Trial Outcomes & Findings for Efficacy and Safety of Oral UT-15C Tablets to Treat Pulmonary Arterial Hypertension (NCT NCT00887978)

NCT ID: NCT00887978

Last Updated: 2013-01-15

Results Overview

Placebo-corrected change in 6MWD from Baseline to Week 16, correlates with the current clinical standard for assessing patient functional status in the treatment of PAH and is considered an objective measure of patient functional status by the American Thoracic Society (ATS). The 6MWD was to be assessed between 3 and 6 hours after the morning dose of study drug and background therapy(ies).

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 310 participants
• Primary outcome timeframe: Baseline and 16 weeks
• Results posted on: 2013-01-15

Participant Flow

The recruitment period for this study was June 2009 to July 2011. Sites were located in North America, Europe and Asia.

The 310 subjects who received a dose of study drug are presented here.

Participant milestones

Measure	UT-15C SR Doses were initiated at 0.25 mg BID and increased by 0.25 mg BID every three days (as clinically indicated based on tolerability and symptoms of PAH), to a max dose of 16 mg BID.	Placebo Identical placebo tablets to UT-15C, doses were titrated in the same manner
Overall Study STARTED	157	153
Overall Study COMPLETED	132	138
Overall Study NOT COMPLETED	25	15

Reasons for withdrawal

Measure	UT-15C SR Doses were initiated at 0.25 mg BID and increased by 0.25 mg BID every three days (as clinically indicated based on tolerability and symptoms of PAH), to a max dose of 16 mg BID.	Placebo Identical placebo tablets to UT-15C, doses were titrated in the same manner
Overall Study Adverse Event	18	5
Overall Study Clinical Worsening	4	4
Overall Study Death	2	3
Overall Study Withdrawal by Subject	1	2
Overall Study Lost to Follow-up	0	1

Baseline Characteristics

Efficacy and Safety of Oral UT-15C Tablets to Treat Pulmonary Arterial Hypertension

Baseline characteristics by cohort

Measure	UT-15C SR n=157 Participants Doses were initiated at 0.25 mg BID and increased by 0.25 mg BID every three days (as clinically indicated based on tolerability and symptoms of PAH), to a max dose of 16 mg BID.	Placebo n=153 Participants Identical placebo tablets to UT-15C, doses were titrated in the same manner	Total n=310 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	119 Participants n=5 Participants	122 Participants n=7 Participants	241 Participants n=5 Participants
Age, Categorical >=65 years	38 Participants n=5 Participants	31 Participants n=7 Participants	69 Participants n=5 Participants
Age Continuous	51.5 years FULL_RANGE 15 • n=5 Participants	50.4 years FULL_RANGE 14.5 • n=7 Participants	51.0 years n=5 Participants
Sex: Female, Male Female	119 Participants n=5 Participants	122 Participants n=7 Participants	241 Participants n=5 Participants
Sex: Female, Male Male	38 Participants n=5 Participants	31 Participants n=7 Participants	69 Participants n=5 Participants
PAH Etiology Idiopathic or familial	104 participants n=5 Participants	99 participants n=7 Participants	203 participants n=5 Participants
PAH Etiology Collagen vascular disease	48 participants n=5 Participants	49 participants n=7 Participants	97 participants n=5 Participants
PAH Etiology HIV infection	2 participants n=5 Participants	4 participants n=7 Participants	6 participants n=5 Participants
PAH Etiology Repaired congenital heart disease	3 participants n=5 Participants	1 participants n=7 Participants	4 participants n=5 Participants
World Health Organization (WHO) Functional Class Class II	43 Participants n=5 Participants	37 Participants n=7 Participants	80 Participants n=5 Participants
World Health Organization (WHO) Functional Class Class III	110 Participants n=5 Participants	115 Participants n=7 Participants	225 Participants n=5 Participants
World Health Organization (WHO) Functional Class Class IV	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
World Health Organization (WHO) Functional Class Unknown	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Baseline Six-minute walk distance	329.4 meters STANDARD_DEVIATION 69.2 • n=5 Participants	336.8 meters STANDARD_DEVIATION 63.5 • n=7 Participants	333 meters STANDARD_DEVIATION 66.4 • n=5 Participants
Background PAH therapy PDE-5i	67 participants n=5 Participants	65 participants n=7 Participants	132 participants n=5 Participants
Background PAH therapy ERA	25 participants n=5 Participants	28 participants n=7 Participants	53 participants n=5 Participants
Background PAH therapy PDE-5i + ERA	65 participants n=5 Participants	60 participants n=7 Participants	125 participants n=5 Participants
Time since PAH diagnosis	2.5 years STANDARD_DEVIATION 2.6 • n=5 Participants	3.3 years STANDARD_DEVIATION 4.1 • n=7 Participants	2.9 years STANDARD_DEVIATION 3.4 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline and 16 weeks

