ch14.18 Pharmacokinetic Study in High-risk Neuroblastoma

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ClinicalTrials.gov Identifier: NCT01592045

Recruitment Status : Completed

First Posted : May 4, 2012

Results First Posted : September 23, 2015

Last Update Posted : September 23, 2015

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

United Therapeutics

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition	Neuroblastoma
Interventions	Biological: ch14.18 -NCI Biological: ch14.18-UTC Biological: Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Biological: Aldesleukin (IL-2) Drug: Isotretinoin
Enrollment	28

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Sequence 1	Sequence 2
Arm/Group Description	UTC ch14.18 for two courses followe...	NCI ch14.18 for two courses followe...
Arm/Group Description	UTC ch14.18 for two courses followed by NCI ch14.18 for three courses ch14.18 -NCI: 25 mg/m^2/day IV for four consecutive days ch14.18-UTC: 17.5 mg/m^2/day IV for four consecutive days Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF): GM-CSF will be administered SC at a dose of 250 mcg/m^2/day for 14 days during Courses 1, 3, and 5. Aldesleukin (IL-2): Aldesleukin (IL-2) will be administered IV at a dose of 3 MIU/m^2/day for the first week and at a dose of 4.5 MIU/m^2/day for the second week during Courses 2 and 4. Isotretinoin: Isotretinoin (13-cis-retinoic acid; ISOT) will be administered by mouth over six courses as follows: If weight > 12 kg: 80 mg/m^2/dose twice daily (total daily dose is 160 mg/m^2/day, divided twice daily). If weight ≤ 12 kg: 2.67 mg/kg/dose twice daily (total daily dose is 5.33 mg/kg/day, divided twice daily).	NCI ch14.18 for two courses followed by UTC ch14.18 for three courses ch14.18 -NCI: 25 mg/m^2/day IV for four consecutive days ch14.18-UTC: 17.5 mg/m^2/day IV for four consecutive days Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF): GM-CSF will be administered SC at a dose of 250 mcg/m^2/day for 14 days during Courses 1, 3, and 5. Aldesleukin (IL-2): Aldesleukin (IL-2) will be administered IV at a dose of 3 MIU/m^2/day for the first week and at a dose of 4.5 MIU/m^2/day for the second week during Courses 2 and 4. Isotretinoin: Isotretinoin (13-cis-retinoic acid; ISOT) will be administered by mouth over six courses as follows: If weight > 12 kg: 80 mg/m^2/dose twice daily (total daily dose is 160 mg/m^2/day, divided twice daily). If weight ≤ 12 kg: 2.67 mg/kg/dose twice daily (total daily dose is 5.33 mg/kg/day, divided twice daily).
Period Title: Overall Study
Started	14	14
Completed Course 1	13	14
Completed Course 2	13	13
Completed Course 3	11	13
Completed Course 4	11	12
Completed Course 5	9	12
Completed	9	12
Not Completed	5	2
Reason Not Completed
Disease Progression	1	1
Adverse Event	1	1
Withdrawal by Subject	1	0
Moved out of country	2	0

Baseline Characteristics

Arm/Group Title		Sequence 1	Sequence 2	Total
Arm/Group Description		UTC ch14.18 for two courses followe...	NCI ch14.18 for two courses followe...	Total of all reporting groups
Arm/Group Description		UTC ch14.18 for two courses followed by NCI ch14.18 for three courses ch14.18 -NCI: 25 mg/m^2/day IV for four consecutive days ch14.18-UTC: 17.5 mg/m^2/day IV for four consecutive days Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF): GM-CSF will be administered SC at a dose of 250 mcg/m^2/day for 14 days during Courses 1, 3, and 5. Aldesleukin (IL-2): Aldesleukin (IL-2) will be administered IV at a dose of 3 MIU/m^2/day for the first week and at a dose of 4.5 MIU/m^2/day for the second week during Courses 2 and 4. Isotretinoin: Isotretinoin (13-cis-retinoic acid; ISOT) will be administered by mouth over six courses as follows: If weight > 12 kg: 80 mg/m^2/dose twice daily (total daily dose is 160 mg/m^2/day, divided twice daily). If weight ≤ 12 kg: 2.67 mg/kg/dose twice daily (total daily dose is 5.33 mg/kg/day, divided twice daily).	NCI ch14.18 for two courses followed by UTC ch14.18 for three courses ch14.18 -NCI: 25 mg/m^2/day IV for four consecutive days ch14.18-UTC: 17.5 mg/m^2/day IV for four consecutive days Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF): GM-CSF will be administered SC at a dose of 250 mcg/m^2/day for 14 days during Courses 1, 3, and 5. Aldesleukin (IL-2): Aldesleukin (IL-2) will be administered IV at a dose of 3 MIU/m^2/day for the first week and at a dose of 4.5 MIU/m^2/day for the second week during Courses 2 and 4. Isotretinoin: Isotretinoin (13-cis-retinoic acid; ISOT) will be administered by mouth over six courses as follows: If weight > 12 kg: 80 mg/m^2/dose twice daily (total daily dose is 160 mg/m^2/day, divided twice daily). If weight ≤ 12 kg: 2.67 mg/kg/dose twice daily (total daily dose is 5.33 mg/kg/day, divided twice daily).	Total of all reporting groups
Overall Number of Baseline Participants		14	14	28
Baseline Analysis Population Description		...
Baseline Analysis Population Description		Twenty-eight subjects were enrolled in this study with all subjects receiving at least one dose of study therapy.
Age, Continuous Mean (Full Range) Unit of measure: Years
	Number Analyzed	14 participants	14 participants	28 participants
		4 (2 to 7)	4 (1 to 9)	4 (1 to 9)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	14 participants	14 participants	28 participants
	Female	6 42.9%	6 42.9%	12 42.9%
	Male	8 57.1%	8 57.1%	16 57.1%
Ethnicity (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	14 participants	14 participants	28 participants
	Hispanic or Latino	4 28.6%	2 14.3%	6 21.4%
	Not Hispanic or Latino	10 71.4%	12 85.7%	22 78.6%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB) Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	14 participants	14 participants	28 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	1 7.1%	1 3.6%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	2 14.3%	1 7.1%	3 10.7%
	White	12 85.7%	11 78.6%	23 82.1%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	1 7.1%	1 3.6%
Region of Enrollment Measure Type: Number Unit of measure: Participants
United States	Number Analyzed	14 participants	14 participants	28 participants
United States		14	14	28
Pre-ASCT Response ^[1] Measure Type: Number Unit of measure: Participants	Number Analyzed	14 participants	14 participants	28 participants
Complete Response (CR)		5	3	8
Very Good Partial Response (VGPR)		5	4	9
Partial Response (PR)		4	7	11
		[1] Measure Description: At pre-ASCT evaluation, subjects must have met the International Neuroblastoma Response Criteria (INRC) for complete response (CR), very good partial response (VGPR) or partial response (PR) for primary site, soft tissue metastases, and bone metastases. Subjects who met those criteria were also required to meet the protocol specified criteria for bone marrow response.

Outcome Measures

1.Primary Outcome


Title	Area Under the Plasma Concentration Curve (AUC)
Description	Twenty-two PK samples will be obtained at the following timepoints: ...
Description	Twenty-two PK samples will be obtained at the following timepoints: Courses 1 and 3: Day: 0 Days: 3, 4, 5 and 6: post ch14.18 Days 7:10 to 14 hours post ch14.18 Days 9 to 11: Single sample Days 14 to 17: Single sample Courses 2 and 4: Day 0: Pre-IL-2 Day 7: Pre-ch14.18 Day 10 (Course 4 only): Post ch14.18 End of Treatment: Within 2 weeks post isotretinoin
Time Frame	PK samples obtained during Courses 1 and 3: Days 0, 3, 4, 5, 6, 7, 9, 10, 11, 14, 15, 16, 17; PK samples obtained during Courses 2 and 4: Days 0, 7, 10; End of Treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	UTC ch14.18	NCI ch14.18
Arm/Group Description:	United Therapeutics Manufactured ch...	NCI Manufactured ch14.18
Arm/Group Description:	United Therapeutics Manufactured ch14.18	NCI Manufactured ch14.18
Overall Number of Participants Analyzed	27	27
Mean (Standard Deviation) Unit of Measure: mcg*hr/mL
	518 (418)	470 (376)

2.Primary Outcome


Title	Peak Plasma Concentration (Cmax)
Description	Twenty-two PK samples will be obtained at the following timepoints: ...
Description	Twenty-two PK samples will be obtained at the following timepoints: Courses 1 and 3: Day: 0 Days: 3, 4, 5 and 6: post ch14.18 Days 7:10 to 14 hours post ch14.18 Days 9 to 11: Single sample Days 14 to 17: Single sample Courses 2 and 4: Day 0: Pre-IL-2 Day 7: Pre-ch14.18 Day 10 (Course 4 only): Post ch14.18 End of Treatment: Within 2 weeks post isotretinoin
Time Frame	PK samples obtained during Courses 1 and 3: Days 0, 3, 4, 5, 6, 7, 9, 10, 11, 14, 15, 16, 17; PK samples obtained during Courses 2 and 4: Days 0, 7, 10; End of Treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]


