Clinical trial NCT01824290: A Study of Tadalafil in Pediatric Participants With Pulmonary Arterial Hypertension (PAH)
Official title: A Double-Blind Efficacy and Safety Study of the Phosphodiesterase Type 5 Inhibitor Tadalafil in Pediatric Patients With Pulmonary Arterial Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypertension, Pulmonary
Lead sponsor: Eli Lilly and Company
Sponsor class: INDUSTRY
First posted: 2013-04-04
Enrollment: 35
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Primary outcomes:
measure: Period 1: Change From Baseline to Week 24 in a 6 Minute Walk (MW) Distance in Meters
timeFrame: Baseline, Week 24
Secondary outcomes:
measure: Period 1: Time to Adjudicated Clinical Worsening (CW)
timeFrame: Baseline through Week 24
measure: Period 1: Percentage of Participants Who Experience CW
timeFrame: Baseline through Week 24
measure: Period 1: Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil at Steady-state
timeFrame: Week 2, Week 4, Week 16 and Week 24
measure: Period 2: Percentage of Participants Who Experience CW
timeFrame: Period 2 Baseline through Study Completion (Up to 24 Months)
measure: Period 2: Time to First Occurrence of CW
timeFrame: Period 2 Baseline through Study Completion (Up to 24 Months)
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Children's Heathcare of Atlanta, Inc. at Egleston
state: Georgia
city: Detroit
country: United States
facility: Childrens Hospital of Michigan
state: Michigan
city: Cincinnati
country: United States
facility: Cincinnati Childrens Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hosp
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt Univeristy School of Medicine
state: Tennessee
city: Houston
country: United States
facility: Texas Childrens Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Primary Childrens Medical Center
state: Utah
city: Wien
country: Austria
facility: AKH
city: Leuven
country: Belgium
facility: Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg
city: Recife
country: Brazil
facility: Pronto Socorro Cardiologico de Pernambuco-PROCAPE
state: PE
city: Porto Alegre
country: Brazil
facility: Irmandade da Santa Casa de Misericordia de Porto Alegre
state: Rio Grande Do Sul
city: Sao Paulo
country: Brazil
facility: Instituto Dante Pazzanese de Cardiologia
state: SP
city: Sao Paulo
country: Brazil
facility: UNIFESP - Escola Paulista de Medicina
state: SP
city: Marseille Cedex 05
country: France
facility: CHU Hopital d'enfants de la Timone
city: Paris Cedex 15
country: France
facility: GH Necker - Enfants Malades
city: Pessac
country: France
facility: Hopital Haut Leveque - Group hospitalier Sud
city: Toulouse Cedex 3
country: France
facility: Chu de Toulouse - Hopital des Enfants
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
state: Baden-Württemberg
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
state: Baden-Württemberg
city: Tel Hashomer
country: Israel
facility: Sheba Medical Center
state: Ramat Gan
city: Petah Tiqva
country: Israel
facility: Schneider Medical Center
city: Genova
country: Italy
facility: Istituto Giannina Gaslini Ospedale Pediatrico I.R.C.C.S.
state: GE
city: Napoli
country: Italy
facility: Ospedale V. Monaldi
city: Roma
country: Italy
facility: Ospedale Bambino Gesu
city: Shibukawa
country: Japan
facility: Gunma Children's Medical Center
state: Gunma
city: Asahikawa
country: Japan
facility: Asahikawa Medical College Hospital
state: Hokkaido
city: Tsu
country: Japan
facility: Mie University Hospital
state: Mie
city: Haebaru-cho, Shimajiri-gun
country: Japan
facility: Okinawa Prefectural Nanbu Medical Center & Children's Med Ct
state: Okinawa
city: Fuchu
country: Japan
facility: Tokyo Metropolitan Children's Medical Center
state: Tokyo
city: Ohta-Ku
country: Japan
facility: Toho University Omori Medical Center
state: Tokyo
city: Setagaya-ku
country: Japan
facility: National Center For Child Health And Development
state: Tokyo
city: Shizuoka
country: Japan
facility: Shizuoka Prefectural Children's Hospital
city: Ciudad de Mexico
country: Mexico
facility: Instituto Nacional de Cardiologia Ignacio Chavez
state: DF
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Warszawa
country: Poland
facility: Instytut Pomnik-Centrum Zdrowia Dziecka
state: Woj Mazowieckie
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Krakow
country: Poland
facility: Uniwersytecki Szpital Dzieciecy w Krakowie-Prokocimiu
city: Wroclaw
country: Poland
facility: Wojewódzki Szpital Specjalistyczny we Wrocławiu
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Ankara
country: Turkey
facility: Hacettepe University Faculty of Medicine
city: Besevler/Ankara
country: Turkey
facility: Gazi University Medical Faculty
Study officials:
affiliation: Eli Lilly and Company
name: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)
role: STUDY_DIRECTOR
References: