Phase 2 Study of Ambrisentan for Liver Function Test Rescue in Pulmonary Arterial Hypertension

• Sponsor: Gilead Sciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00423592
• Collaborator: (none)
• Enrollment: 36
• Duration (Months): 46

Study Details

Study Description

Brief Summary

This Phase 2 study was to determine the incidence of increased serum aminotransferase concentrations (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]), as well as the overall safety and tolerability of ambrisentan, in participants with pulmonary arterial hypertension (PAH), idiopathic PAH (IPAH), or familial PAH (FPAH) who had previously discontinued ERA therapy (bosentan or sitaxsentan) due to increased serum ALT or AST concentrations.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Hypertension	Drug: ambrisentan	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Open-label, Multicenter Study Evaluating Ambrisentan in Subjects With Pulmonary Arterial Hypertension Who Have Previously Discontinued Endothelin Receptor Antagonist Therapy Due to Serum Aminotransferase Abnormalities
• Study Start Date: May 1, 2005
• Actual Primary Completion Date: Jan 1, 2006
• Actual Study Completion Date: Mar 1, 2009

Outcome Measures

Primary Outcome Measures

1. The Incidence of Confirmed Serum Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) Concentrations > 3 x the Upper Limit of Normal (ULN) Considered to be Related to Ambrisentan and Resulted in Discontinuation of Study Drug. [Week 12]

   The number of participants in the safety analysis set with confirmed serum ALT or AST concentrations > 3 x ULN during 12 weeks of ambrisentan therapy that were related to ambrisentan and resulted in discontinuation of study drug. Safety analysis set included all participants who received at least 1 dose of study drug.

Secondary Outcome Measures

1. The Incidence of Confirmed Serum ALT or AST Concentrations > 5 x ULN That Were Related to Ambrisentan and Resulted in Discontinuation of Study Drug. [Week 12]

   The number of participants in the safety analysis set with confirmed serum ALT or AST concentrations > 5 x ULN during 12 weeks of ambrisentan therapy that were related to ambrisentan and resulted in discontinuation of drug. Safety analysis set included all participants who received at least 1 dose of study drug.

2. The Incidence of Confirmed Serum ALT or AST Concentrations > 3 x ULN That Were Related to Ambrisentan and Resulted in Dose Reduction [Week 12]

   The number of participants in the safety analysis set with confirmed serum ALT or AST concentrations > 3 x ULN during 12 weeks of ambrisentan therapy that were related to ambrisentan and resulted in dose reduction. Safety analysis set included all participants who received at least 1 dose of study drug.

3. A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in the 6-Minute Walk Distance Test (6MWD) [Baseline to Week 12]

   The 6MWD test is a measure of exercise tolerance, and measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface.

4. A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in Borg Dyspnea Index Immediately Following Exercise [Baseline to Week 12]

   Change from baseline evaluated after 12 weeks of ambrisentan therapy in Borg dyspnea index (measured as units on a scale) immediately following exercise. Borg Dyspnea Index, a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness).

5. A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in WHO Functional Class [Baseline to Week 12]

   Classes: I) pulmonary hypertension (PH); ordinary physical activity not limited or causes undue dyspnea or fatigue, chest pain, or near syncope. II) PH; ordinary physical activity slightly limited and causes undue dyspnea or fatigue, chest pain, or near syncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope; comfortable at rest. IV) PH; physical activity causes symptoms and increased discomfort; signs of right heart failure; dyspnea/fatigue possibly at rest.

6. A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in Short Form 36 (SF-36) Health Survey Scale - Composite Physical Health [Baseline to Week 12]

   The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). The first 6 concepts constitute the physical component summary. Each item is scored from 0 to 100 (least healthy to most healthy).

7. Secondary Outcome: A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in SF-36 Health Survey Scale - Composite Mental Health [Baseline to Week 12]

   The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). The last 5 concepts constitute the mental component summary. Each item is scored from 0 to 100 (least healthy to most healthy).

8. Secondary Outcome: A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in SF-36 Health Survey Scale - Physical Functioning [Baseline to Week 12]

   The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). Each item is scored from 0 to 100 (least healthy to most healthy).

9. Secondary Outcome: A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in SF-36 Health Survey Scale - Role Physical [Baseline to Week 12]

   The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). Each item is scored from 0 to 100 (least healthy to most healthy).

10. Secondary Outcome: A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in SF-36 Health Survey Scale - Bodily Pain [Baseline to Week 12]

    The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). Each item is scored from 0 to 100 (least healthy to most healthy).

