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

Heart Failure Clinical Trial

Official title:

Dose Rationale for Dapagliflozin and Empagliflozin in Paediatric Heart Failure: a Phase II.a Pharmacokinetics, Ease-of-swallow, Safety and Proof-of-concept Study Among Children 6-18 Years of Age

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06012266
• Other study ID #: 22HL33
• Secondary ID: 2023-000441-16
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: August 2024
• Est. completion date: August 2025

Study information

• Verified date: February 2024
• Source: Centre Hospitalier Universitaire Vaudois
• Contact: Sebastiano A.G. Lava, MD MSc
• Phone: +41 21 314 3556
• Email: webmaster[@]sebastianolava.ch
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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. define a dose rationale for this indication and age group (pharmacokinetic study),

2. assess and monitor safety,

3. assess ease-of-swallow,

4. explore middle-term (4-6 weeks) efficacy and efficacy markers.

Participants will be asked to attend 4 study visits over 4-6 weeks, and one end-study visit 2-12 weeks thereafter. Visits 1 and 3 will entail an 8h day-hospital stay, while Visits 2, 4 and the end-study visit will be outpatient clinics (approximately 2h). Participants will be asked to take the studied drug once daily during the 4-6 weeks of the study period.

All participants will take both Dapagliflozin and Empagliflozin: 6 will start with Dapagliflozin first (Visits 1-2) and then switch to Empagliflozin (Visits 3-4), while 6 will start with Empagliflozin first (Visits 1-2) and then switch to Dapagliflozin (Visits 3-4). No comparison group is foreseen for this study.

Description:

Paediatric heart failure is a relevant healthcare issue, with almost 15'000 yearly hospitalizations just in the USA. Sadly, current heart failure therapy in Paediatrics is still unsatisfactory, with high in-hospital (7-26%), and 5-year mortality (30%-50%).

Among the recent improvements in adult heart failure management, impressive is the discovery that Dapagliflozin and Empagliflozin are able to reduce cardiovascular death or worsening heart failure by 25% on top of optimal medical therapy. Indeed, since 2021, they have been recommended as part of standard heart failure therapy.

In the past, paediatric heart failure trials often failed, mainly because of suboptimal dose or inappropriate formulations and endpoints.

This phase II.a, cross-over, open-label trial is designed to characterize pharmacokinetics (primary outcome), palatability, safety and explore potential efficacy markers (secondary outcomes) of Dapagliflozin and Empagliflozin in 12 heart failure children, so to inform the design and performance of subsequent, state-of-the-art, high-quality efficacy trials.

Participants will first receive Drug A (either Dapagliflozin, n=6, or Empagliflozin, n=6) during 3-5 weeks, followed by the other molecule (Drug B) for 2 weeks. They will have 4 visits, one end-study visit and 11-15 pharmacokinetic samples (depending on their weight). The timing of these samples will be optimized exploiting contemporary modeling and simulation techniques.

Safety evaluation will occur throughout the study, while palatability will be evaluated at Visits 1 (Drug A) and 3 (Dug B), and efficacy markers at Visits 1, 3 and 4.

Pharmacokinetic modeling will characterize primary and secondary pharmacokinetic parameters and allow to define the optimal paediatric dose, informing both current compassionate-care use and the design of future efficacy trials.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 12
• Est. completion date: August 2025
• Est. primary completion date: August 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 18 Years

Eligibility

Inclusion Criteria:

• Children 6 to 18 years of age, followed either as in- or outpatients at the Heart failure unit, Great Ormond Street Hospital NHS Foundation Trust, London or at the Paediatric Cardiology Unit, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University Hospital, Lausanne, Switzerland will be eligible for inclusion.

• 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.

Exclusion Criteria:

• Inability to understand and go through the informed consent procedure.

• Inability to receive medications per os or through a nasogastric tube.

• Patients on either Insulin or Metformin will be excluded from participation. This implies the exclusion of patients with Diabetes mellitus (either type 1 or type 2 or other rare forms) necessitating either insulin or metformin.

• 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.

• There are no blood pressure exclusion criteria foreseen, but participants need to be haemodynamically stable, as assessed by the local investigator (board-certified paediatric cardiologist).

• 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).

• Post-menarchal female patients of childbearing potential cannot be included.

• Known lactose intolerance, galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.

• Known allergies to excipients of either Dapagliflozin or Empagliflozin.

• Significant medical history of active severe medical disease.

• Significant liver disease, Child Pugh Class C, or significant laboratory abnormalities at enrolment.

• Significant gastroenterological or hepatic disease that could significantly impair absorption or metabolism of orally administered drugs.

• Any medical co-morbidity, which is deemed incompatible (or only with relevant risk) with study participation by the treating clinician and/or the study investigator.

• Active urinary tract infection (being treated with antibiotics at the moment of Visit 1) or other relevant bacterial infection, as judged by the treating clinician and/or the study investigator.

• The patient is currently participating in another interventional clinical trial or has participated in such a trial during the <14 days before Visit 1 (or if enrolment in this study is incompatible with the protocol of that preceding trial).

