Trial Outcomes & Findings for Study of C1 Inhibitor (Human) for the Prevention of Angioedema Attacks and Treatment of Breakthrough Attacks in Japanese Subjects With Hereditary Angioedema (HAE) (NCT NCT02865720)

NCT ID: NCT02865720

Last Updated: 2021-06-02

Results Overview

An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered an investigational product and that did not necessarily have a causal relationship with the treatment. TEAEs were defined as all AEs that started during the treatment period and up to 7 days after the last dose of investigational product, or AEs that were seen at baseline but worsened in frequency and/or severity during the treatment period and up to 7 days after the last dose of investigational product.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 8 participants
• Primary outcome timeframe: From start of study drug administration up to Week 12
• Results posted on: 2021-06-02

Participant Flow

The study was conducted in 9 study centers in Japan between 13 Sep 2016 (First participant first visit) and 23 June 2017 (Last participant last visit).

A total of 8 participants were screened and enrolled. Investigational product administrations were planned according to participants' age; 500 units (U) for participants 2 to 5 years and 1000 U for participants 6 years and older. However, as no participants under the age of 6 years were enrolled, only the higher dose of 1000 U was administered.

Participant milestones

Measure	CINRYZE 500 U Participants received 500 U CINRYZE intravenous (IV) injection twice weekly for 12 weeks.	CINRYZE 1000 U Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Overall Study STARTED	0	8
Overall Study COMPLETED	0	8
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Study of C1 Inhibitor (Human) for the Prevention of Angioedema Attacks and Treatment of Breakthrough Attacks in Japanese Subjects With Hereditary Angioedema (HAE)

Baseline characteristics by cohort

Measure	CINRYZE 500 U Participants received 500 U CINRYZE IV injection twice weekly for 12 weeks.	CINRYZE 1000 U n=8 Participants Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.	Total n=8 Participants Total of all reporting groups
Age, Continuous	—	38.4 year STANDARD_DEVIATION 7.27 • n=7 Participants	38.4 year STANDARD_DEVIATION 7.27 • n=5 Participants
Sex: Female, Male Female	—	6 Participants n=7 Participants	6 Participants n=5 Participants
Sex: Female, Male Male	—	2 Participants n=7 Participants	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	—	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	—	8 Participants n=7 Participants	8 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	—	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	—	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	—	8 Participants n=7 Participants	8 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	—	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	—	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	—	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) More than one race	—	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	—	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: From start of study drug administration up to Week 12

Population: ITT-S set included participants who received any amount of investigational product.

An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered an investigational product and that did not necessarily have a causal relationship with the treatment. TEAEs were defined as all AEs that started during the treatment period and up to 7 days after the last dose of investigational product, or AEs that were seen at baseline but worsened in frequency and/or severity during the treatment period and up to 7 days after the last dose of investigational product.

Outcome measures

Measure	CINRYZE 1000 U n=8 Participants Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	7 Participants

PRIMARY outcome

Timeframe: From start of study drug administration up to Week 12

Population: ITT-S set included participants who received any amount of investigational product.

Physical examinations included measurement of body weight and height. Clinically significant abnormalities related to physical examination as determined by investigator were recorded and reported as AE.

Outcome measures

Measure	CINRYZE 1000 U n=8 Participants Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Number of Participants With Clinically Significant Abnormalities in Physical Examination Reported as Adverse Events (AEs)	0 Participants

PRIMARY outcome

Timeframe: Baseline up to Week 12

Population: ITT-S set included participants who received any amount of investigational product.

Vital sign assessments included systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate. Investigator used both absolute values and change from baseline values to determine if the vital sign was potentially clinically important. Criteria for the potential clinical importance of both absolute and change from baseline values were pre-specified as: SBP (less than [<] 90 millimeter of mercury [mmHg]; greater than or equal to [>=] 140 mmHg), DBP (< 60 mmHg; >=90 mmHg) and pulse (less than or equal to [<=] 50 beats per minute [bpm]; >= 100 bpm. A participant's vital sign had to meet both the absolute and change from baseline criteria to be considered as potentially clinically important.

Outcome measures

Measure	CINRYZE 1000 U n=8 Participants Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Number of Participants With Potentially Clinically Important (PCI) Vital Signs Reported as Adverse Events (AEs)	0 Participants

PRIMARY outcome

Timeframe: Baseline up to Week 12

Population: ITT-S set included participants who received any amount of investigational product.

Number of participants with potentially clinically important (PCI) clinical laboratory assessments reported as adverse events were reported.

Outcome measures

Measure	CINRYZE 1000 U n=8 Participants Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Number of Participants With Potentially Clinically Important (PCI) Clinical Laboratory Assessments Reported as Adverse Events (AEs)	0 Participants

PRIMARY outcome

Timeframe: Week 1: Pre-dose, 0.5, 1, 2, 6, 24, 48, 72 and 96 hours (h) post-dose

Population: Pharmacokinetic (PK) set included all participants with evaluable PK profiles.

C1 INH antigen concentration in plasma was determined using an automated nephelometric assay.

Outcome measures

Measure	CINRYZE 1000 U n=8 Participants Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 1 Pre-dose	0.0581 Gram per liter (g/L) Standard Deviation 0.04877
Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 1 0.5 h post-dose	0.1463 Gram per liter (g/L) Standard Deviation 0.04210
Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 1 1 h post-dose	0.1426 Gram per liter (g/L) Standard Deviation 0.05795
Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 1 2 h post-dose	0.1436 Gram per liter (g/L) Standard Deviation 0.04524
Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 1 6 h post-dose	0.1413 Gram per liter (g/L) Standard Deviation 0.04376
Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 1 24 h post-dose	0.1147 Gram per liter (g/L) Standard Deviation 0.03825
Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 1 48 h post-dose	0.0978 Gram per liter (g/L) Standard Deviation 0.04204
Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 1 72 h post-dose	0.0881 Gram per liter (g/L) Standard Deviation 0.04133
Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 1 96 h post-dose	0.0680 Gram per liter (g/L) Standard Deviation NA Standard Deviation is not calculated due to a single participant being evaluable.

PRIMARY outcome

Timeframe: Week 12: Pre-dose, 0.5, 1, 2, 6, 24, 48, 72 and 96 h post-dose

Population: PK set included all participants with evaluable PK profiles.

C1 INH antigen concentration in plasma was determined using an automated nephelometric assay.

Outcome measures

Measure	CINRYZE 1000 U n=8 Participants Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 12 Pre-dose	0.0775 gram per liter (g/L) Standard Deviation 0.04904
Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 12 0.5 h post-dose	0.1660 gram per liter (g/L) Standard Deviation 0.04159
Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 12 1 h post-dose	0.1468 gram per liter (g/L) Standard Deviation 0.03232
Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 12 2 h post-dose	0.1634 gram per liter (g/L) Standard Deviation 0.04500
Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 12 6 h post-dose	0.1573 gram per liter (g/L) Standard Deviation 0.03978
Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 12 24 h post-dose	0.1244 gram per liter (g/L) Standard Deviation 0.04675
Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 12 48 h post-dose	0.1003 gram per liter (g/L) Standard Deviation 0.05030
Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 12 72 h post-dose	0.0836 gram per liter (g/L) Standard Deviation 0.05169
Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 12 96 h post-dose	0.0661 gram per liter (g/L) Standard Deviation 0.05163

PRIMARY outcome

Timeframe: Week 1: Pre-dose, 0.5, 1, 2, 6, 24, 48, 72 and 96 h post-dose

Population: Pharmacodynamic (PD) set included all participants with evaluable PD profiles.

Concentration of plasma complement C4 was reported.

