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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, Multicenter, Dose-Ranging, Crossover Study to Evaluate the Safety and Efficacy of Subcutaneous Administration of CINRYZE® (C1 Esterase Inhibitor [Human]) With Recombinant Human Hyaluronidase (rHuPH20) for the Prevention of Angioedema Attacks in Adolescents and Adults With Hereditary Angioedema

    Summary
    EudraCT number
    2012-000083-24
    Trial protocol
    HU   ES   DE   SE  
    Global end of trial date
    13 Sep 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Sep 2018
    First version publication date
    14 Jun 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    0624-206
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01756157
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shire Development LLC
    Sponsor organisation address
    735 Chesterbrook Boulevard Wayne, Pennsylvania, United States, 19087
    Public contact
    Danielle Tierens, Shire, +32 27917629,
    Scientific contact
    Danielle Tierens, Shire, +32 27917629,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Sep 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Sep 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    1. To evaluate the efficacy of 1000 units (U) and 2000 U doses of CINRYZE (C1 Esterase Inhibitor [Human]) With Recombinant Human Hyaluronidase (rHuPH20) administered by subcutaneous (SC) injection to prevent angiodema attacks. 2. To assess the safety and tolerability of CINRYZE with rHuPH20 administered by SC injection.
    Protection of trial subjects
    The study was performed in accordance with the ethical principles stated in the Declaration of Helsinki and the International Conference on Harmonisation (ICH) Tripartite Guideline for Good Clinical Practice (GCP). Prior to the initiation of any study procedures, the investigators obtained written informed consent from each subject or the assent of the child or minor and written informed consent (permission) from the parent/legal guardian.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Feb 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United States: 36
    Worldwide total number of subjects
    47
    EEA total number of subjects
    11
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    45
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted at 24 sites (United States=20, Europe=4) between 04 February 2013 (first subject dosed) and 13 September 2013 (last subject contact). Of 52 screened subjects, 47 were randomized and treated. The reasons for screen failure were violation of eligibility criteria by 4 subjects and consent withdrawal by 1 subject.

    Pre-assignment
    Screening details
    Due to emergence of, and unexpected incidence and titer of, non-neutralizing anti-rHuPH20 antibodies in some subjects after administration of CINRYZE+rHuPH20, sponsor decided to stop dosing subjects with rHuPH20 and thus close the study. However, the study was completed with collection of safety data as outlined in the protocol.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Treatment sequence A/B
    Arm description
    Subjects received Treatment A in Period 1 and Treatment B in Period 2, as a single 20 milliliter (mL) SC injection per dose. Treatment A: 1000 U CINRYZE with 24,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks. Treatment B: 2000 U CINRYZE with 48,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks. A washout period of at least 7 days and no more than 30 days was maintained between the last dose in Period 1 and the first dose in Period 2.
    Arm type
    Experimental

    Investigational medicinal product name
    rHuPH20
    Investigational medicinal product code
    Other name
    Recombinant human hyaluronidase
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Treatment A in Period 1 and Treatment B in Period 2, as a single 20 mL SC injection per dose. Treatment A: 1000 U CINRYZE with 24,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks. Treatment B: 2000 U CINRYZE with 48,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks.

    Investigational medicinal product name
    CINRYZE
    Investigational medicinal product code
    Other name
    C1 esterase inhibitor (human)
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Treatment A in Period 1 and Treatment B in Period 2, as a single 20 mL SC injection per dose. Treatment A: 1000 U CINRYZE with 24,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks. Treatment B: 2000 U CINRYZE with 48,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks.

    Arm title
    Treatment sequence B/A
    Arm description
    Subjects received Treatment B in Period 1 and Treatment A in Period 2, as a single 20 mL SC injection per dose. Treatment B: 2000 U CINRYZE with 48,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks. Treatment A: 1000 U CINRYZE with 24,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks. A washout period of at least 7 days and no more than 30 days was maintained between the last dose in Period 1 and the first dose in Period 2.
    Arm type
    Experimental

    Investigational medicinal product name
    CINRYZE
    Investigational medicinal product code
    Other name
    C1 esterase inhibitor (human)
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Treatment B in Period 1 and Treatment A in Period 2, as a single 20 mL SC injection per dose. Treatment B: 2000 U CINRYZE with 48,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks. Treatment A: 1000 U CINRYZE with 24,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks.

    Investigational medicinal product name
    rHuPH20
    Investigational medicinal product code
    Other name
    Recombinant human hyaluronidase
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Treatment B in Period 1 and Treatment A in Period 2, as a single 20 mL SC injection per dose. Treatment B: 2000 U CINRYZE with 48,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks. Treatment A: 1000 U CINRYZE with 24,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks.

