Pulmonary Arterial Hypertension
Conditions
Brief summary
The purpose of this study is to see how much study drug is in the blood of children with pulmonary arterial hypertension (PAH) after dosing to establish the correct dose for further clinical research.
Detailed description
During Period I, tadalafil will be administered orally, once daily, at a low dose for approximately 5 weeks followed by a high dose for approximately 5 weeks. Dose levels are calculated based on body weight cohorts. Heavy weight cohort \>=40 kg, middle weight cohort \>=25 kg to \<40 kg. Light weight cohort\<25 kg. Participants who complete Period 1 may continue taking tadalafil in Period 2 for at least 2 years. Starting dose will not exceed the maximum weight range dose established in Period 1 and after the first 3 months of Period 2, the dose may be adjusted based on available safety and efficacy information.
Interventions
DRUGTadalafil- Tablet or Oral suspension
Tadalafil Tablets administered orally. Tadalafil Oral suspension: An aqueous, ready-to-use suspension for oral administration.
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 17 Years
Healthy volunteers
No
Inclusion criteria
* 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). * 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. In the event that a pulmonary artery wedge pressure is unable to be obtained during right heart catheterization, participants 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 * Have a World Health Organization (WHO) functional class value of I, II or III at the time of enrollment
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 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 * History of atrial septostomy or Potts Shunt within 3 months before administration of study drug * Unrepaired congenital heart disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Population Pharmacokinetics: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau) for Tadalafil | Period 1: Pre Dose and 2, 4, 8, 12, and 24 Hours Post Dose on Days 1, 14 and 49; with single dose measures on Day 1 and steady-state measurements on Days 14 and 49 | Population Pharmacokinetics: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau) for Tadalafil. The measure of dispersion reported is 90% Prediction Intervals and not Confidence Intervals. |
| Population Pharmacokinetics: Average Concentration (Cmean,ss) of for Tadalafil at Steady-State. | Period 1: Pre Dose and 2, 4, 8, 12, and 24 Hours Post Dose on Days 1, 14 and 49; with single dose measures on Day 1 and steady-state measurements on Days 14 and 49 | Population Pharmacokinetics: Average Concentration (Cmean,ss) of for tadalafil at steady-state. The measure of dispersion reported is 90% Prediction Intervals and not Confidence Intervals. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Clinical Worsening | Baseline Up to 27 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). |
| Number of Participants With Palatability of the Tadalafil Suspension | Day 35 (high dose) | The Taste Assessment Questionnaire (TAQ) questions were: TAQRES1: Please rate the bitterness level. TAQRES2: Please rate the sweetness level. TAQRES3: Please rate the aftertaste. TAQRES4: Please rate the overall acceptability of the taste for daily use. |
Countries
Canada, France, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
Per protocol, the summary was based on weight cohorts.
Pre-assignment details
This study contains 2 periods: Pharmacokinetics(PK)/safety Period 1 and an open-label safety extension Period 2. Period 1 is approximately 10 weeks (that is, approximately 5 consecutive weeks for each dose \[low and high\]). Period 2 is at least 2 years after participating in Period 1.
Participants by arm
| Arm | Count |
|---|---|
| Light Weight: <25 kg Period 1: 2 milligram (mg) or 4 mg tadalafil administered once daily (QD) in oral suspension formulation for 5 weeks then 8 mg,10 mg,15 mg or 20 mg tadalafil was administered QD in oral suspension formulation for 5 weeks. | 6 |
| Middle Weight: 25 kg to <40 kg Period 1: 5 mg tadalafil tablet administered QD for 5 weeks then 10 mg, 15 mg or 20 mg tablet tadalafil administered QD for 5 weeks. | 7 |
| Heavy Weight: ≥40 kg Period 1: 10 mg tadalafil tablet administered QD for 5 weeks then 20 mg or 40 mg tablet tadalafil administered QD for 5 weeks. | 6 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Period 1: High Dose | Physician Decision | 0 | 1 | 0 |
| Period 2 | Death | 0 | 1 | 1 |
| Period 2 | Non-Compliance with Study Drug | 1 | 0 | 0 |
| Period 2 | Physician Decision | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Light Weight: <25 kg | Middle Weight: 25 kg to <40 kg | Heavy Weight: ≥40 kg |
|---|---|---|---|---|
| Age, Continuous | 10.16 years | 5.00 years | 10.91 years | 14.45 years |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 4 Participants | 5 Participants | 5 Participants |
| Region of Enrollment Canada | 5 Participants | 3 Participants | 1 Participants | 1 Participants |
| Region of Enrollment France | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Poland | 5 Participants | 1 Participants | 2 Participants | 2 Participants |
| Region of Enrollment Spain | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United Kingdom | 3 Participants | 0 Participants | 3 Participants | 0 Participants |
| Region of Enrollment United States | 2 Participants | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 13 Participants | 4 Participants | 5 Participants | 4 Participants |
| Sex: Female, Male Male | 6 Participants | 2 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 1 / 7 | 1 / 6 |
| other Total, other adverse events | 6 / 6 | 7 / 7 | 6 / 6 |
| serious Total, serious adverse events | 1 / 6 | 4 / 7 | 3 / 6 |
Outcome results
Primary
Population Pharmacokinetics: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau) for Tadalafil
Population Pharmacokinetics: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau) for Tadalafil. The measure of dispersion reported is 90% Prediction Intervals and not Confidence Intervals.
Time frame: Period 1: Pre Dose and 2, 4, 8, 12, and 24 Hours Post Dose on Days 1, 14 and 49; with single dose measures on Day 1 and steady-state measurements on Days 14 and 49
Population: All participants who received at least one dose of study drug and had evaluable PK data including all dose levels on Day 1, 14 and 49. Per protocol, the summary reflects potential exposure of the high dose within each weight cohort
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 20 mg Light Weight: <25 kg | Population Pharmacokinetics: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau) for Tadalafil | Not Taking Bosentan | 8170 nanograms* hour per milliliter(ng*hr/mL) |
| 20 mg Light Weight: <25 kg | Population Pharmacokinetics: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau) for Tadalafil | Taking Concomitant Bosentan | 4550 nanograms* hour per milliliter(ng*hr/mL) |
| 20 mg Middle Weight: 25 kg to <40 kg | Population Pharmacokinetics: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau) for Tadalafil | Not Taking Bosentan | 8390 nanograms* hour per milliliter(ng*hr/mL) |
| 20 mg Middle Weight: 25 kg to <40 kg | Population Pharmacokinetics: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau) for Tadalafil | Taking Concomitant Bosentan | 5000 nanograms* hour per milliliter(ng*hr/mL) |
| 40 mg Heavy Weight: ≥40 kg | Population Pharmacokinetics: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau) for Tadalafil | Not Taking Bosentan | 15200 nanograms* hour per milliliter(ng*hr/mL) |
| 40 mg Heavy Weight: ≥40 kg | Population Pharmacokinetics: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau) for Tadalafil | Taking Concomitant Bosentan | 8990 nanograms* hour per milliliter(ng*hr/mL) |
Primary
Population Pharmacokinetics: Average Concentration (Cmean,ss) of for Tadalafil at Steady-State.
Population Pharmacokinetics: Average Concentration (Cmean,ss) of for tadalafil at steady-state. The measure of dispersion reported is 90% Prediction Intervals and not Confidence Intervals.
Time frame: Period 1: Pre Dose and 2, 4, 8, 12, and 24 Hours Post Dose on Days 1, 14 and 49; with single dose measures on Day 1 and steady-state measurements on Days 14 and 49
Population: All participants who received at least one dose of study drug and had evaluable PK data including all dose levels on Day 1, 14 and 49. Per protocol, the summary reflects potential exposure of the high dose within each weight cohort
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 20 mg Light Weight: <25 kg | Population Pharmacokinetics: Average Concentration (Cmean,ss) of for Tadalafil at Steady-State. | Not Taking Bosentan | 340 nanograms per milliliter (ng/mL) |
| 20 mg Light Weight: <25 kg | Population Pharmacokinetics: Average Concentration (Cmean,ss) of for Tadalafil at Steady-State. | Taking Concomitant Bosentan | 190 nanograms per milliliter (ng/mL) |
| 20 mg Middle Weight: 25 kg to <40 kg | Population Pharmacokinetics: Average Concentration (Cmean,ss) of for Tadalafil at Steady-State. | Not Taking Bosentan | 350 nanograms per milliliter (ng/mL) |
| 20 mg Middle Weight: 25 kg to <40 kg | Population Pharmacokinetics: Average Concentration (Cmean,ss) of for Tadalafil at Steady-State. | Taking Concomitant Bosentan | 209 nanograms per milliliter (ng/mL) |
| 40 mg Heavy Weight: ≥40 kg | Population Pharmacokinetics: Average Concentration (Cmean,ss) of for Tadalafil at Steady-State. | Not Taking Bosentan | 633 nanograms per milliliter (ng/mL) |
| 40 mg Heavy Weight: ≥40 kg | Population Pharmacokinetics: Average Concentration (Cmean,ss) of for Tadalafil at Steady-State. | Taking Concomitant Bosentan | 375 nanograms per milliliter (ng/mL) |
Secondary
Number of Participants With Palatability of the Tadalafil Suspension
The Taste Assessment Questionnaire (TAQ) questions were: TAQRES1: Please rate the bitterness level. TAQRES2: Please rate the sweetness level. TAQRES3: Please rate the aftertaste. TAQRES4: Please rate the overall acceptability of the taste for daily use.
