Safety and Efficacy Study of CINRYZE for Prevention of Angioedema Attacks in Children Ages 6-11 With Hereditary Angioedema

Study Overview
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Brief Summary
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Primary Objective - To assess the relative efficacy of two dose levels of CINRYZE (500 Units and 1000 Units) administered by intravenous (IV) injection every 3 or 4 days to prevent angioedema attacks in children 6 to 11 years of age with hereditary angioedema (HAE). Secondary Objectives - To assess the safety and tolerability, characterize the pharmacokinetics (PK) and pharmacodynamics (PD), and assess the immunogenicity of two dose levels of CINRYZE administered by IV injection in children 6 to 11 years of age with HAE.

Official Title
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A Phase 3, Multicenter, Randomized, Single-Blind, Dose-Ranging, Crossover Study to Evaluate the Safety and Efficacy of Intravenous Administration of CINRYZE® (C1 Esterase Inhibitor [Human]) for the Prevention of Angioedema Attacks in Children 6 to 11 Years of Age With Hereditary Angioedema

Conditions
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Hereditary Angioedema (HAE)

Intervention / Treatment
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* Biological: CINRYZE 500
* Biological: CINRYZE 1000


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Type I or Type II HAE. History of angioedema attacks. Exclusion Criteria: History of bleeding or clotting abnormality. Diagnosis of acquired angioedema or known to have C1 INH antibodies. History of allergic reaction to C1 esterase inhibitor or other blood products. Receipt of any experimental agents other than those required for prevention or treatment of angioedema attacks within 30 days prior to screening.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 11 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
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 500/1000<br>500 Units of CINRYZE administered by IV injection twice per week for 12 weeks followed by 1000 Units of CINRYZE administered by IV injection twice per week for 12 weeks | Biological: CINRYZE 500<br>* 500 Units of CINRYZE administered by IV injection<br>Biological: CINRYZE 1000<br>* 1000 Units of CINRYZE administered by IV injection<br>|
| Experimental: 1000/500<br>1000 Units of CINRYZE administered by IV injection twice per week for 12 weeks followed by 500 Units of CINRYZE administered by IV injection twice per week for 12 weeks | Biological: CINRYZE 500<br>* 500 Units of CINRYZE administered by IV injection<br>Biological: CINRYZE 1000<br>* 1000 Units of CINRYZE administered by IV injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Normalized Number of Angioedema Attacks Per Month in a Treatment Period | Angioedema attack was defined as the participant-reported indication of symptoms or signs such as swelling or pain at any location following a report of no swelling or pain on the previous day. Manifestations of an attack that progress from one site to another, prior to complete resolution, was considered a single attack. Attacks that began to regress and then worsened before complete resolution was also considered one attack. Attacks that began then appeared to resolve and then reappeared without a symptom-free calendar day reported after the appearance of resolution were considered 1 attack. Any events of swelling due to trauma or symmetrical nonpainful swelling of the lower extremities were not considered an angioedema attack. The number of attacks was normalized for the number of days participants participated in a given period and expressed as the monthly frequency. | From start of treatment up to 12 weeks during each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Attack-severity Score of Angioedema Attacks Normalized Per Month in a Treatment Period | Severity of the angioedema attack sign/symptom was characterized as None: no symptom; Mild: noticeable symptom but easily tolerated by the participant and did not interfere with routine activities; Moderate: symptom interfered with the participant's ability to attend school or participate in family life and social/recreational activities; Severe: symptom significantly limited the participant's ability to attend school or participate in family life and social/recreational activities. Symptom severity score was assigned as Mild = 1, Moderate = 2 and Severe = 3. Cumulative attack severity score was the sum of the maximum symptom severity scores recorded for each angioedema attack in a treatment period. Cumulative attack-severity score normalized per month [(raw score/number of days of participation in that treatment period)*30.4] was reported here. Cumulative attack-severity score normalized per month ranged from 0 to 10.4 and higher scores represent worse symptoms. | From start of treatment up to 12 weeks during each treatment period | 
| Cumulative Daily-severity Score of Angioedema Attacks Normalized Per Month in a Treatment Period | Severity of the angioedema attack sign/symptom was characterized as None: no symptom; Mild: noticeable but easily tolerated by the participant and did not interfere with routine activities; Moderate: interfered with the participant's ability to attend school or participate in family life and social/recreational activities; Severe: significantly limited the participant's ability to attend school or participate in family life and social/recreational activities. Symptom severity score was assigned as Mild = 1, Moderate = 2 and Severe = 3. Cumulative daily-severity score was the sum of the severity scores recorded for every day of reported symptoms in a treatment period. Cumulative daily-severity score normalized per month [(raw score/number of days of participation in that treatment period)*30.4] was reported here. Cumulative daily-severity score normalized per month ranged from 0 to 15.6 and higher scores represent worse symptoms. | From start of treatment up to 12 weeks during each intervention period | 
| Normalized Number of Angioedema Attacks Per Month Requiring Acute Treatment in a Treatment Period | Angioedema attack was defined as the participant-reported indication of symptoms or signs such as swelling or pain at any location following a report of no swelling or pain on the previous day. Manifestations of an attack that progress from one site to another, prior to complete resolution, was considered a single attack. Attacks that began to regress and then worsened before complete resolution was also considered one attack. Attacks that began then appeared to resolve and then reappeared without a symptom-free calendar day reported after the appearance of resolution were considered 1 attack. Any events of swelling due to trauma or symmetrical nonpainful swelling of the lower extremities were not considered an angioedema attack. The number of attacks requiring acute treatment was normalized for the number of days participants participated in a given period and expressed as the monthly frequency. | From start of treatment up to 12 weeks during each intervention period | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) by Dose Group | An adverse event (AE) was any untoward, undesired, unplanned clinical event in the form of signs, symptoms, disease, or laboratory or physiological observations occurring in a participant participating in a clinical study with the sponsor's product, regardless of causal relationship. TEAEs were defined as events that started or worsened on or after the date and time of the first dose of investigational product and up to 7 days after the last dose of investigational product. | From start of study treatment up to 25 weeks | 
| Plasma Concentration of C1 Esterase Inhibitor (C1 INH) Antigen | C1 INH antigen concentration in plasma was determined using an automated nephelometric assay. | Pre-dose and 1 hour (h) post-dose at Week 1 (Dose 1) and Week 6 (Dose 12); Pre-dose, 1, 2, 4 and 8 h post-dose at Week 12 (Dose 24) of each intervention period | 
| C1 Esterase Inhibitor (C1 INH) Functional Activity in Plasma | The functional activity of C1 INH in plasma samples was determined by a chromogenic assay. | Pre-dose and 1 h post-dose at Week 1 (Dose 1) and Week 6 (Dose 12); Pre-dose, 1, 2, 4 and 8 h post-dose at Week 12 (Dose 24) of each intervention period | 
| Plasma Concentration of Complement C4 | Concentration of Complement C4 in plasma was determined using an automated nephelometric assay. | Pre-dose and 1 h post-dose at Week 1 (Dose 1) and Week 6 (Dose 12); Pre-dose, 1, 2, 4 and 8 h post-dose at Week 12 (Dose 24) of each intervention period | 
| Number of Participants With C1 Esterase Inhibitor (C1 INH) Antibodies in Plasma | The presence of C1 INH antibodies in plasma samples was determined using a proprietary enzyme-linked-immunosorbent-assay. Number of participants with C1 INH Antibodies was reported. | Pre-dose, 1 week post treatment (Week 13, Week 25) and 1 month post treatment follow-up (Week 28) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cinryze, Pediatric, C1 inhibitor, HAE, C1 INH, Prevention