| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary Arterial Hypertension |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pulmonary hypertension is increased blood pressure in the arteries that make up the lungs |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064911 |
| E.1.2 | Term | Pulmonary arterial hypertension |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
-To assess the tolerability & safety of tadalafil in a pediatric population with PAH.
-To compare tadalafil PK profile in a pediatric population with historical adult data.
-To determine appropriate dose ranges for use in the evaluation of efficacy & safety of tadalafil.
-To clinically assess the palatability of the tadalafil suspension.
-To evaluate long-term safety.
-To evaluate clinical worsening defined as: death, lung or heart transplantation, atrial septostomy or potts shunt, hospitalization due to worsening PAH, new onset syncope, initiation of new PAH therapy, or increase of >1 in WHO Functional Class (except for patients already in Class IV) only for patients unable to perform the 6MW test;
worsening of WHO functional class by >1 for patients who can perform a 6MW test & who have a decrease of ≥ 20% in the 6MW distance (for those patients who are ≥6 years of age).
-To evaluate cardiopulmonary hemodynamic changes from Visit 2 to 10 as assessed by Echocardiography. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 (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).
[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 2 years 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] Patients with PAH either naïve to PAH specific therapy or receiving
endothelin receptor antagonists (ERA). 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 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).
[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. |
|
| E.4 | Principal 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 Potts Shunt within 3 months before administration of study drug.
[13] Unrepaired congenital heart disease.
[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 potent CYP3A4 inhibitors, such as antiretroviral therapy (protease inhibitor), systemic ketoconazole or systemic itraconazole, or chronic use of potent CYP3AA inducers, such as rifampicin.
[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 is defined as a spouse, parent, child or sibling, whether biological or legally adopted.
[34] Are Lilly employees, (that is, employees, temporary contract workers, or designees responsible for the conduct of the study). Immediate family of Lilly employees may participate in Lilly-sponsored clinical trials, but are not permitted to participate at a Lilly facility. Immediate family is defined as a spouse, parent, child or sibling, whether biological or legally adopted.
[35] Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational drug or device or off-label 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.
[36] Are allergic to any of the excipients, notably lactose.
[37] 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.
[38] Patients with anatomical deformation of the penis or who are pre-disposed to priapism must be excluded from the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is pharmacokinetic assessment of plasma tadalafil concentration across all patient at end of study.
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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Throughout the duration of the study |
|
| E.5.2 | Secondary 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout the duration of the study |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability, Assessment of the palatability of the tadalafil suspension |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| France |
| Poland |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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