Outcome measures

Measure	CINRYZE 1000 U n=8 Participants Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Concentration of Plasma Complement C4 at Week 1 72 h post-dose	80.5 Milligram per liter (mg/L) Standard Deviation 41.34
Concentration of Plasma Complement C4 at Week 1 Pre-dose	42.8 Milligram per liter (mg/L) Standard Deviation 20.42
Concentration of Plasma Complement C4 at Week 1 0.5 h post-dose	37.5 Milligram per liter (mg/L) Standard Deviation 17.55
Concentration of Plasma Complement C4 at Week 1 1 h post-dose	32.7 Milligram per liter (mg/L) Standard Deviation 18.17
Concentration of Plasma Complement C4 at Week 1 2 h post-dose	43.3 Milligram per liter (mg/L) Standard Deviation 19.48
Concentration of Plasma Complement C4 at Week 1 6 h post-dose	69.0 Milligram per liter (mg/L) Standard Deviation 29.70
Concentration of Plasma Complement C4 at Week 1 24 h post-dose	89.0 Milligram per liter (mg/L) Standard Deviation 33.80
Concentration of Plasma Complement C4 at Week 1 48 h post-dose	82.5 Milligram per liter (mg/L) Standard Deviation 36.00
Concentration of Plasma Complement C4 at Week 1 96 h post-dose	67.0 Milligram per liter (mg/L) Standard Deviation NA Standard Deviation is not calculated due to a single participant being evaluable.

PRIMARY outcome

Timeframe: Week 12: Pre-dose, 0.5, 1, 2, 6, 24, 48, 72 and 96 h post-dose

Population: PD set included all participants with evaluable PD profiles.

Concentration of plasma complement C4 was reported.

Outcome measures

Measure	CINRYZE 1000 U n=8 Participants Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Concentration of Plasma Complement C4 at Week 12 72 h post-dose	77.9 mg/L Standard Deviation 47.39
Concentration of Plasma Complement C4 at Week 12 96 h post-dose	63.2 mg/L Standard Deviation 37.06
Concentration of Plasma Complement C4 at Week 12 Pre-dose	77.9 mg/L Standard Deviation 37.79
Concentration of Plasma Complement C4 at Week 12 0.5 h post-dose	65.0 mg/L Standard Deviation 37.92
Concentration of Plasma Complement C4 at Week 12 1 h post-dose	41.4 mg/L Standard Deviation 13.79
Concentration of Plasma Complement C4 at Week 12 2 h post-dose	67.5 mg/L Standard Deviation 40.19
Concentration of Plasma Complement C4 at Week 12 6 h post-dose	91.1 mg/L Standard Deviation 49.98
Concentration of Plasma Complement C4 at Week 12 24 h post-dose	104 mg/L Standard Deviation 53.35
Concentration of Plasma Complement C4 at Week 12 48 h post-dose	99.3 mg/L Standard Deviation 50.65

PRIMARY outcome

Timeframe: Baseline (Week 1)

Population: PD set included all participants with evaluable PD profiles.

Concentration of plasma complement C1q was reported.

Outcome measures

Measure	CINRYZE 1000 U n=8 Participants Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Concentration of Plasma Complement C1q at Week 1	78.50 International units per milliliter Standard Deviation 36.598

PRIMARY outcome

Timeframe: Baseline up to Week 12

Population: Full analysis set (FAS) included all participants who had at least 1 post-baseline efficacy assessment.

Angioedema attack was defined as any participant-reported (or caregiver-reported) indication of swelling or pain at any location following a report of no swelling or pain on the previous day (that is, there must have been a full symptom-free calendar day preceding the onset of symptoms for an attack to be considered a new attack). NNA was calculated as the overall number of angioedema attacks recorded during the period divided by the number of days in the period and multiplied by 30.4.Number of attacks was normalized for the number of days participants participated in a given period and expressed as the monthly frequency as compared to the historical data where, NNA was the number of angioedema attacks during 3 months prior to study drug administration. Historical data was obtained from medical or angioedema history electronic case report forms (eCRF).

Outcome measures

Measure	CINRYZE 1000 U n=8 Participants Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Normalized Number of Angioedema Attacks (NNA) Per Month Historical	3.375 Angioedema attacks per month Standard Deviation 2.5225
Normalized Number of Angioedema Attacks (NNA) Per Month CINRYZE Treatment	1.826 Angioedema attacks per month Standard Deviation 1.5031

PRIMARY outcome

Timeframe: Baseline up to Week 12

Population: FAS included all participants who had at least 1 post-baseline efficacy assessment.