Arm/Group Title	UTC ch14.18	NCI ch14.18
Arm/Group Description:	United Therapeutics Manufactured ch...	NCI Manufactured ch14.18
Arm/Group Description:	United Therapeutics Manufactured ch14.18	NCI Manufactured ch14.18
Overall Number of Participants Analyzed	27	27
Mean (Standard Deviation) Unit of Measure: ng/mL
	6468 (719)	6689 (853)

Adverse Events

Time Frame	Adverse events (AEs) and serious adverse events (SAEs) were reported at the time of informed consent through 30 days after the last dose of study therapy.
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	UTC ch14.18		NCI ch14.18
Arm/Group Description	United Therapeutics Manufactured ch...		NCI Manufactured ch14.18
Arm/Group Description	United Therapeutics Manufactured ch14.18		NCI Manufactured ch14.18
All-Cause Mortality
	UTC ch14.18		NCI ch14.18
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events Serious Adverse Events
	UTC ch14.18		NCI ch14.18
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/27 (62.96%)		12/27 (44.44%)
Blood and lymphatic system disorders
Anemia ^* 1	0/27 (0.00%)	0	2/27 (7.41%)	2
Cardiac disorders
Palpitations ^* 1	0/27 (0.00%)	0	1/27 (3.70%)	1
Eye disorders
Mydriasis ^* 1	1/27 (3.70%)	1	0/27 (0.00%)	0
Gastrointestinal disorders
Diarrhea ^* 1	1/27 (3.70%)	1	1/27 (3.70%)	1
Abdominal Pain ^* 1	1/27 (3.70%)	1	0/27 (0.00%)	0
Constipation ^* 1	1/27 (3.70%)	1	0/27 (0.00%)	0
Ileus ^* 1	1/27 (3.70%)	1	0/27 (0.00%)	0
Nausea ^* 1	0/27 (0.00%)	0	1/27 (3.70%)	1
Vomiting ^* 1	0/27 (0.00%)	0	1/27 (3.70%)	1
General disorders
Pyrexia ^* 1	5/27 (18.52%)	7	3/27 (11.11%)	7
Disease Progression ^* 1	1/27 (3.70%)	1	0/27 (0.00%)	0
Fatigue ^* 1	1/27 (3.70%)	1	0/27 (0.00%)	0
Malaise ^* 1	1/27 (3.70%)	1	0/27 (0.00%)	0
Hepatobiliary disorders
Hyperbilirubinemia ^* 1	1/27 (3.70%)	1	0/27 (0.00%)	0
Immune system disorders
Anaphylactic Reaction ^* 1	0/27 (0.00%)	0	1/27 (3.70%)	1
Serum Sickness ^* 1	0/27 (0.00%)	0	1/27 (3.70%)	1
Infections and infestations
Device Related Infection ^* 1	3/27 (11.11%)	3	1/27 (3.70%)	1
Gastroenteritis Viral ^* 1	2/27 (7.41%)	2	1/27 (3.70%)	1
Sepsis ^* 1	1/27 (3.70%)	1	1/27 (3.70%)	1
Alpha Hemolytic Stretococcal Infection ^* 1	1/27 (3.70%)	1	0/27 (0.00%)	0
Bacteremia ^* 1	1/27 (3.70%)	1	1/27 (3.70%)	1
Bacterial Infection ^* 1	0/27 (0.00%)	0	1/27 (3.70%)	1
Enterobacter Sepsis ^* 1	1/27 (3.70%)	1	0/27 (0.00%)	0
Influenza ^* 1	0/27 (0.00%)	0	1/27 (3.70%)	1
Pneumonia ^* 1	0/27 (0.00%)	0	1/27 (3.70%)	1
Pneumonia Bacterial ^* 1	0/27 (0.00%)	0	1/27 (3.70%)	1
Streptococcal Bacteremia ^* 1	1/27 (3.70%)	1	0/27 (0.00%)	0
Investigations
Blood Creatinine Increased ^* 1	1/27 (3.70%)	1	0/27 (0.00%)	0
Metabolism and nutrition disorders
Hypokalemia ^* 1	3/27 (11.11%)	3	0/27 (0.00%)	0