Population: Intention to treat analysis

Placebo-corrected change in 6MWD from Baseline to Week 16, correlates with the current clinical standard for assessing patient functional status in the treatment of PAH and is considered an objective measure of patient functional status by the American Thoracic Society (ATS).

The 6MWD was to be assessed between 3 and 6 hours after the morning dose of study drug and background therapy(ies).

Outcome measures

Measure	UT-15C SR n=157 Participants At Week 16, the mean(SD) dose of UT-15C was 3.1mg (1.9).	Placebo n=153 Participants At Week 16, the mean(SD) dose of placebo was 6.1mg (3.6).
6-minute Walk Distance (6MWD) Week 16 Values	370 meters Interval 292.0 to 419.0	365 meters Interval 300.0 to 405.0
6-minute Walk Distance (6MWD) Change from Baseline	15 meters Interval -12.0 to 55.0	11 meters Interval -14.0 to 39.0

SECONDARY outcome

Timeframe: Baseline and 16 Weeks

Population: Intention to treat analysis

Definition of clinical worsening included patients who met at least one of the following criteria during the 16 weeks of study:

1. Death (all causes excluding accident)

2. Transplantation

3. Atrial septostomy

4. Hospitalization as a result of right heart failure

5. Greater than or equal to a 20% decrease in 6MWD from Baseline (or too ill to walk) AND addition of an inhaled prostacyclin analogue, ERA, or PDE-5i

6. Initiation of parenteral prostacyclin therapy (i.e., epoprostenol, iloprost, or treprostinil) for the treatment of PAH

Outcome measures

Measure	UT-15C SR n=157 Participants At Week 16, the mean(SD) dose of UT-15C was 3.1mg (1.9).	Placebo n=153 Participants At Week 16, the mean(SD) dose of placebo was 6.1mg (3.6).
Clinical Worsening Assessment	11 number of clinical worsening events	10 number of clinical worsening events

SECONDARY outcome

Timeframe: Baseline and 16 Weeks

Population: All subjects with a Baseline Borg Score were included in the analysis. One subject in the placebo group did not have a Baseline Borg Score recorded.

The Borg dyspnea score is a 10-point scale rating the maximum level of dyspnea experienced during the six-minute walk test (6MWT). The Borg dyspnea score was assessed immediately following the 6MWT. Scores ranged from 0 (for no shortness of breath) to 10 (for the greatest shortness of breath ever experienced).

Outcome measures

Measure	UT-15C SR n=157 Participants At Week 16, the mean(SD) dose of UT-15C was 3.1mg (1.9).	Placebo n=152 Participants At Week 16, the mean(SD) dose of placebo was 6.1mg (3.6).
Borg Dyspnea Score Change from Baseline	0 score Interval -1.0 to 1.0	0 score Interval -1.0 to 1.0
Borg Dyspnea Score Week 16 Value	3.0 score Inter-Quartile Range 2.47 • Interval 2.0 to 5.0	4.0 score Inter-Quartile Range 2.05 • Interval 2.0 to 5.0

SECONDARY outcome

Timeframe: Baseline and 16 Weeks

Population: Subjects with a WHO functional class assessment at Week 16

Class I: No limitation of physical activity. Class II: Slight limitation of physical activity. Class III: Marked limitation of physical activity. Class IV: Inability to carry out any physical activity without symptoms.

