Trial Outcomes & Findings for C1 Esterase Inhibitor (C1INH-nf) for the Prevention of Acute Hereditary Angioedema (HAE) Attacks (NCT NCT01005888)

NCT ID: NCT01005888

Last Updated: 2021-06-11

Results Overview

An HAE attack was defined as the subject-reported indication of swelling at any location following a report of no swelling on the previous day. Analyses include observed attack counts and normalized attack counts (i.e., the number of attacks observed during each therapy period, normalized for the number of days the subject participated in that period).

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 26 participants
• Primary outcome timeframe: 12 weeks
• Results posted on: 2021-06-11

Participant Flow

A total of 26 subjects were enrolled in the study (see Detailed Description). One subject received open-label C1 esterase inhibitor (C1INH-nf) but withdrew prior to randomization. Another subject was randomized but withdrew prior to receiving study drug. 24 subjects were randomized and began therapy with blinded study drug in Period 1.

Participant milestones

Measure	C1INH-nf First, Then Placebo 1,000 Units (U) of C1INH-nf administered intravenously (IV) every 3 to 4 days (approximately twice weekly) for 12 weeks, followed by matching placebo (saline) administered IV every 3 to 4 days for 12 weeks.	Placebo First, Then C1INH-nf Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks, followed by 1,000 U of C1INH-nf administered IV every 3 to 4 days for 12 weeks.
First Intervention STARTED	12	12
First Intervention COMPLETED	11	11
First Intervention NOT COMPLETED	1	1
Second Intervention STARTED	11	11
Second Intervention COMPLETED	10	10
Second Intervention NOT COMPLETED	1	1

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	C1INH-nf First, Then Placebo n=12 Participants 1,000 U of C1INH-nf administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks, followed by matching placebo (saline) administered IV every 3 to 4 days for 12 weeks.	Placebo First, Then C1INH-nf n=12 Participants Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks, followed by 1,000 U of C1INH-nf administered IV every 3 to 4 days for 12 weeks.	Open-label C1INH-nf Only n=1 Participants One subject received open-label C1INH-nf but withdrew prior to randomization.	Randomized, Not Treated n=1 Participants One subject was randomized but withdrew prior to receiving study drug.	Total n=26 Participants Total of all reporting groups
Age, Categorical <=18 years	2 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	5 Participants n=21 Participants
Age, Categorical Between 18 and 65 years	9 Participants n=5 Participants	10 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	20 Participants n=21 Participants
Age, Categorical >=65 years	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Sex: Female, Male Female	9 Participants n=5 Participants	12 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	22 Participants n=21 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	4 Participants n=21 Participants

PRIMARY outcome

Timeframe: 12 weeks

Population: The Efficacy Dataset (N=22) consisted of all randomized subjects who completed 12 weeks of therapy in Period 1 and received at least one infusion of study drug in Period 2.

An HAE attack was defined as the subject-reported indication of swelling at any location following a report of no swelling on the previous day. Analyses include observed attack counts and normalized attack counts (i.e., the number of attacks observed during each therapy period, normalized for the number of days the subject participated in that period).

Outcome measures

Measure	C1INH-nf n=22 Participants 1,000 U of C1INH-nf administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.	Placebo n=22 Participants Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Number of Hereditary Angioedema (HAE) Attacks During Each Prophylactic Therapy Period Observed	6.1 attacks Standard Deviation 5.43	12.7 attacks Standard Deviation 4.80
Number of Hereditary Angioedema (HAE) Attacks During Each Prophylactic Therapy Period Normalized	6.3 attacks Standard Deviation 5.54	12.7 attacks Standard Deviation 4.65

SECONDARY outcome

Timeframe: 12 weeks

Population: The Safety Dataset (N=24) consisted of all randomized subjects who received at least 1 complete or partial infusion of study drug. 24 subjects began Period 1 (12 C1INH-nf, 12 placebo) and received study drug. 22 subjects crossed over to Period 2 (11 placebo, 11 C1INH-nf) and received study drug. Thus, 23 randomized subjects received each therapy.

At the end of each therapy period, each subject was assigned a yes/no drop-out status. A drop-out was defined as a subject who did not have a Week 12 visit record.

Outcome measures

Measure	C1INH-nf n=23 Participants 1,000 U of C1INH-nf administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.	Placebo n=23 Participants Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Number of Subject Withdrawals During Each Prophylactic Therapy Period Period 1	1 participants	1 participants
Number of Subject Withdrawals During Each Prophylactic Therapy Period Period 2	1 participants	1 participants

SECONDARY outcome

Timeframe: 12 weeks

Population: Efficacy Dataset.

All attacks in each therapy period were assigned a value of 1 (mild), 2 (moderate), or 3 (severe). Attack severity was considered the highest value assigned by the subject to any swelling location during the attack. Average severity was set to 0 if there was no attack in a period.

Outcome measures

Measure	C1INH-nf n=22 Participants 1,000 U of C1INH-nf administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.	Placebo n=22 Participants Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Average Severity of HAE Attacks During Each Prophylactic Therapy Period	1.3 units on a scale Standard Deviation 0.85	1.9 units on a scale Standard Deviation 0.35

SECONDARY outcome

Timeframe: 12 weeks

Population: Efficacy Dataset.

The duration of an attack was measured from the first report of swelling at any one of the five locations (abdominal, genitourinary, facial, respiratory [including laryngeal], or extremity) until the first subsequent report of "no swelling" at all five locations.

Outcome measures

Measure	C1INH-nf n=22 Participants 1,000 U of C1INH-nf administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.	Placebo n=22 Participants Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Average Duration of HAE Attacks During Each Prophylactic Therapy Period	2.1 days Standard Deviation 1.13	3.4 days Standard Deviation 1.39

SECONDARY outcome

Timeframe: 12 weeks

Population: Efficacy Dataset.

The study design allowed for subjects to be treated with open-label C1INH-nf for laryngeal angioedema, if deemed necessary by the investigator, or prior to emergency surgical procedures.

Outcome measures

Measure	C1INH-nf n=22 Participants 1,000 U of C1INH-nf administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.	Placebo n=22 Participants Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Number of Open-label C1INH-nf Infusions Required During Each Prophylactic Therapy Period	4.7 infusions Standard Deviation 8.66	15.4 infusions Standard Deviation 8.41

SECONDARY outcome

Timeframe: Pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12

Population: Efficacy Dataset subjects with data at both sampling time points (N=19 C1INH-nf, N=22 placebo).

Change in antigenic C1INH serum levels from pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12. Pre-infusion samples obtained at Visit 1 of each therapy period (i.e., baseline) were used to determine change at 1 hour post-infusion for all visits.

Outcome measures

Measure	C1INH-nf n=19 Participants 1,000 U of C1INH-nf administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.	Placebo n=22 Participants Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Antigenic C1 Inhibitor (C1INH) Serum Levels Visit 1 pre-infusion	14.3 mg/dL Standard Deviation 15.08	14.2 mg/dL Standard Deviation 14.71
Antigenic C1 Inhibitor (C1INH) Serum Levels Visit 1 change at 1 hour post-infusion	7.9 mg/dL Standard Deviation 3.70	-0.1 mg/dL Standard Deviation 2.17
Antigenic C1 Inhibitor (C1INH) Serum Levels Week 4 change at 1 hour post-infusion	9.8 mg/dL Standard Deviation 5.08	0.1 mg/dL Standard Deviation 5.04
Antigenic C1 Inhibitor (C1INH) Serum Levels Week 8 change at 1 hour post-infusion	7.2 mg/dL Standard Deviation 5.62	-0.3 mg/dL Standard Deviation 3.08
Antigenic C1 Inhibitor (C1INH) Serum Levels Week 12 change at 1 hour post-infusion	8.4 mg/dL Standard Deviation 5.93	1.1 mg/dL Standard Deviation 5.98

SECONDARY outcome

Timeframe: Pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12

Population: Efficacy Dataset subjects with data at both sampling time points (N=20 C1INH-nf, N=22 placebo).

