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

• Sponsor: Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02865720
• Collaborator: (none)
• Enrollment: 8
• Locations: 10
• Arms: 2
• Actual Duration (Months): 9.5
• Patients Per Site: 0.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if an investigational treatment is safe and well tolerated when administered by intravenous (IV) infusion in Japanese subjects with HAE.

Condition or Disease	Intervention/Treatment	Phase
Hereditary Angioedema (HAE)	Drug: CINRYZE 500 U; Drug: CINRYZE 1000 U	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Open-label, Single-period Study to Evaluate the Safety and Treatment Effect of Intravenous Administration of C1 Inhibitor (Human) for the Prevention of Angioedema Attacks and Treatment of Breakthrough Attacks in Japanese Subjects With Hereditary Angioedema (HAE)
• Actual Study Start Date: Sep 8, 2016
• Actual Primary Completion Date: Jun 23, 2017
• Actual Study Completion Date: Jun 23, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Subjects 2 to 5 years of age 500 U of CINRYZE will be administered by IV infusion twice weekly for 12 weeks	Drug: CINRYZE 500 U; IV infusion administered twice weekly
Experimental: Subjects 6 years of age and older 1000 U of CINRYZE will be administered by IV infusion twice weekly for 12 weeks.	Drug: CINRYZE 1000 U; IV infusion administered twice weekly

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment-emergent Adverse Events (TEAEs) [From start of study drug administration up to Week 12]

   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.

2. Number of Participants With Clinically Significant Abnormalities in Physical Examination Reported as Adverse Events (AEs) [From start of study drug administration up to Week 12]

   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.

3. Number of Participants With Potentially Clinically Important (PCI) Vital Signs Reported as Adverse Events (AEs) [Baseline up to Week 12]

   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.

4. Number of Participants With Potentially Clinically Important (PCI) Clinical Laboratory Assessments Reported as Adverse Events (AEs) [Baseline up to Week 12]

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

5. Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 1 [Week 1: Pre-dose, 0.5, 1, 2, 6, 24, 48, 72 and 96 hours (h) post-dose]

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

6. Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 12 [Week 12: Pre-dose, 0.5, 1, 2, 6, 24, 48, 72 and 96 h post-dose]

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

7. Concentration of Plasma Complement C4 at Week 1 [Week 1: Pre-dose, 0.5, 1, 2, 6, 24, 48, 72 and 96 h post-dose]

   Concentration of plasma complement C4 was reported.

8. Concentration of Plasma Complement C4 at Week 12 [Week 12: Pre-dose, 0.5, 1, 2, 6, 24, 48, 72 and 96 h post-dose]

   Concentration of plasma complement C4 was reported.

9. Concentration of Plasma Complement C1q at Week 1 [Baseline (Week 1)]

   Concentration of plasma complement C1q was reported.

10. Normalized Number of Angioedema Attacks (NNA) Per Month [Baseline up to Week 12]

    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).

11. Number of Participants With Angioedema Attacks in Different Anatomic Locations [Baseline up to Week 12]

    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.

12. Average Severity (Intensity) of Angioedema Attacks [Baseline up to Week 12]

    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).

13. Average Duration of Angioedema Attacks [Baseline up to Week 12]

    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.

14. Normalized Number of Angioedema Attacks (NNA) Per Month Treated With Rescue Medication [Baseline up to Week 12]

    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.

15. Number of Participants Achieving Clinical Responder Rate Relative to Historical Data [Baseline up to Week 12]

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

16. Change From Baseline in Angioedema Quality of Life (AE-QoL) in Treatment Period [Baseline, Week 12]

    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.

17. Number of Participants With Breakthrough Angioedema Attacks [Baseline up to Week 12]

    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.

18. Time From Attack Onset to Initial Improvement and Complete Resolution [Baseline up to Week 12]

    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.

19. Time From Onset of Attack to Time Treated by CINRYZE [Baseline up to Week 12]

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

20. Time From Treatment With CINRYZE to Initial Improvement [Baseline up to Week 12]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Be of Japanese descent, defined as born in Japan and having Japanese parents and Japanese maternal and paternal grandparents.

2. Be ≥2 years of age.

3. Meet the following minimum body weight criteria:

• Subjects 2 to 5 years of age must weigh at least 12.5 kg; and

• Subjects 6 years of age and above must weigh at least 25 kg.

1. Have a confirmed diagnosis of Type I or Type II HAE. NOTE: Diagnosis may be based on historical data including family history, clinical symptoms (characteristic attacks), or documentation of low level of C1 INH protein and/or C1 INH activity.

2. Have a history of at least one angioedema attack per month (on average) during the 3 consecutive months immediately before enrollment.

3. Agree to adhere to the protocol-defined schedule of assessments and procedures.

4. Agree to avoid his/her known angioedema attack triggers during the study to the best of his/her ability.

5. If a female of reproductive age, be postmenopausal (≥12 months following cessation of menstruation), surgically sterile, or following an acceptable method of birth control (and agree to continue its use through 1 month after the last dose of study drug):

• Non-hormonal methods (eg, abstinence, barrier control) for at least 1 complete menstrual cycle before the Screening Visit.

• Stable doses of estrogen and/or progestin containing products for at least 2 months before the Screening Visit.

1. If a male of reproductive age, be surgically sterile or agree to follow an acceptable method of birth control (eg, abstinence, barrier control) from the Screening Visit through 2 months after the last dose of study drug.

2. If an adult, be informed of the nature of the study and provide written informed consent before any study-specific procedures are performed.

OR If a child or minor (<20 years of age), have a parent/legal guardian who is informed of the nature of the study provide written informed consent (ie, permission) for the child to participate in the study before any study-specific procedures are performed. Assent will be obtained from children ≥14 years of age.

Exclusion Criteria:

1. Have a history of hypercoagulability (abnormal blood clotting).

2. Have a diagnosis of acquired angioedema or be known to have C1 INH antibodies.

3. Have a history of allergic reaction to C1 INH products, including CINRYZE (or any of the components of CINRYZE) or other blood products.

4. Have received C1 INH therapy or any blood products within 3 days before the first dose of study drug.

5. Have had signs or symptoms of an angioedema attack within 2 days before the first dose of study drug.

6. Have any change (start, stop, or change in dose) in androgen therapy (eg, danazol, oxandrolone, stanozolol, testosterone), tranexamic acid, epsilon-aminocaproic acid (EACA), or other antifibrinolytics within 14 days before the first dose of study drug.

7. If female, have started taking or changed the dose of any hormonal contraceptive regimen or hormone replacement therapy (eg, estrogen/progestin containing products) within 2 months before the first dose of study drug.

8. Be pregnant or breastfeeding.

9. Have received an investigational drug other than those required for prevention or treatment of angioedema attacks within 30 days before the first dose of study drug.

10. Have, as determined by the Investigator and/or the Sponsor's Medical Monitor, any surgical or medical condition that could interfere with the administration of study drug or interpretation of study results.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Toyohashi Municipal Hospital	Toyohashi	Aiti	Japan	441-8570
2	Gunma University Hospital	Maebashi	Gunma	Japan	371-8511
3	Kobe University Hospital	Kobe	Hyogo	Japan	650-0017
4	Heart Life Hospital	Nakagusuku	Nakagami	Japan	901-2417
5	Naha City Hospital	Naha	Okinawa	Japan	902-8511
6	Shiman University Hospital	Izumo	Shimane	Japan	693-8501
7	Asahi General Hospital	Asahi	Tiba	Japan	289-2511
8	Adachi kyosai Hospital	Adachi	Tokyo	Japan	120-0022
9	Hiroshima University Hospital	Hiroshima		Japan	734-8551
10	Tomakomai City Hospital	Tomakomai		Japan	053-8567

Sponsors and Collaborators

• Shire

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

• Study Protocol - Aug 30, 2016
• Statistical Analysis Plan - Jul 21, 2017

More Information

Publications

None provided.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT02865720
• Other Study ID Numbers: SHP616-209; 0624-209
• First Posted: Aug 12, 2016
• Last Update Posted: Jun 2, 2021
• Last Verified: May 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Angioedema; Angioedemas, Hereditary; Complement C1 Inhibitor Protein

Study Results

Participant Flow

Recruitment Details	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).
Pre-assignment Detail	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.

Arm/Group Title	CINRYZE 500 U	CINRYZE 1000 U
Arm/Group Description	Participants received 500 U CINRYZE intravenous (IV) injection twice weekly for 12 weeks.	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Period Title: Overall Study
STARTED	0	8
COMPLETED	0	8
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	CINRYZE 500 U	CINRYZE 1000 U	Total
Arm/Group Description	Participants received 500 U CINRYZE IV injection twice weekly for 12 weeks.	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.	Total of all reporting groups
Overall Participants	0	8	8
Age (year) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [year]	38.4 (7.27)	38.4 (7.27)
Sex: Female, Male (Count of Participants)
Female	6 Infinity	6 75%
Male	2 Infinity	2 25%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 NaN	0 0%
Not Hispanic or Latino	8 Infinity	8 100%
Unknown or Not Reported	0 NaN	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 NaN	0 0%
Asian	8 Infinity	8 100%
Native Hawaiian or Other Pacific Islander	0 NaN	0 0%
Black or African American	0 NaN	0 0%
White	0 NaN	0 0%
More than one race	0 NaN	0 0%
Unknown or Not Reported	0 NaN	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Description	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.
Time Frame	From start of study drug administration up to Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CINRYZE 1000 U
Arm/Group Description	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Measure Participants	8
Count of Participants [Participants]	7 Infinity

2. Primary Outcome

Title	Number of Participants With Clinically Significant Abnormalities in Physical Examination Reported as Adverse Events (AEs)
Description	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.
Time Frame	From start of study drug administration up to Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CINRYZE 1000 U
Arm/Group Description	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Measure Participants	8
Count of Participants [Participants]	0 NaN

3. Primary Outcome

Title	Number of Participants With Potentially Clinically Important (PCI) Vital Signs Reported as Adverse Events (AEs)
Description	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.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CINRYZE 1000 U
Arm/Group Description	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Measure Participants	8
Count of Participants [Participants]	0 NaN

4. Primary Outcome

Title	Number of Participants With Potentially Clinically Important (PCI) Clinical Laboratory Assessments Reported as Adverse Events (AEs)
Description	Number of participants with potentially clinically important (PCI) clinical laboratory assessments reported as adverse events were reported.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CINRYZE 1000 U
Arm/Group Description	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Measure Participants	8
Count of Participants [Participants]	0 NaN

5. Primary Outcome

Title	Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 1
Description	C1 INH antigen concentration in plasma was determined using an automated nephelometric assay.
Time Frame	Week 1: Pre-dose, 0.5, 1, 2, 6, 24, 48, 72 and 96 hours (h) post-dose

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CINRYZE 1000U
Arm/Group Description	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Measure Participants	8
Pre-dose	0.0581 (0.04877)
0.5 h post-dose	0.1463 (0.04210)
1 h post-dose	0.1426 (0.05795)
2 h post-dose	0.1436 (0.04524)
6 h post-dose	0.1413 (0.04376)
24 h post-dose	0.1147 (0.03825)
48 h post-dose	0.0978 (0.04204)
72 h post-dose	0.0881 (0.04133)
96 h post-dose	0.0680 (NA)

6. Primary Outcome

Title	Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 12
Description	C1 INH antigen concentration in plasma was determined using an automated nephelometric assay.
Time Frame	Week 12: Pre-dose, 0.5, 1, 2, 6, 24, 48, 72 and 96 h post-dose

Outcome Measure Data

Analysis Population Description

PK set included all participants with evaluable PK profiles.

Arm/Group Title	CINRYZE 1000 U
Arm/Group Description	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Measure Participants	8
Pre-dose	0.0775 (0.04904)
0.5 h post-dose	0.1660 (0.04159)
1 h post-dose	0.1468 (0.03232)
2 h post-dose	0.1634 (0.04500)
6 h post-dose	0.1573 (0.03978)
24 h post-dose	0.1244 (0.04675)
48 h post-dose	0.1003 (0.05030)
72 h post-dose	0.0836 (0.05169)
96 h post-dose	0.0661 (0.05163)

7. Primary Outcome

Title	Concentration of Plasma Complement C4 at Week 1
Description	Concentration of plasma complement C4 was reported.
Time Frame	Week 1: Pre-dose, 0.5, 1, 2, 6, 24, 48, 72 and 96 h post-dose

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CINRYZE 1000 U
Arm/Group Description	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Measure Participants	8
Pre-dose	42.8 (20.42)
0.5 h post-dose	37.5 (17.55)
1 h post-dose	32.7 (18.17)
2 h post-dose	43.3 (19.48)
6 h post-dose	69.0 (29.70)
24 h post-dose	89.0 (33.80)
48 h post-dose	82.5 (36.00)
72 h post-dose	80.5 (41.34)
96 h post-dose	67.0 (NA)

8. Primary Outcome

Title	Concentration of Plasma Complement C4 at Week 12
Description	Concentration of plasma complement C4 was reported.
Time Frame	Week 12: Pre-dose, 0.5, 1, 2, 6, 24, 48, 72 and 96 h post-dose

Outcome Measure Data

Analysis Population Description

PD set included all participants with evaluable PD profiles.