Dehydration ^* 1	0/27 (0.00%)	0	1/27 (3.70%)	1
Hypercalcemia ^* 1	0/27 (0.00%)	0	1/27 (3.70%)	1
Hypoalbuminemia ^* 1	1/27 (3.70%)	1	0/27 (0.00%)	0
Hyponatremia ^* 1	1/27 (3.70%)	1	0/27 (0.00%)	0
Hypophosphatemia ^* 1	1/27 (3.70%)	1	0/27 (0.00%)	0
Nervous system disorders
Convulsion ^* 1	1/27 (3.70%)	1	0/27 (0.00%)	0
Psychiatric disorders
Agitation ^* 1	1/27 (3.70%)	1	0/27 (0.00%)	0
Renal and urinary disorders
Renal Failure Acute ^* 1	1/27 (3.70%)	1	0/27 (0.00%)	0
Skin and subcutaneous tissue disorders
Herpes Simplex ^* 1	0/27 (0.00%)	0	1/27 (3.70%)	1
Vascular disorders
Capillary Leak Syndrome ^* 1	1/27 (3.70%)	1	0/27 (0.00%)	0
Hypertension ^* 1	0/27 (0.00%)	0	1/27 (3.70%)	1
* Indicates events were collected by non-systematic assessment 1 Term from vocabulary, MedDRA (17.0)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	UTC ch14.18		NCI ch14.18
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/27 (100.00%)		27/27 (100.00%)
Blood and lymphatic system disorders
Anemia ^* 1	15/27 (55.56%)	22	13/27 (48.15%)	15
Neutropenia ^* 1	2/27 (7.41%)	5	1/27 (3.70%)	1
Cardiac disorders
Tachycardia ^* 1	11/27 (40.74%)	18	10/27 (37.04%)	15
Sinus Tachycardia ^* 1	7/27 (25.93%)	14	7/27 (25.93%)	13
Endocrine disorders
Hypothyroidism ^* 1	0/27 (0.00%)	0	2/27 (7.41%)	2
Eye disorders
Periorbital Edema ^* 1	4/27 (14.81%)	4	0/27 (0.00%)	0
Photophobia ^* 1	0/27 (0.00%)	0	2/27 (7.41%)	2
Vision Blurred ^* 1	0/27 (0.00%)	0	2/27 (7.41%)	2
Gastrointestinal disorders
Abdominal Pain ^* 1	13/27 (48.15%)	22	11/27 (40.74%)	21
Constipation ^* 1	4/27 (14.81%)	7	3/27 (11.11%)	4
Diarrhea ^* 1	10/27 (37.04%)	13	13/27 (48.15%)	17
Vomiting ^* 1	10/27 (37.04%)	11	12/27 (44.44%)	21
Nausea ^* 1	9/27 (33.33%)	11	6/27 (22.22%)	10
Cheilitis ^* 1	1/27 (3.70%)	2	3/27 (11.11%)	3
Abdominal Distension ^* 1	2/27 (7.41%)	2	2/27 (7.41%)	2
Gastritis ^* 1	2/27 (7.41%)	2	0/27 (0.00%)	0
Lip Dry ^* 1	0/27 (0.00%)	0	2/27 (7.41%)	2
Lip Swelling ^* 1	2/27 (7.41%)	2	0/27 (0.00%)	0
Oropharyngeal Pain ^* 1	2/27 (7.41%)	2	0/27 (0.00%)	0
General disorders
Pyrexia ^* 1	27/27 (100.00%)	71	27/27 (100.00%)	64
Pain ^* 1	16/27 (59.26%)	28	12/27 (44.44%)	22
Face Odema ^* 1	10/27 (37.04%)	13	8/27 (29.63%)	9
Fatigue ^* 1	5/27 (18.52%)	6	5/27 (18.52%)	10
Malaise ^* 1	3/27 (11.11%)	5	3/27 (11.11%)	5
Chills ^* 1	3/27 (11.11%)	3	2/27 (7.41%)	2
Edema ^* 1	3/27 (11.11%)	4	3/27 (11.11%)	4
Edema Peripheral ^* 1	4/27 (14.81%)	5	3/27 (11.11%)	3
Injection Site Reaction ^* 1	3/27 (11.11%)	3	1/27 (3.70%)	1
Asthenia ^* 1	2/27 (7.41%)	2	1/27 (3.70%)	1
Generalized Edema ^* 1	2/27 (7.41%)	2	0/27 (0.00%)	0
Localized Edema ^* 1	1/27 (3.70%)	1	2/27 (7.41%)	2
Hepatobiliary disorders
Hyperbilirubinemia ^* 1	3/27 (11.11%)	4	2/27 (7.41%)	3
Hypoalbuminemia ^* 1	3/27 (11.11%)	60	1/27 (3.70%)	59
