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

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01824290
• Collaborator: (none)
• Enrollment: 35
• Locations: 43
• Arms: 2
• Actual Duration (Months): 85.1
• Patients Per Site: 0.8
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hypertension, Pulmonary	Drug: Tadalafil; Drug: Placebo; Drug: ERA as specific PAH treatment	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Double-Blind Efficacy and Safety Study of the Phosphodiesterase Type 5 Inhibitor Tadalafil in Pediatric Patients With Pulmonary Arterial Hypertension
• Actual Study Start Date: Feb 5, 2014
• Actual Primary Completion Date: Mar 18, 2019
• Actual Study Completion Date: Mar 10, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tadalafil Period 1: 20 mg or 40 mg administered orally by tablets once a day. Period 2: 20 mg for middle weight and 40 mg for heavy weight administered orally by tablets once a day. Final tadalafil doses for Period 1 (6-month double-blind) were assigned after the weight cohort completion from H6D-MC-LVIG (NCT01484431).Tadalafil doses would range from 5 milligram (mg) to 40 mg depending on body weight cohorts. Heavy weight cohort ≥40 kilogram (kg), Middle weight cohort ≥25 kg to <40 kg: administered orally by tablets once a day. Light weight cohort <25 kg: administered orally by suspension once a day. Participants receiving tadalafil in Period 1 continued to receive tadalafil during Period 2 (2-year open-label extension).	Drug: Tadalafil; Administered orally by tablet form for heavy and middle weight participants. Administered orally by suspension for light weight participants.; Other Names: LY450190 Cialis Adcirca IC351 ; Drug: ERA as specific PAH treatment; All participants were taking endothelin receptor antagonist (ERA) (such as bosentan, ambrisentan and macitentan).
Placebo Comparator: Placebo Period 1: Participants received placebo orally by tablets once a day. Period 2: 20 mg for middle weight and 40 mg for heavy weight administered orally by tablets once a day. Final placebo dose for Period 1 (6-month double-blind) was be assigned after the weight cohort completion from H6D-MC-LVIG (NCT01484431) to maintain blinding depending on body weight cohort. Participants receiving placebo in Period 1 Period 2 (2-year open-label extension) would receive tadalafil in Period 2 at the corresponding tadalafil dose in that participant's weight group.	Drug: Placebo; Administered orally by tablet for heavy and middle weight participants. Administered orally by suspension for light weight participants.; Drug: ERA as specific PAH treatment; All participants were taking endothelin receptor antagonist (ERA) (such as bosentan, ambrisentan and macitentan).

Outcome Measures

Primary Outcome Measures

1. Period 1: Change From Baseline to Week 24 in a 6 Minute Walk (MW) Distance in Meters [Baseline, Week 24]

   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.

Secondary Outcome Measures

1. Period 1: Time to Adjudicated Clinical Worsening (CW) [Baseline through Week 24]

   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.

2. Period 1: Percentage of Participants Who Experience CW [Baseline through Week 24]

   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.

3. Period 1: Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil at Steady-state [Week 2, Week 4, Week 16 and Week 24]

   Period 1: Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil at steady-state

4. Period 2: Percentage of Participants Who Experience CW [Period 2 Baseline through Study Completion (Up to 24 Months)]

   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).