    Number of subjects in period 1
    Treatment sequence A/B Treatment sequence B/A
    Started
    23
    24
    Completed
    22
    22
    Not completed
    1
    2
         Consent withdrawn by subject
    1
    -
         Lost to follow-up
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment sequence A/B
    Reporting group description
    Subjects received Treatment A in Period 1 and Treatment B in Period 2, as a single 20 milliliter (mL) SC injection per dose. Treatment A: 1000 U CINRYZE with 24,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks. Treatment B: 2000 U CINRYZE with 48,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks. A washout period of at least 7 days and no more than 30 days was maintained between the last dose in Period 1 and the first dose in Period 2.

    Reporting group title
    Treatment sequence B/A
    Reporting group description
    Subjects received Treatment B in Period 1 and Treatment A in Period 2, as a single 20 mL SC injection per dose. Treatment B: 2000 U CINRYZE with 48,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks. Treatment A: 1000 U CINRYZE with 24,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks. A washout period of at least 7 days and no more than 30 days was maintained between the last dose in Period 1 and the first dose in Period 2.

    Reporting group values
    Treatment sequence A/B Treatment sequence B/A Total
    Number of subjects
    23 24 47
    Age categorical
    Units: Subjects
    Age continuous
    Intent-to-treat safety (ITT-S) population included all subjects who received any amount of study drug.
    Units: years
        arithmetic mean (standard deviation)
    39.7 ± 13.7 38.3 ± 15.7 -
    Gender categorical
    ITT-S population.
    Units: Subjects
        Female
    15 18 33
        Male
    8 6 14

    End points

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    End points reporting groups
    Reporting group title
    Treatment sequence A/B
    Reporting group description
    Subjects received Treatment A in Period 1 and Treatment B in Period 2, as a single 20 milliliter (mL) SC injection per dose. Treatment A: 1000 U CINRYZE with 24,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks. Treatment B: 2000 U CINRYZE with 48,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks. A washout period of at least 7 days and no more than 30 days was maintained between the last dose in Period 1 and the first dose in Period 2.

    Reporting group title
    Treatment sequence B/A
    Reporting group description
    Subjects received Treatment B in Period 1 and Treatment A in Period 2, as a single 20 mL SC injection per dose. Treatment B: 2000 U CINRYZE with 48,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks. Treatment A: 1000 U CINRYZE with 24,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks. A washout period of at least 7 days and no more than 30 days was maintained between the last dose in Period 1 and the first dose in Period 2.

    Subject analysis set title
    Intent-to-treat efficacy (ITT-E) population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    ITT-E population (N=22) included all subjects who completed both randomized treatment periods and fulfilled a priori defined evaluability criteria.

    Subject analysis set title
    Treatment A (1000 U CINRYZE + 24000 U rHuPH20)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received Treatment A (1000 U CINRYZE with 24,000 U rHuPH20 twice weekly [every 3 or 4 days] for 8 weeks) as a single 20 mL SC injection per dose in each treatment period.

    Subject analysis set title
    Treatment B (2000 U CINRYZE + 48000 U rHuPH20)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received Treatment B (2000 U CINRYZE with 48,000 U rHuPH20 twice weekly [every 3 or 4 days] for 8 weeks) as a single 20 mL SC injection per dose in each treatment period.

    Primary: Normalized Number of Angioedema Attacks During the Treatment Period

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    End point title
    Normalized Number of Angioedema Attacks During the Treatment Period [1]
    End point description
    Angioedema attack was defined as the subject-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. Subjects who were dosed but did not have any attacks in the period were assigned a value of zero. The number of attacks was normalized for the number of days subjects participated in a given period and expressed as the monthly frequency.
    End point type
    Primary
    End point timeframe
    From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: EudraCT database does auto-addition of number of subjects analysed while reporting an explorative analysis of two treatment groups. Due to this format constraint, charts have been uploaded with the accurate details of statistical analyses for this endpoint. Please find the statistical analyses in the attachment below.
    End point values
    Treatment A (1000 U CINRYZE + 24000 U rHuPH20) Treatment B (2000 U CINRYZE + 48000 U rHuPH20)
    Number of subjects analysed
    22 [2]
    22 [3]
    Units: angioedema attacks
        arithmetic mean (confidence interval 95%)
    1.58 (0.88 to 2.29)
    0.97 (0.41 to 1.53)
    Attachments
    Statistical Analyses_Primary_Angioedema Attacks
    Notes
    [2] - ITT-E population
    [3] - ITT-E population
    No statistical analyses for this end point

    Secondary: Cumulative Attack-severity During the Treatment Period

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    End point title
    Cumulative Attack-severity During the Treatment Period
    End point description
    Cumulative Attack-severity score was the sum of the maximum symptom severity recorded for each angioedema attack, which was determined on the last day of symptoms and recorded as None=0, Mild=1, Moderate=2, and Severe=3 and summing over the unique attacks, yields a Cumulative Attack-severity score. None: no angioedema attack symptom; Mild: the angioedema attack symptom was noticeable to the subject but was easily tolerated and did not interfere with routine activities; Moderate: the angioedema attack symptom interfered with work/school or the ability to participate in family life and social activities; Severe: the angioedema attack symptom significantly limited the subject's ability to attend work/school or participate in family life and social activities. Cumulative attack-severity was normalized for the number of days subjects participated in a given period and expressed as the monthly frequency. The scores ranged from 0 to 168 and higher scores represent worse symptoms.
    End point type
    Secondary
    End point timeframe
    From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period
    End point values
    Treatment A (1000 U CINRYZE + 24000 U rHuPH20) Treatment B (2000 U CINRYZE + 48000 U rHuPH20)
    Number of subjects analysed
    22 [4]
    22 [5]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    3.14 ± 3.79
    1.81 ± 2.55
    Notes
    [4] - ITT-E population
    [5] - ITT-E population
    No statistical analyses for this end point

    Secondary: Cumulative Daily-severity During the Treatment Period

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    End point title
    Cumulative Daily-severity During the Treatment Period
    End point description
    Cumulative Daily-severity score was the sum of the severity scores recorded for every day of reported symptoms during the treatment period. Severity scores were recorded as None=0, Mild=1, Moderate=2, and Severe=3. None: no angioedema attack symptom; Mild: the angioedema attack symptom was noticeable to the subject but was easily tolerated and did not interfere with routine activities; Moderate: the angioedema attack symptom interfered with work/school or the ability to participate in family life and social activities; Severe: the angioedema attack symptom significantly limited the subject's ability to attend work/school or participate in family life and social activities. Cumulative daily severity was normalized for the number of days subjects participated in a given period and expressed as the monthly frequency. The scores ranged from 0 to 168 and higher scores represent worse symptoms.
    End point type
    Secondary
    End point timeframe
    From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period
    End point values
    Treatment A (1000 U CINRYZE + 24000 U rHuPH20) Treatment B (2000 U CINRYZE + 48000 U rHuPH20)
    Number of subjects analysed
    22 [6]
    22 [7]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    4.63 ± 5.79
    2.81 ± 4.42
    Notes
    [6] - ITT-E population
    [7] - ITT-E population
    No statistical analyses for this end point

    Secondary: Cumulative Symptomatic Days During the Treatment Period

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    End point title
    Cumulative Symptomatic Days During the Treatment Period
    End point description
    Cumulative symptomatic days was defined as the sum of the symptomatic days of each angioedema attack reported during the treatment period. Subjects who were dosed but did not have any attacks in the period were assigned a value of zero. Cumulative symptomatic days was normalized for the number of days subjects participated in a given period and expressed as the monthly frequency.
    End point type
    Secondary
    End point timeframe
    From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period
    End point values
    Treatment A (1000 U CINRYZE + 24000 U rHuPH20) Treatment B (2000 U CINRYZE + 48000 U rHuPH20)
    Number of subjects analysed
    22 [8]
    22 [9]
    Units: days
        arithmetic mean (standard deviation)
    3.06 ± 3.51
    2.14 ± 3.3
    Notes
    [8] - ITT-E population
    [9] - ITT-E population
    No statistical analyses for this end point

    Secondary: Number of Angioedema Attacks Requiring Acute Treatment During the Treatment Period

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    End point title
    Number of Angioedema Attacks Requiring Acute Treatment During the Treatment Period
    End point description
    Angioedema attack was defined as the subject-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. Subjects who were dosed but did not have any attacks in the period were assigned a value of zero. The number of attacks was normalized for the number of days subjects participated in a given period and expressed as the monthly frequency.
    End point type
    Secondary
    End point timeframe
    From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period
    End point values
    Treatment A (1000 U CINRYZE + 24000 U rHuPH20) Treatment B (2000 U CINRYZE + 48000 U rHuPH20)
    Number of subjects analysed
    22 [10]
    22 [11]
    Units: angioedema attacks
        arithmetic mean (standard deviation)
    0.99 ± 1.51
    0.43 ± 0.89
    Notes
    [10] - ITT-E population
    [11] - ITT-E population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time of first dose of study drug up to 7 days after the last dose of study drug within each treatment period (8 weeks)
    Adverse event reporting additional description
    Treatment-emergent adverse events included adverse events (AEs) that were not present at baseline (that is, prior to the first dose of study drug) but started during or after the first administration of study drug in each treatment period, and AEs that were present at baseline but worsened in frequency and/or severity. ITT-S population.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Treatment A (1000 U CINRYZE + 24000 U rHuPH20)
    Reporting group description
    Subjects received Treatment A (1000 U CINRYZE with 24,000 U rHuPH20 twice weekly [every 3 or 4 days] for 8 weeks) as a single 20 mL SC injection per dose in each treatment period.

