A Study of Tadalafil in Pediatric Participants With Pulmonary Arterial Hypertension (PAH)

Hypertension, Pulmonary Clinical Trial

Official title:

A Double-Blind Efficacy and Safety Study of the Phosphodiesterase Type 5 Inhibitor Tadalafil in Pediatric Patients With Pulmonary Arterial Hypertension

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01824290
• Other study ID #: 10609
• Secondary ID: H6D-MC-LVHV2012-
• Status: Completed
• Phase: Phase 3
• Start date: February 5, 2014
• Est. completion date: March 10, 2021

Study information

• Verified date: November 2021
• Source: Eli Lilly and Company
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 35
• Est. completion date: March 10, 2021
• Est. primary completion date: March 18, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 17 Years

Eligibility

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

Related Conditions & MeSH terms

• Hypertension
• Hypertension, Pulmonary
• Pulmonary Arterial Hypertension

Intervention

Drug:
• Tadalafil
Administered orally by tablet form for heavy and middle weight participants. Administered orally by suspension for light weight participants.
• Placebo
Administered orally by tablet for heavy and middle weight participants. Administered orally by suspension for light weight participants.
• ERA as specific PAH treatment
All participants were taking endothelin receptor antagonist (ERA) (such as bosentan, ambrisentan and macitentan).

Locations

Country	Name	City	State
Austria	AKH	Wien
Belgium	Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg	Leuven
Brazil	Irmandade da Santa Casa de Misericordia de Porto Alegre	Porto Alegre	Rio Grande Do Sul
Brazil	Pronto Socorro Cardiologico de Pernambuco-PROCAPE	Recife	PE
Brazil	Instituto Dante Pazzanese de Cardiologia	Sao Paulo	SP
Brazil	UNIFESP - Escola Paulista de Medicina	Sao Paulo	SP
France	CHU Hopital d'enfants de la Timone	Marseille Cedex 05
France	GH Necker - Enfants Malades	Paris Cedex 15
France	Hopital Haut Leveque - Group hospitalier Sud	Pessac
France	Chu de Toulouse - Hopital des Enfants	Toulouse Cedex 3
Germany	Universitätsklinikum Heidelberg	Heidelberg	Baden-Württemberg
Germany	Universitätsklinikum Ulm	Ulm	Baden-Württemberg
Israel	Schneider Medical Center	Petah Tiqva
Israel	Sheba Medical Center	Tel Hashomer	Ramat Gan
Italy	Istituto Giannina Gaslini Ospedale Pediatrico I.R.C.C.S.	Genova	GE
Italy	Ospedale V. Monaldi	Napoli
Italy	Ospedale Bambino Gesu	Roma
Japan	Asahikawa Medical College Hospital	Asahikawa	Hokkaido
Japan	Tokyo Metropolitan Children's Medical Center	Fuchu	Tokyo
Japan	Okinawa Prefectural Nanbu Medical Center & Children's Med Ct	Haebaru-cho, Shimajiri-gun	Okinawa
Japan	Toho University Omori Medical Center	Ohta-Ku	Tokyo
Japan	National Center For Child Health And Development	Setagaya-ku	Tokyo
Japan	Gunma Children's Medical Center	Shibukawa	Gunma
Japan	Shizuoka Prefectural Children's Hospital	Shizuoka
Japan	Mie University Hospital	Tsu	Mie
Mexico	Instituto Nacional de Cardiologia Ignacio Chavez	Ciudad de Mexico	DF
Netherlands	Universitair Medisch Centrum Groningen	Groningen
Poland	Uniwersyteckie Centrum Kliniczne	Gdansk
Poland	Uniwersytecki Szpital Dzieciecy w Krakowie-Prokocimiu	Krakow
Poland	Instytut Pomnik-Centrum Zdrowia Dziecka	Warszawa	Woj Mazowieckie
Poland	Wojewódzki Szpital Specjalistyczny we Wroclawiu	Wroclaw
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Turkey	Hacettepe University Faculty of Medicine	Ankara
Turkey	Gazi University Medical Faculty	Besevler/Ankara
United States	Children's Heathcare of Atlanta, Inc. at Egleston	Atlanta	Georgia
United States	Cincinnati Childrens Hospital Medical Center	Cincinnati	Ohio
United States	Nationwide Children's Hosp	Columbus	Ohio
United States	Childrens Hospital of Michigan	Detroit	Michigan
United States	Texas Childrens Hospital	Houston	Texas
United States	Vanderbilt Univeristy School of Medicine	Nashville	Tennessee
United States	Primary Childrens Medical Center	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Eli Lilly and Company