Anatomic locations where there was a presence of pain or swelling of any level of severity; mild, moderate or severe at any day during the attack were reported. Mild: the attack symptoms were noticeable but were easily tolerated by the participant and did not interfere with the participant's daily activities. Moderate: the attack symptoms interfered with the participant's ability to attend work/school or participate in family life and social/recreational activities and severe: the attack symptoms significantly limited the participant's ability to attend work/school or participate in family life and social/recreational activities. Number of participants with angioedema attacks in different anatomic locations in treatment period was compared to NNA for historical data. Historical data was based on the typical location of angioedema attacks in the 3 months prior to study drug administration. Here, H refers to historical and T refers to treatment.

Outcome measures

Measure	CINRYZE 1000 U n=8 Participants Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Number of Participants With Angioedema Attacks in Different Anatomic Locations Abdominal/Gastrointestinal: H	7 Participants
Number of Participants With Angioedema Attacks in Different Anatomic Locations Abdominal/Gastrointestinal: T	3 Participants
Number of Participants With Angioedema Attacks in Different Anatomic Locations Cutaneous - Facial: H	3 Participants
Number of Participants With Angioedema Attacks in Different Anatomic Locations Cutaneous - Facial: T	2 Participants
Number of Participants With Angioedema Attacks in Different Anatomic Locations Cutaneous - Extremity or Peripheral: H	6 Participants
Number of Participants With Angioedema Attacks in Different Anatomic Locations Cutaneous - Extremity or Peripheral: T	6 Participants
Number of Participants With Angioedema Attacks in Different Anatomic Locations Genital/Urinary (Includes scrotum or vulva): H	2 Participants
Number of Participants With Angioedema Attacks in Different Anatomic Locations Genital/Urinary (Includes scrotum or vulva): T	4 Participants
Number of Participants With Angioedema Attacks in Different Anatomic Locations Upper Airway (includes laryngeal or pharyngeal): H	2 Participants
Number of Participants With Angioedema Attacks in Different Anatomic Locations Upper Airway (includes laryngeal or pharyngeal):T	1 Participants

PRIMARY outcome

Timeframe: Baseline up to Week 12

Population: FAS included all participants who had at least 1 postbaseline efficacy assessment.

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 participant to any swelling location on any day during the attack. The average severity was derived by dividing the cumulative severity score by the total number of attacks. Average severity was set to 0 if there was no attack in a period. Average severity of angioedema attacks in treatment period compared to the NNA of angioedema attacks for historical data was reported. Historical data was based on the typical severity of angioedema attacks in the 3 months prior to study drug administration. Historical data was obtained from medical or angioedema history electronic case report forms (eCRF).

Outcome measures

Measure	CINRYZE 1000 U n=8 Participants Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Average Severity (Intensity) of Angioedema Attacks Historical	1.875 Units on a scale Standard Deviation 0.8345
Average Severity (Intensity) of Angioedema Attacks CINRYZE Treatment	0.970 Units on a scale Standard Deviation 0.6441

PRIMARY outcome

Timeframe: Baseline up to Week 12

Population: FAS included all participants who had at least 1 post-baseline efficacy assessment.

Average duration of attacks was calculated by dividing the cumulative duration of attacks by the total number of attacks during the treatment period. Historical data was based on the typical severity of angioedema attacks in the 3 months prior to study drug administration. Average duration of angioedema attacks in treatment period was compared to the NNA for historical data. Historical data was obtained from medical or angioedema history eCRF.

Outcome measures

Measure	CINRYZE 1000 U n=8 Participants Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Average Duration of Angioedema Attacks Historical	2.250 Days Standard Deviation 1.0351
Average Duration of Angioedema Attacks CINRYZE Treatment	1.941 Days Standard Deviation 2.0630

PRIMARY outcome

Timeframe: Baseline up to Week 12

Population: FAS included all participants who had at least 1 post-baseline efficacy assessment.

The normalized number of angioedema attacks was calculated as the overall number of angioedema attacks recorded during the period divided by the number of days in the period and multiplied by 30.4. NNA treated with rescue medications were reported for CINRYZE, non-CINRYZE C1-INH or not treated with C1-INH (including attacks treated with any medications other than C1-INH or untreated attacks). CINRYZE was only considered as a rescue medication when treated for breakthrough attack treatment. For historical data, only medications taken prior to the start of drug study drug administration and had an indication of "hereditary angioedema (HAE) management - acute treatment" selected on the prior and concomitant medications and therapy were considered as rescue medications. Historical data was obtained from medical or angioedema history eCRF.

Outcome measures

Measure	CINRYZE 1000 U n=8 Participants Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Normalized Number of Angioedema Attacks (NNA) Per Month Treated With Rescue Medication Historical Data	1.750 Angioedema attacks per month Standard Deviation 2.2660
Normalized Number of Angioedema Attacks (NNA) Per Month Treated With Rescue Medication CINRYZE Treatment	0.477 Angioedema attacks per month Standard Deviation 0.8411

PRIMARY outcome

Timeframe: Baseline up to Week 12

Population: FAS included all participants who had at least 1 post-baseline efficacy assessment.

Number of participants achieving at least 50 percent (%), 70% or 90% reduction in NNA relative to NNA for historical data was reported.

Outcome measures

Measure	CINRYZE 1000 U n=8 Participants Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Number of Participants Achieving Clinical Responder Rate Relative to Historical Data Achieving >= 90% reduction in NNA	2 Participants
Number of Participants Achieving Clinical Responder Rate Relative to Historical Data Achieving >= 50% reduction in NNA	4 Participants
Number of Participants Achieving Clinical Responder Rate Relative to Historical Data Achieving >= 70% reduction in NNA	3 Participants

PRIMARY outcome

Timeframe: Baseline, Week 12

Population: FAS included all participants who had at least 1 post-baseline efficacy assessment.

Angioedema quality of life (AE-QoL) questionnaire was a self-administered validated angioedema disease-specific quality of life instrument. It consisted of 17 specific questions that were associated with work, physical activity, free time, social relations, and diet. Each of the 17 items had a 5-point response scale ranging from 1 (Never) to 5 (Very Often). The questionnaire was scored according to the developers' guidelines to produce a total score and 4 domain scores (functioning, fatigue/mood, fear/shame, nutrition). Raw domain scores (mean of the item scores within each scale) and the raw total score (mean of all item scores) were rescaled using linear transformations into final percentage scores ranging 0 to 100, based on the maximum possible score, where the higher the score the greater the QoL impairment.

Outcome measures

Measure	CINRYZE 1000 U n=8 Participants Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Change From Baseline in Angioedema Quality of Life (AE-QoL) in Treatment Period Total Score (Baseline)	28.3 Score on a scale Standard Deviation 12.79
Change From Baseline in Angioedema Quality of Life (AE-QoL) in Treatment Period Total Score (Change from baseline)	-9.0 Score on a scale Standard Deviation 16.72
Change From Baseline in Angioedema Quality of Life (AE-QoL) in Treatment Period Functioning (Baseline)	16.4 Score on a scale Standard Deviation 11.54
Change From Baseline in Angioedema Quality of Life (AE-QoL) in Treatment Period Functioning (Change from baseline)	-2.3 Score on a scale Standard Deviation 22.39
Change From Baseline in Angioedema Quality of Life (AE-QoL) in Treatment Period Fatigue/Mood (Baseline)	18.8 Score on a scale Standard Deviation 19.59
Change From Baseline in Angioedema Quality of Life (AE-QoL) in Treatment Period Fatigue/Mood (Change from baseline)	-9.4 Score on a scale Standard Deviation 14.00
Change From Baseline in Angioedema Quality of Life (AE-QoL) in Treatment Period Fears/Shame (Baseline)	49.5 Score on a scale Standard Deviation 21.76
Change From Baseline in Angioedema Quality of Life (AE-QoL) in Treatment Period Fears/Shame (Change from baseline)	-14.1 Score on a scale Standard Deviation 21.12
Change From Baseline in Angioedema Quality of Life (AE-QoL) in Treatment Period Nutrition (Baseline)	12.5 Score on a scale Standard Deviation 16.37
Change From Baseline in Angioedema Quality of Life (AE-QoL) in Treatment Period Nutrition (Change from baseline)	-6.3 Score on a scale Standard Deviation 24.09

PRIMARY outcome

Timeframe: Baseline up to Week 12

Population: FAS included all participants who had at least 1 post-baseline efficacy assessment. Number of participants evaluable for this outcome measure was reported.

A breakthrough attack was defined as an angioedema attack that occurs during long-term prevention therapy with CINRYZE (that is, between first study drug and last study drug dose). Number of participants with 1, 2, 3 or more angioedema attacks and who achieved initial improvement and complete resolution were also reported. Breakthrough angioedema attacks assessed by CINRYZE treatment, non-CINRYZE C1 INH treatment and untreated with C1-INH were reported. Here BAA refers to breakthrough angioedema attacks.

Outcome measures

Measure	CINRYZE 1000 U n=8 Participants Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Number of Participants With Breakthrough Angioedema Attacks Treated (CINRYZE)	2 Participants
Number of Participants With Breakthrough Angioedema Attacks Treated (NON-CINRYZE C1 INH)	1 Participants
Number of Participants With Breakthrough Angioedema Attacks Untreated	6 Participants
Number of Participants With Breakthrough Angioedema Attacks Treated (CINRYZE): One BAA	1 Participants
Number of Participants With Breakthrough Angioedema Attacks Treated (CINRYZE): Two BAA	0 Participants
Number of Participants With Breakthrough Angioedema Attacks Treated (CINRYZE): Three BAA	1 Participants
Number of Participants With Breakthrough Angioedema Attacks Treated (NON-CINRYZE C1 INH): One BAA	0 Participants
Number of Participants With Breakthrough Angioedema Attacks Treated (NON-CINRYZE C1 INH): Two BAA	0 Participants
Number of Participants With Breakthrough Angioedema Attacks Treated (NON-CINRYZE C1 INH): Three BAA	1 Participants
Number of Participants With Breakthrough Angioedema Attacks Untreated: One BAA	1 Participants
Number of Participants With Breakthrough Angioedema Attacks Untreated: Two BAA	0 Participants
Number of Participants With Breakthrough Angioedema Attacks Untreated: Three BAA	5 Participants
Number of Participants With Breakthrough Angioedema Attacks Treated (CINRYZE): Initial improvement	2 Participants
Number of Participants With Breakthrough Angioedema Attacks Treated (NON-CINRYZE C1 INH): Initial improvement	1 Participants
Number of Participants With Breakthrough Angioedema Attacks Untreated: Initial improvement	6 Participants
Number of Participants With Breakthrough Angioedema Attacks Treated (CINRYZE): Complete resolution	2 Participants
Number of Participants With Breakthrough Angioedema Attacks Treated (NON-CINRYZE C1 INH): Complete resolution	1 Participants
Number of Participants With Breakthrough Angioedema Attacks Untreated: Complete resolution	6 Participants

PRIMARY outcome

Timeframe: Baseline up to Week 12

Population: FAS included all participants who had at least 1 post-baseline efficacy assessment. Number of participants evaluable for this outcome were reported.

Time to initial improvement (TII) was calculated from the time of study drug administration to initial symptom improvement. Time to complete resolution was defined as the time from the onset of attack to complete resolution of all symptoms. Time to initial improvement and time to complete resolution as assessed by CINRYZE, non-CINRYZE and untreated were reported.

Outcome measures

Measure	CINRYZE 1000 U n=8 Participants Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Time From Attack Onset to Initial Improvement and Complete Resolution Untreated: Complete resolution	61.83 Hours Interval 11.0 to 152.0
Time From Attack Onset to Initial Improvement and Complete Resolution Treated (CINRYZE): TII	13.38 Hours Interval 4.25 to 22.5
Time From Attack Onset to Initial Improvement and Complete Resolution Treated (NON-CINRYZE): TII	6.42 Hours 95% confidence interval lower and upper limits was not calculated due to insufficient number of participants.
Time From Attack Onset to Initial Improvement and Complete Resolution Untreated: TII	10.75 Hours Interval 8.75 to 118.0
Time From Attack Onset to Initial Improvement and Complete Resolution Treated (CINRYZE): Complete resolution	40.67 Hours Interval 23.834 to 57.5
Time From Attack Onset to Initial Improvement and Complete Resolution Treated (NON-CINRYZE): Complete resolution	9.00 Hours 95% confidence interval lower and upper limits was not calculated due to insufficient number of participants.

PRIMARY outcome

Timeframe: Baseline up to Week 12

Population: FAS included all participants who had at least 1 postbaseline efficacy assessment.

The median time from onset of attack to time treated with CINRYZE was reported.

Outcome measures

Measure	CINRYZE 1000 U n=8 Participants Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Time From Onset of Attack to Time Treated by CINRYZE	11.97 Hours Interval 3.05 to 20.884

PRIMARY outcome

Timeframe: Baseline up to Week 12

Population: FAS included all participants who had at least 1 post-baseline efficacy assessment.

Time to initial improvement was calculated from the time of study drug administration to initial symptom improvement. Median time from treatment with CINRYZE to initial improvement was reported.

Outcome measures

Measure	CINRYZE 1000 U n=8 Participants Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Time From Treatment With CINRYZE to Initial Improvement	1.41 Hours Interval 1.2 to 1.617

Adverse Events

CINRYZE 1000 U

Serious events: 2 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Measure	CINRYZE 1000 U n=8 participants at risk Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Congenital, familial and genetic disorders Hereditary angioedema	12.5% 1/8 • Number of events 1 • From start of study drug administration up to Week 12
Cardiac disorders Acute myocardial infarction	12.5% 1/8 • Number of events 1 • From start of study drug administration up to Week 12

Other adverse events

Measure	CINRYZE 1000 U n=8 participants at risk Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Musculoskeletal and connective tissue disorders Arthralgia	25.0% 2/8 • Number of events 2 • From start of study drug administration up to Week 12
Musculoskeletal and connective tissue disorders Intervertebral disc disorder	12.5% 1/8 • Number of events 1 • From start of study drug administration up to Week 12
Gastrointestinal disorders Abdominal pain	12.5% 1/8 • Number of events 1 • From start of study drug administration up to Week 12
Gastrointestinal disorders Constipation	12.5% 1/8 • Number of events 1 • From start of study drug administration up to Week 12
General disorders Chest pain	12.5% 1/8 • Number of events 1 • From start of study drug administration up to Week 12
General disorders Injection site pain	12.5% 1/8 • Number of events 3 • From start of study drug administration up to Week 12
Immune system disorders Seasonal allergy	12.5% 1/8 • Number of events 1 • From start of study drug administration up to Week 12
Infections and infestations Herpes virus infection	12.5% 1/8 • Number of events 2 • From start of study drug administration up to Week 12
Infections and infestations Nasopharyngitis	37.5% 3/8 • Number of events 4 • From start of study drug administration up to Week 12
Injury, poisoning and procedural complications Arthropod bite	12.5% 1/8 • Number of events 1 • From start of study drug administration up to Week 12
Injury, poisoning and procedural complications Ligament sprain	12.5% 1/8 • Number of events 1 • From start of study drug administration up to Week 12
Metabolism and nutrition disorders Diabetes mellitus	12.5% 1/8 • Number of events 1 • From start of study drug administration up to Week 12
Nervous system disorders Cervicobrachial syndrome	12.5% 1/8 • Number of events 1 • From start of study drug administration up to Week 12
Nervous system disorders Headache	25.0% 2/8 • Number of events 3 • From start of study drug administration up to Week 12
Nervous system disorders Somnolence	12.5% 1/8 • Number of events 1 • From start of study drug administration up to Week 12
Product Issues Device failure	12.5% 1/8 • Number of events 1 • From start of study drug administration up to Week 12
Reproductive system and breast disorders Breast disorder	12.5% 1/8 • Number of events 1 • From start of study drug administration up to Week 12
Respiratory, thoracic and mediastinal disorders Cough	12.5% 1/8 • Number of events 1 • From start of study drug administration up to Week 12
Skin and subcutaneous tissue disorders Eczema	12.5% 1/8 • Number of events 1 • From start of study drug administration up to Week 12

Additional Information

Study Director

Shire

Phone: +1 866 842 5335

Email: ClinicalTransparency@shire.com

Results disclosure agreements

• Principal investigator is a sponsor employee If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.
• Publication restrictions are in place

Restriction type: OTHER