Arm/Group Title	CINRYZE 1000 U
Arm/Group Description	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Measure Participants	8
Pre-dose	77.9 (37.79)
0.5 h post-dose	65.0 (37.92)
1 h post-dose	41.4 (13.79)
2 h post-dose	67.5 (40.19)
6 h post-dose	91.1 (49.98)
24 h post-dose	104 (53.35)
48 h post-dose	99.3 (50.65)
72 h post-dose	77.9 (47.39)
96 h post-dose	63.2 (37.06)

9. Primary Outcome

Title	Concentration of Plasma Complement C1q at Week 1
Description	Concentration of plasma complement C1q was reported.
Time Frame	Baseline (Week 1)

Outcome Measure Data

Analysis Population Description

PD set included all participants with evaluable PD profiles.

Arm/Group Title	CINRYZE 1000 U
Arm/Group Description	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Measure Participants	8
Mean (Standard Deviation) [International units per milliliter]	78.50 (36.598)

10. Primary Outcome

Title	Normalized Number of Angioedema Attacks (NNA) Per Month
Description	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).
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CINRYZE 1000 U
Arm/Group Description	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Measure Participants	8
Historical	3.375 (2.5225)
CINRYZE Treatment	1.826 (1.5031)

11. Primary Outcome

Title	Number of Participants With Angioedema Attacks in Different Anatomic Locations
Description	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.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CINRYZE 1000 U
Arm/Group Description	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Measure Participants	8
Abdominal/Gastrointestinal: H	7 Infinity
Abdominal/Gastrointestinal: T	3 Infinity
Cutaneous - Facial: H	3 Infinity
Cutaneous - Facial: T	2 Infinity
Cutaneous - Extremity or Peripheral: H	6 Infinity
Cutaneous - Extremity or Peripheral: T	6 Infinity
Genital/Urinary (Includes scrotum or vulva): H	2 Infinity
Genital/Urinary (Includes scrotum or vulva): T	4 Infinity
Upper Airway (includes laryngeal or pharyngeal): H	2 Infinity
Upper Airway (includes laryngeal or pharyngeal):T	1 Infinity

12. Primary Outcome

Title	Average Severity (Intensity) of Angioedema Attacks
Description	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).
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CINRYZE 1000 U
Arm/Group Description	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Measure Participants	8
Historical	1.875 (0.8345)
CINRYZE Treatment	0.970 (0.6441)

13. Primary Outcome

Title	Average Duration of Angioedema Attacks
Description	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.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CINRYZE 1000 U
Arm/Group Description	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Measure Participants	8
Historical	2.250 (1.0351)
CINRYZE Treatment	1.941 (2.0630)

14. Primary Outcome

Title	Normalized Number of Angioedema Attacks (NNA) Per Month Treated With Rescue Medication
Description	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.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CINRYZE 1000 U
Arm/Group Description	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Measure Participants	8
Historical Data	1.750 (2.2660)
CINRYZE Treatment	0.477 (0.8411)

15. Primary Outcome

Title	Number of Participants Achieving Clinical Responder Rate Relative to Historical Data
Description	Number of participants achieving at least 50 percent (%), 70% or 90% reduction in NNA relative to NNA for historical data was reported.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CINRYZE 1000 U
Arm/Group Description	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Measure Participants	8
Achieving >= 50% reduction in NNA	4 Infinity
Achieving >= 70% reduction in NNA	3 Infinity
Achieving >= 90% reduction in NNA	2 Infinity

16. Primary Outcome

Title	Change From Baseline in Angioedema Quality of Life (AE-QoL) in Treatment Period
Description	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.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CINRYZE 1000 U
Arm/Group Description	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Measure Participants	8
Total Score (Baseline)	28.3 (12.79)
Total Score (Change from baseline)	-9.0 (16.72)
Functioning (Baseline)	16.4 (11.54)
Functioning (Change from baseline)	-2.3 (22.39)
Fatigue/Mood (Baseline)	18.8 (19.59)
Fatigue/Mood (Change from baseline)	-9.4 (14.00)
Fears/Shame (Baseline)	49.5 (21.76)
Fears/Shame (Change from baseline)	-14.1 (21.12)
Nutrition (Baseline)	12.5 (16.37)
Nutrition (Change from baseline)	-6.3 (24.09)

