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A Pharmacokinetics Study for Pediatric Participants With Pulmonary Arterial Hypertension

Primary Purpose

Pulmonary Arterial Hypertension

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Tadalafil- Tablet or Oral suspension
Sponsored by
Eli Lilly and Company
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Arterial Hypertension

Eligibility Criteria

6 Months - 17 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Currently have a diagnosis of PAH that is either:

    • idiopathic (including hereditary), related to collagen vascular disease, related to anorexigen use, associated with surgical repair, of at least 6 month duration, of a congenital systemic to pulmonary shunt (for example, atrial septal defect, ventricular septal defect, patent ductus arteriosus).
  • Have a history of the diagnosis of PAH established by a resting mean pulmonary artery pressure ≥25 mm Hg, pulmonary artery wedge pressure ≤15 mm Hg, and a pulmonary vascular resistance (PVR) ≥3 Wood units via right heart catheterization. In the event that a pulmonary artery wedge pressure is unable to be obtained during right heart catheterization, participants with a left ventricular end diastolic pressure <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 I, II or III at the time of enrollment

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 to 18 mm Hg) aortic or mitral valve disease (that is, 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 as determined by the physician
  • History of atrial septostomy or Potts Shunt within 3 months before administration of study drug
  • Unrepaired congenital heart disease

Sites / Locations

  • Children's Hospital of Colorado
  • Children's Heathcare of Atlanta, Inc. at Egleston
  • Riley Hospital for Children
  • Nationwide Children's Hospital
  • Children's Hospital of Philadelphia
  • For additional information regarding investigative sites for this trial, contact 1-888-545-5972 Mon - Fri, 9 AM to 4 PM or 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri, 9 AM to 5 PM Eastern Time or speak with your personal physician.
  • For additional information regarding investigative sites for this trial, contact 1-888-545-5972 Mon - Fri, 9 AM to 4 PM or 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri, 9 AM to 5 PM Eastern Time or speak with your personal physician.
  • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
  • For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Tadalafil

Arm Description

Light Weight <25 kg Period 1: 2 milligram (mg) or 4 mg tadalafil administered once daily (QD) in oral suspension formulation for 5 weeks then 8 mg,10 mg,15 mg or 20 mg tadalafil was administered QD in oral suspension formulation for 5 weeks. Middle Weight: 25 kg to <40 kg Period 1: 5 mg tadalafil tablet administered QD for 5 weeks then 10 mg, 15 mg or 20 mg tablet tadalafil administered QD for 5 weeks. Heavy: ≥40 kg Period 1: 10 mg tadalafil tablet administered QD for 5 weeks then 20 mg or 40 mg tablet tadalafil administered QD for 5 weeks.

Outcomes

Primary Outcome Measures

Population Pharmacokinetics: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau) for Tadalafil
Population Pharmacokinetics: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau) for Tadalafil. The measure of dispersion reported is 90% Prediction Intervals and not Confidence Intervals.
Population Pharmacokinetics: Average Concentration (Cmean,ss) of for Tadalafil at Steady-State.
Population Pharmacokinetics: Average Concentration (Cmean,ss) of for tadalafil at steady-state. The measure of dispersion reported is 90% Prediction Intervals and not Confidence Intervals.

Secondary Outcome Measures

Percentage of Participants With Clinical Worsening
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).
Number of Participants With Palatability of the Tadalafil Suspension
The Taste Assessment Questionnaire (TAQ) questions were: TAQRES1: Please rate the bitterness level. TAQRES2: Please rate the sweetness level. TAQRES3: Please rate the aftertaste. TAQRES4: Please rate the overall acceptability of the taste for daily use.

Full Information

First Posted
November 30, 2011
Last Updated
September 27, 2019
Sponsor
Eli Lilly and Company
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1. Study Identification

Unique Protocol Identification Number
NCT01484431
Brief Title
A Pharmacokinetics Study for Pediatric Participants With Pulmonary Arterial Hypertension
Official Title
A Multiple Ascending Dose Study of Tadalafil to Assess the Pharmacokinetics and Safety in a Pediatric Population With Pulmonary Arterial Hypertension
Study Type
Interventional

2. Study Status

Record Verification Date
April 2019
Overall Recruitment Status
Completed
Study Start Date
July 17, 2012 (Actual)
Primary Completion Date
April 21, 2017 (Actual)
Study Completion Date
April 3, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Eli Lilly and Company

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to see how much study drug is in the blood of children with pulmonary arterial hypertension (PAH) after dosing to establish the correct dose for further clinical research.
Detailed Description
During Period I, tadalafil will be administered orally, once daily, at a low dose for approximately 5 weeks followed by a high dose for approximately 5 weeks. Dose levels are calculated based on body weight cohorts. Heavy weight cohort >=40 kg, middle weight cohort >=25 kg to <40 kg. Light weight cohort<25 kg. Participants who complete Period 1 may continue taking tadalafil in Period 2 for at least 2 years. Starting dose will not exceed the maximum weight range dose established in Period 1 and after the first 3 months of Period 2, the dose may be adjusted based on available safety and efficacy information.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Arterial Hypertension

