Cardiovascular Disease
Conditions
Keywords
Pulmonary Arterial Hypertension (PAH), safety, FLOLAN, New Thermostable Formulation, dose adjustment, reformulated diluents, currently marketed diluent
Brief summary
This study is a Phase IV, open-label, single-arm study to assess the safety and the necessity of dose adjustment after switching to FLOLAN injection prepared with the reformulated diluent in Japanese patients with PAH who are receiving higher doses of FLOLAN injection than in other countries. The objective is to evaluate the safety and tolerability of the thermostable formulation of FLOLAN injection (that is \[i.e.\], FLOLAN injection prepared with the reformulated diluent) when switched from the existing FLOLAN injection treatment (i.e., FLOLAN injection prepared with the currently marketed diluent). The study will include a screening visit, a run-in period of a maximum of 4 weeks with the existing FLOLAN treatment (i.e., FLOLAN injection prepared with the currently marketed diluent), a 4-week treatment period with the thermostable formulation of FLOLAN injection (i.e., FLOLAN injection prepared with the reformulated diluent) and a one-week follow-up visit. Adequate number of subjects will be enrolled in the study in order to have 10 subjects to complete assessments at 4 weeks, including at least 5 subjects as a subset of subjects who consent to undergo right heart catheterisation (RHC) over 24-hour and at Week 4. FLOLAN is a registered trademark of the GlaxoSmithKline \[GSK\] group of companies.
Interventions
DRUGFLOLAN injection with currently marketed diluent
FLOLAN injection (epoprostenol 0.5 or 1.5) prepared with the currently marketed diluent (epoprostenol sodium+ powder of hydrogen \[pH\] 10.2 - 10.8 diluent) for Injection.
DRUGFLOLAN injection with reformulated diluent
FLOLAN injection (epoprostenol 0.5 or 1.5) prepared with the reformulated diluent (epoprostenol sodium + pH 11.7 - 12.3 diluent) for Injection.
Sponsors
GlaxoSmithKline
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Male or female subjects at least 18 to 75 years at the time of screening; * Subjects must be on FLOLAN therapy for pulmonary arterial hypertension (PAH) as approved in the product label; * Subjects must receive FLOLAN therapy at 45 nanograms (ng)/kilogram (kg)/minute (min) or higher; * Subjects must be on stable doses of their existing FLOLAN treatment for a minimum of one month prior to screening; it is acceptable to adjust within 10% of dose during the last one month period; * Subjects must be on stable doses of any current PAH treatments other than FLOLAN therapy in the last 30 days prior to screening; * Subjects who meet any of the following: A female subject is eligible to participate if she is not pregnant (as confirmed by a negative \[serum or urine\] human chorionic gonadotrophin \[hCG\] test), not lactating, and at least one of the following conditions applies: * Non-reproductive potential defined as: Pre-menopausal females with any of the following: documented tubal ligation, documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, hysterectomy, or documented bilateral oophorectomy. Postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone \[FSH\] and estradiol levels consistent with menopause). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. * Reproductive potential and agrees to follow one of the options listed below in the GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of thermostable formulation of FLOLAN therapy until completion of the follow-up visit. * Subject must agree not to participate in a clinical study involving another investigational drug or device throughout this study; * 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 therapy 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 hospitalised 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 who have participated in a clinical study involving another investigational drug or device within four weeks before screening. * Any concurrent condition that would affect the safety of the subject or in the opinion of the investigator (or subinvestigator) it is not in the best interest of the patient to participate in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Values of Oxygen Saturation | Baseline and up to Week 4 | Oxygen saturation was measured by pulse oximetry at Baseline (BL), 1 hr, 3 hr, 24 hr, Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). |
| Absolute Values of Urea/Blood Urea Nitrogen, Glucose, Chloride, Sodium, Potassium, Magnesium, Phosphorus (Inorganic), and Calcium at Baseline and Week 4 | Baseline and Week 4 | Blood samples were collected for measurement of urea/Blood Urea Nitrogen (Urea/BUN), glucose, chloride, sodium, potassium, magnesium, phosphorus, inorganic, and calcium at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') |
| Absolute Values of Free Triiodothyronine and Free Thyroxine at Baseline and Week 4 | Baseline and Week 4 | Blood samples were collected for measurement of Free Triiodothyronine (FT3) and Free Thyroxine (FT4) at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') |
| Absolute Values of Thyroid Stimulating Hormone at Baseline and Week 4 | Baseline and Week 4 | Blood samples were collected for measurement of Thyroid Stimulating Hormone (TSH) at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') |
| Number of Participants With the Indicated Urinalysis Findings | Baseline and Week 4 | Urine protein, urine glucose, and occult blood were assessed at Baseline (BL) and Week 4 (W4). Dipstick test was performed for routine urinalysis. Abnormal values such as trace, 1+, 2+, 3+ and positive have been reported. The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). |
| Number of Participants With the Indicated Electrocardiogram (ECG) Findings | Baseline, 24 hour and Week 4 | A safety 12-lead ECG was performed at Baseline (BL), 24 hr after switching to the new Flolan diluent and Week 4 (W4). Any abnormal clinically significant (CS) and not clinically significant (NCS) findings were reported. ECG abnormaility with respect to CS and NCS findings were judged by the investigator. The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') |
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Baseline, 1 hour, 3 hour, 24 hour and Week 4 | SBP and DBP were measured at Baseline, 1 hr, 3 hr, 24 hr, Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value. |