Percent change in functional C1INH serum levels from pre-infusion to 1 hour post-infusion at Visit 1 and Weeks 4, 8, and 12. Pre-infusion samples obtained at Visit 1 of each therapy period (i.e., baseline) were used to determine change at 1 hour post-infusion for all visits. Functional C1INH serum levels are expressed as a percent of total detectable C1INH (i.e., functional C1INH/total detectable C1INH).

Outcome measures

Measure	C1INH-nf n=20 Participants 1,000 U of C1INH-nf administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.	Placebo n=22 Participants Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Functional C1INH Serum Levels Visit 1 pre-infusion	33.9 percent of functional C1INH Standard Deviation 17.21	31.7 percent of functional C1INH Standard Deviation 21.54
Functional C1INH Serum Levels Visit 1 percent change at 1 hour post-infusion	32.0 percent of functional C1INH Standard Deviation 18.95	-2.4 percent of functional C1INH Standard Deviation 9.41
Functional C1INH Serum Levels Week 4 percent change at 1 hour post-infusion	36.6 percent of functional C1INH Standard Deviation 17.62	5.3 percent of functional C1INH Standard Deviation 26.16
Functional C1INH Serum Levels Week 8 percent change at 1 hour post-infusion	32.1 percent of functional C1INH Standard Deviation 19.08	5.4 percent of functional C1INH Standard Deviation 15.74
Functional C1INH Serum Levels Week 12 percent change at 1 hour post-infusion	33.9 percent of functional C1INH Standard Deviation 21.07	0.8 percent of functional C1INH Standard Deviation 23.92

OTHER_PRE_SPECIFIED outcome

Timeframe: 12 weeks

Population: Efficacy Dataset.

A day of swelling was defined as a day that a subject reported swelling at any of the five locations (abdominal, genitourinary, facial, respiratory [including laryngeal], or extremity).

Outcome measures

Measure	C1INH-nf n=22 Participants 1,000 U of C1INH-nf administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.	Placebo n=22 Participants Matching placebo (saline) administered IV every 3 to 4 days (approximately twice weekly) for 12 weeks.
Total Number of Days of Swelling During Each Prophylactic Therapy Period	10.1 days Standard Deviation 10.73	29.6 days Standard Deviation 16.90

Adverse Events

C1INH-nf

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	C1INH-nf n=25 participants at risk	Placebo n=23 participants at risk
Respiratory, thoracic and mediastinal disorders Cough	4.0% 1/25 • Up to 6 months (i.e., 24 weeks) of therapy and 3 months of follow-up. 25 subjects received at least 1 dose of study drug and were analyzed for safety; all 25 were exposed to C1INH-nf and 23 were exposed to placebo (see Detailed Description). Presented are treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse reactions considered related to study drug.	0.00% 0/23 • Up to 6 months (i.e., 24 weeks) of therapy and 3 months of follow-up. 25 subjects received at least 1 dose of study drug and were analyzed for safety; all 25 were exposed to C1INH-nf and 23 were exposed to placebo (see Detailed Description). Presented are treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse reactions considered related to study drug.
Skin and subcutaneous tissue disorders Pruritus	4.0% 1/25 • Up to 6 months (i.e., 24 weeks) of therapy and 3 months of follow-up. 25 subjects received at least 1 dose of study drug and were analyzed for safety; all 25 were exposed to C1INH-nf and 23 were exposed to placebo (see Detailed Description). Presented are treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse reactions considered related to study drug.	0.00% 0/23 • Up to 6 months (i.e., 24 weeks) of therapy and 3 months of follow-up. 25 subjects received at least 1 dose of study drug and were analyzed for safety; all 25 were exposed to C1INH-nf and 23 were exposed to placebo (see Detailed Description). Presented are treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse reactions considered related to study drug.
Skin and subcutaneous tissue disorders Rash	4.0% 1/25 • Up to 6 months (i.e., 24 weeks) of therapy and 3 months of follow-up. 25 subjects received at least 1 dose of study drug and were analyzed for safety; all 25 were exposed to C1INH-nf and 23 were exposed to placebo (see Detailed Description). Presented are treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse reactions considered related to study drug.	0.00% 0/23 • Up to 6 months (i.e., 24 weeks) of therapy and 3 months of follow-up. 25 subjects received at least 1 dose of study drug and were analyzed for safety; all 25 were exposed to C1INH-nf and 23 were exposed to placebo (see Detailed Description). Presented are treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse reactions considered related to study drug.
General disorders Chest discomfort	4.0% 1/25 • Up to 6 months (i.e., 24 weeks) of therapy and 3 months of follow-up. 25 subjects received at least 1 dose of study drug and were analyzed for safety; all 25 were exposed to C1INH-nf and 23 were exposed to placebo (see Detailed Description). Presented are treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse reactions considered related to study drug.	0.00% 0/23 • Up to 6 months (i.e., 24 weeks) of therapy and 3 months of follow-up. 25 subjects received at least 1 dose of study drug and were analyzed for safety; all 25 were exposed to C1INH-nf and 23 were exposed to placebo (see Detailed Description). Presented are treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse reactions considered related to study drug.
General disorders Pyrexia	4.0% 1/25 • Up to 6 months (i.e., 24 weeks) of therapy and 3 months of follow-up. 25 subjects received at least 1 dose of study drug and were analyzed for safety; all 25 were exposed to C1INH-nf and 23 were exposed to placebo (see Detailed Description). Presented are treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse reactions considered related to study drug.	0.00% 0/23 • Up to 6 months (i.e., 24 weeks) of therapy and 3 months of follow-up. 25 subjects received at least 1 dose of study drug and were analyzed for safety; all 25 were exposed to C1INH-nf and 23 were exposed to placebo (see Detailed Description). Presented are treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse reactions considered related to study drug.
Nervous system disorders Dizziness	4.0% 1/25 • Up to 6 months (i.e., 24 weeks) of therapy and 3 months of follow-up. 25 subjects received at least 1 dose of study drug and were analyzed for safety; all 25 were exposed to C1INH-nf and 23 were exposed to placebo (see Detailed Description). Presented are treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse reactions considered related to study drug.	0.00% 0/23 • Up to 6 months (i.e., 24 weeks) of therapy and 3 months of follow-up. 25 subjects received at least 1 dose of study drug and were analyzed for safety; all 25 were exposed to C1INH-nf and 23 were exposed to placebo (see Detailed Description). Presented are treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse reactions considered related to study drug.
Skin and subcutaneous tissue disorders Erythema	4.0% 1/25 • Up to 6 months (i.e., 24 weeks) of therapy and 3 months of follow-up. 25 subjects received at least 1 dose of study drug and were analyzed for safety; all 25 were exposed to C1INH-nf and 23 were exposed to placebo (see Detailed Description). Presented are treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse reactions considered related to study drug.	0.00% 0/23 • Up to 6 months (i.e., 24 weeks) of therapy and 3 months of follow-up. 25 subjects received at least 1 dose of study drug and were analyzed for safety; all 25 were exposed to C1INH-nf and 23 were exposed to placebo (see Detailed Description). Presented are treatment-emergent adverse reactions considered to be related to study drug. There were no serious adverse reactions considered related to study drug.

Additional Information

Study Director

Shire

Phone: +1 866 842 5335

Email: ClinicalTransparency@shire.com

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