NCT01808313

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

Completed Phase 3 Results posted Last updated 6 June 2017

What this trial tests

Phase 3 trial testing ambrisentan in Vascular Disease in 134 participants. Completed in 15 August 2014.

Timeline

1 December 2012

Primary endpoint
15 August 2014

15 August 2014

Quick facts

Lead sponsor	GlaxoSmithKline
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	treatment
Enrollment	134
Start date	1 December 2012
Primary completion	15 August 2014
Estimated completion	15 August 2014
Sites	12 locations across China

Drugs / interventions tested

• ambrisentan (AMBRISENTAN) — full drug profile →

Conditions studied

• Vascular Disease — all drugs for Vascular Disease →

Sponsor

GlaxoSmithKline — full company profile →

Who can join

Adults 18 to 75, any sex, with Vascular Disease. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change From Baseline in 6-minutes Walk Test (6MWT) at Week 12 Primary · Baseline and Week 12

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.

Group	Value	95% CI
Ambrisentan	53.59	± 64.494

Change From Baseline in 6MWT at Week 24 Secondary · Baseline and Week 24

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.

Group	Value	95% CI
Ambrisentan	64.36	± 91.173

Number of Participants With a Change From Baseline in Their World Health Organization (WHO) Functional Classification (FC) at Weeks 12 and 24 Secondary · Baseline, Week 12 and Week 24

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 cl

Improved by 2 classes at Week 12

Group	Value	95% CI
Ambrisentan	0

Improved by 1 class at Week 12

Group	Value	95% CI
Ambrisentan	44

Not changing at Week 12

Group	Value	95% CI
Ambrisentan	84

Worsened by 1 class at Week 12

Group	Value	95% CI
Ambrisentan	4

Worsened by 2 classes at Week 12

Group	Value	95% CI
Ambrisentan	1

Improved by 2 classes at Week 24

Group	Value	95% CI
Ambrisentan	0

Improved by 1 class at Week 24

Group	Value	95% CI
Ambrisentan	51

Not changing at Week 24

Group	Value	95% CI
Ambrisentan	77

Change From Baseline in the Borg Dyspnea Index (BDI) at Weeks 12 and 24 Secondary · Baseline, Week 12 and Week 24

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.

Week 12

Group	Value	95% CI
Ambrisentan	-0.34	± 1.521

Week 24

Group	Value	95% CI
Ambrisentan	-0.22	± 1.952

Change From Baseline in the N-Terminal Pro-B-Type Natriuretic Peptide at Weeks 12 and 24 Secondary · Baseline, Week 12 and Week 24

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.

Week 12, n=123

Group	Value	95% CI
Ambrisentan	0.44	± 2.687

Week 24, n=122

Group	Value	95% CI
Ambrisentan	0.37	± 3.103

Number of Participants With the Indicated Event, as an Assessment of Time to Clinical Worsening of Pulmonary Arterial Hypertension (PAH) up to Week 24, Assessed as the First Occurrence of a Particular Event Secondary · Baseline up to Week 24

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.

Death at Week 12

Group	Value	95% CI
Ambrisentan	2

Lung Transplant at Week 12

Group	Value	95% CI
Ambrisentan	0

Hospitalization for PAH at Week 12

Group	Value	95% CI
Ambrisentan	0

Atrial Septostomy at Week 12

Group	Value	95% CI
Ambrisentan	0

IP discon (additional medication) at Week 12

Group	Value	95% CI
Ambrisentan	0

Death at Week 24

Group	Value	95% CI
Ambrisentan	3

Lung Transplant at Week 24

Group	Value	95% CI
Ambrisentan	0

Hospitalization for PAH at Week 24

Group	Value	95% CI
Ambrisentan	1

Number of Participants With Any Adverse Events, Any Serious Adverse Events and Adverse Events Leading to Discontinuation Secondary · From the start of study treatment up to Week 24

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 hospit

Any AEs

Group	Value	95% CI
Ambrisentan	91

Any SAEs

Group	Value	95% CI
Ambrisentan	11

AEs leading to discontinuation

Group	Value	95% CI
Ambrisentan	4

Number of Participants With Physical Examination Findings Secondary · Baseline, Week 12 and Week 24

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.

Group	Value	95% CI
Ambrisentan	NA

Change From Baseline in Electrocardiogram (ECG) Heart Rate Values at Weeks 12 and 24 Secondary · Baseline, Week 12 and Week 24

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.

Week 12, n=124

Group	Value	95% CI
Ambrisentan	-2.0	± 16.65

Week 24, n=118

Group	Value	95% CI
Ambrisentan	-4.6	± 14.68

Change From Baseline in PR Interval, QRS Duration, Uncorrected QT Interval, QT Interval Corrected Bazett's Formula (QTcB) Values at Weeks 12 and 24 Secondary · Baseline, Week 12 and Week 24

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.

PR interval, Week 12, n=122

Group	Value	95% CI
Ambrisentan	0.7	± 16.55

PR interval, Week 24, n=117

Group	Value	95% CI
Ambrisentan	1.5	± 14.84

QRS duration, Week 12, n=124

Group	Value	95% CI
Ambrisentan	-1.5	± 15.84

QRS duration, Week 24, n=118

Group	Value	95% CI
Ambrisentan	0.7	± 14.40

Uncorrected QT Interval, Week 12, n=124

Group	Value	95% CI
Ambrisentan	-0.7	± 37.44

Uncorrected QT Interval, Week 24, n=118

Group	Value	95% CI
Ambrisentan	6.8	± 40.41

Corrected QTcB interval, Week 12, n=123

Group	Value	95% CI
Ambrisentan	-4.9	± 29.74

Corrected QTcB interval, Week 24, n=117

Group	Value	95% CI
Ambrisentan	-1.5	± 37.25

Change From Baseline in Systolic and Diastolic Blood Pressure at the Indicated Time Points up to Week 24 Secondary · Baseline up to Week 24

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.