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Brazil,  France,  Germany,  Israel,  Italy,  Japan,  Mexico,  Netherlands,  Poland,  Spain,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Period 1: Change From Baseline to Week 24 in a 6 Minute Walk (MW) Distance in Meters	6MWD in meters assessed in a subset of participants who are =6 to <18 years of age who are developmentally capable of performing a 6MW test. Change from baseline was derived using mixed model repeated measures (MMRM) with terms for treatment group, visit, baseline 6MWD, and treatment-by-visit interaction.	Baseline, Week 24
Secondary	Period 1: Time to Adjudicated Clinical Worsening (CW)	Clinical worsening was defined as any of the following: death,lung or heart transplantation,atrial septostomy or Potts' shunt,hospitalization for Pulmonary Arterial Hypertension(PAH) progression,new onset syncope,initiation of new PAH therapy(including increase in the dose of existing PAH specific concomitant therapy,such as endothelin receptor agonist or beraprost medication), or increase of 1 or more in World Health Organization(WHO) Functional Class(except for participants already in Class IV;only for participants unable to perform the 6 minute walk(6MW) test;worsening of WHO functional class by 1 or more for participants who can perform a 6 minute walk(6MW) test and who have a decrease of = 20% in the 6 minute walk distance(for those participants who are =6 years of age). Criteria for CW(from Period 1) were adjudicated by an independent,blinded study-specific Clinical Endpoint Committee(CEC).This adjudication was used for data analysis, and was not used to guide subject treatment.	Baseline through Week 24
Secondary	Period 1: Percentage of Participants Who Experience CW	Clinical worsening was defined as any of the following: death,lung or heart transplantation,atrial septostomy or Potts' shunt,hospitalization for Pulmonary Arterial Hypertension(PAH) progression,new onset syncope, initiation of new PAH therapy(including increase in the dose of existing PAH specific concomitant therapy,such as endothelin receptor agonist or beraprost medication),or increase of 1 or more in World Health Organization(WHO) Functional Class(except for participants already in Class IV; only for participants unable to perform the 6 minute walk(6MW) test;worsening of WHO functional class by 1 or more for participants who can perform a 6 minute walk(6MW) test and who have a decrease of = 20% in the 6 minute walk distance(for those participants who are =6 years of age).Criteria for CW(from Period 1) were adjudicated by an independent,blinded study-specific Clinical Endpoint Committee(CEC).This adjudication was used for data analysis, and was not used to guide subject treatment.	Baseline through Week 24
Secondary	Period 1: Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil at Steady-state	Period 1: Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil at steady-state	Week 2, Week 4, Week 16 and Week 24
Secondary	Period 2: Percentage of Participants Who Experience CW	Clinical worsening was defined as any of the following: death, lung or heart transplantation, atrial septostomy or Potts' shunt, hospitalization for Pulmonary Arterial Hypertension (PAH) progression, new onset syncope, initiation of new PAH therapy (including increase in the dose of existing PAH specific concomitant therapy, such as endothelin receptor agonist or beraprost medication), or increase of 1 or more in World Health Organization(WHO) Functional Class (except for participants already in Class IV; only for participants unable to perform the 6 minute walk (6MW) test; worsening of WHO functional class by 1 or more for participants who can perform a 6 minute walk (6MW) test and who have a decrease of = 20% in the 6 minute walk distance (for those participants who are =6 years of age).	Period 2 Baseline through Study Completion (Up to 24 Months)
Secondary	Period 2: Time to First Occurrence of CW	Clinical worsening was defined as any of the following: death, lung or heart transplantation, atrial septostomy or Potts' shunt, hospitalization for Pulmonary Arterial Hypertension (PAH) progression, new onset syncope, initiation of new PAH therapy (including increase in the dose of existing PAH specific concomitant therapy, such as endothelin receptor agonist or beraprost medication), or increase of 1 or more in World Health Organization(WHO) Functional Class (except for participants already in Class IV; only for participants unable to perform the 6 minute walk (6MW) test; worsening of WHO functional class by 1 or more for participants who can perform a 6 minute walk (6MW) test and who have a decrease of = 20% in the 6 minute walk distance (for those participants who are =6 years of age).	Period 2 Baseline through Study Completion (Up to 24 Months)

External Links

•   A Study of Tadalafil in Pediatric Participants With Pulmonary Arterial Hypertension (PAH)