| Change From Baseline in Heart Rate | Baseline and up to Week 4 | Heart rate was measured at Baseline, 1 hr, 3 hr, 24 hr, Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value. |
| Change From Baseline in Body Weight | Baseline and Week 4 | Body weight was measured at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value. Participants with body weight outside and within the clinical concern reference range (\<50kg) has been presented. |
| Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) | Up to Week 4 | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, important medical events which may require medical or surgical interventions. Intention-to-Treat (ITT) population: comprised of all participants who have received at least one dose of the thermostable formulation of FLOLAN. |
| Number of Participants With Mild, Moderate or Severe AEs | Up to Week 4 | Intensity for an AE and SAE is categorized as mild if an event is easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities; moderate if an event is sufficiently discomforting to interfere with normal everyday activities; severe if that prevents normal everyday activities. |
| Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils in Blood at Baseline and Week 4 | Baseline and Week 4 | Blood samples were collected for the measurement of percentage of basophils, eosinophils, lymphocytes, monocytes, and total neutrophils in blood at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hour (hr) prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') |
| Absolute Values of Hemoglobin at Baseline and Week 4 | Baseline and Week 4 | Blood samples were collected for measurement of hemoglobin values at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') |
| Absolute Values of Hematocrit at Baseline and Week 4 | Baseline and Week 4 | Blood samples were collected for measurement of hematocrit values at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') |
| Absolute Values of Platelet Count and White Blood Cell Count at Baseline and Week 4 | Baseline and Week 4 | Blood samples were collected for measurement of platelets and white blood cells (WBC) at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') |
| Absolute Values of Red Blood Cell Count at Baseline and Week 4 | Baseline and Week 4 | Blood samples were collected for measurement of red blood cells at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') |
| Absolute Values of Albumin and Total Protein at Baseline and Week 4 | Baseline and Week 4 | Blood samples were collected for measurement of albumin and total protein at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') |
| Absolute Values of Total and Direct Bilirubin, Creatinine, and Uric Acid at Baseline and Week 4 | Baseline and Week 4 | Blood samples were collected for measurement of total and direct bilirubin, creatinine (CRT), and uric acid (UA) at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') |
| Absolute Values of Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Gamma Glutamyltransferase, Lactate Dehydrogenase and Creatine Kinase at Baseline and Week 4 | Baseline and Week 4 | Blood samples were collected for measurement of Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (ALP), Gamma Glutamyltransferase (GGT), Lactate Dehydrogenase (LDH) and Creatine Kinase (CK) at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With the Reason for the Change Dose of the Thermostable Formulation of FLOLAN | Up to Week 4 | All reasons for FLOLAN dose adjustments after the switch were listed. |
| Change From Baseline in N-terminal Pro B-type Natriuretic Peptide (NT Pro BNP) | Baseline and up to Week 4 | Blood samples were collected at Baseline, 24 hours after the first dose of thermostable formulation of FLOLAN, and Week 4 for measurement of NT pro BNP. The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value. |
| Number of Participants in Each World Health Organization (WHO) Functional Class | Baseline and Week 4 | The WHO functional classes of PAH range from Class I (without limitation in physical activity) to Class IV (inability to perform a physical activity without any symptoms). |
| Number of Participants With Change of WHO Functional Class From Previous Visit | Up to Week 4 | WHO Functional Classification of physical activity limitations: I (no limitation) and IV (unable to carry out any physical activity without symptoms). The change from baseline in WHO class was classified as Improved (decrease in functional class), No Change (functional class stayed the same), and Deteriorated (functional class increased). The change from baseline in WHO functional class at Week 4 has been presented in the table. The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') |
| Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) and Mean Right Atrial Pressure (mRAP) | Baseline and up to Week 4 | mPAP and mRAP are hemodynamic parameters. The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value. |
| Change From Baseline in Pulmonary Vascular Resist (PVR) | Baseline and up to Week 4 | The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value. |
| Change From Baseline in Cardiac Output (CO) | Baseline and up to Week 4 | Cardiac output is the volume of blood pumped by the heart per minute. The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value. |
| Number of Events to Adjust Dose of FLOLAN Based on the Change From Baseline to 3 Hours in Mean Pulmonary Artery Pressure (mPAP) | Up to Week 4 | To assess the frequency of dose adjustment requirements based on the changes from baseline in mPAP up to 3 hours after dosing.The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Participants who gave consent to undergo right heart catheterisation (RHC) over 24-hour and at week 4 were assessed. Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value. |
Countries
Japan
Participant flow
Recruitment details
This study consisted a screening visit, a Run-in period of a maximum of 30 days observation, a 4-week treatment period with the thermostable formulation of FLOLAN, and a one-week follow-up visit.
Pre-assignment details
Ten participants (par.) who gave consent and passed the screening assessments were enrolled in the Run-in period. After the Run-in period, par. underwent Baseline assessments and were switched to thermostable formulation of FLOLAN. All par. underwent right heart catheterisation (RHC) up to 24 hours and at Week 4 after switching to study treatment.
