Hypertension, Pulmonary
Conditions
Brief summary
The main purpose of this study is to evaluate the safety and efficacy of tadalafil in pediatric participants with pulmonary arterial hypertension. Participants will receive study treatment for 6 months in the double-blind period (Period 1), and then will be eligible to enroll into an open-label 2 year extension period (Period 2) during which participants will receive tadalafil.
Interventions
DRUGTadalafil
Administered orally by tablet form for heavy and middle weight participants. Administered orally by suspension for light weight participants.
DRUGPlacebo
Administered orally by tablet for heavy and middle weight participants. Administered orally by suspension for light weight participants.
DRUGERA as specific PAH treatment
All participants were taking endothelin receptor antagonist (ERA) (such as bosentan, ambrisentan and macitentan).
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Months to 17 Years
Healthy volunteers
No
Inclusion criteria
* ≥6 months to \<18 years of age at screening * 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) * Have a history of a diagnosis of PAH established by a resting mean pulmonary artery pressure (mPAP) ≥25 millimeter of mercury (mm Hg), pulmonary artery wedge pressure ≤15 mm Hg, and a pulmonary vascular resistance (PVR) ≥3 Wood units via right heart catheterization (RHC). In the event that a pulmonary artery wedge pressure cannot be obtained during RHC, participants 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 * Have a World Health Organization (WHO) functional class value of II or III at the time of screening * All participants must be receiving an endothelin receptor antagonist (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) * If on conventional PAH medication, including but not restricted to, anticoagulants, diuretics, digoxin, and oxygen therapy, the participant must be on stable doses with no changes (other than weight-based adjustments) for at least 4 weeks before screening * Female participants of childbearing potential must test negative for pregnancy during screening. Furthermore, female participants 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) * Written informed consent from parents (and written assent from appropriately aged participants) will be obtained prior to any study procedure being performed
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 \[pulmonary artery occlusion pressure (PAOP) 15-18 mm Hg\] aortic or mitral valve disease (ie, 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 * Unrepaired congenital heart disease * 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 * Have severe hepatic impairment, Child-Pugh Grade C * Have severe renal insufficiency, defined as receiving renal dialysis or having a measured or estimated creatinine clearance (CC) \<30 millimeter per minute (mL/min) (Schwartz Formula) * Diagnosed with a retinal disorder (eg, hereditary retinal disorders, retinopathy of the preterm participant and other retinal disorders) * Have severe hypotension or uncontrolled hypertension as determined by the Investigator * Have significant parenchymal lung disease * Have bronchopulmonary dysplasia * Concurrent phosphodiesterase type 5 (PDE5) inhibitor therapy (sildenafil or vardenafil) or has received PDE5 inhibitor therapy within 12 weeks prior to the first study drug dosing * Concurrent therapy with prostacyclin or its analogues within 12 weeks of screening * Commenced or discontinued a chronic conventional PAH medication including but not restricted to: diuretics, anti-coagulants, digoxin, and oxygen therapy within 4 weeks of screening * Currently receiving treatment with doxazosin, nitrates, or cancer therapy * Current treatment with potent Cytochrome P450 3A4 (CYP3A4) inhibitors, such as antiretroviral therapy (protease inhibitor), systemic ketoconazole, or systemic itraconazole, or chronic use of potent CYP3A4 inducers, such as rifampicin * Are nursing or pregnant * Have previously completed or withdrawn from this study (LVHV), or any other study investigating tadalafil * Have received tadalafil therapy within 12 weeks prior to the first study drug dosing or are hypersensitive to tadalafil * Have allergy to the excipients, notably lactose * Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved 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 * Unable to take orally administered tablets (without chewing, crushing or breaking) or suspension * Are Investigator site personnel directly affiliated with this study or their immediate families. Immediate family is defined as a spouse, parent, child or sibling, whether biological or legally adopted * Diagnosis of Down syndrome
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Period 1: Change From Baseline to Week 24 in a 6 Minute Walk (MW) Distance in Meters | Baseline, Week 24 | 6MWD in meters assessed in a subset of participants who are ≥6 to \<18 years of age who are developmentally capable of performing a 6MW test. Change from baseline was derived using mixed model repeated measures (MMRM) with terms for treatment group, visit, baseline 6MWD, and treatment-by-visit interaction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Period 1: Time to Adjudicated Clinical Worsening (CW) | Baseline through Week 24 | 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). Criteria for CW(from Period 1) were adjudicated by an independent,blinded study-specific Clinical Endpoint Committee(CEC).This adjudication was used for data analysis, and was not used to guide subject treatment. |
| Period 1: Percentage of Participants Who Experience CW | Baseline through Week 24 | 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).Criteria for CW(from Period 1) were adjudicated by an independent,blinded study-specific Clinical Endpoint Committee(CEC).This adjudication was used for data analysis, and was not used to guide subject treatment. |
| Period 1: Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil at Steady-state | Week 2, Week 4, Week 16 and Week 24 | Period 1: Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil at steady-state |
| Period 2: Percentage of Participants Who Experience CW | Period 2 Baseline through Study Completion (Up to 24 Months) | 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). |
| Period 2: Time to First Occurrence of CW | Period 2 Baseline through Study Completion (Up to 24 Months) | 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). |
Countries
Austria, Belgium, Brazil, France, Germany, Israel, Italy, Japan, Mexico, Netherlands, Poland, Spain, Turkey (Türkiye), United States
Participant flow
Pre-assignment details
Per protocol and statistical analysis plan (SAP), the primary and secondary analysis from period 1 were performed to compare all tadalafil participants together versus all placebo participants together.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Period 1: Participants received placebo orally by tablets once a day. | 18 |
| Tadalafil Period 1: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered orally by tablets once a day. | 17 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Period 1: Double Blind | Entry Criteria Not Met | 1 | 0 | 0 | 0 |
| Period 1: Double Blind | Investigator Reported Clinical Worsening | 1 | 1 | 0 | 0 |
| Period 1: Double Blind | Parent/Caregiver Decision | 1 | 1 | 0 | 0 |
| Period 2: Open-Label Treatment | Adverse Event | 0 | 0 | 0 | 1 |
| Period 2: Open-Label Treatment | Parent/caregiver Decision | 0 | 0 | 1 | 1 |
| Period 2: Open-Label Treatment | Withdrawal by Subject | 0 | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | Total | Tadalafil | Placebo |
|---|---|---|---|
| 6 Minute Walk Distance | 481.1 Meters STANDARD_DEVIATION 132.77 | 485.8 Meters STANDARD_DEVIATION 160.231 | 476.7 Meters STANDARD_DEVIATION 105.11 |
| Age, Continuous | 13.5 years STANDARD_DEVIATION 3.45 | 14.1 years STANDARD_DEVIATION 3.49 | 12.8 years STANDARD_DEVIATION 3.39 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 15 Participants | 8 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 4 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 10 Participants | 5 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 26 Participants | 12 Participants | 14 Participants |
| Region of Enrollment Brazil | 15 Participants | 6 Participants | 9 Participants |
| Region of Enrollment France | 2 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Germany | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Israel | 6 Participants | 4 Participants | 2 Participants |
| Region of Enrollment Japan | 2 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Mexico | 5 Participants | 4 Participants | 1 Participants |
| Region of Enrollment Poland | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Turkey | 3 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Female | 19 Participants | 10 Participants | 9 Participants |
| Sex: Female, Male Male | 16 Participants | 7 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 17 | 0 / 16 | 0 / 16 |
| other Total, other adverse events | 8 / 18 | 15 / 17 | 11 / 16 | 12 / 16 |
| serious Total, serious adverse events | 0 / 18 | 0 / 17 | 4 / 16 | 1 / 16 |
Outcome results
Primary
Period 1: Change From Baseline to Week 24 in a 6 Minute Walk (MW) Distance in Meters
6MWD in meters assessed in a subset of participants who are ≥6 to \<18 years of age who are developmentally capable of performing a 6MW test. Change from baseline was derived using mixed model repeated measures (MMRM) with terms for treatment group, visit, baseline 6MWD, and treatment-by-visit interaction.
Time frame: Baseline, Week 24
Population: All participants who received at least one dose of study drug who were \> = 6 to \< 18 years of age and were capable of performing a 6MW test.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Period 1: Change From Baseline to Week 24 in a 6 Minute Walk (MW) Distance in Meters | 36.60 Meters | Standard Error 20.776 |
| Tadalafil | Period 1: Change From Baseline to Week 24 in a 6 Minute Walk (MW) Distance in Meters | 60.48 Meters | Standard Error 20.41 |
80% CI: [-14.25, 62]
Secondary
Period 1: Percentage of Participants Who Experience CW
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).Criteria for CW(from Period 1) were adjudicated by an independent,blinded study-specific Clinical Endpoint Committee(CEC).This adjudication was used for data analysis, and was not used to guide subject treatment.
Time frame: Baseline through Week 24
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Period 1: Percentage of Participants Who Experience CW | 0 percentage of participants |
| Tadalafil | Period 1: Percentage of Participants Who Experience CW | 0 percentage of participants |
Secondary
Period 1: Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil at Steady-state
Period 1: Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil at steady-state
Time frame: Week 2, Week 4, Week 16 and Week 24
Population: All participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Period 1: Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil at Steady-state | With concomitant bosentan | 3.63 Liter Per Hour (L/hr) | Geometric Coefficient of Variation 38.1 |
| Placebo | Period 1: Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil at Steady-state | No bosentan (ERA: Macitentan) | NA Liter Per Hour (L/hr) | — |
| Tadalafil | Period 1: Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil at Steady-state | With concomitant bosentan | 4.49 Liter Per Hour (L/hr) | Geometric Coefficient of Variation 28.2 |
Secondary
Period 1: Time to Adjudicated Clinical Worsening (CW)
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). Criteria for CW(from Period 1) were adjudicated by an independent,blinded study-specific Clinical Endpoint Committee(CEC).This adjudication was used for data analysis, and was not used to guide subject treatment.
Time frame: Baseline through Week 24
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Period 1: Time to Adjudicated Clinical Worsening (CW) | NA Weeks |
| Tadalafil | Period 1: Time to Adjudicated Clinical Worsening (CW) | NA Weeks |
Secondary
Period 2: Percentage of Participants Who Experience CW
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: Period 2 Baseline through Study Completion (Up to 24 Months)
Population: Period 2: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Period 2: Percentage of Participants Who Experience CW | 12.5 percentage of participants |
| Tadalafil | Period 2: Percentage of Participants Who Experience CW | 18.8 percentage of participants |
Secondary
Period 2: Time to First Occurrence of CW
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: Period 2 Baseline through Study Completion (Up to 24 Months)
Population: Period 2: All participants who received at least one dose of study drug, who entered the open-label treatment Period
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Period 2: Time to First Occurrence of CW | NA Months |
| Tadalafil | Period 2: Time to First Occurrence of CW | NA Months |