| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary Arterial Hypertension |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064911 |
|
| 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 |
| The primary objective of this study is to assess the efficacy of 16 weeks of chronic treatment with oral sildenafil in pediatric subjects, aged 1 to 17 years, with PAH. Primary efficacy will be measured by exercise tolerance, bicycle ergometry testing in those subjects who are developmentally able to perform the exercise paradigm as described in Section 3.3.2 and Appendix E of the protocol. Secondary efficacy will be assessed in all subjects as described in Section 6.4.1.2. of the protocol. |
|
| E.2.2 | Secondary objectives of the trial |
- To assess safety, tolerability, and pharmacokinetics of 16 weeks of chronic treatment with oral sildenafil in pediatric subjects, aged 1 to 17 years with PAH.
- To assess the survival status of subjects who have discontinued study drug |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Male or female subjects aged from 1 to 17 years old. Females of child bearing potential who are sexually active must be practicing a suitable method of birth control so that in the opinion of the investigator, they will not become pregnant during the study;
- Subjects weighing ≥8 kg;
- Subjects who have symptomatic pulmonary arterial hypertension due to one of the
following conditions:
• Primary pulmonary hypertension;
• Pulmonary arterial hypertension in the presence of a small or hemodynamically insignificant congenital systemic to pulmonary shunt lesion that in the opinion of the investigator is not the cause of pulmonary hypertension;
• Pulmonary arterial hypertension associated with collagen vascular disease (e.g.,
scleroderma);
• Pulmonary arterial hypertension associated with congenital systemic-to-pulmonary shunts with a baseline resting room air oxygen saturation ≥88%. If the defect(s) is repaired, it should have been repaired at least 6 months prior to screening. Note: Repairs can be either surgical or via interventional cardiac catheterization (eg, ASD closure device or coil of PDA);
• Pulmonary arterial hypertension associated with d-transposition of the great arteries repaired within the first 30 days of life; or Pulmonary arterial hypertension in subjects who have undergone surgical repair of other congenital heart lesions at least 6 months prior to screening and do not have clinically significant residual left-sided heart disease consistent with the exclusion criteria.
- Subjects with a mean pulmonary artery pressure ≥25 mmHg at rest, PCWP
≤15 mmHg, and PVRI ≥3 Wood units x m2. If PCWP is not available, then mean
LA pressure ≤15 mmHg or LVEDP ≤15 mmHg in the absence of left atrial
obstruction;
Note: Hemodynamic measurements can be performed within 21 days prior to randomization for study purposes. These criteria must be within specified baseline limits for subject to qualify for randomization. Hemodynamic measurements from the retrospective right heart catheterization may be used for qualification provided the subject’s background therapy (class of drug) for PAH did not change for the 10 days prior to the procedure, and has not changed since the procedure was performed.
- Subjects, developmentally able to exercise, whose CPX exercise test functional
capacity is within the following parameters: Peak VO2 ≥10 mL/kg/min and
≤28 mL/kg/min during screening CPX test;
- The investigator must obtain written informed consent and assent where applicable
before the subject is screened for the study. The inclusion of a subject more than once in the same clinical trial is not permissible; and
- Subjects who undergo a large shift in altitude in order to participate in the study (e.g., live at altitude and shift to sea level in order to participate) must reside at the “in study” altitude for at least 90 days prior to baseline and during the study period.
Note: A “large shift is being defined as approximately 5000 feet or 1524 meters. |
|
| E.4 | Principal exclusion criteria |
All exclusion criteria must be adhered to. Subjects with any of following conditions cannot be enrolled into the study.