17. Primary Outcome

Title	Number of Participants With Breakthrough Angioedema Attacks
Description	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.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CINRYZE 1000 U
Arm/Group Description	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Measure Participants	8
Treated (CINRYZE)	2 Infinity
Treated (NON-CINRYZE C1 INH)	1 Infinity
Untreated	6 Infinity
Treated (CINRYZE): One BAA	1 Infinity
Treated (CINRYZE): Two BAA	0 NaN
Treated (CINRYZE): Three BAA	1 Infinity
Treated (NON-CINRYZE C1 INH): One BAA	0 NaN
Treated (NON-CINRYZE C1 INH): Two BAA	0 NaN
Treated (NON-CINRYZE C1 INH): Three BAA	1 Infinity
Untreated: One BAA	1 Infinity
Untreated: Two BAA	0 NaN
Untreated: Three BAA	5 Infinity
Treated (CINRYZE): Initial improvement	2 Infinity
Treated (NON-CINRYZE C1 INH): Initial improvement	1 Infinity
Untreated: Initial improvement	6 Infinity
Treated (CINRYZE): Complete resolution	2 Infinity
Treated (NON-CINRYZE C1 INH): Complete resolution	1 Infinity
Untreated: Complete resolution	6 Infinity

18. Primary Outcome

Title	Time From Attack Onset to Initial Improvement and Complete Resolution
Description	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.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CINRYZE 1000 U
Arm/Group Description	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Measure Participants	8
Treated (CINRYZE): TII	13.38
Treated (NON-CINRYZE): TII	6.42
Untreated: TII	10.75
Treated (CINRYZE): Complete resolution	40.67
Treated (NON-CINRYZE): Complete resolution	9.00
Untreated: Complete resolution	61.83

19. Primary Outcome

Title	Time From Onset of Attack to Time Treated by CINRYZE
Description	The median time from onset of attack to time treated with CINRYZE was reported.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CINRYZE 1000 U
Arm/Group Description	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Measure Participants	8
Median (95% Confidence Interval) [Hours]	11.97

20. Primary Outcome

Title	Time From Treatment With CINRYZE to Initial Improvement
Description	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.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	CINRYZE 1000 U
Arm/Group Description	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
Measure Participants	8
Median (95% Confidence Interval) [Hours]	1.41

Adverse Events

Time Frame	From start of study drug administration up to Week 12
Arm/Group Title	CINRYZE 1000 U
Arm/Group Description	Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks.
All Cause Mortality
	CINRYZE 1000 U
	Affected / at Risk (%)	# Events
Total	0/8 (0%)
Serious Adverse Events
	CINRYZE 1000 U
	Affected / at Risk (%)	# Events
Total	2/8 (25%)
Cardiac disorders
Acute myocardial infarction	1/8 (12.5%)	1
Congenital, familial and genetic disorders
Hereditary angioedema	1/8 (12.5%)	1
Other (Not Including Serious) Adverse Events
	CINRYZE 1000 U
	Affected / at Risk (%)	# Events
Total	7/8 (87.5%)
Gastrointestinal disorders
Abdominal pain	1/8 (12.5%)	1
Constipation	1/8 (12.5%)	1
General disorders
Chest pain	1/8 (12.5%)	1
Injection site pain	1/8 (12.5%)	3
Immune system disorders
Seasonal allergy	1/8 (12.5%)	1
Infections and infestations
Herpes virus infection	1/8 (12.5%)	2
Nasopharyngitis	3/8 (37.5%)	4
Injury, poisoning and procedural complications
Arthropod bite	1/8 (12.5%)	1
Ligament sprain	1/8 (12.5%)	1
Metabolism and nutrition disorders
Diabetes mellitus	1/8 (12.5%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	2/8 (25%)	2
Intervertebral disc disorder	1/8 (12.5%)	1
Nervous system disorders
Cervicobrachial syndrome	1/8 (12.5%)	1
Headache	2/8 (25%)	3
Somnolence	1/8 (12.5%)	1
Product Issues
Device failure	1/8 (12.5%)	1
Reproductive system and breast disorders
Breast disorder	1/8 (12.5%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/8 (12.5%)	1
Skin and subcutaneous tissue disorders
Eczema	1/8 (12.5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.