fuel up! pd-5 inhibitor and exercise capacity in fontan...
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FUEL up! PD-5 inhibitor and exercise
capacity in Fontan patients. (The Fontan Udenafil Exercise Longitudinal Trial)
Stephen M Paridon, M.D.,
Professor of Pediatrics
Division of Cardiology, The Children’s Hospital of Philadelphia
The Perelman School of Medicine at the University of Pennsylvania
Disclosures
• I have no disclosures.
PD-5 inhibitor and exercise capacity in Fontan patients
Spring 2010
• The Phillies will go the World Series for the 3rd straight year.
• The Eagles are poised to return to the Super Bowl.
• I will beat Meryl Cohen and Chitra Ravishankar to Bob Shaddy’s office to explain why one of them, rather than me, should be the CHOP primary investigator on the next PHN grant cycle submission.
• None of these things happened.
• So, we needed a proposal for a multicenter interventional trial to submit with the renewal.
PD-5 inhibitor and exercise capacity in Fontan patients
When we think about medical therapies for the patient with Fontan palliation, we need to consider:
• Myocardial function.
• Atrio-ventricular and semilunar valve function.
• Physiology unique to the Fontan palliation.
• Acute versus chronic therapy.
PD-5 inhibitor and exercise capacity in Fontan patients
When dealing with myocardial and/or valvular dysfunction in single ventricle physiology, our default has been to use what is known from heart failure in adults with structurally normal hearts. The mainstays being remodeling agents including:
• Ace inhibitors
• Beta blockers
• Aldosterone antagonists
• Inotropic drugs
PD-5 inhibitor and exercise capacity in Fontan patients
However, it is becoming increasingly clear that a relatively
elevated pulmonary vascular resistance is a major mechanism
in both acute, and more importantly, chronic medical conditions
associated with Fontan physiology.
• Exercise intolerance.
• PLE/PB.
• Hepatic dysfunction.
• Renal dysfunction.
PD-5 inhibitor and exercise capacity in Fontan patients
Navaratnam et al: Am J Cardiol 2016;117:1667e1671
PD-5 inhibitor and exercise capacity in Fontan patients
Giardini et al,Ann Thorac Surg 2008;85:818 –22
PD-5 inhibitor and exercise capacity in Fontan patients
Diller et al: European Heart Journal (2010) 31, 3073–3083
PD-5 inhibitor and exercise capacity in Fontan patients
Atz et al: J Am Coll Cardiol. 2017
PD-5 inhibitor and exercise capacity in Fontan patients
So, do PDE-5 inhibitors make sense?
• Single dose studies show a significant drop in PVR.
• About a 5 to 10% increase in maximal VO2.
H. Mori et al. International Journal of Cardiology 221 (2016) 122–127
PD-5 inhibitor and exercise capacity in Fontan patients
So, do PDE-5 inhibitors make sense?
• Ventricular function.
• Peripheral vascular function.
• FALD.
• What about more chronic studies?
• SAFO.
PD-5 inhibitor and exercise capacity in Fontan patients
SAFO: An 18 week double blind, placebo controlled, cross-over trial of sildenafil in 28 children and adolescents.
Goldberg et al: Circulation. 2011;123:1185-1193
PD-5 inhibitor and exercise capacity in Fontan patients
Based on these data in the fall of 2011, the PHN approved the development of a phase III clinical trial of a PDE-5 inhibitor in asymptomatic Fontan subjects. We needed to know:
• The right protocol.
• The right endpoints.
• The right drug.
• The right number of sites.
• A three year multi-center trial assessing the rate of decline in %ed maximal VO2 in 12 to 18 year old Fontan subjects.
PD-5 inhibitor and exercise capacity in Fontan patients
The right drug: Fall 2011 to Fall 2012
• Sildenafil: no teenager is going to take a TID drug.
• Tadalafil:
• Udenafil: sometimes serendipity can be a wonderful thing, The beginning of a long relationship with Mezzion Pharma.
PD-5 inhibitor and exercise capacity in Fontan patients
Late 2012 to early 2016: Sand in the gears, or wouldn’t it be great to get a clinical indication and pediatric orphan drug status.
• We need a Phase I/II clinical trial to establish dosage.
• We need to involve the FDA.
• The cost of the study balloons several fold.
• Arranging a working interface between NHLBI and Mezzion Pharma- a first for the NIH.
PD-5 inhibitor and exercise capacity in Fontan patients
Phase I/II trial: early 2013 through late 2014. Five sites and 36 subjects with endpoints of safety and pharmacokinetics.
Goldberg et al: Am Heart J 2017;188:42-52.
PD-5 inhibitor and exercise capacity in Fontan patients
The FDA: Spring of 2014.
• Unrealistic protocol: change to a 6 month double bind placebo control trial with change in unindexed maximal VO2 as the primary endpoint.
• Additional safety monitoring at randomization and early in the follow up period.
• A follow on, one year open label extension trial to assess long term safety (FUEL/OLE).
• Special protocol assessment: fast tract to an indication.
• The clock starts to tick faster.
• Bring in the statisticians and lawyers.
PD-5 inhibitor and exercise capacity in Fontan patients
Sites and Stats:
• Due to FDA time constraints, recruitment time was limited to approximately 18 months.
• Need for relatively conservative power estimates: 400 subjects, randomized 1:1, blocked by site, stratified by sex and ventricular morphology.
• Based on surveys of potential subjects at PHN Core and Auxiliary sites, 24 sites in North America and the Republic of Korea were enlisted in the study.
PD-5 inhibitor and exercise capacity in Fontan patients
The end result is a 6 month study with a very busy first and last day.
PD-5 inhibitor and exercise capacity in Fontan patients
The end result is a 6 month study with a very busy first and last day.
At the FDA’s request, additional
in person visits at 2 weeks and
13 weeks to check heart rate
and blood pressure.
PD-5 inhibitor and exercise capacity in Fontan patients
Problems going forward:
• Final site approvals 08/2016.
• First subject randomized 08/20/2016.
• We missed our first summer enrollment window.
• Recruitment was slower than expected- many families were
put off by the 2 and 13 week in person visits.
PD-5 inhibitor and exercise capacity in Fontan patients
Creative work arounds:
• Visiting nurses to do home visits for the 2 and 13 week data collection.
• Petition the FDA to change the in person visits to telephone visits.
• Add 6 more auxiliary sites, bringing the total number of sites up to 30.
PD-5 inhibitor and exercise capacity in Fontan patients
Current status:
• Approximately 310 subjects randomized.
• Expected enrollment completion in February 2018.
• Largest clinical trial in the Fontan population.
• Data analysis to begin in late Summer of 2018.
• Report to the FDA early 2019.
• Decision by the FDA mid to late 2019.
PD-5 inhibitor and exercise capacity in Fontan patients
Next steps:
• Extended access enrollment.
• Younger ages.
• Different preparations- liquid, gel, intravenous.
• Combination therapies- Udenafil/aldosterone antagonist.
PD-5 inhibitor and exercise capacity in Fontan patients
Thank You.