| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary Arterial Hypertension (PAH) |
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| E.1.1.1 | Medical condition in easily understood language |
Pulmonary Arterial Hypertension is a condition where the blood pressure is too high in the blood vessels between the heart and the lungs.
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| 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 |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065151 |
| E.1.2 | Term | Idiopathic pulmonary arterial hypertension |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065152 |
| E.1.2 | Term | Familial pulmonary arterial hypertension |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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| 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 evaluate the safety and tolerability of a rapid dose titration regimen of SC (subcutaneous) Remodulin therapy in patients with PAH.
Safety and tolerability of the rapid dose titration regimen will be considered to be demonstrated by all clinical trial subjects that complete the 16 week treatment period of the study without experiencing any serious adverse events considered by the investigator to be possibly related to Remodulin. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of this study are to assess the effect of SC (subcutaneous) Remodulin on exercise capacity, NTproBNP, WHO functional class, Borg dyspnoea score, quality of life, right ventricular function, haemodynamics, symptoms of PAH, patient reported site reaction assessment and safety. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The subject is at least 18 years of age at screening.
2. The subject weighs a minimum of 40 kilograms with a body mass index less than 40 kg/m2 at screening.
3. Sexually active women of childbearing potential must use two different forms of highly effective contraception. Medically acceptable forms of effective contraception include: (1) approved hormonal contraceptive (such as birth control pills), (2) barrier methods (such as a condom or diaphragm) used with a spermicide, (3) an intrauterine device (IUD), or (4) partner vasectomy. For women of childbearing potential, a negative serum pregnancy test is required at screening and a negative hCG urine pregnancy test is required at baseline visit. Women of child bearing potential include any female who have experienced menarche and who have not undergone successful surgical sterilisation (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or are not postmenopausal [defined as amenorrhea ≥ 12 consecutive months]. Males participating in the study must use a condom during the length of the study, and for at least 64 days after discontinuing study medication.
4. The subject has a diagnosis of symptomatic idiopathic or heritable PAH.
5. The subject must have a baseline six minute walk distance between 150 and 550 metres, inclusive, in the absence of a concurrent injury, illness (other than PAH or a PAH related condition), or other confounding factor that would prevent the accurate assessment of the subject’s exercise capacity.
6. The subject is either treatment naïve or is receiving an approved PDE-5 inhibitor and/or an approved ERA for at least 60 days prior to screening and on a stable dose for 30 days and is willing to remain on a PDE-5 inhibitor and/or an ERA at the same dose for the duration of the 16-week treatment Phase.
7. The subject must be optimally treated with conventional pulmonary hypertension therapy (e.g. oral vasodilators, oxygen, digoxin, etc) with no additions, discontinuations, or dose changes for at least 14 days prior to screening (excluding diuretics and anticoagulant dose adjustments).
8. The subject has undergone right heart catheterisation at screening (or within 8 weeks before screening*) and been documented to have a mean pulmonary artery pressure (PAPm) of greater than or equal to 25 mmHg, a pulmonary capillary wedge pressure (PCWP) of less than or equal to 15 mmHg, and pulmonary vascular resistance (PVR) of more than 3 Wood units. In the event that a reliable PCWP is unable to be obtained, subjects with clinically normal left heart function and absence of clinically relevant mitral valve disease on echocardiography are eligible for enrollment.[*]
9. The subject has undergone echocardiography at screening with evidence of clinically normal left systolic and diastolic ventricular function, absence of any clinically significant left sided heart disease (e.g. mitral valve stenosis) and absence of unrepaired congenital heart disease. Subjects with clinically insignificant left ventricular diastolic dysfunction due to the effects of right ventricular overload (i.e. right ventricular hypertrophy and/or dilatation) will not be excluded.
10. The subject has a previous ventilation perfusion lung scan and/or high resolution computerised tomography scan of the chest and/or pulmonary angiography that are consistent with the diagnosis of PAH (e.g., low probability of pulmonary embolism; absence of major perfusion defects).
11. The subject has pulmonary function tests done within 9 months of screening with the following:
a. Total lung capacity (TLC) is at least 60% (of predicted value)
b. Forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio is at least 50%
12. In the opinion of the Principal Investigator, the subject is able to communicate effectively with study personnel, is considered reliable, willing and likely to be cooperative with protocol requirements, including attending all study visits, and is mentally and physically capable of learning to administer Remodulin by continuous SC infusion using a micro infusion pump.
13. The subject voluntarily gives written informed consent to participate in the study.
*please refer to the protocol for further information
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| E.4 | Principal exclusion criteria |
1. The subject is pregnant or lactating.
2. The subject has received epoprostenol, treprostinil, intravenous iloprost, or beraprost within 30 days prior to screening (except if used during acute vasoreactivity testing).
3. The subject has had previous intolerance or significant lack of efficacy to prostacyclin or a prostacyclin analogue that resulted in discontinuation or inability to titrate that therapy effectively.
4. The subject has any disease associated with PH other than IPAH or heritable PAH or has had an atrial septostomy.
5. The subject is in WHO functional class IV.
6. The subject has a current diagnosis of uncontrolled sleep apnoea as defined by their physician.
7. The subject has liver function tests (AST or ALT) greater than three times the upper limit of the laboratory reference range and / or an international normalised ratio (INR) greater than 3 units at screening.
8. The subject has a history of active gastro-intestinal ulcer, intracranial haemorrhage, injury or other cause of clinically significant bleeding episode within 6 months before screening, or any other disease / condition that would either jeopardise the safety of the subject and / or interfere with the interpretation of study assessments in the opinion of the Investigator.
9. The subject has a history of ischemic heart disease including previous myocardial infarction or symptomatic coronary artery disease within 6
months of screening, or history of left sided myocardial disease as evidenced by a PCWP (or LVEDP) greater than 15 mmHg or left ventricular ejection fraction (LVEF) less than 40%.
10. The subject has uncontrolled systemic hypertension as evidenced by systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 100 mmHg.
11. The subject has a musculoskeletal disorder (e.g. arthritis affecting the lower limbs, recent hip or knee joint replacement, artificial leg) or any
other disease that is likely to limit ambulation, or is connected to a machine that is not portable.
12. The subject has an unstable psychiatric condition or is mentally incapable of understanding the objectives, nature, or consequences of the trial, or has any condition which in the Investigator’s opinion would constitute an unacceptable risk to the subject’s safety.
13. The subject is receiving an investigational drug, has an investigational device in place or has participated in an investigational drug or device study within 30 days prior to screening. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Not applicable in this study |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Not applicable in this study |
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| E.5.2 | Secondary end point(s) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| For all efficacy endpoints, data from study assessments during the treatment phase will be descriptively compared to baseline assessments. |
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| 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 | No |
| 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 | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| 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 | 1 |
| 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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