11. Secondary Outcome: A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in SF-36 Health Survey Scale - General Health [Baseline to Week 12]

    The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). Each item is scored from 0 to 100 (least healthy to most healthy).

12. Secondary Outcome: A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in SF-36 Health Survey Scale - Vitality [Baseline to Week 12]

    The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). Each item is scored from 0 to 100 (least healthy to most healthy).

13. Secondary Outcome: A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in SF-36 Health Survey Scale - Social Functioning [Baseline to Week 12]

    The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). Each item is scored from 0 to 100 (least healthy to most healthy).

14. Secondary Outcome: A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in SF-36 Health Survey Scale - Role Emotional [Baseline to Week 12]

    The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). Each item is scored from 0 to 100 (least healthy to most healthy).

15. Secondary Outcome: A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in SF-36 Health Survey Scale - Mental Health [Baseline to Week 12]

    The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). Each item is scored from 0 to 100 (least healthy to most healthy).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Summary of Inclusion Criteria:

• Males and Females between 12 and 75 years of age

• Current diagnosis of IPAH, FPAH, or PAH associated with collagen vascular disease, congenital systemic-to-pulmonary shunts, anorexigen use, HIV infection

• Must have previously discontinued bosentan or sitaxsentan therapy due to serum aminotransferase (ALT and/or AST) concentrations > 3 x ULN

• Must have normal (< 1 x ULN) serum ALT and AST concentrations at screening

• Six-minute Walk distance of at least 150 meters at screening

• If receiving sildenafil or a clinically approved prostanoid for PAH, must have been on stable therapy for at least 4 weeks prior to screening

• Subjects with a diagnosis of HIV must have stable disease status during the screening period

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Gilead Sciences

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT00423592
• Other Study ID Numbers: AMB-222
• First Posted: Jan 18, 2007
• Last Update Posted: Jun 17, 2013
• Last Verified: Jun 1, 2013

• Additional relevant MeSH terms: Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Hypertension; Ambrisentan

Study Results

Participant Flow

Arm/Group Title	Ambrisentan
Arm/Group Description	All eligible subjects received 2.5 mg ambrisentan once daily for a period of 4 weeks before increasing the dose to 5 mg once daily. After Week 24, investigators were allowed to adjust the dose of ambrisentan as clinically indicated (available doses were 2.5, 5, and 10 mg).
Period Title: Overall Study
STARTED	36
Completed Preliminary Analysis Cut-off	34
COMPLETED	29
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Ambrisentan
Arm/Group Description	All eligible subjects received 2.5 mg ambrisentan once daily for a period of 4 weeks before increasing the dose to 5 mg once daily. After Week 24, investigators were allowed to adjust the dose of ambrisentan as clinically indicated (available doses were 2.5, 5, and 10 mg).
Overall Participants	36
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	22 61.1%
>=65 years	14 38.9%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.2 (13.39)
Sex: Female, Male (Count of Participants)
Female	31 86.1%
Male	5 13.9%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	28 77.8%
Black	2 5.6%
Asian	2 5.6%
Hispanic	3 8.3%
Other	1 2.8%
Region of Enrollment (participants) [Number]
United States	26 72.2%
Australia	5 13.9%
Netherlands	3 8.3%
Belgium	2 5.6%
Pulmonary Arterial Hypertension Etiology (participants) [Number]
Idiopathic pulmonary arterial hypertension	23 63.9%
Familial pulmonary arterial hypertension	1 2.8%
Associated pulmonary arterial hypertension	12 33.3%
Pulmonary Arterial Hypertension Treatment (participants) [Number]
Ambrisentan only	11 30.6%
Ambrisentan/sildenafil	12 33.3%
Ambrisentan/prostanoid	8 22.2%
Ambrisentan/sildenafil/prostanoid	5 13.9%
World Health Organization (WHO) Functional Class (participants) [Number]
Class I	0 0%
Class II	13 36.1%
Class III	23 63.9%
Class IV	0 0%
Baseline 6-Minute Walk Distance (meters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meters]	397.2 (104.59)
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	27.2 (5.44)
Borg dyspnea index (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	4.2 (2.31)
Cardiac index (L/min/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [L/min/m^2]	2.7 (1.02)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	165.1 (7.22)
Mean pulmonary artery pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	48.4 (13.50)
Pulmonary arterial hypertension present (year) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [year]	3.8 (4.99)
Pulmonary capillary wedge pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	10.1 (5.38)
Pulmonary vascular resistance (mmHg/L/min) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg/L/min]	10.3 (5.75)
Right atrial pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	7.9 (5.29)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	74.1 (15.36)