Related Conditions & MeSH terms

• Heart Failure

Intervention

Drug:
• Dapagliflozin tablet
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)
• Empagliflozin Tablets
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)

Locations

Country	Name	City	State
Switzerland	Centre Hospitalier Universitaire Vaudois (CHUV)	Lausanne	VD
United Kingdom	Great Ormond Street Hospital NHS Foundation Trust	London	Greater London
United Kingdom	University College London	London	Greater London

Sponsors (3)

Lead Sponsor	Collaborator
Centre Hospitalier Universitaire Vaudois	Great Ormond Street Hospital for Children NHS Foundation Trust, University College, London

Countries where clinical trial is conducted

Switzerland,  United Kingdom, 

References & Publications (18)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

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. — View Citation

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. Erratum In: Heart. 2021 Nov;107(22):e15. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Erratum In: J Am Coll Cardiol. 2020 Sep 22;76(12):1505. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Efficacy markers (exploratory), Mechanistic insights - 1: body weight (kg)	To explore the effect of SGLT2 inhibitors on fluid status, body weight will be assessed (outcome: change between Visit 1 and Visit 4).	Visit 1, Visit 4 (Visit 1 = day 1, Visit 4 = week 4 to 6 after study start)
Other	Efficacy markers (exploratory), Mechanistic insights - 2: heart rate (bpm)	To explore the effect of SGLT2 inhibitors on sympathetic activation, heart rate (in bpm) will be assessed (outcome: change between Visit 1 and Visit 4).	Visit 1, Visit 4 (Visit 1 = day 1, Visit 4 = week 4 to 6 after study start)
Other	Efficacy markers (exploratory), Mechanistic insights - 3: blood pressure (SBP/DBP, mmHg)	To explore the effect of SGLT2 inhibitors on sympathetic activation, blood pressure (SBP and DBP, in mmHg) will be assessed (outcome: change between Visit 1 and Visit 4).	Visit 1, Visit 4 (Visit 1 = day 1, Visit 4 = week 4 to 6 after study start)
Other	Efficacy markers (exploratory), Mechanistic insights - 4: b-hydroxybutyrate (mmol/L)	To explore the effect of SGLT2 inhibitors on metabolism shift, b-hydroxybutyrate will be assessed (outcome: change between Visit 1 and Visit 4).	Visit 1, Visit 4 (Visit 1 = day 1, Visit 4 = week 4 to 6 after study start)
Other	Efficacy markers (exploratory), Mechanistic insights - 5: haemoglobin (g/L)	To explore the effect of SGLT2 inhibitors on haemoglobin, haemoglobin will be assessed (outcome: change between Visit 1 and Visit 4).	Visit 1, Visit 4 (Visit 1 = day 1, Visit 4 = week 4 to 6 after study start)
Other	Efficacy markers (exploratory), Mechanistic insights - 6: uric acid (mmol/L)	To explore the effect of SGLT2 inhibitors on uric acid homeostasis, uric acid will be assessed (outcome: change between Visit 1 and Visit 4).	Visit 1, Visit 4 (Visit 1 = day 1, Visit 4 = week 4 to 6 after study start)
Primary	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)
Primary	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)
Primary	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	Safety 1 - eGFR	Creatinine (respectively Cystatin C in DMD participants) will be collected in order to calculate eGFR (bedside Schwartz formula, respectively Filler equation).	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	Safety 2 - Occurrence of hypoglycemia	Blood glucose will be checked three times at Visit 1 and Visit 3 (baseline, at the time of 2nd PK sampling, which will be individualized but will be at approximately 2-3h post-intake, and before discharge at 8h post-intake), as well as once at Visits 2 and 4 (together with PK sampling). Outcome measure: number of patients experiencing 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)
Secondary	Safety 3 - Occurrence of ketoacidosis	The outcome is presence (or absence) of ketoacidosis. This will be assessed at Visits 1, 2, 3, and 4. Outcome measure: number of patients experiencing 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)
Secondary	Ease-of-swallow	Ease of swallow will be assessed by means of facial hedonic scales, according to our standard procedure, at Visit 1 (Drug A), and Visit 3 (Drug B). (Scale 1 to 4, 1 being the worse and 4 the best score: very difficult - difficult - possible - easy to swallow.)	Visit 1, Visit 3 (Visit 1 = day 1, Visit 3 = week 3 to 5 after study start)
Secondary	Efficacy and efficacy markers (exploratory) 1 - Heart failure severity class	Symptoms, clinical signs, NYHA (if >8 years of age) / Ross (if <8 years of age) class assignment. NYHA and Ross heart failure classes share the same scale of I (no limitation of physical activity) to IV (symptoms at rest). Analysis will be performed at Visit 1, Visit 3 and Visit 4. Outcome: change between Visit 1 and Visit 4.	Visits 1, 3 and 4 (Visit 1 = day 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start)
Secondary	Efficacy and efficacy markers (exploratory) 2 - NT-proBNP level	Analysis will be performed at Visits 1, 3 and 4. Outcome: change between Visit 1 and Visit 4.	Visits 1, 3 and 4 (Visit 1 = day 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start)
Secondary	Efficacy and efficacy markers (exploratory) 3 - Echocardiography 1: Left-ventricular end-diastolic diameter (LVEDd)	LVEDd (mm) will be measured at Visits 1, 3 and 4. Outcome: change between Visit 1 and Visit 4.	Visits 1, 3 and 4 (Visit 1 = day 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start)
Secondary	Efficacy and efficacy markers (exploratory) 4 - Echocardiography 2: Left-ventricular end-systolic diameter (LVESd)	LVESd (mm) will be measured at Visits 1, 3 and 4. Outcome: change between Visit 1 and Visit 4.	Visits 1, 3 and 4 (Visit 1 = day 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start)
Secondary	Efficacy and efficacy markers (exploratory) 5 - Echocardiography 3: Fractional shortening (FS)	FS (%) will be measured at Visits 1, 3 and 4. Outcome: change between Visit 1 and Visit 4.	Visits 1, 3 and 4 (Visit 1 = day 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start)
Secondary	Efficacy and efficacy markers (exploratory) 6 - Echocardiography 4: Left ventricular ejection fraction (LV-EF)	LV-EF (%) will be measured at Visits 1, 3 and 4. Outcome: change between Visit 1 and Visit 4.	Visits 1, 3 and 4 (Visit 1 = day 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start)