Immune system disorders
Hypersensitivity ^* 1	2/27 (7.41%)	3	3/27 (11.11%)	4
Infections and infestations
Device Related Infection ^* 1	4/27 (14.81%)	5	2/27 (7.41%)	2
Gastroenteritis Viral ^* 1	2/27 (7.41%)	2	1/27 (3.70%)	1
Clostridium Difficile Infection ^* 1	2/27 (7.41%)	2	0/27 (0.00%)	0
Injury, poisoning and procedural complications
Contusion ^* 1	4/27 (14.81%)	4	0/27 (0.00%)	0
Investigations
Platelet Count Decreased ^* 1	12/27 (44.44%)	18	12/27 (44.44%)	17
Alanine Aminotransferase Increased ^* 1	18/27 (66.67%)	27	9/27 (33.33%)	15
Neutrophil Count Decreased ^* 1	11/27 (40.74%)	19	9/27 (33.33%)	11
Lymphocyte Count Decreased ^* 1	2/27 (7.41%)	3	4/27 (14.81%)	6
White Blood Cell Count Decreased ^* 1	6/27 (22.22%)	8	8/27 (29.63%)	12
Aspartate Aminotransferase Increased ^* 1	14/27 (51.85%)	27	14/27 (51.85%)	27
Urine Output Decreased ^* 1	5/27 (18.52%)	11	4/27 (14.81%)	5
Blood Creatinine Increased ^* 1	3/27 (11.11%)	8	6/27 (22.22%)	6
Blood Alkaline Phosphatase Increased ^* 1	2/27 (7.41%)	4	5/27 (18.52%)	5
Blood Bilirubin Increased ^* 1	6/27 (22.22%)	8	3/27 (11.11%)	6
International Normalized Ratio Increased ^* 1	4/27 (14.81%)	6	3/27 (11.11%)	4
Weight Decreased ^* 1	2/27 (7.41%)	2	3/27 (11.11%)	3
Weight Increased ^* 1	3/27 (11.11%)	5	4/27 (14.81%)	5
Activated Partial Thromboplastin Time Prolonged ^* 1	3/27 (11.11%)	4	3/27 (11.11%)	5
Electrocardiogram QT Prolonged ^* 1	2/27 (7.41%)	2	1/27 (3.70%)	1
Blood Chloride Increased ^* 1	1/27 (3.70%)	2	2/27 (7.41%)	3
Blood Triglycerides Increased ^* 1	2/27 (7.41%)	2	0/27 (0.00%)	0
Eosinophil Count Increased ^* 1	2/27 (7.41%)	3	2/27 (7.41%)	3
Gamma-Glutamyltransferase Increased ^* 1	2/27 (7.41%)	2	1/27 (3.70%)	2
Metabolism and nutrition disorders
Hypokalemia ^* 1	25/27 (92.59%)	65	23/27 (85.19%)	55
Hyponatremia ^* 1	21/27 (77.78%)	48	20/27 (74.07%)	43
Hypocalcemia ^* 1	15/27 (55.56%)	30	15/27 (55.56%)	26
Hyperglycemia ^* 1	10/27 (37.04%)	15	8/27 (29.63%)	14
Hypophosphatemia ^* 1	5/27 (18.52%)	5	6/27 (22.22%)	6
Hypoalbuminemia ^* 1	23/27 (85.19%)	60	26/27 (96.30%)	59
Hypertriglyceridemia ^* 1	12/27 (44.44%)	14	10/27 (37.04%)	10
Decreased Appetite ^* 1	6/27 (22.22%)	9	7/27 (25.93%)	8
Hypercalcemia ^* 1	6/27 (22.22%)	8	4/27 (14.81%)	6
Hypoglycemia ^* 1	5/27 (18.52%)	5	8/27 (29.63%)	10
Hypomagnesemia ^* 1	8/27 (29.63%)	18	7/27 (25.93%)	15
Hyperkalemia ^* 1	4/27 (14.81%)	4	4/27 (14.81%)	7
Fluid Retention ^* 1	3/27 (11.11%)	3	2/27 (7.41%)	2
Hyperphosphatemia ^* 1	0/27 (0.00%)	0	2/27 (7.41%)	3
Musculoskeletal and connective tissue disorders
Pain in Extremity ^* 1	9/27 (33.33%)	14	11/27 (40.74%)	18
Back Pain ^* 1	4/27 (14.81%)	5	2/27 (7.41%)	3
Neck Pain ^* 1	2/27 (7.41%)	2	1/27 (3.70%)	1
Musculoskeletal Pain ^* 1	2/27 (7.41%)	2	0/27 (0.00%)	0