Outcome Measures

1. Primary Outcome

Title	The Incidence of Confirmed Serum Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) Concentrations > 3 x the Upper Limit of Normal (ULN) Considered to be Related to Ambrisentan and Resulted in Discontinuation of Study Drug.
Description	The number of participants in the safety analysis set with confirmed serum ALT or AST concentrations > 3 x ULN during 12 weeks of ambrisentan therapy that were related to ambrisentan and resulted in discontinuation of study drug. Safety analysis set included all participants who received at least 1 dose of study drug.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

The Safety analysis set was defined as all subjects who received at least 1 dose of study drug. All subjects who received at least 1 dose of ambrisentan were followed (to the extent possible) to the end of the study and included in the analyses of safety.

Arm/Group Title	Ambrisentan
Arm/Group Description	All eligible subjects received 2.5 mg ambrisentan once daily for a period of 4 weeks before increasing the dose to 5 mg once daily. After Week 24, investigators were allowed to adjust the dose of ambrisentan as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	36
Number [Participants]	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	Sample size: 30 participants; 80% power to rule out 50% recurrence rate of serum ALT/AST abnormalities following ambrisentan treatment (assumes 25% recurrence rate); 99% power to rule out 75% recurrence rate (assumes 37.5% recurrence rate). H_0 = proportion of subjects experiencing primary endpoint at 12% vs 1-sided alternative of < 12%. P-value from exact binomial test. Summary statistics included the estimated proportion, 95% confidence interval (CI), and the p-value of the hypothesis test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Exact binomial test
	Comments	A 1-sample test for a binomial proportion was performed.
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; 0.0 to 9.7
	Parameter Dispersion	Type: Standard Deviation; Value: 0.0
	Estimation Comments

2. Secondary Outcome

Title	The Incidence of Confirmed Serum ALT or AST Concentrations > 5 x ULN That Were Related to Ambrisentan and Resulted in Discontinuation of Study Drug.
Description	The number of participants in the safety analysis set with confirmed serum ALT or AST concentrations > 5 x ULN during 12 weeks of ambrisentan therapy that were related to ambrisentan and resulted in discontinuation of drug. Safety analysis set included all participants who received at least 1 dose of study drug.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

The Safety analysis set was defined as all subjects who received at least 1 dose of study drug. All subjects who received at least 1 dose of ambrisentan were followed (to the extent possible) to the end of the study and included in the analyses of safety.

Arm/Group Title	Ambrisentan
Arm/Group Description	All eligible subjects received 2.5 mg ambrisentan once daily for a period of 4 weeks before increasing the dose to 5 mg once daily. After Week 24, investigators were allowed to adjust the dose of ambrisentan as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	36
Number [participants]	0 0%

3. Secondary Outcome

Title	The Incidence of Confirmed Serum ALT or AST Concentrations > 3 x ULN That Were Related to Ambrisentan and Resulted in Dose Reduction
Description	The number of participants in the safety analysis set with confirmed serum ALT or AST concentrations > 3 x ULN during 12 weeks of ambrisentan therapy that were related to ambrisentan and resulted in dose reduction. Safety analysis set included all participants who received at least 1 dose of study drug.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

The Safety analysis set was defined as all subjects who received at least 1 dose of study drug. All subjects who received at least 1 dose of ambrisentan were followed (to the extent possible) to the end of the study and included in the analyses of safety.

Arm/Group Title	Ambrisentan
Arm/Group Description	All eligible subjects received 2.5 mg ambrisentan once daily for a period of 4 weeks before increasing the dose to 5 mg once daily. After Week 24, investigators were allowed to adjust the dose of ambrisentan as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	36
Number [participants]	0 0%

4. Secondary Outcome

Title	A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in the 6-Minute Walk Distance Test (6MWD)
Description	The 6MWD test is a measure of exercise tolerance, and measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

The Intention-to-Treat (ITT) analysis set was defined as all subjects who received at least 1 dose of study drug and had at least 1 postdose efficacy value.

