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

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ClinicalTrials.gov Identifier: NCT02052141
Recruitment Status : Completed
First Posted : January 31, 2014
Results First Posted : August 28, 2018
Last Update Posted : December 12, 2018
Sponsor:
Information provided by (Responsible Party):
Shire

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Hereditary Angioedema (HAE) Biological: CINRYZE 500 Biological: CINRYZE 1000 Phase 3

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Primary Purpose: Prevention
Official Title: 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
Actual Study Start Date : March 20, 2014
Actual Primary Completion Date : May 4, 2017
Actual Study Completion Date : May 4, 2017


Arm Intervention/treatment
Experimental: 500/1000
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
500 Units of CINRYZE administered by IV injection

Biological: CINRYZE 1000
1000 Units of CINRYZE administered by IV injection

Experimental: 1000/500
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
500 Units of CINRYZE administered by IV injection

Biological: CINRYZE 1000
1000 Units of CINRYZE administered by IV injection




Primary Outcome Measures :
  1. Normalized Number of Angioedema Attacks Per Month in a Treatment Period [ Time Frame: From start of treatment up to 12 weeks during each 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.


Secondary Outcome Measures :
  1. Cumulative Attack-severity Score of Angioedema Attacks Normalized Per Month in a Treatment Period [ Time Frame: From start of treatment up to 12 weeks during each 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.

  2. Cumulative Daily-severity Score of Angioedema Attacks Normalized Per Month in a Treatment Period [ Time Frame: From start of treatment up to 12 weeks during each intervention 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.

  3. Normalized Number of Angioedema Attacks Per Month Requiring Acute Treatment in a Treatment Period [ Time Frame: From start of treatment up to 12 weeks during each intervention 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.

  4. Number of Participants With Treatment-emergent Adverse Events (TEAEs) by Dose Group [ Time Frame: From start of study treatment up to 25 weeks ]
    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.

  5. Plasma Concentration of C1 Esterase Inhibitor (C1 INH) Antigen [ Time Frame: 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 INH antigen concentration in plasma was determined using an automated nephelometric assay.

  6. C1 Esterase Inhibitor (C1 INH) Functional Activity in Plasma [ Time Frame: 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 ]
    The functional activity of C1 INH in plasma samples was determined by a chromogenic assay.

  7. Plasma Concentration of Complement C4 [ Time Frame: 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 ]
    Concentration of Complement C4 in plasma was determined using an automated nephelometric assay.

  8. Number of Participants With C1 Esterase Inhibitor (C1 INH) Antibodies in Plasma [ Time Frame: Pre-dose, 1 week post treatment (Week 13, Week 25) and 1 month post treatment follow-up (Week 28) ]
    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.



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Ages Eligible for Study:   6 Years to 11 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02052141


Locations
United States, Colorado
Asthma and Allergy Associates, P.C
Colorado Springs, Colorado, United States, 80907
United States, Nevada
Nevada Access to Research and Education Society
Las Vegas, Nevada, United States, 89106
United States, Oregon
Oregon Allergy Associates
Eugene, Oregon, United States, 97401
Germany
Klinikum der J.W. Goethe Universitat
Frankfurt, Germany, 60590
HZRM Hamophilie Zentrum Rhein Main GmbH
Mörfelden-Walldorf, Germany, 64546
Israel
Tel Aviv Sourasky Medical Center
Tel Aviv, Israel, 64239
Mexico
Instituto Nacional de Pediatria
Mexico City, Mexico, 04530
Romania
Clinical County Hospital Mures
Targu-Mures, Romania, 540072
Sponsors and Collaborators
Shire
Investigators
Study Director: Study Director Shire
  Study Documents (Full-Text)

Documents provided by Shire:
Study Protocol  [PDF] January 26, 2015
Statistical Analysis Plan  [PDF] May 25, 2017


Publications of Results:
Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT02052141     History of Changes
Other Study ID Numbers: 0624-301
2013-002453-29 ( EudraCT Number )
SHP616-301 ( Other Identifier: Shire )
First Posted: January 31, 2014    Key Record Dates
Results First Posted: August 28, 2018
Last Update Posted: December 12, 2018
Last Verified: November 2018

Keywords provided by Shire:
Pediatric
C1 inhibitor
HAE
Cinryze
C1 INH
Prevention

Additional relevant MeSH terms:
Angioedemas, Hereditary
Angioedema
Vascular Diseases
Cardiovascular Diseases
Urticaria
Skin Diseases, Vascular
Skin Diseases
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Genetic Diseases, Inborn
Complement C1 Inhibitor Protein
Complement C1 Inactivator Proteins
Complement Inactivating Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs