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

NCT01824290 | Completed Phase 3 Results DMC

• 3 other identifiers: 10609H6D-MC-LVHV2012-002354-23
• Study Type: interventional
• Target: 35
• Locations: 14 countries
• Sites: 43

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.

Conditions

Hypertension, Pulmonary

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Period 1: Time to Adjudicated Clinical Worsening (CW)

  Baseline through Week 24

• Period 1: Percentage of Participants Who Experience CW

  Baseline through Week 24

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

  Week 2, Week 4, Week 16 and Week 24

• Period 2: Percentage of Participants Who Experience CW

  Period 2 Baseline through Study Completion (Up to 24 Months)

• Period 2: Time to First Occurrence of CW

  Period 2 Baseline through Study Completion (Up to 24 Months)

Study Arms (2)

Tadalafil

EXPERIMENTAL

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; Drug: ERA as specific PAH treatment

Placebo

PLACEBO COMPARATOR

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; Drug: ERA as specific PAH treatment

Interventions

Tadalafil DRUG

Administered orally by tablet form for heavy and middle weight participants. Administered orally by suspension for light weight participants.

Also known as: LY450190, Cialis, Adcirca, IC351

Tadalafil

Placebo DRUG

Administered orally by tablet for heavy and middle weight participants. Administered orally by suspension for light weight participants.

Placebo

ERA as specific PAH treatment DRUG

All participants were taking endothelin receptor antagonist (ERA) (such as bosentan, ambrisentan and macitentan).

Placebo; Tadalafil

Eligibility Criteria

• Age: 6 Months - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• ≥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

You may not qualify if:

• 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

Sponsors & Collaborators

• Eli Lilly and Company: lead

Study Sites (43)

Children's Heathcare of Atlanta, Inc. at Egleston

Atlanta, Georgia, 30322, United States

Location

Childrens Hospital of Michigan

Detroit, Michigan, 48201, United States

Location

Cincinnati Childrens Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Nationwide Children's Hosp

Columbus, Ohio, 43205-2664, United States

Location

Vanderbilt Univeristy School of Medicine

Nashville, Tennessee, 37212-2372, United States

Location

Texas Childrens Hospital

Houston, Texas, 77030, United States

Location

Primary Childrens Medical Center

Salt Lake City, Utah, 84132, United States

Location

AKH

Vienna, 1090, Austria

Location

Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg

Leuven, 3000, Belgium

Location

Pronto Socorro Cardiologico de Pernambuco-PROCAPE

Recife, Pernambuco, 50100-060, Brazil

Location

Irmandade da Santa Casa de Misericordia de Porto Alegre

Porto Alegre, Rio Grande do Sul, 90020-090, Brazil

Location

Instituto Dante Pazzanese de Cardiologia

São Paulo, São Paulo, 04012-180, Brazil

Location

UNIFESP - Escola Paulista de Medicina

São Paulo, São Paulo, 04037-002, Brazil

Location

CHU Hopital d'enfants de la Timone

Marseille, 13385, France

Location

GH Necker - Enfants Malades

Paris, 75743, France

Location

Hopital Haut Leveque - Group hospitalier Sud

Pessac, 33604, France

Location

Chu de Toulouse - Hopital des Enfants

Toulouse, 31026, France

Location

Universitätsklinikum Heidelberg

Heidelberg, Baden-Wurttemberg, 69120, Germany

Location

Universitätsklinikum Ulm

Ulm, Baden-Wurttemberg, 89075, Germany

Location

Sheba Medical Center

Tel Litwinsky, Ramat Gan, 5265601, Israel

Location

Schneider Medical Center

Petah Tikva, 4920235, Israel

Location

Istituto Giannina Gaslini Ospedale Pediatrico I.R.C.C.S.

Genova, GE, 16147, Italy

Location

Ospedale V. Monaldi

Napoli, 80131, Italy

Location

Ospedale Bambino Gesu

Roma, 00165, Italy

Location

Gunma Children's Medical Center

Shibukawa, Gunma, 377-8577, Japan

Location

Asahikawa Medical College Hospital

Asahikawa, Hokkaido, 078-8510, Japan

Location

Mie University Hospital

Tsu, Mie-ken, 514-8507, Japan

Location

Okinawa Prefectural Nanbu Medical Center & Children's Med Ct

Haebaru-cho, Shimajiri-gun, Okinawa, 901-1193, Japan

Location

Tokyo Metropolitan Children's Medical Center

Fuchū, Tokyo, 183-8561, Japan

Location

Toho University Omori Medical Center

Ohta-Ku, Tokyo, 143-8541, Japan

Location

National Center For Child Health And Development

Setagaya-ku, Tokyo, 157-8535, Japan

Location

Shizuoka Prefectural Children's Hospital

Shizuoka, 420-8660, Japan

Location

Instituto Nacional de Cardiologia Ignacio Chavez

Mexico City, Mexico City, 14080, Mexico

Location

Universitair Medisch Centrum Groningen

Groningen, 9713 GZ, Netherlands

Location

Instytut Pomnik-Centrum Zdrowia Dziecka

Warsaw, Woj Mazowieckie, 04-730, Poland

Location

Uniwersyteckie Centrum Kliniczne

Gdansk, 80-952, Poland

Location

Uniwersytecki Szpital Dzieciecy w Krakowie-Prokocimiu

Krakow, 30-633, Poland

Location

Wojewódzki Szpital Specjalistyczny we Wrocławiu

Wroclaw, 51-124, Poland

Location

Hospital Universitari Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Universitario Ramon y Cajal

Madrid, 28034, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Hacettepe University Faculty of Medicine

Ankara, 06100, Turkey (Türkiye)

Location

Gazi University Medical Faculty

Besevler/Ankara, 06500, Turkey (Türkiye)

Location

Related Links

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

MeSH Terms

Conditions

Hypertension, Pulmonary

Interventions

Tadalafil

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Carbolines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indole Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 3-Ring

Limitations and 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.

Results Point of Contact

• Title: Chief Medical Officer
• Organization: Eli Lilly and Company

ClinicalTrials.gov@lilly.com

800-545-5979

Study Officials

• 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 DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 1, 2013
• First Posted: April 4, 2013
• Study Start: February 5, 2014
• Primary Completion: March 18, 2019
• Study Completion: March 10, 2021
• Last Updated: November 5, 2021
• Results First Posted: March 23, 2020

Record last verified: 2021-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.
• Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.

Locations

NL (1); JP (8); DE (2); BR (4); AU (1); IT (3); ME (1); IL (2); FR (4); PL (4); US (7); BE (1); ES (3); TU (2)