Trial Outcomes & Findings for C1 Esterase Inhibitor (C1INH-nf) for the Treatment of Acute Hereditary Angioedema (HAE) Attacks (NCT NCT00289211)

Results Overview

Randomized subjects assessed their symptoms every 15 minutes up to 4 hours after the initial dose of blinded study drug 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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

83 participants

Primary outcome timeframe

Within 4 hours after initial treatment

Results posted on

2021-06-11

Participant Flow

Participant milestones

Participant milestones
Measure	C1INH-nf 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.	Placebo Matching placebo (saline) administered IV. If there was no response to treatment 60 minutes after the first dose, a second placebo (saline) dose could be administered.	Open-label C1INH-nf Only Twelve subjects were never randomized but received open-label C1INH-nf for treatment of laryngeal angioedema and/or prior to emergency surgical procedures. These subjects were analyzed for safety only.
Overall Study STARTED	36	35	12
Overall Study COMPLETED	36	34	2
Overall Study NOT COMPLETED	0	1	10

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	C1INH-nf n=36 Participants 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.	Placebo n=35 Participants Matching placebo (saline) administered IV. If there was no response to treatment 60 minutes after the first dose, a second placebo (saline) dose could be administered.	Open-label C1INH-nf Only n=12 Participants Twelve subjects were never randomized but received open-label C1INH-nf for treatment of laryngeal angioedema and/or prior to emergency surgical procedures. These subjects were analyzed for safety only.	Total n=83 Participants Total of all reporting groups
Age, Continuous	36.8 years STANDARD_DEVIATION 17.68 • n=5 Participants	37.0 years STANDARD_DEVIATION 13.76 • n=7 Participants	36.3 years STANDARD_DEVIATION 19.42 • n=5 Participants	36.8 years STANDARD_DEVIATION 16.20 • n=4 Participants
Sex: Female, Male Female	27 Participants n=5 Participants	28 Participants n=7 Participants	6 Participants n=5 Participants	61 Participants n=4 Participants
Sex: Female, Male Male	9 Participants n=5 Participants	7 Participants n=7 Participants	6 Participants n=5 Participants	22 Participants n=4 Participants

PRIMARY outcome

Timeframe: Within 4 hours after initial treatment

Population: Intent-to-treat (ITT) Population (all randomized subjects). Since less than 50% of subjects in the placebo group achieved the endpoint, median time to event was not estimable (NE). Further, the number of censored events in the C1INH-nf and placebo groups precluded estimation of the 95% confidence interval (CI) upper bound for median time to event.

Randomized subjects assessed their symptoms every 15 minutes up to 4 hours after the initial dose of blinded study drug 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.

Outcome measures

Outcome measures
Measure	C1INH-nf n=36 Participants 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.	Placebo n=35 Participants Matching placebo (saline) administered IV. If there was no response to treatment 60 minutes after the first dose, a second placebo (saline) dose could be administered.
Time to Beginning of Substantial Relief of the Defining Symptom	2.0 hours Interval 1.0 to 4.0	4.0 hours Interval 2.0 to 4.0

SECONDARY outcome

Timeframe: Within 4 hours after initial treatment

Population: ITT-Efficacy (ITT-E) Population (N=68; 3 of the 71 randomized \[ie, ITT\] subjects were excluded from the ITT-E Population, as it was later determined that they did not experience a definitive hereditary angioedema \[HAE\] attack).

Randomized subjects assessed their symptoms every 15 minutes up to 4 hours after the initial dose of blinded study drug 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.

Outcome measures

Outcome measures
Measure	C1INH-nf n=35 Participants 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.	Placebo n=33 Participants Matching placebo (saline) administered IV. If there was no response to treatment 60 minutes after the first dose, a second placebo (saline) dose could be administered.
Number of Subjects With Beginning of Substantial Relief of the Defining Symptom	21 participants	14 participants

SECONDARY outcome

Timeframe: 72 hours

Population: ITT Population.

Randomized subjects were contacted 72-96 hours (3-4 days) after discharge from the study site to determine when complete resolution of the HAE attack occurred.

Outcome measures

Outcome measures
Measure	C1INH-nf n=36 Participants 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.	Placebo n=35 Participants Matching placebo (saline) administered IV. If there was no response to treatment 60 minutes after the first dose, a second placebo (saline) dose could be administered.
Time to Complete Resolution of the HAE Attack	12.3 hours Interval 10.1 to 18.0	31.6 hours Interval 17.8 to 46.0

SECONDARY outcome

Timeframe: Pre-infusion to 1-, 2-, 4-, and 12 hours post-infusion

Population: ITT-E subjects (N=68) with data available.

Change in antigenic C1INH serum levels from pre-infusion to 1-, 2-, 4-, and 12 hours after the initial dose of blinded study drug.

Outcome measures

Outcome measures
Measure	C1INH-nf n=35 Participants 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.	Placebo n=33 Participants Matching placebo (saline) administered IV. If there was no response to treatment 60 minutes after the first dose, a second placebo (saline) dose could be administered.
Antigenic C1 Inhibitor (C1INH) Serum Levels Pre-infusion (N=34, N=33)	14.7 mg/dL Standard Deviation 22.21	13.0 mg/dL Standard Deviation 16.42
Antigenic C1 Inhibitor (C1INH) Serum Levels Change at 1 hour post-infusion (N=35, N=32)	6.7 mg/dL Standard Deviation 8.86	-0.9 mg/dL Standard Deviation 9.25
Antigenic C1 Inhibitor (C1INH) Serum Levels Change at 2 hours post-infusion (N=23, N=27)	11.7 mg/dL Standard Deviation 12.86	0.5 mg/dL Standard Deviation 6.73
Antigenic C1 Inhibitor (C1INH) Serum Levels Change at 4 hours post-infusion (N=28, N=23)	8.6 mg/dL Standard Deviation 8.92	0.4 mg/dL Standard Deviation 6.72
Antigenic C1 Inhibitor (C1INH) Serum Levels Change at 12 hours post-infusion (N=19, N=13)	5.6 mg/dL Standard Deviation 11.21	-0.8 mg/dL Standard Deviation 4.39

SECONDARY outcome

Timeframe: Pre-infusion to 1-, 2-, 4-, and 12 hours post-infusion

Population: ITT-E subjects (N=68) with data available.

Percent change in functional C1INH serum levels from pre-infusion to 1-, 2-, 4-, and 12 hours after the initial dose of blinded study drug. Functional C1INH serum levels are expressed as a percent of total detectable C1INH (ie, functional C1INH/total detectable C1INH).

Outcome measures

Outcome measures
Measure	C1INH-nf n=35 Participants 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.	Placebo n=32 Participants Matching placebo (saline) administered IV. If there was no response to treatment 60 minutes after the first dose, a second placebo (saline) dose could be administered.
Functional C1INH Serum Levels Percent change 4 hours post-infusion (N=28, N=25)	34.5 percent of functional C1INH Standard Deviation 28.22	4.3 percent of functional C1INH Standard Deviation 26.02
Functional C1INH Serum Levels Pre-infusion (N=34, N=31)	35.6 percent of functional C1INH Standard Deviation 22.62	33.7 percent of functional C1INH Standard Deviation 29.04
Functional C1INH Serum Levels Percent change 1 hour post-infusion (N=35, N=32)	31.5 percent of functional C1INH Standard Deviation 23.94	-6.4 percent of functional C1INH Standard Deviation 23.73
Functional C1INH Serum Levels Percent change 2 hours post-infusion (N=23, N=26)	45.6 percent of functional C1INH Standard Deviation 23.70	1.0 percent of functional C1INH Standard Deviation 12.43
Functional C1INH Serum Levels Percent change 12 hours post-infusion (N=19, N=14)	34.8 percent of functional C1INH Standard Deviation 17.24	5.1 percent of functional C1INH Standard Deviation 32.09

SECONDARY outcome

Timeframe: Pre-infusion to 1-, 2-, 4-, and 12 hours post-infusion

Population: ITT-E subjects (N=68) with data available.

Change in complement C4 serum levels from pre-infusion to 1-, 2-, 4-, and 12 hours after the initial dose of blinded study drug.

Outcome measures

Outcome measures
Measure	C1INH-nf n=35 Participants 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.	Placebo n=32 Participants Matching placebo (saline) administered IV. If there was no response to treatment 60 minutes after the first dose, a second placebo (saline) dose could be administered.
Complement C4 Serum Levels Change at 12 hours post-infusion (N=19, N=14)	2.9 mg/dL Standard Deviation 6.33	0.1 mg/dL Standard Deviation 2.07
Complement C4 Serum Levels Pre-infusion (N=35, N=32)	8.1 mg/dL Standard Deviation 7.79	6.7 mg/dL Standard Deviation 5.32
Complement C4 Serum Levels Change at 1 hour post-infusion (N=33, N=30)	-0.7 mg/dL Standard Deviation 5.59	-0.9 mg/dL Standard Deviation 1.96
Complement C4 Serum Levels Change at 2 hours post-infusion (N=21, N=26)	-1.7 mg/dL Standard Deviation 8.12	-1.1 mg/dL Standard Deviation 2.13
Complement C4 Serum Levels Change at 4 hours post-infusion (N=26, N=22)	-1.0 mg/dL Standard Deviation 5.62	-0.5 mg/dL Standard Deviation 1.90

Adverse Events

C1INH-nf

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	C1INH-nf n=71 participants at risk	Placebo n=12 participants at risk
Skin and subcutaneous tissue disorders Dermatitis contact	1.4% 1/71 • 3 months. As the study design allowed for all subjects (even those randomized to placebo) to receive C1INH-nf, safety data are presented by actual treatment received (C1INH-nf 71, placebo 12), not randomized treatment group (see Detailed Description). Presented are all treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse events reported in this study.	0.00% 0/12 • 3 months. As the study design allowed for all subjects (even those randomized to placebo) to receive C1INH-nf, safety data are presented by actual treatment received (C1INH-nf 71, placebo 12), not randomized treatment group (see Detailed Description). Presented are all treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse events reported in this study.
General disorders Injection site rash	1.4% 1/71 • 3 months. As the study design allowed for all subjects (even those randomized to placebo) to receive C1INH-nf, safety data are presented by actual treatment received (C1INH-nf 71, placebo 12), not randomized treatment group (see Detailed Description). Presented are all treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse events reported in this study.	0.00% 0/12 • 3 months. As the study design allowed for all subjects (even those randomized to placebo) to receive C1INH-nf, safety data are presented by actual treatment received (C1INH-nf 71, placebo 12), not randomized treatment group (see Detailed Description). Presented are all treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse events reported in this study.
Metabolism and nutrition disorders Tetany	0.00% 0/71 • 3 months. As the study design allowed for all subjects (even those randomized to placebo) to receive C1INH-nf, safety data are presented by actual treatment received (C1INH-nf 71, placebo 12), not randomized treatment group (see Detailed Description). Presented are all treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse events reported in this study.	8.3% 1/12 • 3 months. As the study design allowed for all subjects (even those randomized to placebo) to receive C1INH-nf, safety data are presented by actual treatment received (C1INH-nf 71, placebo 12), not randomized treatment group (see Detailed Description). Presented are all treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse events reported in this study.

Additional Information

Study Director

Shire

Phone: +1 866 842 5335

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER