| 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 | 18.0 |
| 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 |
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 |
|
| E.2.2 | Secondary objectives of the trial |
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 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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. |
|
| E.4 | Principal 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. |
|
| E.5 End points |
| E.5.1 | 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. |
|
| E.5.1.1 | 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.
|
|
| E.5.2 | 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.
|
|
| E.5.2.1 | 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.
|
|
| 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 | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Austria |
| Belgium |
| Brazil |
| Canada |
| France |
| Germany |
| Italy |
| Japan |
| Mexico |
| Netherlands |
| Poland |
| Romania |
| Spain |
| Switzerland |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
Print