Time frame: Day 35 (high dose)
Population: Participants who received at least one oral suspension dose of study drug in the Light-weight cohort (≥2 years of age). Per protocol, palatability of the tadalafil suspension was evaluated in the Light-weight cohort only.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 20 mg Light Weight: <25 kg | Number of Participants With Palatability of the Tadalafil Suspension | TAQRES3:No aftertaste | 2 Participants |
| 20 mg Light Weight: <25 kg | Number of Participants With Palatability of the Tadalafil Suspension | TAQRES4: Not acceptable | 0 Participants |
| 20 mg Light Weight: <25 kg | Number of Participants With Palatability of the Tadalafil Suspension | TAQRES4: Slightly acceptable | 0 Participants |
| 20 mg Light Weight: <25 kg | Number of Participants With Palatability of the Tadalafil Suspension | TAQRES4: Acceptable | 2 Participants |
| 20 mg Light Weight: <25 kg | Number of Participants With Palatability of the Tadalafil Suspension | TAQRES4: Very acceptable | 1 Participants |
| 20 mg Light Weight: <25 kg | Number of Participants With Palatability of the Tadalafil Suspension | TAQRES1: Extremely bitter | 0 Participants |
| 20 mg Light Weight: <25 kg | Number of Participants With Palatability of the Tadalafil Suspension | TAQRES1: Very bitter | 0 Participants |
| 20 mg Light Weight: <25 kg | Number of Participants With Palatability of the Tadalafil Suspension | TAQRES1: Moderately bitter | 0 Participants |
| 20 mg Light Weight: <25 kg | Number of Participants With Palatability of the Tadalafil Suspension | TAQRES1: Slightly bitter | 0 Participants |
| 20 mg Light Weight: <25 kg | Number of Participants With Palatability of the Tadalafil Suspension | TAQRES1: Not bitter | 3 Participants |
| 20 mg Light Weight: <25 kg | Number of Participants With Palatability of the Tadalafil Suspension | TAQRES2: Extremely sweet | 1 Participants |
| 20 mg Light Weight: <25 kg | Number of Participants With Palatability of the Tadalafil Suspension | TAQRES2: Very sweet | 0 Participants |
| 20 mg Light Weight: <25 kg | Number of Participants With Palatability of the Tadalafil Suspension | TAQRES2: Moderately sweet | 1 Participants |
| 20 mg Light Weight: <25 kg | Number of Participants With Palatability of the Tadalafil Suspension | TAQRES2: Slightly sweet | 1 Participants |
| 20 mg Light Weight: <25 kg | Number of Participants With Palatability of the Tadalafil Suspension | TAQRES2: Not sweet | 0 Participants |
| 20 mg Light Weight: <25 kg | Number of Participants With Palatability of the Tadalafil Suspension | TAQRES3: Extreme aftertaste | 0 Participants |
| 20 mg Light Weight: <25 kg | Number of Participants With Palatability of the Tadalafil Suspension | TAQRES3: Strong aftertaste | 1 Participants |
| 20 mg Light Weight: <25 kg | Number of Participants With Palatability of the Tadalafil Suspension | TAQRES3: Moderate aftertaste | 0 Participants |
| 20 mg Light Weight: <25 kg | Number of Participants With Palatability of the Tadalafil Suspension | TAQRES3:Slight aftertaste | 0 Participants |
Secondary
Percentage of Participants With Clinical Worsening
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: Baseline Up to 27 Months
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 20 mg Light Weight: <25 kg | Percentage of Participants With Clinical Worsening | 50.00 percentage of participants |
| 20 mg Middle Weight: 25 kg to <40 kg | Percentage of Participants With Clinical Worsening | 28.57 percentage of participants |
| 40 mg Heavy Weight: ≥40 kg | Percentage of Participants With Clinical Worsening | 33.33 percentage of participants |