Nervous system disorders
Headache ^* 1	4/27 (14.81%)	5	1/27 (3.70%)	1
Lethargy ^* 1	1/27 (3.70%)	2	2/27 (7.41%)	2
Psychiatric disorders
Irritability ^* 1	5/27 (18.52%)	8	4/27 (14.81%)	9
Agitation ^* 1	4/27 (14.81%)	7	4/27 (14.81%)	4
Anxiety ^* 1	2/27 (7.41%)	2	3/27 (11.11%)	4
Abnormal Behavior ^* 1	2/27 (7.41%)	2	1/27 (3.70%)	1
Insomnia ^* 1	1/27 (3.70%)	1	2/27 (7.41%)	2
Restlessness ^* 1	1/27 (3.70%)	1	2/27 (7.41%)	2
Renal and urinary disorders
Urinary Retention ^* 1	7/27 (25.93%)	7	4/27 (14.81%)	7
Hematuria ^* 1	2/27 (7.41%)	3	4/27 (14.81%)	5
Proteinuria ^* 1	3/27 (11.11%)	5	5/27 (18.52%)	10
Dysuria ^* 1	2/27 (7.41%)	2	0/27 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Hypoxia ^* 1	5/27 (18.52%)	7	5/27 (18.52%)	9
Cough ^* 1	13/27 (48.15%)	16	13/27 (48.15%)	21
Rhinorrea ^* 1	2/27 (7.41%)	3	3/27 (11.11%)	4
Nasal Congestion ^* 1	1/27 (3.70%)	1	3/27 (11.11%)	3
Tachypnea ^* 1	3/27 (11.11%)	3	1/27 (3.70%)	1
Sneezing ^* 1	0/27 (0.00%)	0	2/27 (7.41%)	2
Upper Respiratory Tract Infection ^* 1	0/27 (0.00%)	0	2/27 (7.41%)	3
Skin and subcutaneous tissue disorders
Pruritus ^* 1	17/27 (62.96%)	21	14/27 (51.85%)	18
Dry Skin ^* 1	6/27 (22.22%)	6	6/27 (22.22%)	6
Rash ^* 1	7/27 (25.93%)	10	7/27 (25.93%)	7
Urticaria ^* 1	8/27 (29.63%)	9	6/27 (22.22%)	10
Rash Maculo-Papular ^* 1	3/27 (11.11%)	4	2/27 (7.41%)	3
Vascular disorders
Hypotension ^* 1	12/27 (44.44%)	18	9/27 (33.33%)	13
Capillary Leak Syndrome ^* 1	6/27 (22.22%)	10	6/27 (22.22%)	9
Hypertension ^* 1	7/27 (25.93%)	15	7/27 (25.93%)	17
Flushing ^* 1	2/27 (7.41%)	2	3/27 (11.11%)	3
* Indicates events were collected by non-systematic assessment 1 Term from vocabulary, MedDRA (17.0)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Institution and/or Principal Investigator agree not to publish or publicly present any interim results of the Study without the prior written consent of Sponsor, not to be unreasonably withheld or delayed, except as provided below. Institution and/or Principal Investigator further agree to provide Sponsor with drafts of any such publication or presentation for review and approval no less than 30 days prior to submission for publication or the date of public presentation.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Allison Lim
Organization:	United Therapeutics Corporation
Phone:	919-425-8799
EMail:	alim@unither.com

Layout table for additonal information

Responsible Party:	United Therapeutics
ClinicalTrials.gov Identifier:	NCT01592045
Other Study ID Numbers:	DIV-NB-201
First Submitted:	April 30, 2012
First Posted:	May 4, 2012
Results First Submitted:	June 3, 2015
Results First Posted:	September 23, 2015
Last Update Posted:	September 23, 2015

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