SBP; pre-6MWT; Week 4; n=131

Group	Value	95% CI
Ambrisentan	-1.6	± 11.57

SBP; post-6MWT; Week 4; n=131

Group	Value	95% CI
Ambrisentan	0.7	± 15.36

SBP; pre-6MWT; Week 8; n=126

Group	Value	95% CI
Ambrisentan	-2.2	± 13.89

SBP; post-6MWT, Week 8; n=126

Group	Value	95% CI
Ambrisentan	2.3	± 17.36

SBP; pre-6MWT; Week 12; n=126

Group	Value	95% CI
Ambrisentan	-1.9	± 15.08

SBP; post-6MWT; Week 12; n=125

Group	Value	95% CI
Ambrisentan	0.3	± 18.23

SBP; pre-6MWT; Week 16; n=124

Group	Value	95% CI
Ambrisentan	-1.8	± 14.55

SBP; post-6MWT; Week 16; n=123

Group	Value	95% CI
Ambrisentan	1.7	± 17.71

Change From Baseline in Heart Rate at the Indicated Time Points up to Week 24 Secondary · Baseline up to Week 24

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

Heart Rate; pre-6MWT; Week 4; n=131

Group	Value	95% CI
Ambrisentan	-0.7	± 12.12

Heart Rate; post-6MWT; Week 4; n=131

Group	Value	95% CI
Ambrisentan	-2.1	± 18.26

Heart Rate; pre-6MWT; Week 8; n=126

Group	Value	95% CI
Ambrisentan	-1.2	± 13.10

Heart Rate; post-6MWT, Week 8; n=126

Group	Value	95% CI
Ambrisentan	-0.2	± 17.39

Heart Rate; pre-6MWT; Week 12; n=126

Group	Value	95% CI
Ambrisentan	-1.7	± 12.27

Heart Rate; post-6MWT; Week 12; n=124

Group	Value	95% CI
Ambrisentan	0.6	± 18.23

Heart Rate; post-6MWT 1M; Week 12; n=124

Group	Value	95% CI
Ambrisentan	-0.9	± 15.11

Heart Rate; post-6MWT 2 M; Week 12; n=124

Group	Value	95% CI
Ambrisentan	-2.2	± 13.51

Adverse events — posted to ClinicalTrials.gov

Time frame: On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug (up to Week 24). Reporting threshold: 3%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Ambrisentan

Serious: 11/134 (8%)

Deaths: —

Serious adverse events (13 terms)

Reaction	System	Ambrisentan
Sudden cardiac death	General disorders	—
Atrial flutter	Cardiac disorders	—
Cardiac failure	Cardiac disorders	—
Supraventricular tachycardia	Cardiac disorders	—
Oedema peripheral	General disorders	—
Bronchitis	Infections and infestations	—
Lung infection	Infections and infestations	—
Pneumonia	Infections and infestations	—
Ascites	Gastrointestinal disorders	—
Diarrhoea	Gastrointestinal disorders	—
Haemorrhagic anaemia	Blood and lymphatic system disorders	—
Cerebral haemorrhage	Nervous system disorders	—
Cystitis glandularis	Renal and urinary disorders	—

Other adverse events (13 terms — click to expand)

Reaction	System	Ambrisentan
Oedema peripheral	General disorders	—
Flushing	Vascular disorders	—
Alanine aminotransferase increased	Investigations	—
Aspartate aminotransferase increased	Investigations	—
Blood bilirubin increased	Investigations	—
Gamma-glutamyltransferase increased	Investigations	—
Headache	Nervous system disorders	—
Nausea	Gastrointestinal disorders	—
Cough	Respiratory, thoracic and mediastinal disorders	—
Decreased appetite	Metabolism and nutrition disorders	—
Dizziness	Nervous system disorders	—
Upper respiratory tract infection	Infections and infestations	—
Blood glucose increased	Investigations	—

Most-reported serious reactions: Sudden cardiac death, Atrial flutter, Cardiac failure, Supraventricular tachycardia, Oedema peripheral, Bronchitis, Lung infection, Pneumonia.

Data from ClinicalTrials.gov NCT01808313 adverse events section.

Sponsor's own description

This open label, single-arm, non-controlled, multicentre study will determine the effect of ambrisentan on exercise capacity (6MWT) in Chinese subjects with PAH. The study consists of a screening period of 4 weeks, a 12-week primary evaluation period (PEP) and a 12-week dose-adjustment period (DAP). Ambrisentan 5 mg will be administered to eligible subjects for 12 weeks (PEP).

Publications & conference data

3 peer-reviewed publications reference this trial (live from Europe PMC):

1. Evaluation of efficacy, safety and tolerability of Ambrisentan in Chinese adults with pulmonary arterial hypertension: a prospective open label cohort study.
   Huo Y, Jing ZC, Zeng XF, Liu JM, et al · · 2016 · cited 5× · PMID 27770771 · DOI 10.1186/s12872-016-0361-9
2. Efficacy and safety of ambrisentan in Chinese patients with connective tissue disease-pulmonary arterial hypertension: a post-hoc analysis.
   Li M, Jing ZC, Li Y, Huo Y, et al · · 2020 · cited 2× · PMID 32680480 · DOI 10.1186/s12872-020-01591-1
3. Effect of ambrisentan on echocardiographic and Doppler measures from patients in China with pulmonary arterial hypertension.
   Zhao QH, Peng FH, Yu ZX, Zhang GC, et al · · 2020 · cited 1× · PMID 32799568 · DOI 10.1080/14779072.2020.1807942