Open-Label C1 Esterase Inhibitor (C1INH-nf) for the Treatment of Acute Hereditary Angioedema (HAE) Attacks (CHANGE 2)

• ClinicalTrials.gov Identifier: NCT00438815
• Recruitment Status: Completed
• First Posted: February 22, 2007
• Results First Posted: June 9, 2010
• Last Update Posted: April 15, 2014
• Sponsor: Shire
• Information provided by: Shire

• Study Type: Interventional
• Study Design: Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hereditary Angioedema
• Intervention: Biological: C1 esterase inhibitor [human] (C1INH-nf)
• Enrollment: 113

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Open-label C1INH-nf
Arm/Group Description	1,000 Units (U) of C1 esterase inhibitor (C1INH-nf) administered intravenously (IV). If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered.
Period Title: Overall Study
Started	113
Completed	43
Not Completed	70
Reason Not Completed
Transferred to LEVP2006-4 (NCT00462709)	30
3-month follow-up no longer required	12
Noncompliance with protocol requirements	9
Transitioned to commercial C1INH-nf	6
Lost to Follow-up	6
Withdrawal by Subject	6
Death	1

Baseline Characteristics

Arm/Group Title		Open-label C1INH-nf
Arm/Group Description		1,000 U of C1INH-nf administered IV. If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered.
Overall Number of Baseline Participants		113
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	113 participants
		34.5 (17.6)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	113 participants
	Female	75 66.4%
	Male	38 33.6%

Outcome Measures

1. Primary Outcome

Title	Number of Hereditary Angioedema (HAE) Attacks Treated With C1INH-nf
Description	[Not Specified]
Time Frame	Duration of the study (2.5 years)

Outcome Measure Data

Analysis Population Description

Intent-to-treat Efficacy (ITT-E) Population (N=101; the number of subjects who received at least one dose of C1INH-nf for the treatment of an acute HAE attack).

Arm/Group Title	Open-label C1INH-nf
Arm/Group Description:	1,000 U of C1INH-nf administered IV. If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered.
Overall Number of Participants Analyzed	101
Measure Type: Number; Unit of Measure: attacks
Conservative Analysis	609
Less Conservative Analysis	598

2. Primary Outcome

Title	Percent of HAE Attacks With Substantial Relief of the Defining Symptom
Description	Subjects were to assess their symptoms every 15 minutes up to 4 hours after the initial dose or until substantial relief of the defining symptom was achieved. The conservative analysis defined substantial relief as 3 consecutive assessments of improvement of the defining symptom; any attack that did not have 3 consecutive documented reports of improvement was considered a treatment failure. In the less conservative analysis, attacks also were considered to have responded if clinical improvement of the defining symptom occurred but data were incomplete due to cessation of symptom assessments.
Time Frame	Within 4 hours after initial treatment

Outcome Measure Data

Analysis Population Description

ITT-E Population (N=101; the number of subjects who received at least one dose of C1INH-nf for the treatment of an acute HAE attack).

Arm/Group Title	Open-label C1INH-nf
Arm/Group Description:	1,000 U of C1INH-nf administered IV. If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered.
Overall Number of Participants Analyzed	101
Measure Type: Number; Unit of Measure: percent of attacks
Conservative Analysis	87
Less Conservative Analysis	95

3. Secondary Outcome

Title	Time to Beginning of Substantial Relief of the Defining Symptom
Description	Subjects were to assess their symptoms every 15 minutes up to 4 hours after the initial dose or until substantial relief of the defining symptom was achieved. Substantial relief was defined as 3 consecutive assessments of improvement of the defining symptom. Beginning of substantial relief was considered the first of the 3 consecutive assessments.
Time Frame	Within 4 hours after initial treatment

Outcome Measure Data

Analysis Population Description

ITT-E Population.

Arm/Group Title	Open-label C1INH-nf
Arm/Group Description:	1,000 U of C1INH-nf administered IV. If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered.
Overall Number of Participants Analyzed	101
Median (95% Confidence Interval); Unit of Measure: hours
	0.75; (0.50 to 1.00)

4. Secondary Outcome

Title	Time to Beginning of Substantial Relief of the Defining Symptom for Subjects Who Received Multiple Treatments
Description	For attack number 1, the number of censored observations precluded estimation of the 95% confidence interval (CI) upper bound for median time to event (subjects who did not experience beginning of substantial relief of the defining symptom within 4 hours after initial treatment were included in the analysis as censored observations). Entry of 4.0 hours indicates that data were not estimable (NE); as non-numeric data are not supported by the 95% CI field, entry of the actual result (ie, NE or >4.0) was not possible.
Time Frame	Within 4 hours after initial treatment

Outcome Measure Data

Analysis Population Description

ITT-E subjects with at least 10 HAE attacks during the study (N=15).

Arm/Group Title	Open-label C1INH-nf
Arm/Group Description:	1,000 U of C1INH-nf administered IV. If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered.
Overall Number of Participants Analyzed	15
Median (95% Confidence Interval); Unit of Measure: hours
Attack number 1	1.50; (0.75 to 4.00)
Attack number 2	0.50; (0.25 to 2.50)
Attack number 3	0.50; (0.50 to 0.75)
Attack number 4	0.50; (0.25 to 1.00)
Attack number 5	0.75; (0.50 to 1.25)
Attack number 6	0.50; (0.25 to 1.25)
Attack number 7	0.75; (0.50 to 0.75)
Attack number 8	0.50; (0.25 to 0.75)
Attack number 9	0.25; (0.25 to 0.50)
Attack number 10	0.50; (0.25 to 0.75)

5. Secondary Outcome

Title	Antigenic C1 Inhibitor (C1INH) Serum Levels
Description	Change in antigenic C1INH serum levels from pre-infusion to 1 hour after the initial dose of study drug.
Time Frame	Pre-infusion to 1 hour post-infusion

Outcome Measure Data

Analysis Population Description

ITT-E subjects with data at both sampling time points (N=84).

Arm/Group Title	Open-label C1INH-nf
Arm/Group Description:	1,000 U of C1INH-nf administered IV. If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered.
Overall Number of Participants Analyzed	84
Mean (Standard Deviation); Unit of Measure: mg/dL
Pre-infusion	10.7 (13.91)
Increase at 1 hour post-infusion	9.6 (12.98)

6. Secondary Outcome

Title	Functional C1INH Serum Levels
Description	Percent change in functional C1INH serum levels from pre-infusion to 1 hour after the initial dose of study drug. Functional C1INH serum levels are expressed as a percent of total detectable C1INH (ie, functional C1INH/total detectable C1INH).
Time Frame	Pre-infusion to 1 hour post-infusion

Outcome Measure Data

Analysis Population Description

ITT-E subjects with data at both sampling time points (N=82).

Arm/Group Title	Open-label C1INH-nf
Arm/Group Description:	1,000 U of C1INH-nf administered IV. If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered.
Overall Number of Participants Analyzed	82
Mean (Standard Deviation); Unit of Measure: percent of functional C1INH
Pre-infusion	27.0 (19.30)
Percent increase at 1 hour post-infusion	39.2 (18.04)

7. Secondary Outcome

Title	Complement C4 Serum Levels
Description	Change in complement C4 serum levels from pre-infusion to 1 hour after the initial dose of study drug.
Time Frame	Pre-infusion to 1 hour post-infusion

Outcome Measure Data

Analysis Population Description

ITT-E subjects with data at both sampling time points (N=74).

