LVHV: Tadalafil in Pediatric patients with PAH
|Principal Investigator: Ronald Day|
|Keywords: Tadalafil , Pediatric , Pulmondary Arterial Hypertension||Department: Pediatric Administration|
|IRB Number: 00063669||Co Investigator:|
|Specialty: Pediatric Cardiology|
Currently no therapies are approved in the United States (US) for the treatment of children with pulmonary arterial hypertension (PAH). There is a growing body of evidence, however, supporting the use of therapies approved in the adult population with PAH, that has led to widespread off-label use in this pediatric population. There continues to be, however, a need for robust data to inform prescribing physicians regarding the safety and efficacy of all treatment options, including tadalafil, in the pediatric PAH population.
This is the first Phase 3 study of tadalafil for use in treating PAH in pediatric patients.
- For the United States (US) regulatory assessment, the primary objective of Period 1 is to evaluate the efficacy of tadalafil compared with placebo in improving 6-minute walk (6MW) distance from Baseline to Week 24, as assessed in a subset of patients ≥6 to <18 years of age who are developmentally capable of performing a 6MW test.
- For the European Union (EU) regulatory assessment, the primary objective of Period 1 is to evaluate the efficacy of tadalafil compared with placebo, as measured by time to clinical worsening (CW) in pediatric PAH patients through Week 24.
Period 2: The primary objective of Period 2 is to evaluate long-term safety of tadalafil while providing continued access to tadalafil for pediatric patients with PAH who participated in Period 1.
Period 1: The secondary objectives of Period 1 are as follows:
- Assess the efficacy of tadalafil compared with placebo on time to CW (for the US regulatory assessment) and the incidence of CW.
- Assess the efficacy of tadalafil compared with placebo on 6MW distance in a subset of patients ≥6 to <18 years of age who are developmentally capable of performing a 6MW test (for the EU regulatory assessment).
- Characterize the population pharmacokinetics (PK) of tadalafil in pediatric pulmonary arterial hypertension (PAH) patients.
- Assess the safety of tadalafil as compared with placebo.
Period 2: The secondary objective of Period 2 is to evaluate the incidence of, and time to CW.
Period 1: Additional objectives of Period 1 are as follows:
- Assess the efficacy of tadalafil compared with placebo on changes in World Health Organization (WHO) functional classification.
- Explore by cardiac magnetic resonance imaging (MRI), changes from Day 1 to Week 24 in the following cardiac MRI parameters:
- left-ventricular (LV) ejection fraction
- right-ventricular (RV) end diastolic volume
- RV end systolic volume
- RV ejection fraction
- Evaluate by echocardiography, changes from Day 1 to Week 24 in the following echocardiographic parameters:
- tricuspid annular plane systolic excursion (TAPSE)
- eccentricity index, pericardial effusion
- maximal tricuspid regurgitant velocity
Assess physician and caregiver-reported health outcome, as measured by Clinical Global Impression of Improvement (CGI-I), and in a subset of patients ≥5 years of age, Child Health Questionnaire Parent Form 28 (CHQ-PF28).
Evaluate change from Day 1 to Week 24 in N-terminal prohormone brain natriuretic peptide (NT-Pro-BNP) concentrations
- Diagnosis of PAH that is either:
- idiopathic, including hereditary;
- related to connective tissue disease;
- related to anorexigen use;
- associated with surgical repair of at least 6-month duration of simple congenital systemic to pulmonary shunt (eg, atrial septal defect, ventricular septal defect, patent ductus arteriosus)
- History of a diagnosis of PAH established by a resting mean pulmonary artery pressure (mPAP) greater than or equal to 25 mm Hg, pulmonary artery wedge pressure less than or equal to 15 mm Hg, and a pulmonary vascular resistance (PVR) greater than or equal to 3 Wood units via right heart catheterization (RHC). In the event that a pulmonary artery wedge pressure cannot be obtained during RHC, patients with a left ventricular end diastolic pressure (LVEDP) <15 mm Hg, with normal left heart function, and absence of mitral stenosis on echocardiography can be eligible for enrollment.
- Receiving an endothelin receptor antagonist (ERA, eg, bosentan or ambrisentan) and must be on a maintenance dose with no change in dose (other than weight-based adjustments) for at least 12 weeks prior to screening and have a screening aspartate transaminase (AST)/alanine transaminase (ALT) <3 times the upper limit of normal (ULN).
- If on conventional PAH medication, including but not restricted to, anticoagulants, diuretics, digoxin, and oxygen therapy, the patient must be on stable doses with no changes (other than weight-based adjustments) for at least 4 weeks before screening.
- Female patients of childbearing potential must test negative for pregnancy during screening.
- Female patients must agree to abstain from sexual activity or to use 2 different reliable methods of birth control as determined by the Investigator during the study.
Written informed consent from parents (and written assent from appropriately aged patients).
Pulmonary hypertension related to conditions other than specified above.
- History of left-sided heart disease, including any of the following:
- clinically significant (pulmonary artery occlusion pressure [PAOP] 15-18 mm Hg) aortic or mitral valve disease (i.e., aortic stenosis, aortic insufficiency, mitral stenosis, moderate or greater mitral regurgitation);
- pericardial constriction;
- restrictive or congestive cardiomyopathy;
- left ventricular ejection fraction < 40% by multigated radionucleotide angiogram (MUGA), angiography, or echocardiography;
- left ventricular shortening fraction < 22% by echocardiography;
- life-threatening cardiac arrhythmias;
- symptomatic coronary artery disease within 5 years of study entry.
- Unrepaired congenital heart disease.
- History of angina pectoris or other condition that was treated with long- or short-acting nitrates within 12 weeks before administration of study drug.
- Severe hepatic impairment, Child-Pugh Grade C.
- Severe renal insufficiency, defined as receiving renal dialysis or having a measured or estimated creatinine clearance (CC) <30 mL/min (Schwartz Formula).
- Retinal disorder (eg, hereditary retinal disorders, retinopathy of the preterm patient and other retinal disorders).
- Severe hypotension or uncontrolled hypertension as determined by the Investigator.
- Significant parenchymal lung disease or bronchopulmonary dysplasia.
- Concurrent phosphodiesterase type 5 (PDE5) inhibitor therapy (sildenafil or vardenafil) or has received PDE5 inhibitor therapy within 12 weeks prior to the first study drug dosing (Day 1, Visit 2).
- Concurrent therapy with prostacyclin or its analogues within 12 weeks of screening.
- Commenced or discontinued a chronic conventional PAH medication including but not restricted to: diuretics, anti-coagulants, digoxin, and oxygen therapy within 4 weeks of screening.
- Currently receiving treatment with doxazosin, nitrates, or cancer therapy.
- Current treatment with potent CYP3A4 inhibitors, such as antiretroviral therapy (protease inhibitor), systemic ketoconazole, or systemic itraconazole, or chronic use of potent CYP3A4 inducers, such as rifampicin.
- Nursing or pregnant.
- Received tadalafil therapy within 12 weeks prior to the first study drug dosing or are hypersensitive to tadalafil.
- Allergy to the excipients, notably lactose
- Unable to take orally administered tablets (without chewing, crushing or breaking) or suspension.
Diagnosis of Down syndrome.