Arm/Group Title	Ambrisentan
Arm/Group Description	All eligible subjects received 2.5 mg ambrisentan once daily for a period of 4 weeks before increasing the dose to 5 mg once daily. After Week 24, investigators were allowed to adjust the dose of ambrisentan as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	35
Mean (Standard Deviation) [meters]	23.4 (49.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	Hypothesis testing and descriptive statistics were carried out on the last-observation-carried-forward (LOCF) 6-minute walk distance change from baseline.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	23.4
	Confidence Interval	(2-Sided) 95%; 6.3 to 40.4
	Parameter Dispersion	Type: Standard Deviation; Value: 49.60
	Estimation Comments

5. Secondary Outcome

Title	A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in Borg Dyspnea Index Immediately Following Exercise
Description	Change from baseline evaluated after 12 weeks of ambrisentan therapy in Borg dyspnea index (measured as units on a scale) immediately following exercise. Borg Dyspnea Index, a measure of perceived shortness of breath: 0 units on a scale (none) to 10 units on a scale (maximum breathlessness).
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

The Intention-to-Treat (ITT) analysis set was defined as all subjects who received at least 1 dose of study drug and had at least 1 postdose efficacy value.

Arm/Group Title	Ambrisentan
Arm/Group Description	All eligible subjects received 2.5 mg ambrisentan once daily for a period of 4 weeks before increasing the dose to 5 mg once daily. After Week 24, investigators were allowed to adjust the dose of ambrisentan as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	35
Mean (Standard Deviation) [Units on a scale]	-0.5 (1.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	Hypothesis testing and descriptive statistics were carried out on the last-observation-carried-forward (LOCF) Borg dyspnea index change from baseline.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.046
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -1.0 to 0.0
	Parameter Dispersion	Type: Standard Deviation; Value: 1.51
	Estimation Comments

6. Secondary Outcome

Title	A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in WHO Functional Class
Description	Classes: I) pulmonary hypertension (PH); ordinary physical activity not limited or causes undue dyspnea or fatigue, chest pain, or near syncope. II) PH; ordinary physical activity slightly limited and causes undue dyspnea or fatigue, chest pain, or near syncope; comfortable at rest. III) PH; physical activity markedly limited and less than ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope; comfortable at rest. IV) PH; physical activity causes symptoms and increased discomfort; signs of right heart failure; dyspnea/fatigue possibly at rest.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

The Intention-to-Treat (ITT) analysis set was defined as all subjects who received at least 1 dose of study drug and had at least 1 postdose efficacy value.

Arm/Group Title	Ambrisentan
Arm/Group Description	All eligible subjects received 2.5 mg ambrisentan once daily for a period of 4 weeks before increasing the dose to 5 mg once daily. After Week 24, investigators were allowed to adjust the dose of ambrisentan as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	35
Improved	15 41.7%
No Change	18 50%
Deteriorated	2 5.6%

7. Secondary Outcome

Title	A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in Short Form 36 (SF-36) Health Survey Scale - Composite Physical Health
Description	The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). The first 6 concepts constitute the physical component summary. Each item is scored from 0 to 100 (least healthy to most healthy).
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

The Intention-to-Treat (ITT) analysis set was defined as all subjects who received at least 1 dose of study drug and had at least 1 postdose efficacy value.

Arm/Group Title	Ambrisentan
Arm/Group Description	All eligible subjects received 2.5 mg ambrisentan once daily for a period of 4 weeks before increasing the dose to 5 mg once daily. After Week 24, investigators were allowed to adjust the dose of ambrisentan as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	28
Mean (Standard Deviation) [Units on a scale]	4.6 (6.44)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	Seven subjects were evaluated by the incorrect version of the SF-36 questionnaire at the baseline visit and were not included in the analysis; therefore n = 28 for mean baseline scores, and n = 28 for mean change from baseline at Week 12.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.6
	Confidence Interval	(2-Sided) 95%; 2.1 to 7.1
	Parameter Dispersion	Type: Standard Deviation; Value: 6.44
	Estimation Comments

8. Secondary Outcome

Title	Secondary Outcome: A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in SF-36 Health Survey Scale - Composite Mental Health
Description	The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). The last 5 concepts constitute the mental component summary. Each item is scored from 0 to 100 (least healthy to most healthy).
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

The Intention-to-Treat (ITT) analysis set was defined as all subjects who received at least 1 dose of study drug and had at least 1 postdose efficacy value.