5. Period 2: Time to First Occurrence of CW [Period 2 Baseline through Study Completion (Up to 24 Months)]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Months to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Heathcare of Atlanta, Inc. at Egleston	Atlanta	Georgia	United States	30322
2	Childrens Hospital of Michigan	Detroit	Michigan	United States	48201
3	Cincinnati Childrens Hospital Medical Center	Cincinnati	Ohio	United States	45229
4	Nationwide Children's Hosp	Columbus	Ohio	United States	43205-2664
5	Vanderbilt Univeristy School of Medicine	Nashville	Tennessee	United States	37212-2372
6	Texas Childrens Hospital	Houston	Texas	United States	77030
7	Primary Childrens Medical Center	Salt Lake City	Utah	United States	84132
8	AKH	Wien		Austria	1090
9	Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg	Leuven		Belgium	3000
10	Pronto Socorro Cardiologico de Pernambuco-PROCAPE	Recife	PE	Brazil	50100-060
11	Irmandade da Santa Casa de Misericordia de Porto Alegre	Porto Alegre	Rio Grande Do Sul	Brazil	90020-090
12	Instituto Dante Pazzanese de Cardiologia	Sao Paulo	SP	Brazil	04012-180
13	UNIFESP - Escola Paulista de Medicina	Sao Paulo	SP	Brazil	04037-002
14	CHU Hopital d'enfants de la Timone	Marseille Cedex 05		France	13385
15	GH Necker - Enfants Malades	Paris Cedex 15		France	75743
16	Hopital Haut Leveque - Group hospitalier Sud	Pessac		France	33604
17	Chu de Toulouse - Hopital des Enfants	Toulouse Cedex 3		France	31026
18	Universitätsklinikum Heidelberg	Heidelberg	Baden-Württemberg	Germany	69120
19	Universitätsklinikum Ulm	Ulm	Baden-Württemberg	Germany	89075
20	Sheba Medical Center	Tel Hashomer	Ramat Gan	Israel	5265601
21	Schneider Medical Center	Petah Tiqva		Israel	4920235
22	Istituto Giannina Gaslini Ospedale Pediatrico I.R.C.C.S.	Genova	GE	Italy	16147
23	Ospedale V. Monaldi	Napoli		Italy	80131
24	Ospedale Bambino Gesu	Roma		Italy	00165
25	Gunma Children's Medical Center	Shibukawa	Gunma	Japan	377-8577
26	Asahikawa Medical College Hospital	Asahikawa	Hokkaido	Japan	078-8510
27	Mie University Hospital	Tsu	Mie	Japan	514-8507
28	Okinawa Prefectural Nanbu Medical Center & Children's Med Ct	Haebaru-cho, Shimajiri-gun	Okinawa	Japan	901-1193
29	Tokyo Metropolitan Children's Medical Center	Fuchu	Tokyo	Japan	183-8561
30	Toho University Omori Medical Center	Ohta-Ku	Tokyo	Japan	143-8541
31	National Center For Child Health And Development	Setagaya-ku	Tokyo	Japan	157-8535
32	Shizuoka Prefectural Children's Hospital	Shizuoka		Japan	420-8660
33	Instituto Nacional de Cardiologia Ignacio Chavez	Ciudad de Mexico	DF	Mexico	14080
34	Universitair Medisch Centrum Groningen	Groningen		Netherlands	9713 GZ
35	Instytut Pomnik-Centrum Zdrowia Dziecka	Warszawa	Woj Mazowieckie	Poland	04-730
36	Uniwersyteckie Centrum Kliniczne	Gdansk		Poland	80-952
37	Uniwersytecki Szpital Dzieciecy w Krakowie-Prokocimiu	Krakow		Poland	30-633
38	Wojewódzki Szpital Specjalistyczny we Wrocławiu	Wroclaw		Poland	51-124
39	Hospital Universitari Vall d'Hebron	Barcelona		Spain	08035
40	Hospital Universitario Ramon y Cajal	Madrid		Spain	28034
41	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
42	Hacettepe University Faculty of Medicine	Ankara		Turkey	06100
43	Gazi University Medical Faculty	Besevler/Ankara		Turkey	06500

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

• Study Director: 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), Eli Lilly and Company

Study Documents (Full-Text)

• Study Protocol - Dec 13, 2018
• Statistical Analysis Plan - Mar 28, 2019

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT01824290
• Other Study ID Numbers: 10609; H6D-MC-LVHV; 2012-002354-23
• First Posted: Apr 4, 2013
• Last Update Posted: Nov 5, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Hypertension; Tadalafil

Study Results

Participant Flow

Pre-assignment Detail	Per protocol and statistical analysis plan (SAP), the primary and secondary analysis from period 1 were performed to compare all tadalafil participants together versus all placebo participants together.

Arm/Group Title	Placebo	Tadalafil	Placebo/Tadalafil	Tadalafil/Tadalafil
Arm/Group Description	Period 1: Participants received placebo orally by tablets once a day.	Period 1: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered tadalafil orally by tablets once a day.	Period 2: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered tadalafil orally by tablets once a day. Participants had received placebo during period 1.	Period 2: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered tadalafil orally by tablets once a day. Participants had received tadalafil during period 1.
Period Title: Period 1: Double Blind
STARTED	18	17	0	0
Received at Least One Dose of Study Drug	18	17	0	0
Received 20 mg	0	4	0	0
Received 40 mg	0	13	0	0
COMPLETED	15	15	0	0
NOT COMPLETED	3	2	0	0
Period Title: Period 1: Double Blind
STARTED	0	0	16	16
Received 20 mg	0	0	3	3
Received 40 mg	0	0	13	13
COMPLETED	0	0	13	13
NOT COMPLETED	0	0	3	3