Arm/Group Title	Open-label C1INH-nf
Arm/Group Description:	1,000 U of C1INH-nf administered IV. If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered.
Overall Number of Participants Analyzed	74
Mean (Standard Deviation); Unit of Measure: mg/dL
Pre-infusion	5.3 (5.41)
Change at 1 hour post-infusion	-0.2 (1.51)

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	Presented are all treatment-emergent adverse reactions considered to be related to C1INH-nf.
Arm/Group Title	Open-label C1INH-nf
Arm/Group Description	1,000 U of C1INH-nf administered IV. If there was no response to treatment 60 minutes after the first dose, a second 1,000 U dose could be administered.
All-Cause Mortality
	Open-label C1INH-nf
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events
	Open-label C1INH-nf
	Affected / at Risk (%)
Total	0/113 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0.5%
	Open-label C1INH-nf
	Affected / at Risk (%)
Total	1/113 (0.88%)
General disorders
Infusion site pain 1	1/113 (0.88%)
Skin and subcutaneous tissue disorders
Rash 1	1/113 (0.88%)
1 Term from vocabulary, MedDRA (9.0)

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.

Clinical Study Agreement. Most restrictive provision - PI will not publish results until after first of: multicenter publication is published or 24 months from study end. Thereafter, PI may publish his results. PI must provide copy of proposed publication to sponsor for pre-review. If sponsor requests, PI must delete sponsor confidential information before publication and/or delay publication for 90 days so sponsor can file for patents or take other action to protect its patent rights.

Results Point of Contact

• Name/Title: Chief Scientific Officer
• Organization: ViroPharma
• Phone: 610-458-7300

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Baker JW, Craig TJ, Riedl MA, Banerji A, Fitts D, Kalfus IN, Uknis ME. Nanofiltered C1 esterase inhibitor (human) for hereditary angioedema attacks in pregnant women. Allergy Asthma Proc. 2013 Mar-Apr;34(2):162-9. doi: 10.2500/aap.2013.34.3645.

Lumry W, Manning ME, Hurewitz DS, Davis-Lorton M, Fitts D, Kalfus IN, Uknis ME. Nanofiltered C1-esterase inhibitor for the acute management and prevention of hereditary angioedema attacks due to C1-inhibitor deficiency in children. J Pediatr. 2013 May;162(5):1017-22.e1-2. doi: 10.1016/j.jpeds.2012.11.030. Epub 2013 Jan 11.

Grant JA, White MV, Li HH, Fitts D, Kalfus IN, Uknis ME, Lumry WR. Preprocedural administration of nanofiltered C1 esterase inhibitor to prevent hereditary angioedema attacks. Allergy Asthma Proc. 2012 Jul-Aug;33(4):348-53. doi: 10.2500/aap.2012.33.3585.

Riedl MA, Hurewitz DS, Levy R, Busse PJ, Fitts D, Kalfus I. Nanofiltered C1 esterase inhibitor (human) for the treatment of acute attacks of hereditary angioedema: an open-label trial. Ann Allergy Asthma Immunol. 2012 Jan;108(1):49-53. doi: 10.1016/j.anai.2011.10.017. Epub 2011 Nov 21.

Zuraw BL, Busse PJ, White M, Jacobs J, Lumry W, Baker J, Craig T, Grant JA, Hurewitz D, Bielory L, Cartwright WE, Koleilat M, Ryan W, Schaefer O, Manning M, Patel P, Bernstein JA, Friedman RA, Wilkinson R, Tanner D, Kohler G, Gunther G, Levy R, McClellan J, Redhead J, Guss D, Heyman E, Blumenstein BA, Kalfus I, Frank MM. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. 2010 Aug 5;363(6):513-22. doi: 10.1056/NEJMoa0805538.

• Responsible Party: Chief Scientific Officer, ViroPharma
• ClinicalTrials.gov Identifier: NCT00438815 History of Changes
• Other Study ID Numbers: LEVP2006-1
• First Submitted: February 21, 2007
• First Posted: February 22, 2007
• Results First Submitted: March 31, 2010
• Results First Posted: June 9, 2010
• Last Update Posted: April 15, 2014