Efficacy Study of Ambrisentan in Chinese Patients With Pulmonary Arterial Hypertension (PAH)

The 6MWT measures the distance that a participant can walk in a period of 6 minutes. Change from Baseline was calculated as the Week 12 value minus the Baseline value. Baseline 6MWT comprised of an average of the last two consecutive measurements prior to dosing that varied by not greater than 10 percent (%). If only one measurement was available, that measurement was used as the Baseline value. The last observation carried forward method was used to impute missing values.

The 6MWT measures the distance that a participant can walk in a period of 6 minutes. Change from Baseline was calculated as the Week 24 value minus the Baseline value. Baseline 6MWT comprised of an average of the last two consecutive measurements prior to dosing that varied by not greater than 10%. If only one measurement was available, that measurement was used as the Baseline value. The last observation carried forward method was used to impute missing values.

The WHO FC was determined by the investigator as follows: Class I- Participants with pulmonary hypertension (PH) but without resulting limitation of physical activity, II- Participants with PH resulting in slight limitation of physical activity, III- Participants with PH resulting in marked limitation of physical activity, IV- Participants with PH with inability to carry out any physical activity without symptoms. Changes from Baseline in functional class were summarized at Weeks 12 and 24. The number of participants improving by 2 classes, improving by 1 class, not changing, worsening by 1 class or worsening by 2 classes from Baseline at Weeks 12 and 24 were evaluated. The Baseline value was the last non-missing assessment value before treatment. Only participants with non-missing Baseline values and at least one non-missing post-Baseline value of the response variable were included. The last observation carried forward method was used to impute missing values.

The BDI was calculated by using a 10-point scale (0 = None, 10 = Maximum). Change from Baseline was calculated as the Week 12 and 24 values minus the Baseline values. The BDI indicates the degree of exertion, breathlessness, fatigue, or difficulty breathing after completion of the 6MWT. The lower values, 0 as the lowest, indicates no exertion, fatigue, or breathlessness felt, and 10 would be the maximum amount of exertion felt as assessed by each participant. The last observation carried forward method was used to impute missing values.

N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) is a surrogate maker of heart failure and was measured by a central laboratory. Mean change from Baseline at Weeks 12 and 24 were calculated as the Weeks 12 and 24 values minus the Baseline values.Observed data was analyzed (no imputation technique was performed for missing data). Log transformed mean change from Baseline at Weeks 12 and 24 data are summarized.

Time to clinical worsening is defined as the time from Baseline to the first occurrence of death, lung transplantation, hospitalization for PAH treatment, atrial septostomy, or Investigational product (IP) discontinuation (discon) due to change to other PAH treatment. Time to clinical worsening was measured as the number of participants who experienced these events during 12 and 24 Weeks.

An adverse event (AE) is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. A serious adverse event (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, a congenital anomaly/birth defect, or important medical events that jeopardize the participants or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition.

Complete physical examinations of each participant by the investigator were performed at the Screening Visit, Week 12 and Week 24 Visit/Early withdrawal visits. The physical examination included an examination of the following: general appearance, skin, head, ears, eyes, nose, throat, neck, thyroid, lymph nodes, cardiovascular system, respiratory system, abdomen, musculoskeletal system, neurological system and height. Physical examination summary results were not collected therefore there is no data to present for this outcome measure.

Heart rate was measured in order to monitor vital signs by the 12-lead ECG at Baseline, Weeks 12 and 24. Change from Baseline in ECG heart rate is summarized for each post-Baseline assessment at Weeks 12 and 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last non-missing observed value before treatment.

The ECG parameters, PR interval, QRS duration, uncorrected QT interval, QTcB were measured at Baseline, Weeks 12 and 24. Change from Baseline in ECG heart rate is summarized for each post-Baseline assessment up to Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last non-missing observed value before treatment.

Blood pressure measurements (pre-6MWT and post-6MWT) were taken to monitor vital signs and included systolic blood pressure (SBP) and diastolic blood pressure (DBP) at the Baseline, Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in SBP and DBP were summarized for each post-Baseline assessment upto Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last non-missing observed value before treatment.

Vital sign monitoring included heart rate measurements at (pre-6MWT and post-6MWT at the Baseline visit, Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in heart rate was summarized for each post-Baseline assessment up to Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last non-missing value observed before treatment. At Baseline, Weeks 12 and 28, heart rate was recorded at the end of the 6MWT and at 1 minute (M), 2 M and 3 M, after completion of the 6MWT with the participants seated, and the time that heart rate recovered to the level of pre-6MWT.

Oral temperature was used to monitor vital signs and collected at the Screening visit.

Blood samples were collected for the measurement of ALT, ALP, AST and BILT at the Baseline visit and up to Week 24. Shift from Baseline (BL) was calculated as the individual maximum of post-BL value minus the BL value. The BL value is defined as the last pre-treatment value observed. Threshold values for the liver function test results, which were considered as potential values of clinical concern, were 3 times the upper limit of normal (ULN) for ALT, AST and ALP and 2 times the ULN for BILT. Maximum liver function abnormal values of post-BL are summarized.

Blood samples were collected for the measurement of basophils, eosinophils, lymphocytes, monocytes, total neutrophils, platelet count and WBC count at the Baseline visit and Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in the basophils, eosinophils, lymphocytes, monocytes, total neutrophils, platelet count and WBC count values were summarized for each post-Baseline assessment until Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Blood samples were collected for the measurement of hemoglobin at the Baseline visit and Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in the hemoglobin count values were summarized for each post-Baseline assessment until Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Blood samples were collected for the measurement of hematocrit at the Baseline visit and Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in the hematocrit values were summarized for each post-Baseline assessment until Week 24. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The Baseline value is defined as the last Pre-treatment value observed. The unit of measure is defined as the proprtion of red blood cells in blood.

Blood samples were collected for the measurement of mean corpuscle hemoglobin at the Baseline visit and Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in the hemoglobin values were summarized for each post-Baseline assessment until Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Blood samples were collected for the measurement of mean corpuscle volume at the Baseline visit and Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in the mean corpuscle volume values were summarized for each post-Baseline assessment until Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Blood samples were collected for the measurement of RBC count at the Baseline visit and Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in the red blood cell count values were summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Blood samples were collected for the measurement of albumin, globulin and total protein at the Baseline visit and Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in the albumin, globulin and total protein values were summarized for each post-Baseline assessment until Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Blood samples were collected for the measurement of alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino transferase (AST), creatine kinase (CK), gamma glutamyl transferase (GGT) and lactate dehydrogenase (LDH) at the Baseline visit and Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in the ALP, ALT, AST, CK, GGT and LDH values were summarized for each post-Baseline assessment until Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Blood samples were collected for the measurement of direct bilirubin, total bilirubin, creatinine and uric acid at the Baseline visit and Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in the direct bilirubin, total bilirubin, creatinine and uric acid values were summarized for each post-Baseline assessment until Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Blood samples were collected for the measurement of calcium, cholesterol, chloride, glucose, potassium, magnesium, sodium, inorganic phosphorus, triglycerides and urea/Bun at the Baseline visit and Weeks 4, 8, 12, 16, 20 and 24. Change from Baseline in the calcium, cholesterol, chloride, glucose, potassium, magnesium, sodium, inorganic phosphorus, triglycerides and urea/BUN values were summarized for each post-Baseline assessment until Week 24. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Urine samples were collected for urinalysis at Baseline and Week 24. The Number of participants with urinalysis to negative and positives (trace, +, ++ and +++) data at Baseline and Week 24 are summarized for urine bilirubin (UBIL), urine glucose (UGLU), urine ketones (UKET), urine nitrite (UNIT), urine protein (UM) and urine urobilinogen (UUBIL) were performed with dipstick method. Other urinalysis parameters included urine pH (UpH), urine specific gravity (USG). The Baseline value is defined as the last pre-treatment value observed.