Baseline Characteristics

Arm/Group Title	Placebo	Tadalafil	Total
Arm/Group Description	Period 1: Participants received placebo orally by tablets once a day.	Period 1: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered orally by tablets once a day.	Total of all reporting groups
Overall Participants	18	17	35
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	12.8 (3.39)	14.1 (3.49)	13.5 (3.45)
Sex: Female, Male (Count of Participants)
Female	9 50%	10 58.8%	19 54.3%
Male	9 50%	7 41.2%	16 45.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 38.9%	8 47.1%	15 42.9%
Not Hispanic or Latino	6 33.3%	4 23.5%	10 28.6%
Unknown or Not Reported	5 27.8%	5 29.4%	10 28.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 5.6%	3 17.6%	4 11.4%
Asian	1 5.6%	1 5.9%	2 5.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 11.1%	1 5.9%	3 8.6%
White	14 77.8%	12 70.6%	26 74.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
Japan	1 5.6%	1 5.9%	2 5.7%
Turkey	2 11.1%	1 5.9%	3 8.6%
Brazil	9 50%	6 35.3%	15 42.9%
Mexico	1 5.6%	4 23.5%	5 14.3%
Israel	2 11.1%	4 23.5%	6 17.1%
France	1 5.6%	1 5.9%	2 5.7%
Germany	1 5.6%	0 0%	1 2.9%
Poland	1 5.6%	0 0%	1 2.9%
6 Minute Walk Distance (Meters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Meters]	476.7 (105.11)	485.8 (160.231)	481.1 (132.77)

Outcome Measures

1. Primary Outcome

Title	Period 1: Change From Baseline to Week 24 in a 6 Minute Walk (MW) Distance in Meters
Description	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.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug who were > = 6 to < 18 years of age and were capable of performing a 6MW test.

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Period 1: Participants received placebo orally by tablets once a day.	Period 1: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered orally by tablets once a day.
Measure Participants	15	15
Least Squares Mean (Standard Error) [Meters]	36.60 (20.776)	60.48 (20.410)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Tadalafil
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	23.88
	Confidence Interval	(2-Sided) 80%; -14.25 to 62.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 29.114
	Estimation Comments

2. Secondary Outcome

Title	Period 1: Time to Adjudicated Clinical Worsening (CW)
Description	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.
Time Frame	Baseline through Week 24

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug.

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Period 1: Participants received placebo orally by tablets once a day.	Period 1: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered orally by tablets once a day.
Measure Participants	18	17
Median (95% Confidence Interval) [Weeks]	NA	NA

3. Secondary Outcome

Title	Period 1: Percentage of Participants Who Experience CW
Description	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.
Time Frame	Baseline through Week 24

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug.

Arm/Group Title	Placebo	Tadalafil
Arm/Group Description	Period 1: Participants received placebo orally by tablets once a day.	Period 1: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered orally by tablets once a day.
Measure Participants	18	17
Number [percentage of participants]	0 0%	0 0%

4. Secondary Outcome

Title	Period 1: Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil at Steady-state
Description	Period 1: Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil at steady-state
Time Frame	Week 2, Week 4, Week 16 and Week 24

Outcome Measure Data

Analysis Population Description

All participants who received at least one dose of study drug and had evaluable PK data.

Arm/Group Title	20 mg Tadalafil	40 mg Tadalafil
Arm/Group Description	Period 1: 20 mg tadalafil administered orally by tablets once a day with concomitant endothelin receptor antagonist (ERA).	Period 1: 40 mg tadalafil administered orally by tablets once a day with concomitant ERA.
Measure Participants	4	13
With concomitant bosentan	3.63 (38.1)	4.49 (28.2)
No bosentan (ERA: Macitentan)	NA (NA)

5. Secondary Outcome

Title	Period 2: Percentage of Participants Who Experience CW
Description	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).
Time Frame	Period 2 Baseline through Study Completion (Up to 24 Months)

Outcome Measure Data

Analysis Population Description

Period 2: All participants who received at least one dose of study drug.

Arm/Group Title	Placebo/Tadalafil - Open-Label Treatment	Tadalafil/Tadalafil - Open-Label Treatment
Arm/Group Description	Period 2: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered tadalafil orally by tablets once a day. Participants had received placebo during period 1.	Period 2: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered tadalafil orally by tablets once a day. Participants had received tadalafil during period 1.
Measure Participants	16	16
Number [percentage of participants]	12.5 69.4%	18.8 110.6%

6. Secondary Outcome

Title	Period 2: Time to First Occurrence of CW
Description	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).
Time Frame	Period 2 Baseline through Study Completion (Up to 24 Months)

Outcome Measure Data

Analysis Population Description

Period 2: All participants who received at least one dose of study drug, who entered the open-label treatment Period

Arm/Group Title	Placebo/Tadalafil - Open-Label Treatment	Tadalafil/Tadalafil - Open-Label Treatment
Arm/Group Description	Period 2: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered tadalafil orally by tablets once a day. Participants had received placebo during period 1.	Period 2: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered tadalafil orally by tablets once a day. Participants had received tadalafil during period 1.
Measure Participants	16	16
Median (95% Confidence Interval) [Months]	NA	NA

Adverse Events

Time Frame	Baseline Up To 24 Months
Adverse Event Reporting Description	All participants who received at least one dose of study drug. Gender specific events only occurring in male or female participants have had the number of participants at risk adjusted accordingly.
Arm/Group Title	Placebo - Double Blind		Tadalafil - Double Blind		Placebo/Tadalafil - Open-Label Treatment		Tadalafil/Tadalafil - Open-Label Treatment
Arm/Group Description	Period 1: Participants received placebo orally by tablets once a day.		Period 1: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered tadalafil orally by tablets once a day.		Period 2: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered tadalafil orally by tablets once a day. Participants had received placebo during period 1.		Period 2: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered tadalafil orally by tablets once a day. Participants had received tadalafil during period 1.
All Cause Mortality
	Placebo - Double Blind		Tadalafil - Double Blind		Placebo/Tadalafil - Open-Label Treatment		Tadalafil/Tadalafil - Open-Label Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/17 (0%)		0/16 (0%)		0/16 (0%)
Serious Adverse Events
	Placebo - Double Blind		Tadalafil - Double Blind		Placebo/Tadalafil - Open-Label Treatment		Tadalafil/Tadalafil - Open-Label Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/17 (0%)		4/16 (25%)		1/16 (6.3%)
Blood and lymphatic system disorders
Anaemia	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/16 (0%)	0
Cardiac disorders
Acute right ventricular failure	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Infections and infestations
Gastroenteritis	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/16 (0%)	0
Pneumonia	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/16 (0%)	0
Respiratory, thoracic and mediastinal disorders
Haemoptysis	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/16 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo - Double Blind		Tadalafil - Double Blind		Placebo/Tadalafil - Open-Label Treatment		Tadalafil/Tadalafil - Open-Label Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/18 (44.4%)		15/17 (88.2%)		11/16 (68.8%)		12/16 (75%)
Blood and lymphatic system disorders
Anaemia	0/18 (0%)	0	0/17 (0%)	0	2/16 (12.5%)	2	0/16 (0%)	0
Eosinophilia	1/18 (5.6%)	1	0/17 (0%)	0	0/16 (0%)	0	0/16 (0%)	0
Cardiac disorders
Palpitations	0/18 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/16 (0%)	0
Supraventricular tachycardia	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Tachycardia	0/18 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/16 (0%)	0
Ventricular extrasystoles	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/16 (0%)	0
Ear and labyrinth disorders
Ear pain	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Eye disorders
Asthenopia	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/16 (0%)	0
Photopsia	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Gastrointestinal disorders
Abdominal pain upper	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	2/16 (12.5%)	2
Dental caries	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Enterocolitis	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/16 (0%)	0
Gastrooesophageal reflux disease	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/16 (0%)	0
Irritable bowel syndrome	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Nausea	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Plicated tongue	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Vomiting	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	3/16 (18.8%)	3
General disorders
Asthenia	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/16 (0%)	0
Exercise tolerance decreased	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Pyrexia	0/18 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/16 (0%)	0
Immune system disorders
Hypersensitivity	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/16 (0%)	0
Seasonal allergy	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	2
Infections and infestations
Acute sinusitis	0/18 (0%)	0	0/17 (0%)	0	2/16 (12.5%)	2	0/16 (0%)	0
Ascariasis	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Body tinea	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Bronchitis	1/18 (5.6%)	1	0/17 (0%)	0	0/16 (0%)	0	0/16 (0%)	0
Ear infection	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	2
Gastroenteritis	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Impetigo	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/16 (0%)	0
