Hereditary Angioedema (HAE)
Conditions
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.
Interventions
DRUGCINRYZE 500 U
IV infusion administered twice weekly
DRUGCINRYZE 1000 U
IV infusion administered twice weekly
Sponsors
Shire
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
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. 4. 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. 5. Have a history of at least one angioedema attack per month (on average) during the 3 consecutive months immediately before enrollment. 6. Agree to adhere to the protocol-defined schedule of assessments and procedures. 7. Agree to avoid his/her known angioedema attack triggers during the study to the best of his/her ability. 8. 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. 9. 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. 10. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| Concentration of Plasma Complement C1q at Week 1 | Baseline (Week 1) | Concentration of plasma complement C1q was reported. |
| 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). |
| 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. |
| 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). |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Japan
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| CINRYZE 500 U Participants received 500 U CINRYZE IV injection twice weekly for 12 weeks. | 0 |
| CINRYZE 1000 U Participants received 1000 U CINRYZE IV injection twice weekly for 12 weeks. | 8 |
| Total | 8 |
Baseline characteristics
| Characteristic | Total | CINRYZE 1000 U |
|---|---|---|
| Age, Continuous | 38.4 year STANDARD_DEVIATION 7.27 | 38.4 year STANDARD_DEVIATION 7.27 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 8 |
| other Total, other adverse events | 7 / 8 |
| serious Total, serious adverse events | 2 / 8 |
Outcome results
Primary
Average Duration of Angioedema Attacks
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
Population: FAS included all participants who had at least 1 post-baseline efficacy assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CINRYZE 1000 U | Average Duration of Angioedema Attacks | CINRYZE Treatment | 1.941 Days | Standard Deviation 2.063 |
| CINRYZE 1000 U | Average Duration of Angioedema Attacks | Historical | 2.250 Days | Standard Deviation 1.0351 |
Primary
Average Severity (Intensity) of Angioedema Attacks
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
Population: FAS included all participants who had at least 1 postbaseline efficacy assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CINRYZE 1000 U | Average Severity (Intensity) of Angioedema Attacks | Historical | 1.875 Units on a scale | Standard Deviation 0.8345 |
| CINRYZE 1000 U | Average Severity (Intensity) of Angioedema Attacks | CINRYZE Treatment | 0.970 Units on a scale | Standard Deviation 0.6441 |
Primary
Change From Baseline in Angioedema Quality of Life (AE-QoL) in Treatment Period
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
Population: FAS included all participants who had at least 1 post-baseline efficacy assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | 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
Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 1
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
Population: Pharmacokinetic (PK) set included all participants with evaluable PK profiles.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | 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 0.0421 |
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 1 | 96 h post-dose | 0.0680 Gram per liter (g/L) | — |
Primary
Concentration of C1 Esterase Inhibitor (C1 INH) Antigen (Protein Volume) at Week 12
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
Population: PK set included all participants with evaluable PK profiles.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | 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 0.045 |
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | 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 0.0503 |
| CINRYZE 1000 U | 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 |
| CINRYZE 1000 U | 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
Concentration of Plasma Complement C1q at Week 1
Concentration of plasma complement C1q was reported.
Time frame: Baseline (Week 1)
Population: PD set included all participants with evaluable PD profiles.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CINRYZE 1000 U | Concentration of Plasma Complement C1q at Week 1 | 78.50 International units per milliliter | Standard Deviation 36.598 |
Primary
Concentration of Plasma Complement C4 at Week 1
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
Population: Pharmacodynamic (PD) set included all participants with evaluable PD profiles.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CINRYZE 1000 U | Concentration of Plasma Complement C4 at Week 1 | Pre-dose | 42.8 Milligram per liter (mg/L) | Standard Deviation 20.42 |
| CINRYZE 1000 U | Concentration of Plasma Complement C4 at Week 1 | 0.5 h post-dose | 37.5 Milligram per liter (mg/L) | Standard Deviation 17.55 |
| CINRYZE 1000 U | Concentration of Plasma Complement C4 at Week 1 | 1 h post-dose | 32.7 Milligram per liter (mg/L) | Standard Deviation 18.17 |
| CINRYZE 1000 U | Concentration of Plasma Complement C4 at Week 1 | 2 h post-dose | 43.3 Milligram per liter (mg/L) | Standard Deviation 19.48 |
| CINRYZE 1000 U | Concentration of Plasma Complement C4 at Week 1 | 6 h post-dose | 69.0 Milligram per liter (mg/L) | Standard Deviation 29.7 |
| CINRYZE 1000 U | Concentration of Plasma Complement C4 at Week 1 | 24 h post-dose | 89.0 Milligram per liter (mg/L) | Standard Deviation 33.8 |
| CINRYZE 1000 U | Concentration of Plasma Complement C4 at Week 1 | 48 h post-dose | 82.5 Milligram per liter (mg/L) | Standard Deviation 36 |
| CINRYZE 1000 U | Concentration of Plasma Complement C4 at Week 1 | 72 h post-dose | 80.5 Milligram per liter (mg/L) | Standard Deviation 41.34 |
| CINRYZE 1000 U | Concentration of Plasma Complement C4 at Week 1 | 96 h post-dose | 67.0 Milligram per liter (mg/L) | — |
Primary
Concentration of Plasma Complement C4 at Week 12
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
Population: PD set included all participants with evaluable PD profiles.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CINRYZE 1000 U | Concentration of Plasma Complement C4 at Week 12 | 48 h post-dose | 99.3 mg/L | Standard Deviation 50.65 |
| CINRYZE 1000 U | Concentration of Plasma Complement C4 at Week 12 | 72 h post-dose | 77.9 mg/L | Standard Deviation 47.39 |
| CINRYZE 1000 U | Concentration of Plasma Complement C4 at Week 12 | Pre-dose | 77.9 mg/L | Standard Deviation 37.79 |
| CINRYZE 1000 U | Concentration of Plasma Complement C4 at Week 12 | 0.5 h post-dose | 65.0 mg/L | Standard Deviation 37.92 |
| CINRYZE 1000 U | Concentration of Plasma Complement C4 at Week 12 | 1 h post-dose | 41.4 mg/L | Standard Deviation 13.79 |
| CINRYZE 1000 U | Concentration of Plasma Complement C4 at Week 12 | 2 h post-dose | 67.5 mg/L | Standard Deviation 40.19 |
| CINRYZE 1000 U | Concentration of Plasma Complement C4 at Week 12 | 6 h post-dose | 91.1 mg/L | Standard Deviation 49.98 |
| CINRYZE 1000 U | Concentration of Plasma Complement C4 at Week 12 | 24 h post-dose | 104 mg/L | Standard Deviation 53.35 |
| CINRYZE 1000 U | Concentration of Plasma Complement C4 at Week 12 | 96 h post-dose | 63.2 mg/L | Standard Deviation 37.06 |
Primary
Normalized Number of Angioedema Attacks (NNA) Per Month
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
Population: Full analysis set (FAS) included all participants who had at least 1 post-baseline efficacy assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CINRYZE 1000 U | Normalized Number of Angioedema Attacks (NNA) Per Month | Historical | 3.375 Angioedema attacks per month | Standard Deviation 2.5225 |
| CINRYZE 1000 U | Normalized Number of Angioedema Attacks (NNA) Per Month | CINRYZE Treatment | 1.826 Angioedema attacks per month | Standard Deviation 1.5031 |
Primary
Normalized Number of Angioedema Attacks (NNA) Per Month Treated With Rescue Medication
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
Population: FAS included all participants who had at least 1 post-baseline efficacy assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CINRYZE 1000 U | Normalized Number of Angioedema Attacks (NNA) Per Month Treated With Rescue Medication | Historical Data | 1.750 Angioedema attacks per month | Standard Deviation 2.266 |
| CINRYZE 1000 U | 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
Number of Participants Achieving Clinical Responder Rate Relative to Historical Data
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
Population: FAS included all participants who had at least 1 post-baseline efficacy assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CINRYZE 1000 U | Number of Participants Achieving Clinical Responder Rate Relative to Historical Data | Achieving >= 70% reduction in NNA | 3 Participants |
| CINRYZE 1000 U | Number of Participants Achieving Clinical Responder Rate Relative to Historical Data | Achieving >= 50% reduction in NNA | 4 Participants |
| CINRYZE 1000 U | Number of Participants Achieving Clinical Responder Rate Relative to Historical Data | Achieving >= 90% reduction in NNA | 2 Participants |
Primary
Number of Participants With Angioedema Attacks in Different Anatomic Locations
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
Population: FAS included all participants who had at least 1 post-baseline efficacy assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CINRYZE 1000 U | Number of Participants With Angioedema Attacks in Different Anatomic Locations | Abdominal/Gastrointestinal: H | 7 Participants |
| CINRYZE 1000 U | Number of Participants With Angioedema Attacks in Different Anatomic Locations | Abdominal/Gastrointestinal: T | 3 Participants |
| CINRYZE 1000 U | Number of Participants With Angioedema Attacks in Different Anatomic Locations | Cutaneous - Facial: H | 3 Participants |
| CINRYZE 1000 U | Number of Participants With Angioedema Attacks in Different Anatomic Locations | Cutaneous - Facial: T | 2 Participants |
| CINRYZE 1000 U | Number of Participants With Angioedema Attacks in Different Anatomic Locations | Cutaneous - Extremity or Peripheral: H | 6 Participants |
| CINRYZE 1000 U | Number of Participants With Angioedema Attacks in Different Anatomic Locations | Cutaneous - Extremity or Peripheral: T | 6 Participants |
| CINRYZE 1000 U | Number of Participants With Angioedema Attacks in Different Anatomic Locations | Genital/Urinary (Includes scrotum or vulva): H | 2 Participants |
| CINRYZE 1000 U | Number of Participants With Angioedema Attacks in Different Anatomic Locations | Genital/Urinary (Includes scrotum or vulva): T | 4 Participants |
| CINRYZE 1000 U | Number of Participants With Angioedema Attacks in Different Anatomic Locations | Upper Airway (includes laryngeal or pharyngeal): H | 2 Participants |
| CINRYZE 1000 U | Number of Participants With Angioedema Attacks in Different Anatomic Locations | Upper Airway (includes laryngeal or pharyngeal):T | 1 Participants |
Primary
Number of Participants With Breakthrough Angioedema Attacks
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
Population: FAS included all participants who had at least 1 post-baseline efficacy assessment. Number of participants evaluable for this outcome measure was reported.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CINRYZE 1000 U | Number of Participants With Breakthrough Angioedema Attacks | Treated (CINRYZE) | 2 Participants |
| CINRYZE 1000 U | Number of Participants With Breakthrough Angioedema Attacks | Treated (NON-CINRYZE C1 INH) | 1 Participants |
| CINRYZE 1000 U | Number of Participants With Breakthrough Angioedema Attacks | Untreated | 6 Participants |
| CINRYZE 1000 U | Number of Participants With Breakthrough Angioedema Attacks | Treated (CINRYZE): One BAA | 1 Participants |
| CINRYZE 1000 U | Number of Participants With Breakthrough Angioedema Attacks | Treated (CINRYZE): Two BAA | 0 Participants |
| CINRYZE 1000 U | Number of Participants With Breakthrough Angioedema Attacks | Treated (CINRYZE): Three BAA | 1 Participants |
| CINRYZE 1000 U | Number of Participants With Breakthrough Angioedema Attacks | Treated (NON-CINRYZE C1 INH): One BAA | 0 Participants |
| CINRYZE 1000 U | Number of Participants With Breakthrough Angioedema Attacks | Treated (NON-CINRYZE C1 INH): Two BAA | 0 Participants |
| CINRYZE 1000 U | Number of Participants With Breakthrough Angioedema Attacks | Treated (NON-CINRYZE C1 INH): Three BAA | 1 Participants |
| CINRYZE 1000 U | Number of Participants With Breakthrough Angioedema Attacks | Untreated: One BAA | 1 Participants |
| CINRYZE 1000 U | Number of Participants With Breakthrough Angioedema Attacks | Untreated: Two BAA | 0 Participants |
| CINRYZE 1000 U | Number of Participants With Breakthrough Angioedema Attacks | Untreated: Three BAA | 5 Participants |
| CINRYZE 1000 U | Number of Participants With Breakthrough Angioedema Attacks | Treated (CINRYZE): Initial improvement | 2 Participants |