Arm/Group Title	Ambrisentan
Arm/Group Description	All eligible subjects received 2.5 mg ambrisentan once daily for a period of 4 weeks before increasing the dose to 5 mg once daily. After Week 24, investigators were allowed to adjust the dose of ambrisentan as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	28
Mean (Standard Deviation) [Units on a scale]	3.4 (8.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	Seven subjects were evaluated by the incorrect version of the SF-36 questionnaire at the baseline visit and were not included in the analysis; therefore n = 28 for mean baseline scores, and n = 28 for mean change from baseline at Week 12.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.059
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.4
	Confidence Interval	(2-Sided) 95%; -0.1 to 6.8
	Parameter Dispersion	Type: Standard Deviation; Value: 8.98
	Estimation Comments

9. Secondary Outcome

Title	Secondary Outcome: A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in SF-36 Health Survey Scale - Physical Functioning
Description	The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). Each item is scored from 0 to 100 (least healthy to most healthy).
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

The Intention-to-Treat (ITT) analysis set was defined as all subjects who received at least 1 dose of study drug and had at least 1 postdose efficacy value.

Arm/Group Title	Ambrisentan
Arm/Group Description	All eligible subjects received 2.5 mg ambrisentan once daily for a period of 4 weeks before increasing the dose to 5 mg once daily. After Week 24, investigators were allowed to adjust the dose of ambrisentan as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	28
Mean (Standard Deviation) [Units on a scale]	4.4 (6.86)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	Seven subjects were evaluated by the incorrect version of the SF-36 questionnaire at the baseline visit and were not included in the analysis; therefore n = 28 for mean baseline scores, and n = 28 for mean change from baseline at Week 12.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.4
	Confidence Interval	(2-Sided) 95%; 1.7 to 7.0
	Parameter Dispersion	Type: Standard Deviation; Value: 6.86
	Estimation Comments

10. Secondary Outcome

Title	Secondary Outcome: A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in SF-36 Health Survey Scale - Role Physical
Description	The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). Each item is scored from 0 to 100 (least healthy to most healthy).
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

The Intention-to-Treat (ITT) analysis set was defined as all subjects who received at least 1 dose of study drug and had at least 1 postdose efficacy value.

Arm/Group Title	Ambrisentan
Arm/Group Description	All eligible subjects received 2.5 mg ambrisentan once daily for a period of 4 weeks before increasing the dose to 5 mg once daily. After Week 24, investigators were allowed to adjust the dose of ambrisentan as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	28
Mean (Standard Deviation) [Units on a scale]	7.2 (10.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	Seven subjects were evaluated by the incorrect version of the SF-36 questionnaire at the baseline visit and were not included in the analysis; therefore n = 28 for mean baseline scores, and n = 28 for mean change from baseline at Week 12.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.2
	Confidence Interval	(2-Sided) 95%; 3.1 to 11.3
	Parameter Dispersion	Type: Standard Deviation; Value: 10.56
	Estimation Comments

11. Secondary Outcome

Title	Secondary Outcome: A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in SF-36 Health Survey Scale - Bodily Pain
Description	The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). Each item is scored from 0 to 100 (least healthy to most healthy).
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

The Intention-to-Treat (ITT) analysis set was defined as all subjects who received at least 1 dose of study drug and had at least 1 postdose efficacy value.

Arm/Group Title	Ambrisentan
Arm/Group Description	All eligible subjects received 2.5 mg ambrisentan once daily for a period of 4 weeks before increasing the dose to 5 mg once daily. After Week 24, investigators were allowed to adjust the dose of ambrisentan as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	28
Mean (Standard Deviation) [Units on a scale]	3.1 (6.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	Seven subjects were evaluated by the incorrect version of the SF-36 questionnaire at the baseline visit and were not included in the analysis; therefore n = 28 for mean baseline scores, and n = 28 for mean change from baseline at Week 12.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.1
	Confidence Interval	(2-Sided) 95%; 0.6 to 5.6
	Parameter Dispersion	Type: Standard Deviation; Value: 6.40
	Estimation Comments

12. Secondary Outcome

Title	Secondary Outcome: A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in SF-36 Health Survey Scale - General Health
Description	The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). Each item is scored from 0 to 100 (least healthy to most healthy).
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

The Intention-to-Treat (ITT) analysis set was defined as all subjects who received at least 1 dose of study drug and had at least 1 postdose efficacy value.

Arm/Group Title	Ambrisentan
Arm/Group Description	All eligible subjects received 2.5 mg ambrisentan once daily for a period of 4 weeks before increasing the dose to 5 mg once daily. After Week 24, investigators were allowed to adjust the dose of ambrisentan as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	28
Mean (Standard Deviation) [Units on a scale]	3.0 (7.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	Seven subjects were evaluated by the incorrect version of the SF-36 questionnaire at the baseline visit and were not included in the analysis; therefore n = 28 for mean baseline scores, and n = 28 for mean change from baseline at Week 12.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.046
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.0
	Confidence Interval	(2-Sided) 95%; 0.1 to 5.8
	Parameter Dispersion	Type: Standard Deviation; Value: 7.45
	Estimation Comments

13. Secondary Outcome

Title	Secondary Outcome: A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in SF-36 Health Survey Scale - Vitality
Description	The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). Each item is scored from 0 to 100 (least healthy to most healthy).
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

The Intention-to-Treat (ITT) analysis set was defined as all subjects who received at least 1 dose of study drug and had at least 1 postdose efficacy value.

Arm/Group Title	Ambrisentan
Arm/Group Description	All eligible subjects received 2.5 mg ambrisentan once daily for a period of 4 weeks before increasing the dose to 5 mg once daily. After Week 24, investigators were allowed to adjust the dose of ambrisentan as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	28
Mean (Standard Deviation) [Units on a scale]	4.5 (7.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	Seven subjects were evaluated by the incorrect version of the SF-36 questionnaire at the baseline visit and were not included in the analysis; therefore n = 28 for mean baseline scores, and n = 28 for mean change from baseline at Week 12.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.5
	Confidence Interval	(2-Sided) 95%; 1.7 to 7.3
	Parameter Dispersion	Type: Standard Deviation; Value: 7.23
	Estimation Comments

14. Secondary Outcome

Title	Secondary Outcome: A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in SF-36 Health Survey Scale - Social Functioning
Description	The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). Each item is scored from 0 to 100 (least healthy to most healthy).
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

The Intention-to-Treat (ITT) analysis set was defined as all subjects who received at least 1 dose of study drug and had at least 1 postdose efficacy value.

Arm/Group Title	Ambrisentan
Arm/Group Description	All eligible subjects received 2.5 mg ambrisentan once daily for a period of 4 weeks before increasing the dose to 5 mg once daily. After Week 24, investigators were allowed to adjust the dose of ambrisentan as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	28
Mean (Standard Deviation) [Units on a scale]	3.5 (9.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	Seven subjects were evaluated by the incorrect version of the SF-36 questionnaire at the baseline visit and were not included in the analysis; therefore n = 28 for mean baseline scores, and n = 28 for mean change from baseline at Week 12.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.059
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.5
	Confidence Interval	(2-Sided) 95%; -0.1 to 7.2
	Parameter Dispersion	Type: Standard Deviation; Value: 9.41
	Estimation Comments

15. Secondary Outcome

Title	Secondary Outcome: A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in SF-36 Health Survey Scale - Role Emotional
Description	The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). Each item is scored from 0 to 100 (least healthy to most healthy).
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

The Intention-to-Treat (ITT) analysis set was defined as all subjects who received at least 1 dose of study drug and had at least 1 postdose efficacy value.

Arm/Group Title	Ambrisentan
Arm/Group Description	All eligible subjects received 2.5 mg ambrisentan once daily for a period of 4 weeks before increasing the dose to 5 mg once daily. After Week 24, investigators were allowed to adjust the dose of ambrisentan as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	28
Mean (Standard Deviation) [Units on a scale]	3.9 (13.96)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	Seven subjects were evaluated by the incorrect version of the SF-36 questionnaire at the baseline visit and were not included in the analysis; therefore n = 28 for mean baseline scores, and n = 28 for mean change from baseline at Week 12.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.152
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.9
	Confidence Interval	(2-Sided) 95%; -1.5 to 9.3
	Parameter Dispersion	Type: Standard Deviation; Value: 13.96
	Estimation Comments

16. Secondary Outcome

Title	Secondary Outcome: A Change From Baseline Evaluated After 12 Weeks of Ambrisentan Therapy in SF-36 Health Survey Scale - Mental Health
Description	The SF-36 Health Survey is a self-reporting, multi-item scale measuring 8 health concepts: 1) physical functioning, 2) role limitations due to physical health problems, 3) bodily pain, 4) general health, 5) vitality (energy/fatigue), 6) social functioning, 7) role limitations due to emotional problems and 8) mental health (psychological distress and psychological well-being). Each item is scored from 0 to 100 (least healthy to most healthy).
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

The Intention-to-Treat (ITT) analysis set was defined as all subjects who received at least 1 dose of study drug and had at least 1 postdose efficacy value.

Arm/Group Title	Ambrisentan
Arm/Group Description	All eligible subjects received 2.5 mg ambrisentan once daily for a period of 4 weeks before increasing the dose to 5 mg once daily. After Week 24, investigators were allowed to adjust the dose of ambrisentan as clinically indicated (available doses were 2.5, 5, and 10 mg).
Measure Participants	28
Mean (Standard Deviation) [Units on a scale]	3.9 (5.78)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ambrisentan
	Comments	Seven subjects were evaluated by the incorrect version of the SF-36 questionnaire at the baseline visit and were not included in the analysis; therefore n = 28 for mean baseline scores, and n = 28 for mean change from baseline at Week 12.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.9
	Confidence Interval	(2-Sided) 95%; 1.7 to 6.2
	Parameter Dispersion	Type: Standard Deviation; Value: 5.78
	Estimation Comments

Adverse Events

Time Frame	Baseline to Week 189
Adverse Event Reporting Description	Median exposure to study drug was 108.1 weeks (2.08 years). Two subjects discontinued ambrisentan because of adverse events after 1 and 3 weeks, respectively. Reporting interval for all other subjects was from 36 to 189 weeks.
Arm/Group Title	Ambrisentan
Arm/Group Description	All eligible subjects received 2.5 mg ambrisentan once daily for a period of 4 weeks before increasing the dose to 5 mg once daily. After Week 24, investigators were allowed to adjust the dose of ambrisentan as clinically indicated (available doses were 2.5, 5, and 10 mg).
All Cause Mortality
	Ambrisentan
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ambrisentan
	Affected / at Risk (%)	# Events
Total	17/36 (47.2%)
Blood and lymphatic system disorders
anaemia	2/36 (5.6%)
microcytic anaemia	1/36 (2.8%)
Cardiac disorders
acute coronary syndrome	1/36 (2.8%)
acute myocardial infarction	1/36 (2.8%)
atrial fibrillation	2/36 (5.6%)
atrial tachycardia	1/36 (2.8%)
cardiac arrest	1/36 (2.8%)
coronary artery disease	1/36 (2.8%)
palpitations	1/36 (2.8%)
right ventricular failure	1/36 (2.8%)
supraventricular tachycardia	1/36 (2.8%)
Congenital, familial and genetic disorders
gastrointestinal arteriovenous malformation	1/36 (2.8%)
Gastrointestinal disorders
diarrhoea	1/36 (2.8%)
General disorders
chest pain	1/36 (2.8%)
infusion site pain	1/36 (2.8%)
Infections and infestations
catheter site cellulitis	1/36 (2.8%)
central line infection	1/36 (2.8%)
gastroenteritis	1/36 (2.8%)
gastroenteritis viral	1/36 (2.8%)
lobar pneumonia	1/36 (2.8%)
pneumococcal sepsis	1/36 (2.8%)
pneumonia	1/36 (2.8%)
staphylococcal bacteraemia	1/36 (2.8%)
upper respiratory tract infection	1/36 (2.8%)
Investigations
blood potassium increased	1/36 (2.8%)
Metabolism and nutrition disorders
dehydration	2/36 (5.6%)
hypokalaemia	1/36 (2.8%)
hyponatraemia	1/36 (2.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
breast cancer	1/36 (2.8%)
Nervous system disorders
dizziness	1/36 (2.8%)
dizziness postural	1/36 (2.8%)
ischaemic stroke	1/36 (2.8%)
sciatica	1/36 (2.8%)
syncope	1/36 (2.8%)
Psychiatric disorders
depression	1/36 (2.8%)
Renal and urinary disorders
azotaemia	1/36 (2.8%)
Respiratory, thoracic and mediastinal disorders
chronic obstructive airways disease exacerbated	1/36 (2.8%)
hypoxia	1/36 (2.8%)
pulmonary embolism	1/36 (2.8%)
pulmonary hypertension	5/36 (13.9%)
Other (Not Including Serious) Adverse Events
	Ambrisentan
