A study in children with Pulmonary Arterial Hypertension to assess the safety of Tadalafil as the dose increases, as well as how the drug works in the body

• Register: EUCTR
• Last refreshed on: 8 October 2021
• Main ID: EUCTR2011-001873-24-ES
• Date of registration: 26/10/2011
• Prospective Registration: Yes
• Primary sponsor: Eli Lilly and Company
• Public title: A study in children with Pulmonary Arterial Hypertension to assess the safety of Tadalafil as the dose increases, as well as how the drug works in the body
• Scientific title: A multiple ascending dose study of Tadalafil to assess the pharmacokinetics and safety in a pediatric population with Pulmonary Arterial Hypertension
• Date of first enrolment: 13/01/2012
• Target sample size: 24
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-001873-24
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: no; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Canada, France, Poland, Spain, 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:
Pediatric patients (?6 months to <18 years of age) at time of screening with confirmed PAH.
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1] ?6 months to <18 years of age (at screening).
[2] Currently have a diagnosis of PAH that is either:
- idiopathic,
- related to collagen vascular disease,
- related to anorexigen use,
- associated with an atrial-ventricular septal defect (with resting arterial oxygen saturation ?88% on room air at screening), or with surgical repair, of at least 6 month duration, of a congenital systemic-to pulmonary shunt (for example, ventricular septal defect, patent ductus arteriosus).
[3] 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 within 1 year of
screening. In the event that a pulmonary artery wedge pressure is unable to be obtained during right heart catheterization, patients 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.
[4] Have a WHO functional class value of I, II or III at the time of enrollment.
[5] If on an ERA (that is, bosentan or ambrisentan), must be on a maintenance dose, with no change in dose (other than weight-based adjustments) for ?12 weeks prior to screening and have a screening aspartate transaminase (AST) or alanine transaminase (ALT) <3 times the upper limit of normal.
[6] If on conventional PAH medication, including but not restricted to, calcium channel blockers, 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] Have a chest radiograph (CXR) within 6 months of screening that shows clear lung fields or no more than mild patchy (not diffuse) interstitial infiltrates.
[8] 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 a reliable method of birth control as determined by the investigator during the study.
Examples of reliable birth control methods include abstinence; 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).
[9] Written informed consent from parents or guardians (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: 24
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:
Patients are not eligible to be included in the study if they meet any of the following exclusion criteria:
[10] Have pulmonary hypertension related to conditions other than specified above, including but not limited to chronic thromboembolic disease, portal pulmonary hypertension, leftsided heart disease or lung disease and hypoxia.
[11] 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.
[12] History of atrial septostomy or Potts Shunt within 3 months before administration of study drug.
[13] Unrepaired congenital heart disease except associated with an atrial-ventricular septal defect.
[14] Concurrent PDE-5 inhibitor therapy (sildenafil or vardenafil) or has received PDE-5 inhibitor therapy within 24 hours prior to the first study drug dosing (baseline visit).
[15] Concurrent therapy with prostacyclin or its analogues.
[16] Commence or discontinue a conventional PAH medication including but not restricted to: calcium channel blockers, diuretics, anti-coagulants, digoxin, and oxygen therapy within 4 weeks prior to screening.
[17] 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.
[18] Currently receiving treatment with doxazosin, nitrates or cancer therapy.
[19] Current treatment with antiretroviral therapy (protease inhibitor), systemic ketoconazole or systemic itraconazole.
[20] Are nursing or pregnant.
[21] Have a WHO functional class value of IV at the time of enrollment.
[22] Have severe hepatic cirrhosis, Child-Pugh Grade C.
[23] Have severe renal insufficiency, defined as receiving renal dialysis or having a measured or estimated creatinine clearance (CC) < 30 mL/min (Schwartz Formula):
All Females and Pre-adolescent Males:
Ccr (mL/min/1.73 m2) = 0.55 × Height (cm) / SCr (mg/dL)
Adolescent Males:
Ccr (mL/min/1.73 m2) = 0.70 × Height (cm) / SCr (mg/dL)
Where Ccr is Creatinine Clearance and SCr is Serum Creatinine
[24] Have severe hypotension or uncontrolled hypertension as determined by the Investigator.
[25] Diagnosed with a retinal disorder (for example, hereditary retinal disorders, retinopathy of the preterm and other retinal disorders)
[26] Have significant parenchymal lung disease.
[27] Have bronchopulmonary dysplasia.
[28] Have hemoglobinopathies.
[29] Have a history of drug, alcohol, or substance abuse within the past 6 months or present use, as assessed by the investigator.
[30] Have previously completed or withdrawn from this study (Study LVIG), or any other study investigating tadalafil.
[31] Have previously taken tadalafil or are hypersensitive to tadalafil.
[32] Unable to take orally administered tablet (without chewing, crushing or breaking) or liquid suspension.
[33] Investigator site personnel (or their immediate family) directly affiliated with this study. Immediate family i

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

Health Condition(s) or Problem(s) studied

Pulmonary Arterial Hypertension
MedDRA version: 14.0 Level: PT Classification code 10064911 Term: Pulmonary arterial hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders

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

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-

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-

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-

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-

Product Name: LY450190
Product Code: LY450190
Pharmaceutical Form: Oral suspension
INN or Proposed INN: TADALAFIL
CAS Number: 171596-29-5
Other descriptive name: LY450190
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2.0-

Primary Outcome(s)

Main Objective: Main objective of the trial is to characterize the pharmacokinetics (PK) of tadalafil in a pediatric population with pulmonary arterial hypertension (PAH) to establish an appropriate dose range for further clinical research.

Primary end point(s): Safety: Safety will be evaluated using spontaneously reported adverse events, clinical laboratory data, vital signs, physical examinations, and centralized 12-lead electrocardiograms (ECGs) as outlined in the schedule of events.

Bioanalytical: Plasma concentrations of tadalafil.

Pharmacokinetic/Pharmacodynamic: The pharmacokinetic parameters estimated during analysis will include area under the concentration-time curve (AUC), maximal concentration (Cmax), time of Cmax (tmax), apparent clearance (CL/F), apparent volume of distribution (Vz/F), and terminal half-life (t½), as appropriate.

Timepoint(s) of evaluation of this end point: Throughout the duration of the study

Secondary Objective: Secondary Objectives:
- To assess the tolerability and safety of tadalafil in a pediatric population with PAH.
- To compare tadalafil PK profile in a pediatric population with historical adult data from Study H6D-MC-LVGY.
- To assess the palatability of the tadalafil suspension.

Open-label Extension Objective (Period 2):
- To evaluate long-term safety while providing continued access to tadalafil for pediatric patients completing Period 1.
- To evaluate clinical worsening (CW), defined as any of the following: death, lung or heart transplantation, atrial septostomy or potts shunt, hospitalization due to worsening PAH, new onset syncope, initiation of new PAH therapy, worsening of World Health Organization (WHO) functional class by 1 or more, and decreasing of 20% in the 6-minute walk (6MW) test (for those patients ?7 years of age).

Secondary Outcome(s)

Secondary end point(s): NA

Timepoint(s) of evaluation of this end point: NA

Secondary ID(s)

H6D-MC-LVIG

Source(s) of Monetary Support

Eli Lilly and Company

Ethics review

Status: Approved
Approval date: 13/12/2011
Contact:

Results

• Results available: Yes
• Date Posted: 13/10/2019
• Date Completed: 03/04/2019
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-001873-24/results