 29958420 BACKGROUND

• Rossano JW, Kim JJ, Decker JA, Price JF, Zafar F, Graves DE, Morales DL, Heinle JS, Bozkurt B, Towbin JA, Denfield SW, Dreyer WJ, Jefferies JL. Prevalence, morbidity, and mortality of heart failure-related hospitalizations in children in the United States: a population-based study. J Card Fail. 2012 Jun;18(6):459-70. doi: 10.1016/j.cardfail.2012.03.001. Epub 2012 Apr 10.

  PMID: 22633303 BACKGROUND

• Ahmed H, VanderPluym C. Medical management of pediatric heart failure. Cardiovasc Diagn Ther. 2021 Feb;11(1):323-335. doi: 10.21037/cdt-20-358.

  PMID: 33708503 BACKGROUND

• Andrews RE, Fenton MJ, Dominguez T, Burch M; British Congenital Cardiac Association. Heart failure from heart muscle disease in childhood: a 5-10 year follow-up study in the UK and Ireland. ESC Heart Fail. 2016 Jun;3(2):107-114. doi: 10.1002/ehf2.12082. Epub 2016 Jan 24.

  PMID: 27812385 BACKGROUND

• Newland DM, Law YM, Albers EL, Friedland-Little JM, Ahmed H, Kemna MS, Hong BJ. Early Clinical Experience with Dapagliflozin in Children with Heart Failure. Pediatr Cardiol. 2023 Jan;44(1):146-152. doi: 10.1007/s00246-022-02983-0. Epub 2022 Aug 10.

  PMID: 35948644 BACKGROUND

• Towbin JA, Lowe AM, Colan SD, Sleeper LA, Orav EJ, Clunie S, Messere J, Cox GF, Lurie PR, Hsu D, Canter C, Wilkinson JD, Lipshultz SE. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA. 2006 Oct 18;296(15):1867-76. doi: 10.1001/jama.296.15.1867.

  PMID: 17047217 BACKGROUND

• McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Belohlavek J, Bohm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukat A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjostrand M, Langkilde AM; DAPA-HF Trial Committees and Investigators. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019 Nov 21;381(21):1995-2008. doi: 10.1056/NEJMoa1911303. Epub 2019 Sep 19.

  PMID: 31535829 BACKGROUND

• Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Bohm M, Choi DJ, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F; EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020 Oct 8;383(15):1413-1424. doi: 10.1056/NEJMoa2022190. Epub 2020 Aug 28.

  PMID: 32865377 BACKGROUND

• Authors/Task Force Members:; McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, Burri H, Butler J, Celutkiene J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GMC, Ruschitzka F, Kathrine Skibelund A; ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2022 Jan;24(1):4-131. doi: 10.1002/ejhf.2333.

  PMID: 35083827 BACKGROUND

• Cella M, Knibbe C, Danhof M, Della Pasqua O. What is the right dose for children? Br J Clin Pharmacol. 2010 Oct;70(4):597-603. doi: 10.1111/j.1365-2125.2009.03591.x. No abstract available.

  PMID: 21087295 BACKGROUND

• Benjamin DK Jr, Smith PB, Jadhav P, Gobburu JV, Murphy MD, Hasselblad V, Baker-Smith C, Califf RM, Li JS. Pediatric antihypertensive trial failures: analysis of end points and dose range. Hypertension. 2008 Apr;51(4):834-40. doi: 10.1161/HYPERTENSIONAHA.107.108886. Epub 2008 Mar 10.

  PMID: 18332283 BACKGROUND

• European Union. Ethical considerations for clinical trials on medicinal products conducted with the paediatric population. Eur J Health Law. 2008 Jul;15(2):223-50. doi: 10.1163/157180908x333228.

  PMID: 18988606 BACKGROUND

• Bellanti F, Della Pasqua O. Modelling and simulation as research tools in paediatric drug development. Eur J Clin Pharmacol. 2011 May;67 Suppl 1(Suppl 1):75-86. doi: 10.1007/s00228-010-0974-3. Epub 2011 Jan 19.

  PMID: 21246352 BACKGROUND

• Bellanti F, Di Iorio VL, Danhof M, Della Pasqua O. Sampling Optimization in Pharmacokinetic Bridging Studies: Example of the Use of Deferiprone in Children With beta-Thalassemia. J Clin Pharmacol. 2016 Sep;56(9):1094-103. doi: 10.1002/jcph.708. Epub 2016 Apr 1.

  PMID: 26785826 BACKGROUND

• Lava SA, Simonetti GD, Bianchetti AA, Ferrarini A, Bianchetti MG. Prevention of vitamin D insufficiency in Switzerland: a never-ending story. Int J Pharm. 2013 Nov 30;457(1):353-6. doi: 10.1016/j.ijpharm.2013.08.068. No abstract available.

  PMID: 24216246 BACKGROUND

• Braunwald E. Gliflozins in the Management of Cardiovascular Disease. N Engl J Med. 2022 May 26;386(21):2024-2034. doi: 10.1056/NEJMra2115011. No abstract available.

  PMID: 35613023 BACKGROUND

• Zelniker TA, Braunwald E. Mechanisms of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020 Feb 4;75(4):422-434. doi: 10.1016/j.jacc.2019.11.031.

  PMID: 32000955 BACKGROUND

• Joshi SS, Singh T, Newby DE, Singh J. Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure. Heart. 2021 Jun 11;107(13):1032-1038. doi: 10.1136/heartjnl-2020-318060.

  PMID: 33637556 BACKGROUND

MeSH Terms

Conditions

Heart Failure

Interventions

dapagliflozin; empagliflozin

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Study Officials

• Sebastiano A.G. Lava, MD MSc

  Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sebastiano A.G. Lava, MD MSc

CONTACT

+41 21 314 3556; webmaster@sebastianolava.ch

Craig Laurence, MD

CONTACT

craig.laurence@gosh.nhs.uk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator, "Chef de clinique"

Model Details: Order of drug intake will be balanced and randomized, with 6 patients starting with Dapagliflozin (Visits 1-2) and subsequently switching to Empagliflozin (Visits 3-4), and 6 patients starting with Empagliflozin (Visits 1-2) and subsequently switching to Dapagliflozin (Visits 3-4).

Study Record Dates

• First Submitted: August 4, 2023
• First Posted: August 25, 2023
• Study Start: August 1, 2024
• Primary Completion: August 1, 2025
• Study Completion: August 1, 2025
• Last Updated: February 7, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

CH (1); GB (2)