- Subjects with pulmonary hypertension secondary to sickle cell disease, any other
disease known to be associated with PAH, or any etiology other than those specified in the inclusion criteria;
- Left-sided heart disease, including any of the following:
• Aortic or mitral valve disease (greater than mild);
• Restrictive or congestive cardiomyopathy;
• PCWP or LVEDP > 15mmHg;
• LVEF <40% determined by MUGA, angiography or echocardiography;
• LV shortening fraction <22% determined by echocardiography;
• Symptomatic coronary disease (demonstrable ischemia)
- Pericardial constriction;
- Subjects with significant (2+ for regurgitation) valvular disease other than tricuspid or pulmonary regurgitation;
- Acutely decompensated heart failure within previous 30 days from screening;
- Subjects who have had an atrial septostomy within previous 6 months of screening;
- Subjects with hemodynamic instability or hypo- or hypertension at screening, i.e., SBP outside of 70-140 mmHg;
- Subjects with a history of stroke, myocardial infarction or life threatening arrhythmia
within 6 months of screening;
- Subjects with moderate to severe restrictive pulmonary disease (Total Lung Capacity or Forced Vital Capacity ≤60% of normal) or history of severe lung disease;
- Subjects with bronchopulmonary dysplasia (BPD) and other chronic lung diseases;
- Subjects with history of pulmonary embolism;
- Subjects whose CPX test is limited by conditions other than pulmonary hypertensionassociated dyspnea or fatigue;
- Subjects with known hereditary degenerative retinal disorders such as retinitis
pigmentosa;
- Subjects who are known to be HIV positive;
- Subjects with impairment of renal function (serum creatinine >2.5 × ULN ) or hepatic
function (ALT and/or AST >3 × ULN; and/or bilirubin ≥2 mg/dL). Hematological
abnormalities (e.g., severe anemia, Hgb <10 g/dL, leukopenia, WBC <2500/µL);
- Subjects who previously received bosentan and whose liver function tests taken at
screening are >2 × ULN;
- Subjects with any medical condition which in the opinion of the investigator may
interfere with treatment, evaluation of safety, and/or efficacy. Abnormalities of
questionable clinical significance must be discussed with a Pfizer clinician prior to
inclusion of the subject;
- Change in class of medication for CHF or PAH within the 10 days prior to qualifying
right heart catheterization. (Note: Discontinuation of coumadin, start of heparin, and
the re-starting of coumadin for cardiac catheterization is not considered change in dose or class.);
- Subjects who are currently prescribed and/or taking nitrates or nitric oxide donors in any form (oral, sublingual, buccal, transdermal, inhalational or aerosols). Acute
vasodilator testing with nitric oxide is permitted during hemodynamic evaluation;
- Subjects taking chronic arginine supplementation including Heart Bar;
- Subjects who within 3 months of screening have had therapy involving parenteral
inotropic medication (e.g., dobutamine or milrinone) or parenteral vasodilators (e.g..
nitroprusside);
- Subjects on alpha-blockers or potent cytochrome P450 3A4 inhibitors (e.g.,
erythromycin, ketoconazole, itraconazole and protease inhibitors);
- Subjects who are currently receiving Ritonavir or Nicorandil;
Subjects receiving chronic treatment with off-label sildenafil are excluded. Subjects
receiving an endothelin antagonist (e.g., bosentan) or, prostacyclin/prostacyclin
analogue within 30 days of randomization are excluded. Use of prostacyclin for acute
vasodilator testing during cardiac catheterization is allowed;
- Pregnant or lactating female;
- Subjects who have any medical or psychological condition or social circumstances that would impair their ability to participate reliably in the study or who may increase the risk to themselves or others by participating;
- Current or past illicit drug use or alcoholism excepting if abstinence can be
documented for ≥1 year;
- Participation in another clinical trial of an investigational drug or device (including
placebo) within 30 days of screening for entry into the present study; or
Note: If a subject has previously taken part in Study A1481134 or A1481157 at least 30 days prior to screening of this study and fulfills all inclusion criteria may be considered for entry into this study.
- In the opinion of the investigator, a subject who is not likely to complete the study for any reason.
- Subjects with known hereditary degenerative retinal disorders (such as retinitis
pigmentosa) or history of non-arteritic anterior ischemic optic neuropathy (NAION). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percent change in peak VO2 normalized to body weight from baseline to Week 16 assessed by CPX testing (bicycle ergometry). As described previously, this endpoint will be evaluated in those subjects who are developmentally able to perform the CPX test. |
|
| 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 | No |
| 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 | Yes |
| 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.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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