A Study of Tadalafil in Pediatric Participants With Pulmonary Arterial Hypertension (PAH)
Condition: Hypertension, Pulmonary
MeSH terms: Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Hypertension
Intervention: Tadalafil; Placebo; ERA as specific PAH treatment
Intervention description: Administered orally by tablet form for heavy and middle weight participants. Administered orally by suspension for light weight participants.; Administered orally by tablet for heavy and middle weight participants. Administered orally by suspension for light weight participants.; All participants were taking endothelin receptor antagonist (ERA) (such as bosentan, ambrisentan and macitentan).
Intervention MeSH terms: Tadalafil
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 35.0
Sex: All
Minimum age: 6 Months
Maximum age: 17 Years
Healthy volunteers: No

Summary:

      The main purpose of this study is to evaluate the safety and efficacy of tadalafil in
      pediatric participants with pulmonary arterial hypertension. Participants will receive study
      treatment for 6 months in the double-blind period (Period 1), and then will be eligible to
      enroll into an open-label 2 year extension period (Period 2) during which participants will
      receive tadalafil.
    

Eligibility criteria:

        Inclusion Criteria:

          -  ≥6 months to <18 years of age at screening

          -  Currently have a 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 congenital
                  systemic to pulmonary shunt (eg, atrial septal defect, ventricular septal defect,
                  patent ductus arteriosus)

          -  Have a history of a diagnosis of PAH established by a resting mean pulmonary artery
             pressure (mPAP) ≥25 millimeter of mercury (mm Hg), pulmonary artery wedge pressure ≤15
             mm Hg, and a pulmonary vascular resistance (PVR) ≥3 Wood units via right heart
             catheterization (RHC). In the event that a pulmonary artery wedge pressure cannot be
             obtained during RHC, participants 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

          -  Have a World Health Organization (WHO) functional class value of II or III at the time
             of screening

          -  All participants must be receiving an endothelin receptor antagonist (ERA) (such as
             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 participant must be on stable doses with
             no changes (other than weight-based adjustments) for at least 4 weeks before screening

          -  Female participants of childbearing potential must test negative for pregnancy during
             screening. Furthermore, female participants must agree to abstain from sexual activity
             or to use two different reliable methods of birth control as determined by the
             Investigator during the study. Examples of reliable birth control methods include true
             abstinence as a lifestyle choice (periodic sexual abstinence method is not
             acceptable); the use of oral contraceptives; a reliable barrier method of birth
             control (diaphragms with contraceptive jelly; cervical caps with contraceptive jelly;
             condoms with contraceptive foam; intrauterine devices)

          -  Written informed consent from parents (and written assent from appropriately aged
             participants) will be obtained prior to any study procedure being performed

        Exclusion Criteria:

          -  Have pulmonary hypertension related to conditions other than specified above,
             including but not limited to chronic thromboembolic disease, portal pulmonary
             hypertension, left-sided heart disease or lung disease and hypoxia

          -  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 (ie, 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

          -  Have a history of angina pectoris or other condition that was treated with long- or
             short-acting nitrates within 12 weeks before administration of study drug

          -  Have severe hepatic impairment, Child-Pugh Grade C

          -  Have severe renal insufficiency, defined as receiving renal dialysis or having a
             measured or estimated creatinine clearance (CC) <30 millimeter per minute (mL/min)
             (Schwartz Formula)

          -  Diagnosed with a retinal disorder (eg, hereditary retinal disorders, retinopathy of
             the preterm participant and other retinal disorders)

          -  Have severe hypotension or uncontrolled hypertension as determined by the Investigator

          -  Have significant parenchymal lung disease

          -  Have 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

          -  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 Cytochrome P450 3A4 (CYP3A4) inhibitors, such as
             antiretroviral therapy (protease inhibitor), systemic ketoconazole, or systemic
             itraconazole, or chronic use of potent CYP3A4 inducers, such as rifampicin

          -  Are nursing or pregnant

          -  Have previously completed or withdrawn from this study (LVHV), or any other study
             investigating tadalafil

          -  Have received tadalafil therapy within 12 weeks prior to the first study drug dosing
             or are hypersensitive to tadalafil

          -  Have allergy to the excipients, notably lactose

          -  Are currently enrolled in, or discontinued within the last 30 days from, a clinical
             trial involving an investigational product or non-approved use of a drug or device, or
             concurrently enrolled in any other type of medical research judged not to be
             scientifically or medically compatible with this study by the Sponsor

          -  Unable to take orally administered tablets (without chewing, crushing or breaking) or
             suspension

          -  Are Investigator site personnel directly affiliated with this study or their immediate
             families. Immediate family is defined as a spouse, parent, child or sibling, whether
             biological or legally adopted

          -  Diagnosis of Down syndrome