Outcome measures

Measure	UT-15C SR n=131 Participants At Week 16, the mean(SD) dose of UT-15C was 3.1mg (1.9).	Placebo n=136 Participants At Week 16, the mean(SD) dose of placebo was 6.1mg (3.6).
World Health Organization (WHO) Functional Class WHO Class I	1 participants	3 participants
World Health Organization (WHO) Functional Class WHO Class II	58 participants	47 participants
World Health Organization (WHO) Functional Class WHO Class III	70 participants	83 participants
World Health Organization (WHO) Functional Class WHO Class IV	2 participants	3 participants

SECONDARY outcome

Timeframe: Baseline and 16 Weeks

Population: Subjects without Baseline assessments of PAH symptoms were not included in the analysis.

Symptoms of PAH including fatigue, dyspnea, edema, dizziness, syncope, chest pain and orthopnea were assessed by the physician at Baseline and Week 16. Severity grade values (i.e., 0, 1, 2 or 3) for each symptom were provided each subject. A severity of 0 indicated no symptoms, the maximum severity was 3, indicating severe symptoms. Mean change in symptom severity from Baseline to Week 16 is described.

Outcome measures

Measure	UT-15C SR n=156 Participants At Week 16, the mean(SD) dose of UT-15C was 3.1mg (1.9).	Placebo n=150 Participants At Week 16, the mean(SD) dose of placebo was 6.1mg (3.6).
Symptoms of PAH Change in Dizziness Symptoms	0.1 units on a scale Standard Deviation 1.0	0.0 units on a scale Standard Deviation 1.0
Symptoms of PAH Change in Fatigue Symptoms	0.0 units on a scale Standard Deviation 0.9	0.0 units on a scale Standard Deviation 1.0
Symptoms of PAH Change in Dyspnea Symptoms	-0.1 units on a scale Standard Deviation 0.9	-0.2 units on a scale Standard Deviation 0.9
Symptoms of PAH Change in Edema Symptoms	0.0 units on a scale Standard Deviation 1.0	0.0 units on a scale Standard Deviation 0.9
Symptoms of PAH Change in Syncope Symptoms	0.2 units on a scale Standard Deviation 0.8	0.2 units on a scale Standard Deviation 0.7
Symptoms of PAH Change in Chest Pain Symptoms	0.1 units on a scale Standard Deviation 1.0	0.1 units on a scale Standard Deviation 1.0
Symptoms of PAH Change in Orthopnea Symptoms	0.2 units on a scale Standard Deviation 1.0	0.1 units on a scale Standard Deviation 0.9

SECONDARY outcome

Timeframe: Baseline and 16 Weeks

Population: Subjects without a Dyspnea Fatigue Index score at Baseline were not included in the analysis.

The dyspnea-fatigue index was assessed at Baseline and Week 16. Each of the three components of the dyspnea-fatigue index were rated on a scale 0 to 4, with 0 being the worst condition and 4 being the best condition for each component. The dyspnea-fatigue index is computed by summing the three component scores.

Outcome measures

Measure	UT-15C SR n=154 Participants At Week 16, the mean(SD) dose of UT-15C was 3.1mg (1.9).	Placebo n=149 Participants At Week 16, the mean(SD) dose of placebo was 6.1mg (3.6).
Dyspnea Fatigue Index	5.7 units on a scale Standard Deviation 2.6	6.0 units on a scale Standard Deviation 2.5

SECONDARY outcome

Timeframe: Baseline and 16 Weeks

Population: Subjects who were missing Week 16 samples were not included in the analysis.

Serum N-terminal pro-BNP concentration was assessed at Baseline and Week 16.

Outcome measures

Measure	UT-15C SR n=120 Participants At Week 16, the mean(SD) dose of UT-15C was 3.1mg (1.9).	Placebo n=135 Participants At Week 16, the mean(SD) dose of placebo was 6.1mg (3.6).
N-terminal proBNP (NT-proBNP) Week 16 Value	1310 pg/mL Standard Deviation 1663	1627 pg/mL Standard Deviation 2401
N-terminal proBNP (NT-proBNP) Change from Baseline	135 pg/mL Standard Deviation 913	136 pg/mL Standard Deviation 1242

SECONDARY outcome

Timeframe: Baseline and 16 Weeks

Population: Subjects in countries where the CAMPHOR has not been validated in the local language were not included in these analyses. Additionally, only subjects with completed questionnaires at Baseline and Week 16 were analyzed.

Change in CAMPHOR Scores from Baseline to Week 16. The CAMPHOR is a health related quality of life instrument validated for pulmonary hypertension that assesses impairment (symptoms), disability (activities) and quality of life. The questionnaire is divided into three sections; Symptoms (Scores 0-25; high scores indicate more symptoms), Activity (Score 0-30; low score indicates good functioning)and Quality of Life (0-25; high scores indicate poor QoL). The sum of these scores equates to the Total score (0-80). In the CAMPHOR scores, lower scores indicate improvements.

Outcome measures

Measure	UT-15C SR n=102 Participants At Week 16, the mean(SD) dose of UT-15C was 3.1mg (1.9).	Placebo n=85 Participants At Week 16, the mean(SD) dose of placebo was 6.1mg (3.6).
Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) Symptom Score	10.0 units on a scale Interval 6.0 to 16.0	9.0 units on a scale Interval 4.0 to 14.0
Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) Activity Score	10.0 units on a scale Interval 7.0 to 14.0	10.0 units on a scale Interval 6.0 to 13.0
Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) Quality of Life Score	9.0 units on a scale Interval 4.0 to 15.0	5.0 units on a scale Interval 1.5 to 13.0
Quality of Life (QoL) Assessment: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) Total Score	28.0 units on a scale Interval 19.0 to 43.0	24.5 units on a scale Interval 12.0 to 40.5

POST_HOC outcome

Timeframe: Baseline and 16 Weeks

Population: Subjects with IPAH/HPAH

Covariate analysis of change in 6MWD by PAH etiology, specifically idiopathic or heritable PAH

Outcome measures

Measure	UT-15C SR n=104 Participants At Week 16, the mean(SD) dose of UT-15C was 3.1mg (1.9).	Placebo n=99 Participants At Week 16, the mean(SD) dose of placebo was 6.1mg (3.6).
6-minute Walk Distance by PAH Etiology: Idiopathic PAH (IPAH) / Heritable PAH(HPAH)	21.5 meters Interval -0.5 to 64.5	13 meters Interval -14.0 to 39.0

POST_HOC outcome

Timeframe: 16 weeks

Population: Subjects receiving only a PDE-5i at Baseline

Outcome measures

Measure	UT-15C SR n=67 Participants At Week 16, the mean(SD) dose of UT-15C was 3.1mg (1.9).	Placebo n=65 Participants At Week 16, the mean(SD) dose of placebo was 6.1mg (3.6).
6-minute Walk Distance by Background PAH Therapy: PDE-5i Only	30 meters Interval 4.0 to 55.0	14 meters Interval -7.0 to 39.0

POST_HOC outcome

Timeframe: Baseline and 16 weeks

Population: Subjects who were only receiving an ERA at Baseline

Outcome measures

Measure	UT-15C SR n=25 Participants At Week 16, the mean(SD) dose of UT-15C was 3.1mg (1.9).	Placebo n=28 Participants At Week 16, the mean(SD) dose of placebo was 6.1mg (3.6).
6-minute Walk Test by Background PAH Therapy: ERA Only	-5 meters Interval -43.0 to 42.0	-2.5 meters Interval -49.0 to 30.0

POST_HOC outcome

Timeframe: 16 weeks

Population: Subjects receiving both an ERA and a PDE-5i at Baseline.