| CINRYZE 1000 U | Number of Participants With Breakthrough Angioedema Attacks | Treated (NON-CINRYZE C1 INH): Initial improvement | 1 Participants |
| CINRYZE 1000 U | Number of Participants With Breakthrough Angioedema Attacks | Untreated: Initial improvement | 6 Participants |
| CINRYZE 1000 U | Number of Participants With Breakthrough Angioedema Attacks | Treated (CINRYZE): Complete resolution | 2 Participants |
| CINRYZE 1000 U | Number of Participants With Breakthrough Angioedema Attacks | Treated (NON-CINRYZE C1 INH): Complete resolution | 1 Participants |
| CINRYZE 1000 U | Number of Participants With Breakthrough Angioedema Attacks | Untreated: Complete resolution | 6 Participants |
Primary
Number of Participants With Clinically Significant Abnormalities in Physical Examination Reported as Adverse Events (AEs)
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
Population: ITT-S set included participants who received any amount of investigational product.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CINRYZE 1000 U | Number of Participants With Clinically Significant Abnormalities in Physical Examination Reported as Adverse Events (AEs) | 0 Participants |
Primary
Number of Participants With Potentially Clinically Important (PCI) Clinical Laboratory Assessments Reported as Adverse Events (AEs)
Number of participants with potentially clinically important (PCI) clinical laboratory assessments reported as adverse events were reported.
Time frame: Baseline up to Week 12
Population: ITT-S set included participants who received any amount of investigational product.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CINRYZE 1000 U | Number of Participants With Potentially Clinically Important (PCI) Clinical Laboratory Assessments Reported as Adverse Events (AEs) | 0 Participants |
Primary
Number of Participants With Potentially Clinically Important (PCI) Vital Signs Reported as Adverse Events (AEs)
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
Population: ITT-S set included participants who received any amount of investigational product.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CINRYZE 1000 U | Number of Participants With Potentially Clinically Important (PCI) Vital Signs Reported as Adverse Events (AEs) | 0 Participants |
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
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
Population: ITT-S set included participants who received any amount of investigational product.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CINRYZE 1000 U | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 7 Participants |
Primary
Time From Attack Onset to Initial Improvement and Complete Resolution
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
Population: FAS included all participants who had at least 1 post-baseline efficacy assessment. Number of participants evaluable for this outcome were reported.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| CINRYZE 1000 U | Time From Attack Onset to Initial Improvement and Complete Resolution | Treated (CINRYZE): TII | 13.38 Hours |
| CINRYZE 1000 U | Time From Attack Onset to Initial Improvement and Complete Resolution | Treated (NON-CINRYZE): TII | 6.42 Hours |
| CINRYZE 1000 U | Time From Attack Onset to Initial Improvement and Complete Resolution | Untreated: TII | 10.75 Hours |
| CINRYZE 1000 U | Time From Attack Onset to Initial Improvement and Complete Resolution | Treated (CINRYZE): Complete resolution | 40.67 Hours |
| CINRYZE 1000 U | Time From Attack Onset to Initial Improvement and Complete Resolution | Treated (NON-CINRYZE): Complete resolution | 9.00 Hours |
| CINRYZE 1000 U | Time From Attack Onset to Initial Improvement and Complete Resolution | Untreated: Complete resolution | 61.83 Hours |
Primary
Time From Onset of Attack to Time Treated by CINRYZE
The median time from onset of attack to time treated with CINRYZE was reported.
Time frame: Baseline up to Week 12
Population: FAS included all participants who had at least 1 postbaseline efficacy assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CINRYZE 1000 U | Time From Onset of Attack to Time Treated by CINRYZE | 11.97 Hours |
Primary
Time From Treatment With CINRYZE to Initial Improvement
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
Population: FAS included all participants who had at least 1 post-baseline efficacy assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CINRYZE 1000 U | Time From Treatment With CINRYZE to Initial Improvement | 1.41 Hours |