Study of a New Thermo Stable Formulation of Epoprostenol Sodium to Treat Pulmonary Arterial Hypertension (PAH)

Study Overview
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Brief Summary
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The purpose of this multicentre, open label, single-arm study in approximately 20 adult patients is to evaluate the Impact on lifestyle of a new thermo stable formulation of epoprostenol sodium in subjects with Pulmonary Arterial Hypertension (PAH).

Detailed Description
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This is a multicentre, open label, single-arm study in approximately 20 adult patients (18 - 75 years old) designed to evaluate the Impact on lifestyle of a new thermo stable formulation of epoprostenol sodium in subjects with Pulmonary Arterial Hypertension (PAH). The co-primary objectives are 1) to describe the effect of the new thermo stable formulation of epoprostenol sodium on quality of life and 2) to determine the dose titration requirement in patients switching from the currently marketed FLOLAN (epoprostenol sodium) to the new thermo stable formulation. Secondary objectives include assessing the safety, tolerability and efficacy of the thermo stable formulation of epoprostenol sodium and the exploratory objective is to evaluate the effect of the new thermo stable formulation of epoprostenol sodium on haemodynamic parameters in a subset of subjects. Subjects who are already receiving FLOLAN (epoprostenol sodium) for the treatment of PAH and have been on a stable dose for at least 3 months and on stable doses of other PAH treatments for at least 30 days prior to screening will be enrolled. After a screening visit, eligible subjects will have a 4-week run-in period with their existing FLOLAN (epoprostenol sodium) treatment. At the end of the 4-week period, they will be admitted to the clinic for baseline assessments and for switching to study medication (the new thermo stable formulation of epoprostenol sodium). Subjects will remain in hospital for a minimum of 6 hours to ensure clinical and hemodynamic stability prior to discharge. Subjects may stay in hospital for up to 24-48 hours after switching to the new thermo stable formulation of epoprostenol sodium at the discretion of the investigator. Dose titration requirement will be assessed at the time of discharge. Haemodynamic parameters will be obtained in a subgroup of subjects enrolled in centres where the collection of haemodynamic data is considered part of the standard of care. Subjects will receive the study medication as a continuous intravenous infusion for a 4-week treatment period. Those who complete the 4-week treatment period will have the option of entering an extension phase of the study to continue receiving the new formulation.

Official Title
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A Single-arm, Open Label Study Evaluating the Impact on Lifestyle of a New Thermo Stable Formulation of FLOLAN® in Subjects With Pulmonary Arterial Hypertension (PAH). (FLOLAN® is a Registered Trademark of the GlaxoSmithKline Group of Companies.)

Conditions
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Hypertension, Pulmonary

Intervention / Treatment
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* Drug: current marketed FLOLAN (epoprostenol sodium)
* Drug: new thermo stable formulation of epoprostenol sodium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult male or female at least 18 to 75 years at the time of screening. Subjects must have been on FLOLAN (epoprostenol sodium) therapy for pulmonary arterial hypertension (PAH) as approved in the product label. Subjects must be on stable doses of their existing FLOLAN (epoprostenol sodium) treatment for a minimum of 3 months prior to screening. Subjects must be on stable doses of any current PAH treatments other than FLOLAN (epoprostenol sodium) in the last 30 days. Subjects must walk a distance of at least 150 meters during six-minute walk distance test (6MWD). This test must be completed during the Screening Visit. A female subject is eligible to participate if she is of non-childbearing potential or of childbearing potential, has a negative pregnancy test at screen, and agrees to use one of the contraception methods listed in the protocol. Subjects must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved informed consent form and must sign the form prior to the initiation of any study procedures. Exclusion Criteria: Subjects who are given FLOLAN (epoprostenol sodium) for a condition or in a manner that is outside the approved indication. Subjects with congestive heart failure arising from severe left ventricular dysfunction. Subjects, with or without supplemental oxygen, who have a resting arterial oxygen saturation (SaO2) <90% as measured by pulse oximetry at screening. Subjects have been hospitalized as an emergency or visited the emergency room for a condition related to PAH or treatment for PAH in the last 3 months. The subject's clinical condition is such that they are not expected to remain clinically stable for the duration of the study. Female subjects who are pregnant or breastfeeding. Subjects who have demonstrated noncompliance with previous medical regimens. Subjects who have a history of abusing alcohol or illicit drugs within 1 year. Subjects with a diagnosis of active hepatitis (hepatitis B surface antibody and hepatitis C antibody). Subjects who have participated in a clinical study involving another investigational drug or device within four weeks before screening. Subjects who had history malignancies within the past 5 years, with the exception of basal cell carcinoma of the skin or in situ carcinoma of the cervix. Any concurrent condition that would affect the safety of the subject or in the opinion of the investigator it is not in the best interest of the patient to participate in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All subjects<br>Subjects enter the study already taking current marketed FLOLAN (epoprostenol sodium) and continue for 4 weeks (run-in). At baseline, they will be swopped to the new thermo stable formulation of epoprostenol sodium for 4 weeks (or longer if they continue in the extension phase of the study). | Drug: current marketed FLOLAN (epoprostenol sodium)<br>* continuous intravenous infusion<br>Drug: new thermo stable formulation of epoprostenol sodium<br>* continuous intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Medical Outcomes Study Short Form 36 (SF-36) | Subject-rated measure of health status comprised of 36 items: 8 subscale scores (physical functioning, role limitations due to physical health problems, bodily pain, general health, vitality, social functioning, role limitations due to emotional problems, and mental health), 2 summary scores (physical component and mental component), and a self-evaluated change in health status. Subscale and summary scores range: 0-100. Higher subscale and summary scores was considered as better health status. Change from Baseline was calculated as score at observation minus score at baseline. Baseline was defined as Visit 2 i.e. Day-14 (+ or - 7 days). | Baseline (Visit 2 i.e. Day-14 [+ or - 7 days]) and Week 4 (Visit 3) | 
| Change From Baseline in Study Specific Participant Acceptance Survey | Study-specific questionnaire comprised the pre-defined15 questions which included activities of daily living assessment. Participants rated the question on a scale of 1 to 10, where 1 was do not agree and 10 was strongly agree. Change from Baseline was calculated as score at observation minus score at Baseline. Changes from Baseline was assessed for Questions 2 to 12. Baseline was defined as Visit 2 i.e. Day-14 (+ or - 7 days). | Baseline (Visit 2 i.e. Day-14 [+ or - 7 days]) and Week 4 (Visit 3). | 
| Change From Baseline in Dose of Thermo Stable Epoprostenol Sodium at Week 4 | Dose titration requirement was assessed at the time of discharge. Change from Baseline was calculated as score at observation minus score at Baseline. Units- nanogram per kilogram per minute (ng/kg/min). Baseline was Visit 2 i.e . Day-14 (+ or - 7 days). | Baseline (Visit 2 i.e. Day-14 [+ or - 7 days]) and Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Treatment Emergent Adverse Events (AEs) and Treatment Emergent Serious Adverse Events(SAEs) | An AE was defined as any untoward medical occurrence that occurred during the course of the trial after study treatment had started. An adverse event was therefore any unfavourable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. An SAE is any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, congenital anomaly/birth defect and medically significant and all events of possible drug-induced liver injury with hyperbilirubinaemia. Only treatment emergent AEs and SAEs were reported in this outcome measure. Specifically, this study reported 2 SAEs, but only 1 was categorized as treatment emergent. | Up to visit 3 (Week 4) | 