Participants by arm
| Arm | Count |
|---|---|
| FLOLAN With New Diluent Japanese par. with pulmonary arterial hypertension (PAH) received FLOLAN prepared with the current marketed diluent (epoprostenol sodium + Potential of Hydrogen \[pH\] 10.2-10.8 diluent) for Injection in run-in period for a maximum of 30 days, and then switched to FLOLAN prepared with new diluent (epoprostenol sodium + pH 11.7-12.3 diluent) for Injection for 4-weeks in the treatment period. Par. received dose of 47.6 to 113.8 nanogram per kilogram per minute (ng/kg/min) during the treatment period. | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | FLOLAN With New Diluent |
|---|---|
| Age, Continuous | 35.8 Years STANDARD_DEVIATION 7.35 |
| Race/Ethnicity, Customized Asian - Japanese Heritage | 10 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 2 / 10 |
| serious Total, serious adverse events | 0 / 10 |
Outcome results
Primary
Absolute Values of Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Gamma Glutamyltransferase, Lactate Dehydrogenase and Creatine Kinase at Baseline and Week 4
Blood samples were collected for measurement of Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (ALP), Gamma Glutamyltransferase (GGT), Lactate Dehydrogenase (LDH) and Creatine Kinase (CK) at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline')
Time frame: Baseline and Week 4
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FLOLAN With New Diluent | Absolute Values of Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Gamma Glutamyltransferase, Lactate Dehydrogenase and Creatine Kinase at Baseline and Week 4 | CK, BL | 40.8 International units per liter (IU/L) | Standard Deviation 15.13 |
| FLOLAN With New Diluent | Absolute Values of Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Gamma Glutamyltransferase, Lactate Dehydrogenase and Creatine Kinase at Baseline and Week 4 | CK, W4 | 44.7 International units per liter (IU/L) | Standard Deviation 17.22 |
| FLOLAN With New Diluent | Absolute Values of Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Gamma Glutamyltransferase, Lactate Dehydrogenase and Creatine Kinase at Baseline and Week 4 | ALT, BL | 15.9 International units per liter (IU/L) | Standard Deviation 7.56 |
| FLOLAN With New Diluent | Absolute Values of Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Gamma Glutamyltransferase, Lactate Dehydrogenase and Creatine Kinase at Baseline and Week 4 | ALT, W4 | 19.6 International units per liter (IU/L) | Standard Deviation 21.71 |
| FLOLAN With New Diluent | Absolute Values of Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Gamma Glutamyltransferase, Lactate Dehydrogenase and Creatine Kinase at Baseline and Week 4 | AST, BL | 14.0 International units per liter (IU/L) | Standard Deviation 3.89 |
| FLOLAN With New Diluent | Absolute Values of Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Gamma Glutamyltransferase, Lactate Dehydrogenase and Creatine Kinase at Baseline and Week 4 | AST, W4 | 16.4 International units per liter (IU/L) | Standard Deviation 11.35 |
| FLOLAN With New Diluent | Absolute Values of Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Gamma Glutamyltransferase, Lactate Dehydrogenase and Creatine Kinase at Baseline and Week 4 | ALP, BL | 181.0 International units per liter (IU/L) | Standard Deviation 57.02 |
| FLOLAN With New Diluent | Absolute Values of Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Gamma Glutamyltransferase, Lactate Dehydrogenase and Creatine Kinase at Baseline and Week 4 | ALP, W4 | 175.2 International units per liter (IU/L) | Standard Deviation 69.45 |
| FLOLAN With New Diluent | Absolute Values of Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Gamma Glutamyltransferase, Lactate Dehydrogenase and Creatine Kinase at Baseline and Week 4 | GGT, BL | 22.7 International units per liter (IU/L) | Standard Deviation 17.46 |
| FLOLAN With New Diluent | Absolute Values of Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Gamma Glutamyltransferase, Lactate Dehydrogenase and Creatine Kinase at Baseline and Week 4 | GGT, W4 | 22.1 International units per liter (IU/L) | Standard Deviation 17.69 |
| FLOLAN With New Diluent | Absolute Values of Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Gamma Glutamyltransferase, Lactate Dehydrogenase and Creatine Kinase at Baseline and Week 4 | LDH, BL | 165.2 International units per liter (IU/L) | Standard Deviation 33.77 |
| FLOLAN With New Diluent | Absolute Values of Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Gamma Glutamyltransferase, Lactate Dehydrogenase and Creatine Kinase at Baseline and Week 4 | LDH, W4 | 160.8 International units per liter (IU/L) | Standard Deviation 34.81 |
Primary
Absolute Values of Albumin and Total Protein at Baseline and Week 4
Blood samples were collected for measurement of albumin and total protein at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline')
Time frame: Baseline and Week 4
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FLOLAN With New Diluent | Absolute Values of Albumin and Total Protein at Baseline and Week 4 | Albumin, BL | 43.8 G/L | Standard Deviation 6.03 |
| FLOLAN With New Diluent | Absolute Values of Albumin and Total Protein at Baseline and Week 4 | Albumin, W4 | 41.1 G/L | Standard Deviation 2.64 |
| FLOLAN With New Diluent | Absolute Values of Albumin and Total Protein at Baseline and Week 4 | Total protein, BL | 68.0 G/L | Standard Deviation 7.27 |
| FLOLAN With New Diluent | Absolute Values of Albumin and Total Protein at Baseline and Week 4 | Total protein, W4 | 63.9 G/L | Standard Deviation 4.51 |
Primary
Absolute Values of Free Triiodothyronine and Free Thyroxine at Baseline and Week 4
Blood samples were collected for measurement of Free Triiodothyronine (FT3) and Free Thyroxine (FT4) at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline')
Time frame: Baseline and Week 4
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FLOLAN With New Diluent | Absolute Values of Free Triiodothyronine and Free Thyroxine at Baseline and Week 4 | FT3, BL | 5.0974 picomoles per litre (pmol/L) | Standard Deviation 1.26044 |
| FLOLAN With New Diluent | Absolute Values of Free Triiodothyronine and Free Thyroxine at Baseline and Week 4 | FT3, W4 | 4.9280 picomoles per litre (pmol/L) | Standard Deviation 0.47048 |
| FLOLAN With New Diluent | Absolute Values of Free Triiodothyronine and Free Thyroxine at Baseline and Week 4 | FT4, BL | 14.6847 picomoles per litre (pmol/L) | Standard Deviation 3.46426 |
| FLOLAN With New Diluent | Absolute Values of Free Triiodothyronine and Free Thyroxine at Baseline and Week 4 | FT4, W4 | 14.2857 picomoles per litre (pmol/L) | Standard Deviation 2.47336 |
Primary
Absolute Values of Hematocrit at Baseline and Week 4
Blood samples were collected for measurement of hematocrit values at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline')
Time frame: Baseline and Week 4
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FLOLAN With New Diluent | Absolute Values of Hematocrit at Baseline and Week 4 | BL | 0.3969 Liter (L) | Standard Deviation 0.0323 |
| FLOLAN With New Diluent | Absolute Values of Hematocrit at Baseline and Week 4 | W4 | 0.3662 Liter (L) | Standard Deviation 0.02682 |
Primary
Absolute Values of Hemoglobin at Baseline and Week 4
Blood samples were collected for measurement of hemoglobin values at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline')
Time frame: Baseline and Week 4
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FLOLAN With New Diluent | Absolute Values of Hemoglobin at Baseline and Week 4 | BL | 135.5 Gram/Liter (G/L) | Standard Deviation 13.37 |
| FLOLAN With New Diluent | Absolute Values of Hemoglobin at Baseline and Week 4 | W4 | 124.1 Gram/Liter (G/L) | Standard Deviation 10.31 |
Primary
Absolute Values of Oxygen Saturation
Oxygen saturation was measured by pulse oximetry at Baseline (BL), 1 hr, 3 hr, 24 hr, Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline').
Time frame: Baseline and up to Week 4
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FLOLAN With New Diluent | Absolute Values of Oxygen Saturation | BL | 97.6 Percentage | Standard Deviation 0.7 |
| FLOLAN With New Diluent | Absolute Values of Oxygen Saturation | 1 hr | 98.0 Percentage | Standard Deviation 1.15 |
| FLOLAN With New Diluent | Absolute Values of Oxygen Saturation | 3 hr | 97.6 Percentage | Standard Deviation 1.51 |
| FLOLAN With New Diluent | Absolute Values of Oxygen Saturation | 24 hr | 97.7 Percentage | Standard Deviation 1.16 |
| FLOLAN With New Diluent | Absolute Values of Oxygen Saturation | Week 4 | 97.8 Percentage | Standard Deviation 1.55 |
Primary
Absolute Values of Platelet Count and White Blood Cell Count at Baseline and Week 4
Blood samples were collected for measurement of platelets and white blood cells (WBC) at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline')
Time frame: Baseline and Week 4
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FLOLAN With New Diluent | Absolute Values of Platelet Count and White Blood Cell Count at Baseline and Week 4 | Platelet count, BL | 181.9 Giga/Liter (GI/L) | Standard Deviation 75.46 |
| FLOLAN With New Diluent | Absolute Values of Platelet Count and White Blood Cell Count at Baseline and Week 4 | Platelet count, W4 | 153.4 Giga/Liter (GI/L) | Standard Deviation 51.58 |
| FLOLAN With New Diluent | Absolute Values of Platelet Count and White Blood Cell Count at Baseline and Week 4 | WBC count, BL | 0.0065 Giga/Liter (GI/L) | Standard Deviation 0.00125 |
| FLOLAN With New Diluent | Absolute Values of Platelet Count and White Blood Cell Count at Baseline and Week 4 | WBC count, W4 | 0.0063 Giga/Liter (GI/L) | Standard Deviation 0.0014 |
Primary
Absolute Values of Red Blood Cell Count at Baseline and Week 4
Blood samples were collected for measurement of red blood cells at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline')
Time frame: Baseline and Week 4
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FLOLAN With New Diluent | Absolute Values of Red Blood Cell Count at Baseline and Week 4 | BL | 0.0482 terabinary/liter (Ti/L)) | Standard Deviation 0.00357 |
| FLOLAN With New Diluent | Absolute Values of Red Blood Cell Count at Baseline and Week 4 | W4 | 0.0446 terabinary/liter (Ti/L)) | Standard Deviation 0.00344 |
Primary
Absolute Values of Thyroid Stimulating Hormone at Baseline and Week 4
Blood samples were collected for measurement of Thyroid Stimulating Hormone (TSH) at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline')
Time frame: Baseline and Week 4
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FLOLAN With New Diluent | Absolute Values of Thyroid Stimulating Hormone at Baseline and Week 4 | TSH, BL | 2.426 milliunits per litre (mU/L) | Standard Deviation 4.4045 |
| FLOLAN With New Diluent | Absolute Values of Thyroid Stimulating Hormone at Baseline and Week 4 | TSH, W4 | 1.822 milliunits per litre (mU/L) | Standard Deviation 2.5287 |
Primary
Absolute Values of Total and Direct Bilirubin, Creatinine, and Uric Acid at Baseline and Week 4
Blood samples were collected for measurement of total and direct bilirubin, creatinine (CRT), and uric acid (UA) at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline')
Time frame: Baseline and Week 4
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FLOLAN With New Diluent | Absolute Values of Total and Direct Bilirubin, Creatinine, and Uric Acid at Baseline and Week 4 | Total Bilirubin, BL | 9.063 Micromoles per liter | Standard Deviation 2.912 |
| FLOLAN With New Diluent | Absolute Values of Total and Direct Bilirubin, Creatinine, and Uric Acid at Baseline and Week 4 | Total Bilirubin, W4 | 8.550 Micromoles per liter | Standard Deviation 3.2244 |
| FLOLAN With New Diluent | Absolute Values of Total and Direct Bilirubin, Creatinine, and Uric Acid at Baseline and Week 4 | Direct Bilirubin, BL | 0.855 Micromoles per liter | Standard Deviation 0.9012 |
| FLOLAN With New Diluent | Absolute Values of Total and Direct Bilirubin, Creatinine, and Uric Acid at Baseline and Week 4 | Direct Bilirubin, W4 | 1.368 Micromoles per liter | Standard Deviation 1.0815 |
| FLOLAN With New Diluent | Absolute Values of Total and Direct Bilirubin, Creatinine, and Uric Acid at Baseline and Week 4 | CRT, BL | 58.1672 Micromoles per liter | Standard Deviation 7.19132 |
| FLOLAN With New Diluent | Absolute Values of Total and Direct Bilirubin, Creatinine, and Uric Acid at Baseline and Week 4 | CRT, W4 | 50.4764 Micromoles per liter | Standard Deviation 8.28689 |
| FLOLAN With New Diluent | Absolute Values of Total and Direct Bilirubin, Creatinine, and Uric Acid at Baseline and Week 4 | UA, BL | 349.1476 Micromoles per liter | Standard Deviation 93.83901 |
| FLOLAN With New Diluent | Absolute Values of Total and Direct Bilirubin, Creatinine, and Uric Acid at Baseline and Week 4 | UA, W4 | 313.4596 Micromoles per liter | Standard Deviation 70.10066 |
Primary
Absolute Values of Urea/Blood Urea Nitrogen, Glucose, Chloride, Sodium, Potassium, Magnesium, Phosphorus (Inorganic), and Calcium at Baseline and Week 4
Blood samples were collected for measurement of urea/Blood Urea Nitrogen (Urea/BUN), glucose, chloride, sodium, potassium, magnesium, phosphorus, inorganic, and calcium at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline')
Time frame: Baseline and Week 4
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FLOLAN With New Diluent | Absolute Values of Urea/Blood Urea Nitrogen, Glucose, Chloride, Sodium, Potassium, Magnesium, Phosphorus (Inorganic), and Calcium at Baseline and Week 4 | Magnesium, BL | 0.8467 Millimoles per litre (mmol/L) | Standard Deviation 0.06767 |
| FLOLAN With New Diluent | Absolute Values of Urea/Blood Urea Nitrogen, Glucose, Chloride, Sodium, Potassium, Magnesium, Phosphorus (Inorganic), and Calcium at Baseline and Week 4 | Magnesium, W4 | 0.7891 Millimoles per litre (mmol/L) | Standard Deviation 0.03242 |
| FLOLAN With New Diluent | Absolute Values of Urea/Blood Urea Nitrogen, Glucose, Chloride, Sodium, Potassium, Magnesium, Phosphorus (Inorganic), and Calcium at Baseline and Week 4 | Phosphorus, inorganic, BL | 1.2399 Millimoles per litre (mmol/L) | Standard Deviation 0.15686 |
| FLOLAN With New Diluent | Absolute Values of Urea/Blood Urea Nitrogen, Glucose, Chloride, Sodium, Potassium, Magnesium, Phosphorus (Inorganic), and Calcium at Baseline and Week 4 | Urea/BUN, BL | 4.6767 Millimoles per litre (mmol/L) | Standard Deviation 1.07034 |
| FLOLAN With New Diluent | Absolute Values of Urea/Blood Urea Nitrogen, Glucose, Chloride, Sodium, Potassium, Magnesium, Phosphorus (Inorganic), and Calcium at Baseline and Week 4 | Urea/BUN, W4 | 4.4625 Millimoles per litre (mmol/L) | Standard Deviation 0.99917 |
| FLOLAN With New Diluent | Absolute Values of Urea/Blood Urea Nitrogen, Glucose, Chloride, Sodium, Potassium, Magnesium, Phosphorus (Inorganic), and Calcium at Baseline and Week 4 | Glucose, BL | 4.9959 Millimoles per litre (mmol/L) | Standard Deviation 0.34814 |
| FLOLAN With New Diluent | Absolute Values of Urea/Blood Urea Nitrogen, Glucose, Chloride, Sodium, Potassium, Magnesium, Phosphorus (Inorganic), and Calcium at Baseline and Week 4 | Glucose, W4 | 5.7675 Millimoles per litre (mmol/L) | Standard Deviation 2.05053 |
| FLOLAN With New Diluent | Absolute Values of Urea/Blood Urea Nitrogen, Glucose, Chloride, Sodium, Potassium, Magnesium, Phosphorus (Inorganic), and Calcium at Baseline and Week 4 | Chloride, BL | 103.8 Millimoles per litre (mmol/L) | Standard Deviation 4.64 |
| FLOLAN With New Diluent | Absolute Values of Urea/Blood Urea Nitrogen, Glucose, Chloride, Sodium, Potassium, Magnesium, Phosphorus (Inorganic), and Calcium at Baseline and Week 4 | Chloride, W4 | 103.9 Millimoles per litre (mmol/L) | Standard Deviation 4.01 |
| FLOLAN With New Diluent | Absolute Values of Urea/Blood Urea Nitrogen, Glucose, Chloride, Sodium, Potassium, Magnesium, Phosphorus (Inorganic), and Calcium at Baseline and Week 4 | Sodium, BL | 139.6 Millimoles per litre (mmol/L) | Standard Deviation 1.96 |
| FLOLAN With New Diluent | Absolute Values of Urea/Blood Urea Nitrogen, Glucose, Chloride, Sodium, Potassium, Magnesium, Phosphorus (Inorganic), and Calcium at Baseline and Week 4 | Sodium, W4 | 138.0 Millimoles per litre (mmol/L) | Standard Deviation 1.76 |
| FLOLAN With New Diluent | Absolute Values of Urea/Blood Urea Nitrogen, Glucose, Chloride, Sodium, Potassium, Magnesium, Phosphorus (Inorganic), and Calcium at Baseline and Week 4 | Potassium, BL | 3.61 Millimoles per litre (mmol/L) | Standard Deviation 0.373 |
| FLOLAN With New Diluent | Absolute Values of Urea/Blood Urea Nitrogen, Glucose, Chloride, Sodium, Potassium, Magnesium, Phosphorus (Inorganic), and Calcium at Baseline and Week 4 | Potassium, W4 | 3.56 Millimoles per litre (mmol/L) | Standard Deviation 0.255 |
| FLOLAN With New Diluent | Absolute Values of Urea/Blood Urea Nitrogen, Glucose, Chloride, Sodium, Potassium, Magnesium, Phosphorus (Inorganic), and Calcium at Baseline and Week 4 | Phosphorus, inorganic, W4 | 1.1947 Millimoles per litre (mmol/L) | Standard Deviation 0.19553 |
| FLOLAN With New Diluent | Absolute Values of Urea/Blood Urea Nitrogen, Glucose, Chloride, Sodium, Potassium, Magnesium, Phosphorus (Inorganic), and Calcium at Baseline and Week 4 | Calcium, BL | 2.2380 Millimoles per litre (mmol/L) | Standard Deviation 0.131 |
| FLOLAN With New Diluent | Absolute Values of Urea/Blood Urea Nitrogen, Glucose, Chloride, Sodium, Potassium, Magnesium, Phosphorus (Inorganic), and Calcium at Baseline and Week 4 | Calcium, W4 | 2.1357 Millimoles per litre (mmol/L) | Standard Deviation 0.07174 |
Primary
Change From Baseline in Body Weight
Body weight was measured at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value. Participants with body weight outside and within the clinical concern reference range (\<50kg) has been presented.
Time frame: Baseline and Week 4
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FLOLAN With New Diluent | Change From Baseline in Body Weight | > clinical concern range, BL | 0 Participants |
| FLOLAN With New Diluent | Change From Baseline in Body Weight | < clinical concern range, BL | 6 Participants |
| FLOLAN With New Diluent | Change From Baseline in Body Weight | > clinical concern range, W4 | 0 Participants |
| FLOLAN With New Diluent | Change From Baseline in Body Weight | < clinical concern range, W4 | 6 Participants |
Primary
Change From Baseline in Heart Rate
Heart rate was measured at Baseline, 1 hr, 3 hr, 24 hr, Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value.
Time frame: Baseline and up to Week 4
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FLOLAN With New Diluent | Change From Baseline in Heart Rate | 1 hr | 1.4 Beats per minute (bpm) | Standard Deviation 11.57 |
| FLOLAN With New Diluent | Change From Baseline in Heart Rate | 3 hr | 2.3 Beats per minute (bpm) | Standard Deviation 11.54 |
| FLOLAN With New Diluent | Change From Baseline in Heart Rate | 24 hr | 5.1 Beats per minute (bpm) | Standard Deviation 9.27 |
| FLOLAN With New Diluent | Change From Baseline in Heart Rate | Week 4 | 4.0 Beats per minute (bpm) | Standard Deviation 9.76 |
Primary
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
SBP and DBP were measured at Baseline, 1 hr, 3 hr, 24 hr, Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value.
Time frame: Baseline, 1 hour, 3 hour, 24 hour and Week 4
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FLOLAN With New Diluent | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, 1 hr | 4.2 Millimeters of mercury (mmHg) | Standard Deviation 5.77 |
| FLOLAN With New Diluent | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, 3 hr | 1.2 Millimeters of mercury (mmHg) | Standard Deviation 7.73 |
| FLOLAN With New Diluent | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, 24 hr | 1.1 Millimeters of mercury (mmHg) | Standard Deviation 10.17 |
| FLOLAN With New Diluent | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, Week 4 | 2.1 Millimeters of mercury (mmHg) | Standard Deviation 8.12 |
| FLOLAN With New Diluent | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, 1 hr | -0.6 Millimeters of mercury (mmHg) | Standard Deviation 8.06 |
| FLOLAN With New Diluent | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, 3 hr | 0.7 Millimeters of mercury (mmHg) | Standard Deviation 5.52 |
| FLOLAN With New Diluent | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, 24 hr | 0.9 Millimeters of mercury (mmHg) | Standard Deviation 6.98 |
| FLOLAN With New Diluent | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, Week 4 | 2.5 Millimeters of mercury (mmHg) | Standard Deviation 8.03 |
Primary
Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, important medical events which may require medical or surgical interventions. Intention-to-Treat (ITT) population: comprised of all participants who have received at least one dose of the thermostable formulation of FLOLAN.
Time frame: Up to Week 4
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FLOLAN With New Diluent | Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) | Any AE | 2 Participants |
| FLOLAN With New Diluent | Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) | Any Drug-Related AE | 1 Participants |
| FLOLAN With New Diluent | Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) | Any SAE | 0 Participants |
Primary
Number of Participants With Mild, Moderate or Severe AEs
Intensity for an AE and SAE is categorized as mild if an event is easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities; moderate if an event is sufficiently discomforting to interfere with normal everyday activities; severe if that prevents normal everyday activities.
Time frame: Up to Week 4
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FLOLAN With New Diluent | Number of Participants With Mild, Moderate or Severe AEs | Mild, Nausea | 1 Participants |
| FLOLAN With New Diluent | Number of Participants With Mild, Moderate or Severe AEs | Mild, Hepatic function abnormal | 1 Participants |
Primary
Number of Participants With the Indicated Electrocardiogram (ECG) Findings
A safety 12-lead ECG was performed at Baseline (BL), 24 hr after switching to the new Flolan diluent and Week 4 (W4). Any abnormal clinically significant (CS) and not clinically significant (NCS) findings were reported. ECG abnormaility with respect to CS and NCS findings were judged by the investigator. The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline')
Time frame: Baseline, 24 hour and Week 4
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FLOLAN With New Diluent | Number of Participants With the Indicated Electrocardiogram (ECG) Findings | BL, NCS | 9 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Electrocardiogram (ECG) Findings | BL, CS | 1 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Electrocardiogram (ECG) Findings | 24 hr, NCS | 9 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Electrocardiogram (ECG) Findings | 24 hr, CS | 1 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Electrocardiogram (ECG) Findings | W4, NCS | 10 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Electrocardiogram (ECG) Findings | W4, CS | 0 Participants |
Primary
Number of Participants With the Indicated Urinalysis Findings
Urine protein, urine glucose, and occult blood were assessed at Baseline (BL) and Week 4 (W4). Dipstick test was performed for routine urinalysis. Abnormal values such as trace, 1+, 2+, 3+ and positive have been reported. The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline').
Time frame: Baseline and Week 4
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine glucose, BL, 2+ | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine glucose, BL, 3+ | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine glucose, BL, Positive | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine glucose, W4, Trace | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine glucose, BL, 1+ | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine glucose, BL, Trace | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine glucose, W4, 1+ | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine glucose, W4, 2+ | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine glucose, W4, 3+ | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine glucose, W4, Positive | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine occult blood, BL, Trace | 2 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine occult blood, BL, 1+ | 1 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine occult blood, BL, 2+ | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine occult blood, BL, 3+ | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine occult blood, BL, Positive | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine occult blood, W4, Trace | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine occult blood, W4, 1+ | 1 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine occult blood, W4, 2+ | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine occult blood, W4, 3+ | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine occult blood, W4, Positive | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine protein, BL, Trace | 5 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine protein, BL, 1+ | 1 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine protein, BL, 2+ | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine protein, BL, 3+ | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine protein, BL, Positive | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine protein, W4, Trace | 2 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine protein, W4, 1+ | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine protein, W4, 2+ | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine protein, W4, 3+ | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Indicated Urinalysis Findings | Urine protein, W4, Positive | 0 Participants |
Primary
Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils in Blood at Baseline and Week 4
Blood samples were collected for the measurement of percentage of basophils, eosinophils, lymphocytes, monocytes, and total neutrophils in blood at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hour (hr) prior to the first dose of the new diluent formulation ('Visit 2 - Baseline')
Time frame: Baseline and Week 4
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FLOLAN With New Diluent | Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils in Blood at Baseline and Week 4 | Basophils BL | 0.61 Percentage | Standard Deviation 0.331 |
| FLOLAN With New Diluent | Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils in Blood at Baseline and Week 4 | Basophils W4 | 0.45 Percentage | Standard Deviation 0.321 |
| FLOLAN With New Diluent | Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils in Blood at Baseline and Week 4 | Eosinophils BL | 2.66 Percentage | Standard Deviation 1.789 |
| FLOLAN With New Diluent | Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils in Blood at Baseline and Week 4 | Eosinophils W4 | 3.25 Percentage | Standard Deviation 3.221 |
| FLOLAN With New Diluent | Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils in Blood at Baseline and Week 4 | Lymphocytes BL | 22.87 Percentage | Standard Deviation 4.181 |
| FLOLAN With New Diluent | Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils in Blood at Baseline and Week 4 | Lymphocytes W4 | 22.37 Percentage | Standard Deviation 6.453 |
| FLOLAN With New Diluent | Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils in Blood at Baseline and Week 4 | Monocytes BL | 5.16 Percentage | Standard Deviation 1.766 |
| FLOLAN With New Diluent | Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils in Blood at Baseline and Week 4 | Monocytes W4 | 4.46 Percentage | Standard Deviation 1.71 |
| FLOLAN With New Diluent | Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils in Blood at Baseline and Week 4 | Total Neutrophils BL | 68.70 Percentage | Standard Deviation 6.134 |
| FLOLAN With New Diluent | Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils in Blood at Baseline and Week 4 | Total Neutrophils W4 | 69.47 Percentage | Standard Deviation 8.623 |
Secondary
Change From Baseline in Cardiac Output (CO)
Cardiac output is the volume of blood pumped by the heart per minute. The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value.
Time frame: Baseline and up to Week 4
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FLOLAN With New Diluent | Change From Baseline in Cardiac Output (CO) | 1hr | -0.070 liter/minute | Standard Deviation 1.232 |
| FLOLAN With New Diluent | Change From Baseline in Cardiac Output (CO) | 3hr | 0.460 liter/minute | Standard Deviation 1.1843 |
| FLOLAN With New Diluent | Change From Baseline in Cardiac Output (CO) | 24hr | -0.020 liter/minute | Standard Deviation 0.8854 |
| FLOLAN With New Diluent | Change From Baseline in Cardiac Output (CO) | Week 4 | 0.408 liter/minute | Standard Deviation 0.97 |
Secondary
Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) and Mean Right Atrial Pressure (mRAP)
mPAP and mRAP are hemodynamic parameters. The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value.
Time frame: Baseline and up to Week 4
Population: ITT Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FLOLAN With New Diluent | Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) and Mean Right Atrial Pressure (mRAP) | mPAP, 1hr | 0.5 mmHg | Standard Deviation 2.17 |
| FLOLAN With New Diluent | Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) and Mean Right Atrial Pressure (mRAP) | mPAP, 3hr | 1.5 mmHg | Standard Deviation 3.66 |
| FLOLAN With New Diluent | Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) and Mean Right Atrial Pressure (mRAP) | mPAP, 24hr | -0.5 mmHg | Standard Deviation 3.41 |
| FLOLAN With New Diluent | Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) and Mean Right Atrial Pressure (mRAP) | mPAP, Week4 | 1.9 mmHg | Standard Deviation 2.96 |
| FLOLAN With New Diluent | Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) and Mean Right Atrial Pressure (mRAP) | mRAP, 1hr | -0.9 mmHg | Standard Deviation 2.42 |
| FLOLAN With New Diluent | Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) and Mean Right Atrial Pressure (mRAP) | mRAP, 3hr | -0.1 mmHg | Standard Deviation 3.07 |
| FLOLAN With New Diluent | Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) and Mean Right Atrial Pressure (mRAP) | mRAP, 24hr | 0.3 mmHg | Standard Deviation 3.89 |
| FLOLAN With New Diluent | Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) and Mean Right Atrial Pressure (mRAP) | mRAP, Week4 | 1.5 mmHg | Standard Deviation 3.06 |
Secondary
Change From Baseline in N-terminal Pro B-type Natriuretic Peptide (NT Pro BNP)
Blood samples were collected at Baseline, 24 hours after the first dose of thermostable formulation of FLOLAN, and Week 4 for measurement of NT pro BNP. The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value.
Time frame: Baseline and up to Week 4
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FLOLAN With New Diluent | Change From Baseline in N-terminal Pro B-type Natriuretic Peptide (NT Pro BNP) | 24 hr | -1.8 nanogram/liter | Standard Deviation 21.14 |
| FLOLAN With New Diluent | Change From Baseline in N-terminal Pro B-type Natriuretic Peptide (NT Pro BNP) | Week 4 | 33.7 nanogram/liter | Standard Deviation 103.66 |
Secondary
Change From Baseline in Pulmonary Vascular Resist (PVR)
The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value.
Time frame: Baseline and up to Week 4
Population: ITT population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| FLOLAN With New Diluent | Change From Baseline in Pulmonary Vascular Resist (PVR) | 1hr | 0.204 millimeter mercury/liter/minute | Standard Deviation 2.2976 |
| FLOLAN With New Diluent | Change From Baseline in Pulmonary Vascular Resist (PVR) | 3hr | -0.077 millimeter mercury/liter/minute | Standard Deviation 0.9716 |
| FLOLAN With New Diluent | Change From Baseline in Pulmonary Vascular Resist (PVR) | 24hr | 0.196 millimeter mercury/liter/minute | Standard Deviation 1.2514 |
| FLOLAN With New Diluent | Change From Baseline in Pulmonary Vascular Resist (PVR) | Week 4 | 0.368 millimeter mercury/liter/minute | Standard Deviation 1.5393 |
Secondary
Number of Events to Adjust Dose of FLOLAN Based on the Change From Baseline to 3 Hours in Mean Pulmonary Artery Pressure (mPAP)
To assess the frequency of dose adjustment requirements based on the changes from baseline in mPAP up to 3 hours after dosing.The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Participants who gave consent to undergo right heart catheterisation (RHC) over 24-hour and at week 4 were assessed. Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value.
Time frame: Up to Week 4
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FLOLAN With New Diluent | Number of Events to Adjust Dose of FLOLAN Based on the Change From Baseline to 3 Hours in Mean Pulmonary Artery Pressure (mPAP) | Yes | 0 Number of events |
| FLOLAN With New Diluent | Number of Events to Adjust Dose of FLOLAN Based on the Change From Baseline to 3 Hours in Mean Pulmonary Artery Pressure (mPAP) | No | 10 Number of events |
Secondary
Number of Participants in Each World Health Organization (WHO) Functional Class
The WHO functional classes of PAH range from Class I (without limitation in physical activity) to Class IV (inability to perform a physical activity without any symptoms).
Time frame: Baseline and Week 4
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FLOLAN With New Diluent | Number of Participants in Each World Health Organization (WHO) Functional Class | WHO Class I, BL | 1 Participants |
| FLOLAN With New Diluent | Number of Participants in Each World Health Organization (WHO) Functional Class | WHO Class II, BL | 9 Participants |
| FLOLAN With New Diluent | Number of Participants in Each World Health Organization (WHO) Functional Class | WHO Class III, BL | 0 Participants |
| FLOLAN With New Diluent | Number of Participants in Each World Health Organization (WHO) Functional Class | WHO Class IV, BL | 0 Participants |
| FLOLAN With New Diluent | Number of Participants in Each World Health Organization (WHO) Functional Class | WHO Class I, W4 | 0 Participants |
| FLOLAN With New Diluent | Number of Participants in Each World Health Organization (WHO) Functional Class | WHO Class II, W4 | 10 Participants |
| FLOLAN With New Diluent | Number of Participants in Each World Health Organization (WHO) Functional Class | WHO Class III, W4 | 0 Participants |
| FLOLAN With New Diluent | Number of Participants in Each World Health Organization (WHO) Functional Class | WHO Class IV, W4 | 0 Participants |
Secondary
Number of Participants With Change of WHO Functional Class From Previous Visit
WHO Functional Classification of physical activity limitations: I (no limitation) and IV (unable to carry out any physical activity without symptoms). The change from baseline in WHO class was classified as Improved (decrease in functional class), No Change (functional class stayed the same), and Deteriorated (functional class increased). The change from baseline in WHO functional class at Week 4 has been presented in the table. The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline')
Time frame: Up to Week 4
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FLOLAN With New Diluent | Number of Participants With Change of WHO Functional Class From Previous Visit | Improved | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With Change of WHO Functional Class From Previous Visit | Deteriorated | 1 Participants |
| FLOLAN With New Diluent | Number of Participants With Change of WHO Functional Class From Previous Visit | No change | 9 Participants |
Secondary
Number of Participants With the Reason for the Change Dose of the Thermostable Formulation of FLOLAN
All reasons for FLOLAN dose adjustments after the switch were listed.
Time frame: Up to Week 4
Population: ITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FLOLAN With New Diluent | Number of Participants With the Reason for the Change Dose of the Thermostable Formulation of FLOLAN | Adverse event | 0 Participants |
| FLOLAN With New Diluent | Number of Participants With the Reason for the Change Dose of the Thermostable Formulation of FLOLAN | Other | 2 Participants |