Outcome measures

Measure	UT-15C SR n=65 Participants At Week 16, the mean(SD) dose of UT-15C was 3.1mg (1.9).	Placebo n=60 Participants At Week 16, the mean(SD) dose of placebo was 6.1mg (3.6).
6-minute Walk Test by Background PAH Therapy: ERA + PDE-5i	14.0 meters Interval -17.0 to 59.0	15.5 meters Interval -14.5 to 39.0

POST_HOC outcome

Timeframe: Baseline and 16 weeks

Population: Subjects who have been diagnosed with PAH between 0 to 0.9 years prior to Baseline.

Outcome measures

Measure	UT-15C SR n=40 Participants At Week 16, the mean(SD) dose of UT-15C was 3.1mg (1.9).	Placebo n=38 Participants At Week 16, the mean(SD) dose of placebo was 6.1mg (3.6).
6-minute Walk Distance by Time to PAH Diagnosis: 0 - 0.9 Years	21.5 meters Interval -12.5 to 50.5	-6.0 meters Interval -63.0 to 26.0

POST_HOC outcome

Timeframe: 16 Weeks

Population: Subjects who had been diagnosed with PAH between 0.9 and 1.74 years prior to Baseline.

Outcome measures

Measure	UT-15C SR n=40 Participants At Week 16, the mean(SD) dose of UT-15C was 3.1mg (1.9).	Placebo n=37 Participants At Week 16, the mean(SD) dose of placebo was 6.1mg (3.6).
6-minute Walk Distance by Time Since PAH Diagnosis: 0.9 - 1.74 Years	20.1 meters Interval 1.0 to 61.0	13.0 meters Interval -2.0 to 45.0

POST_HOC outcome

Timeframe: Baseline and 16 weeks

Population: Subjects who were diagnosed with PAH between 1.8 and 3.5 years prior to Baseline.

Outcome measures

Measure	UT-15C SR n=40 Participants At Week 16, the mean(SD) dose of UT-15C was 3.1mg (1.9).	Placebo n=37 Participants At Week 16, the mean(SD) dose of placebo was 6.1mg (3.6).
6-minute Walk Distance by Years Since PAH Diagnosis: 1.8 - 3.5 Years	15.5 meter Interval -16.0 to 51.5	4.0 meter Interval -14.0 to 42.0

POST_HOC outcome

Timeframe: Baseline and 16 weeks

Population: Subjects who had been diagnosed with PAH for 3.6 to 26.4 years prior to Baseline.

Outcome measures

Measure	UT-15C SR n=37 Participants At Week 16, the mean(SD) dose of UT-15C was 3.1mg (1.9).	Placebo n=41 Participants At Week 16, the mean(SD) dose of placebo was 6.1mg (3.6).
6-minute Walk Distance by Time Since PAH Diagnosis: 3.6 - 26.4 Years	14.0 meters Interval -23.0 to 59.0	16.0 meters Interval -5.0 to 36.0

Adverse Events

UT-15C SR

Serious events: 23 serious events

Other events: 157 other events

Deaths: 0 deaths

Placebo

Serious events: 23 serious events

Other events: 136 other events

Deaths: 0 deaths

Serious adverse events

Measure	UT-15C SR n=157 participants at risk At Week 16, the mean(SD) dose of UT-15C was 3.1 (1.9).	Placebo n=153 participants at risk At Week 16, the mean(SD) dose of placebo was 6.1 (3.6).
Musculoskeletal and connective tissue disorders Back pain	1.3% 2/157 • Number of events 2 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Injury, poisoning and procedural complications Fall	1.3% 2/157 • Number of events 2 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Respiratory, thoracic and mediastinal disorders Hemoptysis	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.65% 1/153 • Number of events 1 • Adverse events were recorded throughout the 16 week study.
General disorders Sudden death	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.65% 1/153 • Number of events 1 • Adverse events were recorded throughout the 16 week study.
Cardiac disorders Atrial fibrillation	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/157 • Adverse events were recorded throughout the 16 week study.	0.65% 1/153 • Number of events 1 • Adverse events were recorded throughout the 16 week study.
Cardiac disorders Cardiac failure	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Cardiac disorders Cardio-respiratory arrest	0.00% 0/157 • Adverse events were recorded throughout the 16 week study.	0.65% 1/153 • Number of events 1 • Adverse events were recorded throughout the 16 week study.
Nervous system disorders Cerebrovascular accident	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/157 • Adverse events were recorded throughout the 16 week study.	0.65% 1/153 • Number of events 3 • Adverse events were recorded throughout the 16 week study.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/157 • Adverse events were recorded throughout the 16 week study.	0.65% 1/153 • Number of events 1 • Adverse events were recorded throughout the 16 week study.
Nervous system disorders Depressed level of consciousness	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Gastrointestinal disorders Diverticulum	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Nervous system disorders Dizziness	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Cardiac disorders Right ventricular failure	3.2% 5/157 • Number of events 5 • Adverse events were recorded throughout the 16 week study.	1.3% 2/153 • Number of events 2 • Adverse events were recorded throughout the 16 week study.
Respiratory, thoracic and mediastinal disorders Dyspnea	2.5% 4/157 • Number of events 4 • Adverse events were recorded throughout the 16 week study.	1.3% 2/153 • Number of events 2 • Adverse events were recorded throughout the 16 week study.
Infections and infestations Lower respiratory tract infection	1.9% 3/157 • Number of events 3 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	1.3% 2/157 • Number of events 2 • Adverse events were recorded throughout the 16 week study.	2.6% 4/153 • Number of events 4 • Adverse events were recorded throughout the 16 week study.
Metabolism and nutrition disorders Fluid overload	1.3% 2/157 • Number of events 2 • Adverse events were recorded throughout the 16 week study.	0.65% 1/153 • Number of events 1 • Adverse events were recorded throughout the 16 week study.
General disorders Pyrexia	1.3% 2/157 • Number of events 2 • Adverse events were recorded throughout the 16 week study.	0.65% 1/153 • Number of events 2 • Adverse events were recorded throughout the 16 week study.
Nervous system disorders Dysarthria	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Metabolism and nutrition disorders Fluid retention	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Infections and infestations Gastroenteritis	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Metabolism and nutrition disorders Hypervolemia	0.00% 0/157 • Adverse events were recorded throughout the 16 week study.	0.65% 1/153 • Number of events 1 • Adverse events were recorded throughout the 16 week study.
Nervous system disorders Hypoesthesia	0.00% 0/157 • Adverse events were recorded throughout the 16 week study.	0.65% 1/153 • Number of events 1 • Adverse events were recorded throughout the 16 week study.
Metabolism and nutrition disorders Hypoglycemia	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Metabolism and nutrition disorders Hypokalemia	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Infections and infestations Infection	0.00% 0/157 • Adverse events were recorded throughout the 16 week study.	0.65% 1/153 • Number of events 2 • Adverse events were recorded throughout the 16 week study.
General disorders Peripheral edema	0.00% 0/157 • Adverse events were recorded throughout the 16 week study.	0.65% 1/153 • Number of events 1 • Adverse events were recorded throughout the 16 week study.
Respiratory, thoracic and mediastinal disorders Orthopnea	0.00% 0/157 • Adverse events were recorded throughout the 16 week study.	0.65% 1/153 • Number of events 1 • Adverse events were recorded throughout the 16 week study.
Cardiac disorders Palpitations	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Nervous system disorders Presyncope	0.00% 0/157 • Adverse events were recorded throughout the 16 week study.	0.65% 1/153 • Number of events 1 • Adverse events were recorded throughout the 16 week study.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Musculoskeletal and connective tissue disorders Rheumatoid arthritis	0.00% 0/157 • Adverse events were recorded throughout the 16 week study.	0.65% 1/153 • Number of events 1 • Adverse events were recorded throughout the 16 week study.
Injury, poisoning and procedural complications Rib fracture	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Infections and infestations Sepsis	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Skin and subcutaneous tissue disorders Stasis dermatitis	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Infections and infestations Tracheobronchitis	0.00% 0/157 • Adverse events were recorded throughout the 16 week study.	0.65% 1/153 • Number of events 1 • Adverse events were recorded throughout the 16 week study.
Infections and infestations Upper respiratory tract infection	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Skin and subcutaneous tissue disorders Urticaria	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Gastrointestinal disorders Lower gastrointestinal hemorrhage	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Vascular disorders Deep vein thrombosis	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Psychiatric disorders Affect lability	0.00% 0/157 • Adverse events were recorded throughout the 16 week study.	0.65% 1/153 • Number of events 1 • Adverse events were recorded throughout the 16 week study.
Hepatobiliary disorders Hepatic ischemia	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Surgical and medical procedures Joint arthroplasty	0.64% 1/157 • Number of events 1 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Reproductive system and breast disorders Ovarian mass	0.00% 0/157 • Adverse events were recorded throughout the 16 week study.	0.65% 1/153 • Number of events 1 • Adverse events were recorded throughout the 16 week study.

