A clinical trial looking at the use and safety of tadalafil for the treatment of pulmonary arterial hypertension in children.

• Register: EUCTR
• Last refreshed on: 25 November 2019
• Main ID: EUCTR2012-002354-23-GB
• Date of registration: 16/01/2013
• Prospective Registration: Yes
• Primary sponsor: Eli Lilly and Company
• Public title: A clinical trial looking at the use and safety of tadalafil for the treatment of pulmonary arterial hypertension in children.
• Scientific title: A Double-Blind Efficacy and Safety Study of the Phosphodiesterase Type 5 Inhibitor Tadalafil in Pediatric Patients with Pulmonary Arterial Hypertension
• Target sample size: 134
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-002354-23
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belgium, Brazil, Canada, France, Germany, Italy, Japan, Mexico, Netherlands, Poland, Romania, Spain, Switzerland, United Kingdom, United States

Contacts

• Name: Clinical Trial Information
• Affiliation: Eli Lilly

• Name: Clinical Trial Information
• Affiliation: Eli Lilly

Key inclusion & exclusion criteria

Inclusion criteria:
[1] =6 months to <18 years of age (at screening).
[2] 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)
[3] Have a history of a diagnosis of PAH established by a resting mean pulmonary artery pressure (mPAP) =25 mm Hg, pulmonary artery wedge pressure =15 mm Hg, and a PVR =3 Wood units via right heart catheterization (RHC). In the event that a pulmonary artery wedge pressure cannot be obtained during RHC, patients 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.
[4] Have a WHO functional class value of II or III at the time of screening.
[5] All subjects must be receiving an 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).
[6] If on conventional PAH medication, including but not restricted to, anticoagulants, diuretics, digoxin, and oxygen therapy, the patient must be on stable doses with no changes (other than weight-based adjustments) for at least 4 weeks before screening.
[7] Female patients of childbearing potential must test negative for pregnancy during screening. Furthermore, female patients 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).
[8] Written informed consent from parents (and written assent from appropriately aged patients) will be obtained prior to any study procedure being performed.
Are the trial subjects under 18? yes
Number of subjects for this age range: 134
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
[1] Pulmonary hypertension related to conditions other than specified in inclusion criteria.
[2] 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 (i.e., 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.
[3] History of atrial septostomy or Potts Shunt within 3 months before administration of study drug.
[4] Unrepaired congenital heart disease.
[5] History of angina pectoris or other condition that was treated with long- or short-acting nitrates within 12 weeks before administration of study drug.
[6] WHO functional class value of either I or IV at the time of screening.
[7] Severe hepatic impairment, Child-Pugh Grade C.
[8] Severe renal insufficiency, defined as receiving renal dialysis or having a measured or estimated creatinine clearance (CC) < 30 mL/min (Schwartz Formula)
[9] Retinal disorder (e.g., hereditary retinal disorders, retinopathy of the preterm patient and other retinal disorders)
[10] Severe hypotension or uncontrolled hypertension as determined by the Investigator.
[11] Significant parenchymal lung disease.
[12] Bronchopulmonary dysplasia.
[13] Concurrent PDE5 inhibitor therapy (sildenafil or vardenafil) or has received PDE5 inhibitor therapy within 24 hours prior to the first study drug dosing.
[14] Concurrent therapy with prostacyclin or its analogues.
[15] Previously completed or withdrawn from this study (LVHV), or any other study investigating tadalafil.
[16] Commenced or discontinued a chronic PAH medication including but not restricted to: calcium channel blockers, diuretics, anti-coagulants, digoxin, and oxygen therapy within four weeks of screening.
[17] Currently receiving treatment with doxazosin, nitrates, or cancer therapy.
[18] Current treatment with potent CYP3A4 inhibitors, such as antiretroviral therapy (protease inhibitor), systemic ketoconazole, or systemic itraconazole, or chronic use of potent CYP3A4 inducers, such as rifampicin.
[19] History of loss of vision in 1 eye because of nonarteritic anterior ischemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous phosphodiesterase type 5 (PDE5) inhibitor exposure.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]

Pulmonary Arterial Hypertension
MedDRA version: 15.1 Level: PT Classification code 10064911 Term: Pulmonary arterial hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders

Intervention(s)

Trade Name: Cialis 2.5 mg film-coated tablets
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: TADALAFIL
CAS Number: 171596-29-5
Current Sponsor code: LY450190
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2.5-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Cialis 5 mg film-coated tablets
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: TADALAFIL
CAS Number: 171596-29-5
Current Sponsor code: LY450190
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Cialis 10 mg film-coated tablets
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: TADALAFIL
CAS Number: 171596-29-5
Current Sponsor code: LY450190
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Cialis 20 mg film-coated tablets
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: TADALAFIL
CAS Number: 171596-29-5
Current Sponsor code: LY450190
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: Tadalafil oral suspension
Product Code: LY450190
Pharmaceutical Form: Oral suspension
INN or Proposed INN: TADALAFIL
CAS Number: 171596-29-5
Current Sponsor code: LY450190
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2-
Pharmaceutical form of the placebo: Oral suspension
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: Period 1 primary objectives:

For the EU regulatory assessment, the primary objective of Period 1 is to evaluate the efficacy of tadalafil compared with placebo, as measured by time to clinical worsening (CW) in pediatric PAH patients through Week 24.

For the United States (US) regulatory assessment, the primary objective of Period 1 is to evaluate the efficacy of tadalafil compared with placebo in improving 6-minute walk distance from bBaseline to Week-24 as assessed in a subset of patients =6 to <18 years of age who are developmentally capable of performing a 6MW test.

Period 2 Primary Objective:
The primary objective of Period 2 is to evaluate long-term safety of tadalafil while providing continued access to tadalafil for pediatric patients with PAH who participated in Period 1

Timepoint(s) of evaluation of this end point: For time to first occurrence of clinical worsening -throughout the duration of the study.

For 6 minute-walk distance in meters - day 1, weeks 4, 8,12,16, 20, 24,1 year and 2 year.

Secondary Objective: Period 1 secondary objectives:
• Assess the efficacy of tadalafil compared with placebo on time to CW (for the US regulatory assessment) and the incidence of CW.
• Assess the efficacy of tadalafil compared with placebo on 6-minute walk (6MW) distance in a subset of patients =6 to <18 years of age who are developmentally capable of performing a 6MW test (for the EU regulatory assessment).
• Characterize the population PK of tadalafil in pediatric PAH patients.
• Assess the safety of tadalafil compared with placebo.

Period 2 secondary objectives:
• The secondary objective of Period 2 is to evaluate the incidence of, and time to CW

Primary end point(s): For the EU regulatory assessment, the primary endpoint for this study is time to first occurrence of clinical worsening.

For the US regulatory assessment, the primary endpoint for this study is 6 minute-walk distance in meters assessed in a subset of patients =6 to <18 years of age who are developmentally capable of performing a 6MW test.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: For clinical worsening -throughout the duration of the study.

For 6 minute-walk distance in meters day 1, weeks 4, 8,12,16, 20, 24,1 year and 2 year.

For PK assessment - at weeks 2, 4, 16 and 24.

Secondary end point(s): Period 1
•Time to clinical worsening (for the US regulatory assessment) and the incidence of clinical worsening
•6 minute walk (MW) distance in meters measured in subset of patients who are =6 to <18 years of age and who are developmentally capable of performing a 6MW test (for the EU regulatory assessment).
•Population PK assessment of plasma tadalafil concentrations at steady-state.

Period 2
•Incidence of and time to clinical worsening
•6MW distance in meters measured in subset of patients who are =6 to <18 years of age and who are developmentally capable of performing a 6MW test.

Secondary ID(s)

H6D-MC-LVHV

Source(s) of Monetary Support

Eli Lilly and Company