	Affected / at Risk (%)	# Events
Total	36/36 (100%)
Blood and lymphatic system disorders
anaemia	8/36 (22.2%)
lymphadenopathy	2/36 (5.6%)
Cardiac disorders
atrial fibrillation	4/36 (11.1%)
bradycardia	2/36 (5.6%)
coronary artery disease	2/36 (5.6%)
palpitations	8/36 (22.2%)
tricuspid valve incompetence	3/36 (8.3%)
Ear and labyrinth disorders
vertigo	3/36 (8.3%)
Eye disorders
conjunctival haemorrhage	2/36 (5.6%)
vision blurred	2/36 (5.6%)
Gastrointestinal disorders
abdominal pain	4/36 (11.1%)
abdominal pain upper	2/36 (5.6%)
constipation	3/36 (8.3%)
diarrhoea	7/36 (19.4%)
dyspepsia	3/36 (8.3%)
gastrooesophageal reflux disease	4/36 (11.1%)
nausea	9/36 (25%)
oesophagitis	2/36 (5.6%)
toothache	3/36 (8.3%)
vomiting	2/36 (5.6%)
General disorders
asthenia	2/36 (5.6%)
chest discomfort	4/36 (11.1%)
chest pain	4/36 (11.1%)
chills	2/36 (5.6%)
fatigue	9/36 (25%)
influenza like illness	2/36 (5.6%)
infusion site pain	3/36 (8.3%)
non-cardiac chest pain	2/36 (5.6%)
oedema peripheral	19/36 (52.8%)
pyrexia	5/36 (13.9%)
Immune system disorders
drug hypersensitivity	2/36 (5.6%)
Infections and infestations
bronchitis	4/36 (11.1%)
bronchitis acute	3/36 (8.3%)
eye infection	2/36 (5.6%)
herpes zoster	2/36 (5.6%)
influenza	2/36 (5.6%)
infusion site infection	2/36 (5.6%)
localised infection	2/36 (5.6%)
lower respiratory tract infection	2/36 (5.6%)
nasopharyngitis	5/36 (13.9%)
pharyngitis	3/36 (8.3%)
respiratory tract infection	5/36 (13.9%)
sinusitis	7/36 (19.4%)
upper respiratory tract infection	8/36 (22.2%)
urinary tract infection	6/36 (16.7%)
viral upper respiratory tract infection	2/36 (5.6%)
Injury, poisoning and procedural complications
contusion	2/36 (5.6%)
fall	2/36 (5.6%)
post procedural pain	2/36 (5.6%)
Investigations
excercise capacity decreased	2/36 (5.6%)
international normalised ratio increased	4/36 (11.1%)
weight increased	3/36 (8.3%)
Metabolism and nutrition disorders
dehydration	2/36 (5.6%)
fluid retention	3/36 (8.3%)
hypokalaemia	2/36 (5.6%)
hypomagnesaemia	2/36 (5.6%)
Musculoskeletal and connective tissue disorders
arthralgia	4/36 (11.1%)
back pain	3/36 (8.3%)
neck pain	2/36 (5.6%)
pain in extremity	6/36 (16.7%)
pain in jaw	2/36 (5.6%)
shoulder pain	2/36 (5.6%)
Nervous system disorders
dizziness	5/36 (13.9%)
dizziness postural	2/36 (5.6%)
headache	13/36 (36.1%)
tremor	2/36 (5.6%)
Psychiatric disorders
anxiety	6/36 (16.7%)
depression	2/36 (5.6%)
insomnia	7/36 (19.4%)
Respiratory, thoracic and mediastinal disorders
cough	6/36 (16.7%)
crackles lung	2/36 (5.6%)
dysphonia	2/36 (5.6%)
dyspnoea	4/36 (11.1%)
dyspnoea exacerbated	12/36 (33.3%)
dyspnoea exertional	4/36 (11.1%)
epistaxis	4/36 (11.1%)
hypoxia	2/36 (5.6%)
nasal congestion	5/36 (13.9%)
pharyngolaryngeal pain	2/36 (5.6%)
pleuritic pain	3/36 (8.3%)
pulmonary hypertension	4/36 (11.1%)
rales	2/36 (5.6%)
rhinitis allergic	3/36 (8.3%)
rhinorrhoea	3/36 (8.3%)
wheezing	2/36 (5.6%)
Skin and subcutaneous tissue disorders
dry skin	2/36 (5.6%)
erythema	2/36 (5.6%)
pruritis	2/36 (5.6%)
rash	4/36 (11.1%)
rash macular	2/36 (5.6%)
Vascular disorders
flushing	7/36 (19.4%)
hypotension	3/36 (8.3%)

Limitations/Caveats

Seven subjects were excluded from the change from baseline analysis of the SF-36 Health Survey because the incorrect version of the SF-36 questionnaire was used for evaluation at baseline, which made comparisons problematic.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.