Other adverse events

Measure	UT-15C SR n=157 participants at risk At Week 16, the mean(SD) dose of UT-15C was 3.1 (1.9).	Placebo n=153 participants at risk At Week 16, the mean(SD) dose of placebo was 6.1 (3.6).
Nervous system disorders Headache	71.3% 112/157 • Number of events 145 • Adverse events were recorded throughout the 16 week study.	39.9% 61/153 • Number of events 69 • Adverse events were recorded throughout the 16 week study.
Gastrointestinal disorders Diarrhea	55.4% 87/157 • Number of events 105 • Adverse events were recorded throughout the 16 week study.	24.8% 38/153 • Number of events 42 • Adverse events were recorded throughout the 16 week study.
Gastrointestinal disorders Nausea	46.5% 73/157 • Number of events 77 • Adverse events were recorded throughout the 16 week study.	22.2% 34/153 • Number of events 35 • Adverse events were recorded throughout the 16 week study.
Vascular disorders Flushing	35.0% 55/157 • Number of events 64 • Adverse events were recorded throughout the 16 week study.	10.5% 16/153 • Number of events 18 • Adverse events were recorded throughout the 16 week study.
Musculoskeletal and connective tissue disorders Pain in jaw	24.8% 39/157 • Number of events 39 • Adverse events were recorded throughout the 16 week study.	6.5% 10/153 • Number of events 10 • Adverse events were recorded throughout the 16 week study.
Gastrointestinal disorders Vomiting	21.0% 33/157 • Number of events 38 • Adverse events were recorded throughout the 16 week study.	10.5% 16/153 • Number of events 20 • Adverse events were recorded throughout the 16 week study.
Nervous system disorders Dizziness	19.1% 30/157 • Number of events 36 • Adverse events were recorded throughout the 16 week study.	9.8% 15/153 • Number of events 15 • Adverse events were recorded throughout the 16 week study.
Musculoskeletal and connective tissue disorders Pain in extremity	17.2% 27/157 • Number of events 29 • Adverse events were recorded throughout the 16 week study.	7.2% 11/153 • Number of events 12 • Adverse events were recorded throughout the 16 week study.
Respiratory, thoracic and mediastinal disorders Dyspnea	15.9% 25/157 • Number of events 27 • Adverse events were recorded throughout the 16 week study.	6.5% 10/153 • Number of events 15 • Adverse events were recorded throughout the 16 week study.
General disorders Fatigue	14.6% 23/157 • Number of events 25 • Adverse events were recorded throughout the 16 week study.	10.5% 16/153 • Number of events 17 • Adverse events were recorded throughout the 16 week study.
Musculoskeletal and connective tissue disorders Myalgia	11.5% 18/157 • Number of events 18 • Adverse events were recorded throughout the 16 week study.	6.5% 10/153 • Number of events 11 • Adverse events were recorded throughout the 16 week study.
Infections and infestations Upper respiratory tract infection	10.8% 17/157 • Number of events 18 • Adverse events were recorded throughout the 16 week study.	8.5% 13/153 • Number of events 13 • Adverse events were recorded throughout the 16 week study.