Influenza	0/18 (0%)	0	3/17 (17.6%)	3	0/16 (0%)	0	1/16 (6.3%)	1
Nasopharyngitis	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	2	3/16 (18.8%)	4
Otitis media acute	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Paronychia	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Pharyngitis	0/18 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	2/16 (12.5%)	4
Rhinitis	0/18 (0%)	0	1/17 (5.9%)	1	2/16 (12.5%)	2	0/16 (0%)	0
Sinusitis	1/18 (5.6%)	1	1/17 (5.9%)	1	0/16 (0%)	0	1/16 (6.3%)	2
Tonsillitis	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Tracheobronchitis	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/16 (0%)	0
Upper respiratory tract infection	1/18 (5.6%)	1	3/17 (17.6%)	3	0/16 (0%)	0	2/16 (12.5%)	2
Urinary tract infection	1/18 (5.6%)	1	1/17 (5.9%)	1	0/16 (0%)	0	1/16 (6.3%)	1
Vaginal infection	0/9 (0%)	0	1/10 (10%)	1	0/8 (0%)	0	0/10 (0%)	0
Viral infection	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/16 (0%)	0
Viral tonsillitis	1/18 (5.6%)	1	0/17 (0%)	0	0/16 (0%)	0	0/16 (0%)	0
Viral upper respiratory tract infection	0/18 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/16 (0%)	0
Injury, poisoning and procedural complications
Bone contusion	0/18 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/16 (0%)	0
Penis injury	0/9 (0%)	0	0/7 (0%)	0	1/8 (12.5%)	1	0/6 (0%)	0
Investigations
Blood creatine phosphokinase increased	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Hepatic enzyme increased	0/18 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/16 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/16 (0%)	0
Dyslipidaemia	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Vitamin b12 deficiency	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/16 (0%)	0
Vitamin d deficiency	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/16 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/18 (5.6%)	1	2/17 (11.8%)	2	0/16 (0%)	0	2/16 (12.5%)	2
Back pain	0/18 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/16 (0%)	0
Musculoskeletal chest pain	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/16 (0%)	0
Pain in extremity	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Patellofemoral pain syndrome	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/16 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pharyngeal neoplasm	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Nervous system disorders
Dizziness	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	3/16 (18.8%)	3
Headache	2/18 (11.1%)	6	5/17 (29.4%)	5	2/16 (12.5%)	2	3/16 (18.8%)	3
Presyncope	0/18 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	1/16 (6.3%)	1
Somnolence	0/18 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/16 (0%)	0
Syncope	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Psychiatric disorders
Anxiety	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/16 (0%)	0
Excessive masturbation	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Insomnia	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Reproductive system and breast disorders
Menorrhagia	0/9 (0%)	0	1/10 (10%)	1	1/8 (12.5%)	1	1/10 (10%)	2
Metrorrhagia	0/9 (0%)	0	0/10 (0%)	0	0/8 (0%)	0	1/10 (10%)	1
Penis disorder	0/9 (0%)	0	1/7 (14.3%)	1	0/8 (0%)	0	0/6 (0%)	0
Polymenorrhoea	0/9 (0%)	0	0/10 (0%)	0	0/8 (0%)	0	1/10 (10%)	1
Spontaneous penile erection	0/9 (0%)	0	1/7 (14.3%)	2	1/8 (12.5%)	1	0/6 (0%)	0
Uterine haemorrhage	0/9 (0%)	0	0/10 (0%)	0	1/8 (12.5%)	1	0/10 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Dyspnoea	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Epistaxis	1/18 (5.6%)	1	2/17 (11.8%)	2	1/16 (6.3%)	1	1/16 (6.3%)	1
Oropharyngeal pain	0/18 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	1/16 (6.3%)	1
Pulmonary arterial hypertension	1/18 (5.6%)	1	0/17 (0%)	0	0/16 (0%)	0	0/16 (0%)	0
Respiratory distress	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Skin and subcutaneous tissue disorders
Dermatitis allergic	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	2
Haemorrhage subcutaneous	0/18 (0%)	0	1/17 (5.9%)	3	0/16 (0%)	0	0/16 (0%)	0
Livedo reticularis	1/18 (5.6%)	1	0/17 (0%)	0	0/16 (0%)	0	0/16 (0%)	0
Photosensitivity reaction	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Pruritus	0/18 (0%)	0	0/17 (0%)	0	1/16 (6.3%)	1	0/16 (0%)	0
Rash	0/18 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/16 (0%)	0
Swelling face	0/18 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/16 (0%)	0
Social circumstances
Menarche	1/9 (11.1%)	1	0/10 (0%)	0	0/8 (0%)	0	0/10 (0%)	0
Vascular disorders
Deep vein thrombosis	0/18 (0%)	0	0/17 (0%)	0	0/16 (0%)	0	1/16 (6.3%)	1
Flushing	0/18 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/16 (0%)	0
Hypotension	0/18 (0%)	0	1/17 (5.9%)	1	0/16 (0%)	0	0/16 (0%)	0

Limitations/Caveats

The study is mainly descriptive in a small number of children with PAH and there were no participants enrolled in the light weight cohort.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.