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tadalafil
Arm Type
Experimental
Arm Description
Light Weight <25 kg Period 1: 2 milligram (mg) or 4 mg tadalafil administered once daily (QD) in oral suspension formulation for 5 weeks then 8 mg,10 mg,15 mg or 20 mg tadalafil was administered QD in oral suspension formulation for 5 weeks. Middle Weight: 25 kg to <40 kg Period 1: 5 mg tadalafil tablet administered QD for 5 weeks then 10 mg, 15 mg or 20 mg tablet tadalafil administered QD for 5 weeks. Heavy: ≥40 kg Period 1: 10 mg tadalafil tablet administered QD for 5 weeks then 20 mg or 40 mg tablet tadalafil administered QD for 5 weeks.
Intervention Type
Drug
Intervention Name(s)
Tadalafil- Tablet or Oral suspension
Other Intervention Name(s)
LY450190
Intervention Description
Tadalafil Tablets administered orally. Tadalafil Oral suspension: An aqueous, ready-to-use suspension for oral administration.
Primary Outcome Measure Information:
Title
Population Pharmacokinetics: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau) for Tadalafil
Description
Population Pharmacokinetics: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau) for Tadalafil. The measure of dispersion reported is 90% Prediction Intervals and not Confidence Intervals.
Time Frame
Period 1: Pre Dose and 2, 4, 8, 12, and 24 Hours Post Dose on Days 1, 14 and 49; with single dose measures on Day 1 and steady-state measurements on Days 14 and 49
Title
Population Pharmacokinetics: Average Concentration (Cmean,ss) of for Tadalafil at Steady-State.
Description
Population Pharmacokinetics: Average Concentration (Cmean,ss) of for tadalafil at steady-state. The measure of dispersion reported is 90% Prediction Intervals and not Confidence Intervals.
Time Frame
Period 1: Pre Dose and 2, 4, 8, 12, and 24 Hours Post Dose on Days 1, 14 and 49; with single dose measures on Day 1 and steady-state measurements on Days 14 and 49
Secondary Outcome Measure Information:
Title
Percentage of Participants With Clinical Worsening
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
Baseline Up to 27 Months
Title
Number of Participants With Palatability of the Tadalafil Suspension
Description
The Taste Assessment Questionnaire (TAQ) questions were: TAQRES1: Please rate the bitterness level. TAQRES2: Please rate the sweetness level. TAQRES3: Please rate the aftertaste. TAQRES4: Please rate the overall acceptability of the taste for daily use.
Time Frame
Day 35 (high dose)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Months
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Currently have a diagnosis of PAH that is either: idiopathic (including hereditary), related to collagen vascular disease, related to anorexigen use, associated with surgical repair, of at least 6 month duration, of a congenital systemic to pulmonary shunt (for example, atrial septal defect, ventricular septal defect, patent ductus arteriosus). Have a history of the diagnosis of PAH established by a resting mean pulmonary artery pressure ≥25 mm Hg, pulmonary artery wedge pressure ≤15 mm Hg, and a pulmonary vascular resistance (PVR) ≥3 Wood units via right heart catheterization. In the event that a pulmonary artery wedge pressure is unable to be obtained during right heart catheterization, participants with a left ventricular end diastolic pressure <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 I, II or III at the time of enrollment 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 to 18 mm Hg) aortic or mitral valve disease (that is, 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 as determined by the physician History of atrial septostomy or Potts Shunt within 3 months before administration of study drug Unrepaired congenital heart disease
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon-Fri 9AM-5PM Eastern time (UTC/GMT - 5 hours, EST)
Organizational Affiliation
Eli Lilly and Company
Official's Role
Study Director
Facility Information:
Facility Name
Children's Hospital of Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Children's Heathcare of Atlanta, Inc. at Egleston
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Riley Hospital for Children
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202-5225
Country
United States
Facility Name
Nationwide Children's Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205-2664
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
For additional information regarding investigative sites for this trial, contact 1-888-545-5972 Mon - Fri, 9 AM to 4 PM or 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri, 9 AM to 5 PM Eastern Time or speak with your personal physician.
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3T 1C5
Country
Canada
Facility Name
For additional information regarding investigative sites for this trial, contact 1-888-545-5972 Mon - Fri, 9 AM to 4 PM or 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri, 9 AM to 5 PM Eastern Time or speak with your personal physician.
City
Toronto
ZIP/Postal Code
M5G 1X8
Country
Canada
Facility Name
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
City
Marseille
ZIP/Postal Code
13385
Country
France
Facility Name
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
City
Paris
ZIP/Postal Code
75743
Country
France
Facility Name
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
City
Toulouse
ZIP/Postal Code
31026
Country
France
Facility Name
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
City
Gdansk
ZIP/Postal Code
80-952
Country
Poland
Facility Name
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
City
Warszawa
ZIP/Postal Code
00-576
Country
Poland
Facility Name
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
City
Warszawa
ZIP/Postal Code
04-730
Country
Poland
Facility Name
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Facility Name
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
City
Madrid
ZIP/Postal Code
28041
Country
Spain
Facility Name
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
City
Bloomsbury
State/Province
London
ZIP/Postal Code
WC1N 3JH
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
IPD Sharing 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.
IPD Sharing Access Criteria
A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
IPD Sharing URL
https://vivli.org/
Citations:
PubMed Identifier
34379314
Citation
Ferguson-Sells L, Velez de Mendizabal N, Li B, Small D. Population Pharmacokinetics of Tadalafil in Pediatric Patients with Pulmonary Arterial Hypertension: A Combined Adult/Pediatric Model. Clin Pharmacokinet. 2022 Feb;61(2):249-262. doi: 10.1007/s40262-021-01052-8. Epub 2021 Aug 11.
Results Reference
derived
Links:
URL
https://www.lillytrialguide.com/en-US/studies/pediatric-pulmonary-arterial-hypertension/LVIG#?postal=
Description
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A Pharmacokinetics Study for Pediatric Participants With Pulmonary Arterial Hypertension

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