A Study to Evaluate the Safety and Effect of Escalating Doses of CINRYZE

Study Overview
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Brief Summary
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The objectives of the study were: To assess the safety and tolerability of escalating doses of CINRYZE. To assess the effect of an escalating dose algorithm for CINRYZE on hereditary angioedema (HAE) attack rates. To assess the immunogenicity of CINRYZE.

Detailed Description
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Qualifying subjects entered a 3-step dose escalation algorithm: Step 1: 1500 Units twice per week (starting dosing regimen for all subjects in the study) Step 2: 2000 Units twice per week Step 3: 2500 Units twice per week Each step consisted of 12 weeks of safety monitoring, followed by calculation of average monthly angioedema attack rate based on subject reports of angioedema symptoms (regardless of intensity) and actual duration of therapy for that step. If a subject was deemed a success at a given step and the investigator and medical monitor determined that it was safe for the subject to continue on that dose, the subject entered a 3 month follow-up period at that dose level with continued safety monitoring. The subject could not re-enter the study for purposes of dose escalation during the follow-up period. If a subject was not deemed a success, the subject initiated the next highest step of the dose escalation algorithm provided that the investigator and medical monitor agreed that dose escalation was appropriate. If at the end of Step 3 (2500 Units), a subject was not deemed a success, then the Week 12 visit represented study completion and the subject was referred to the physician who manages their HAE care.

Official Title
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A Phase 4 Study to Evaluate the Safety and Effect of Escalating Doses of CINRYZE® (C1 Inhibitor [Human]) as Prophylactic Therapy in Subjects With Inadequately Controlled Hereditary Angioedema Attacks

Conditions
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Hereditary Angioedema

Intervention / Treatment
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* Biological: C1 inhibitor (human) [C1 INH]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible for this protocol, subjects must: Be ≥6 years of age and ≥25 kg body weight. Have a confirmed diagnosis of HAE with a documented history of swelling of the face, extremities, gastrointestinal tract, genitalia, or larynx and a history of at least one of the following: C1 INH gene mutation C4 level below the lower limit of the reference range C1 INH antigen level below the lower limit of the reference range Functional C1 INH level below the lower limit of the reference range Family history of HAE (i.e., grandparent, parent, sibling) Have a history of >1.0 HAE attack per month (average) of any severity during the 3 consecutive months prior to screening while receiving the recommended CINRYZE dosing of 1000 Units every 3 to 4 days via intravenous injection. 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, have a parent/legal guardian who is willing and able to provide written informed consent for the child to participate in the study (with assent from the child when appropriate). Exclusion Criteria: To be eligible for this protocol, subjects must not: 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. Have a history of abnormal blood clotting or other coagulopathy. Be taking prescription anticoagulant medication. Have a history of allergic reaction to CINRYZE or other blood products. Have participated in any other investigational drug study within the past 30 days (other than CINRYZE protocols). Have received any blood products (other than CINRYZE) within 60 days prior to screening. Have any of the following laboratory values at screening: Hemoglobin <8 g/dL White blood cell count <2 x 10^9/L or >20 x 10^9/L Platelet count <50 x 10^9/L or >400 x 10^9/L Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >2.0 x the upper limit of normal Blood urea nitrogen and/or creatinine >2.0 x the upper limit of normal Be pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CINRYZE<br>There were 3 potential dose escalation steps: Step 1: 1500 Units of CINRYZE (C1 inhibitor [human]) administered by IV infusion twice per week for 12 weeks Step 2: 2000 Units of CINRYZE (C1 inhibitor [human]) administered by IV infusion twice per week for 12 weeks Step 3: 2500 Units of CINRYZE (C1 inhibitor [human]) administered by IV infusion twice per week for 12 weeks | Biological: C1 inhibitor (human) [C1 INH]<br> <br> * Other names: C1 esterase inhibitor (human);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Adverse Events, Hospitalizations, Thrombotic Events, Treatment-emergent C1 INH Antibodies, Post-baseline Toxicity Grade Increases in Clinical Laboratory Parameters, and Post-dose Vital Signs Changes of Potential Clinical Importance | Events reported during the 3 month follow-up period are counted with the dose level at which they occurred. | 12 to 24 weeks at each dose level | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Effect of Escalating Doses of CINRYZE on HAE Attack Rates | Two definitions of success were applied in this study: 1) Per-protocol success - Average angioedema attack rate of ≤1.0 per month at the end of any dose escalation step (Week 12). The a priori definition of study success was 4 or more subjects with per-protocol success. 2) Investigator-determined success - Based on the investigator's clinical judgment, an average monthly angioedema attack rate demonstrating improvement sufficient for progression to follow-up. In addition, subjects who were not a per-protocol or investigator-determined success, but who experienced a reduction of >1.0 attack per month from their historical angioedema attack rate at the end of any dose escalation step (Week 12), were summarized. | 12 weeks at each dose level |