    Reporting group title
    Treatment B (2000 U CINRYZE + 48000 U rHuPH20)
    Reporting group description
    Subjects received Treatment B (2000 U CINRYZE with 48,000 U rHuPH20 twice weekly [every 3 or 4 days] for 8 weeks) as a single 20 mL SC injection per dose in each treatment period.

    Serious adverse events
    Treatment A (1000 U CINRYZE + 24000 U rHuPH20) Treatment B (2000 U CINRYZE + 48000 U rHuPH20)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 46 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Treatment A (1000 U CINRYZE + 24000 U rHuPH20) Treatment B (2000 U CINRYZE + 48000 U rHuPH20)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 44 (95.45%)
    46 / 46 (100.00%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 46 (0.00%)
         occurrences all number
    2
    0
    Congenital, familial and genetic disorders
    Hereditary angioedema
         subjects affected / exposed
    32 / 44 (72.73%)
    28 / 46 (60.87%)
         occurrences all number
    108
    69
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 44 (4.55%)
    3 / 46 (6.52%)
         occurrences all number
    2
    3
    General disorders and administration site conditions
    Injection site reactions
         subjects affected / exposed
    37 / 44 (84.09%)
    40 / 46 (86.96%)
         occurrences all number
    1113
    1212
    Injection site extravasation
         subjects affected / exposed
    4 / 44 (9.09%)
    9 / 46 (19.57%)
         occurrences all number
    15
    32
    Fatigue
         subjects affected / exposed
    4 / 44 (9.09%)
    1 / 46 (2.17%)
         occurrences all number
    5
    1
    Chest discomfort
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 46 (0.00%)
         occurrences all number
    2
    0
    Injury associated with device
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 46 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 46 (2.17%)
         occurrences all number
    2
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    3 / 44 (6.82%)
    2 / 46 (4.35%)
         occurrences all number
    3
    2
    Back pain
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 46 (0.00%)
         occurrences all number
    2
    0
    Pain in extremity
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 46 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 44 (9.09%)
    1 / 46 (2.17%)
         occurrences all number
    4
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Oct 2012
    1. Added the evaluation of subject experience with self administration of study drug as secondary objective 2. Included prophylactic treatment with other C1 inhibitor (INH) therapy in inclusion criteria 3. Excluded subjects who received androgen therapy within 7 days prior to the first dose of study drug in Period 1 4. Clarified additional study staff to be unblinded for the purposes of pharmacokinetic/pharmacodynamic (PK/PD) assessments and review of drug accountability 5. Added recording of details regarding any therapy received during the previous 12 months hereditary angioedema (HAE) management and delineated other C1 INH therapy as part of prophylaxis 6. Added upper extremity examinations for monitoring venous thromboembolism 7. Sample collection was modified for PK/PD, C1 INH and rHuPH20 antibodies 8. Included an additional study diary (Angioedema Activity Score) 9. Added a self-administration survey to gather information regarding the ease of syringe use, “injection button” use, training, and overall long-term use 10. An exploratory endpoint of response status (responder/non-responder) during each treatment period was added 11. Added an additional Angioedema Quality of Life (AE-QoL) questionnaire 12. Changed from target of achieving 36 to 34 subjects 13. Suspected unexpected serious adverse reactions (SUSARs) were to be reported to relevant competent authorities 14. Added the recommendation that the subject be in a semi-reclined (semi-Fowler) position during the injection 15. Added a section to indicate that for the purposes of this study, rHuPH20 antibodies were considered laboratory events of special interest 16. Subjects to be trained (and supervised) in self-administration of SC CINRYZE in Period 2 17. Added preliminary results of an ex vivo thrombogenicity study, new safety data regarding the development of rHuPH20 antibodies in an unrelated development program, updated PK/PD and safety data from Study 0624-204 (NCT01426763)

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Aug 2013
    Following discussions with the Food and drug administration (FDA) in August 2013, study drug (CINRYZE with rHuPH20) dosing was discontinued in this study as a precaution related to the emergence of, and unexpected incidence and titer of, non-neutralizing anti-rHuPH20 antibodies in some subjects. As a result, on 01 August 2013, the Sponsor decided to close the study. These antibodies had not been associated with any adverse clinical effects and were of unknown clinical significance. Data from the study continued to be collected and analyzed to inform ongoing safety assessment and design of future HAE studies. The Sponsor continued to follow subjects who developed anti-rHuPH20 antibodies in accordance with guidance from the FDA and to report anti-rHuPH20 antibody findings in an expedited manner.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Results of time to first angioedema attack and effects of C1 INH and C4 levels on clinical outcome during treatment period were not reported due to early termination of the study.
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