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

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

The objectives of the study were:

1. To assess the safety and tolerability of escalating doses of CINRYZE.
2. To assess the effect of an escalating dose algorithm for CINRYZE on hereditary angioedema (HAE) attack rates.
3. To assess the immunogenicity of CINRYZE.

Study Overview

• Status: Completed
• Conditions: Hereditary Angioedema
• Intervention / Treatment: Biological: C1 inhibitor (human) [C1 INH]

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85251
      • Allergy, Asthma and Immunology Associates
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Family Allergy and Asthma Center
  • Maryland
    • Wheaton, Maryland, United States, 20902
      • Institute for Asthma and Allergy
  • New York
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Medical Center
  • Oregon
    • Eugene, Oregon, United States, 97401
      • Allergy and Asthma Research Group
    • Lake Oswego, Oregon, United States, 97035
      • Baker Allergy, Asthma and Dermatology Research Center
  • Tennessee
    • Knoxville, Tennessee, United States, 37909
      • East Tennessee Center for Clinical Research
  • Texas
    • Bryan, Texas, United States, 77802
    • Dallas, Texas, United States, 75231
      • AARA Research Center
  • Washington
    • Spokane, Washington, United States, 99204
      • Marycliff Allergy Specialist

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

To be eligible for this protocol, subjects must:

1. Be ≥6 years of age and ≥25 kg body weight.

2. 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)
3. 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.

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

   OR

5. 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:

1. 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.
2. Have a history of abnormal blood clotting or other coagulopathy.
3. Be taking prescription anticoagulant medication.
4. Have a history of allergic reaction to CINRYZE or other blood products.
5. Have participated in any other investigational drug study within the past 30 days (other than CINRYZE protocols).
6. Have received any blood products (other than CINRYZE) within 60 days prior to screening.

7. 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
8. Be pregnant or breastfeeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CINRYZE; 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]; Other Names: C1 esterase inhibitor (human); CINRYZE

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Shire

Study record dates

Study Major Dates

• Study Start (Actual): August 31, 2009
• Primary Completion (Actual): May 24, 2012
• Study Completion (Actual): May 24, 2012

Study Registration Dates

• First Submitted: June 3, 2009
• First Submitted That Met QC Criteria: June 4, 2009
• First Posted (Estimate): June 5, 2009

Study Record Updates

• Last Update Posted (Actual): June 23, 2021
• Last Update Submitted That Met QC Criteria: June 17, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Hypersensitivity, Immediate; Genetic Diseases, Inborn; Skin Diseases, Vascular; Hypersensitivity; Urticaria; Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Angioedema; Angioedemas, Hereditary; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Complement C1 Inhibitor Protein; Complement C1 Inactivator Proteins; Complement C1s
• Other Study ID Numbers: 0624-400; SHP616-400 (Other Identifier: Sponsor)