| Number of Participants With Infusion Site Reactions During Treatment Period | Infusion site reactions were reported during the treatment period. Infusion site was inspected for erythema, excoriation, induration, skin necrosis or signs of local sepsis. | Baseline visit (Visit 2) to Week 4 (Visit 3) | 
| Change From Baseline in Vital Signs at Week 4 : Systolic and Diastolic Blood Pressure | Systolic blood pressure is a measure of blood pressure while the heart is beating. Diastolic blood pressure is a measure of blood pressure while the heart is relaxed. Change from Baseline was calculated as the value at the indicated time points minus the value at Baseline. Baseline was Visit 2 i.e. Day-14 (+ or - 7 days). | Baseline (Visit 2 i.e. Day-14 [+ or - 7 days]) and Week 4(Visit 3) | 
| Change From Baseline in Vital Signs at Week 4: Heart Rate | Summary mean change in heart rate measured in beats per minute (beats/min or BPM). Change from Baseline was calculated as the value at the indicated time points minus the value at Baseline. Baseline was Visit 2 i.e. Day-14 (+ or - 7 days). | Baseline (Visit 2 i.e. Day-14 [+ or - 7 days]) to Week 4 | 
| Number of Participants With Abnormal Clinical Chemistry | Abnormal clinical chemistry was analyzed as follows: serum alanine aminotransferase (ALT/SGPT) >= 3 x upper limit of normal (ULN) , aspartate aminotransferase (AST/SGOT) >= 3 x ULN , total bilirubin >= 34.2, creatinine >= 176.8. | Up to 1 week after Week 4 (Follow-up) | 
| Number of Participants With Abnormal Hematology | Values for hemoglobin, hematocrit, and platelet count were analyzed. Participants with abnormal values have been reported. The low and high value concern were as follows: hemoglobin (Males < 98, >180.0) (females <91, >161.0)grams per litre (g/L); hematocrit (Males < 32.0, >54.0) (females <29.0, >50.6) fraction (1); platelet count (< 100, > 500) gram international units per litre (gI/L). | Up to 1 week after Week 4 (Follow-up) | 
| Number of Participants With Abnormal Urinalysis | Dipstick method was used to measure blood, glucose and protein. Data was analyzed up to 1 week after Week 4 (Follow-up visit). | Up to 1 week after Week 4 (Follow-up) | 
| Change From Baseline in Six Minute Walk Distance Test (6MWD) After 4-weeks of Treatment | This assessment was a non-encouraged test that measures the distance walked for a duration of 6 minutes. Change from Baseline was calculated as value at observation minus value at Baseline. Baseline visit was Visit 2 i.e. Day-14 (+ or - 7 days). | Baseline (Visit 2 i.e. Day-14 [+ or - 7 days]) and Week 4 | 
| Breathlessness After 6MWD - Borg Dyspnoea Index (BDI) | The BDI was calculated by using a 10-point scale (0 = None, 10 = Maximum) and indicates the degree of breathlessness after completion of the 6-minute walk test. The BDI scale was assessed by each participant. Change from Baseline = score at observation minus score at Baseline. Baseline visit was Visit 2 i.e. Day-14 (+ or - 7 days). | Baseline (Visit 2 i.e. Day-14 [+ or - 7 days]) to Week 4 | 
| World Health Organization [WHO] Functional Class at Baseline and After 4- Weeks of Treatment | World Health Organization functional class was analyzed as class I, class II, class III and class IV. World Health Organization functional class was analyzed at Baseline (Visit 2 i.e. Day-14 [+ or - 7 days]) and Week 4. The classed were defined as Class I: No symptoms of pulmonary arterial hypertension with exercise or at rest, Class II: No symptoms at rest but uncomfortable and short of breath with normal activity, Class III: May not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting and Class IV: Symptoms at rest and severe symptoms with any activity. Hence the severity increased from class I (better) to Class IV (worse). | Baseline (Visit 2 i.e. Day-14 [+ or - 7 days]) and Week 4 | 
| Mean Oxygen Saturation in Blood Over Time | Pulse oximetry (oxygen saturation) was analyzed. Data for Pulse oximetry (oxygen saturation) was analyzed up to the treatment follow up (1 week after Visit 3 [Week 4]). | up to the treatment follow up (1 week after Visit 3 [Week 4]) | 
| Number of Participants With Urine Pregnancy Test Positive | Urine samples were collected for urine pregnancy test. Urine samples were collected at up to the treatment follow up (1 week after Visit 3 [Week 4]). Number of participants with urine pregnancy test positive has been reported. | up to the treatment follow up (1 week after Visit 3 [Week 4]) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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flolan, pulmonary arterial hypertension, thermo stable formulation, epoprostenol sodium, modified sterile diluent