General disorders Peripheral edema	10.8% 17/157 • Number of events 18 • Adverse events were recorded throughout the 16 week study.	6.5% 10/153 • Number of events 10 • Adverse events were recorded throughout the 16 week study.
Gastrointestinal disorders Abdominal pain	7.6% 12/157 • Number of events 13 • Adverse events were recorded throughout the 16 week study.	7.2% 11/153 • Number of events 11 • Adverse events were recorded throughout the 16 week study.
Musculoskeletal and connective tissue disorders Arthralgia	7.6% 12/157 • Number of events 13 • Adverse events were recorded throughout the 16 week study.	5.9% 9/153 • Number of events 9 • Adverse events were recorded throughout the 16 week study.
Gastrointestinal disorders Abdominal pain upper	7.6% 12/157 • Number of events 13 • Adverse events were recorded throughout the 16 week study.	4.6% 7/153 • Number of events 7 • Adverse events were recorded throughout the 16 week study.
Musculoskeletal and connective tissue disorders Back pain	7.6% 12/157 • Number of events 13 • Adverse events were recorded throughout the 16 week study.	3.9% 6/153 • Number of events 6 • Adverse events were recorded throughout the 16 week study.
Musculoskeletal and connective tissue disorders Muscle spasms	7.6% 12/157 • Number of events 12 • Adverse events were recorded throughout the 16 week study.	3.3% 5/153 • Number of events 5 • Adverse events were recorded throughout the 16 week study.
Metabolism and nutrition disorders Decreased appetite	7.6% 12/157 • Number of events 14 • Adverse events were recorded throughout the 16 week study.	2.6% 4/153 • Number of events 4 • Adverse events were recorded throughout the 16 week study.
Gastrointestinal disorders Dyspepsia	7.0% 11/157 • Number of events 12 • Adverse events were recorded throughout the 16 week study.	5.2% 8/153 • Number of events 8 • Adverse events were recorded throughout the 16 week study.
Respiratory, thoracic and mediastinal disorders Nasal congestion	6.4% 10/157 • Number of events 10 • Adverse events were recorded throughout the 16 week study.	0.00% 0/153 • Adverse events were recorded throughout the 16 week study.
Respiratory, thoracic and mediastinal disorders Nasopharyngitis	10.8% 17/157 • Number of events 19 • Adverse events were recorded throughout the 16 week study.	16.3% 25/153 • Number of events 28 • Adverse events were recorded throughout the 16 week study.
General disorders Chest Pain	5.7% 9/157 • Number of events 9 • Adverse events were recorded throughout the 16 week study.	6.5% 10/153 • Number of events 11 • Adverse events were recorded throughout the 16 week study.
Cardiac disorders Palpitations	3.8% 6/157 • Number of events 6 • Adverse events were recorded throughout the 16 week study.	7.8% 12/153 • Number of events 12 • Adverse events were recorded throughout the 16 week study.

Additional Information

Kevin Laliberte, PharmD

United Therapeutics Corporation

Phone: 919-425-8350

Email: klaliberte@unither.com

Results disclosure agreements

• Principal investigator is a sponsor employee Any publication of the results of this trial must be consistent with the United Therapeutics publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.
• Publication restrictions are in place

Restriction type: OTHER