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| ID | Type | Description | Link |
|---|---|---|---|
| 2012-000083-24 | EudraCT Number |
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The primary objectives of the study are to evaluate the safety, tolerability, and efficacy of two doses of CINRYZE with recombinant human hyaluronidase (rHuPH20) administered by subcutaneous (SC) injection to prevent angioedema attacks.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| SC CINRYZE with rHuPH20 Dose Level 1 followed by Dose Level 2 | Experimental | SC CINRYZE with rHuPH20 Dose Level 1 twice weekly (every 3 or 4 days) for 8 weeks followed by SC CINRYZE with rHuPH20 Dose Level 2 twice weekly (every 3 or 4 days) for 8 weeks. |
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| SC CINRYZE with rHuPH20 Dose Level 2 followed by Dose Level 1 | Experimental | SC CINRYZE with rHuPH20 Dose Level 2 twice weekly (every 3 or 4 days) for 8 weeks followed by SC CINRYZE with rHuPH20 Dose Level 1 twice weekly (every 3 or 4 days) for 8 weeks. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| CINRYZE with rHuPH20 | Biological |
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| Measure | Description | Time Frame |
|---|---|---|
| Normalized Number of Angioedema Attacks During the 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. Participants 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 participants participated in a given period and expressed as the monthly frequency. | From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period |
| Measure | Description | Time Frame |
|---|---|---|
| Cumulative Attack-severity During the Treatment Period | Cumulative Attack-severity score was the sum of maximum symptom severity recorded for each angioedema attack, 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 participant 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 participant's ability to attend work/school or participate in family life and social activities. Cumulative attack-severity was normalized for the number of days participants participated in a given period and expressed as the monthly frequency. The scores ranged from 0 to 168 and higher scores represent worse symptoms. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Study Director | Takeda | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| ViroPharma Investigational Site | Birmingham | Alabama | 35209 | United States | ||
| ViroPharma Investigational Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27931305 | Result | Riedl MA, Lumry WR, Li HH, Banerji A, Bernstein JA, Ba M, Bjrkander J, Magerl M, Maurer M, Rockich K, Chen H, Schranz J. Subcutaneous administration of human C1 inhibitor with recombinant human hyaluronidase in patients with hereditary angioedema. Allergy Asthma Proc. 2016 Nov;37(6):489-500. doi: 10.2500/aap.2016.37.4006. | |
| 36326435 |
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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.
This study was conducted at 24 sites (United States=20, Europe=4) between 04 February 2013 (first participant dosed) and 13 September 2013 (last participant contact). Of 52 screened participants, 47 were randomized and treated. Screen failure reasons were consent withdrawn by 1 participant and violation of eligibility criteria by 4 participants.
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| ID | Title | Description |
|---|---|---|
| FG000 | Treatment Sequence A/B | Participants received Treatment A in Period 1 and Treatment B in Period 2; for 8 weeks each as a single 20 milliliter (mL) subcutaneous (SC) injection per dose. 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. 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. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| First Intervention Period |
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| From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period |
| Cumulative Daily-severity During the Treatment Period | 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 participant 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 participant's ability to attend work/school or participate in family life and social activities. Cumulative daily severity was normalized for the number of days participants participated in a given period and expressed as the monthly frequency. The scores ranged from 0 to 168 and higher scores represent worse symptoms. | From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period |
| Cumulative Symptomatic Days During the Treatment Period | Cumulative symptomatic days was defined as the sum of the symptomatic days of each angioedema attack reported during the treatment period. Participants 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 participants participated in a given period and expressed as the monthly frequency. | From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period |
| Number of Angioedema Attacks Requiring Acute Treatment During the 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. Participants 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 participants participated in a given period and expressed as the monthly frequency. | From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period |
| Scottsdale |
| Arizona |
| 85251 |
| United States |
| ViroPharma Investigational Site | Bentonville | Arkansas | 72712 | United States |
| ViroPharma Investigational Site | Walnut Creek | California | 94598 | United States |
| ViroPharma Investigational Site | Colorado Springs | Colorado | 80907 | United States |
| ViroPharma Investigational Site | Tampa | Florida | 33613 | United States |
| ViroPharma Investigational Site | Boston | Massachusetts | 02114 | United States |
| ViroPharma Investigational Site | Las Vegas | Nevada | 89106 | United States |
| ViroPharma Investigational Site | Mineola | New York | 11501 | United States |
| ViroPharma Investigational Site | Cincinnati | Ohio | 45267 | United States |
| ViroPharma Investigational Site | Columbus | Ohio | 43235 | United States |
| ViroPharma Investigational Site | Lake Oswego | Oregon | 97035 | United States |
| ViroPharma Investigational Site | Hershey | Pennsylvania | 17033 | United States |
| ViroPharma Investigational Site | Pittsburgh | Pennsylvania | 15241 | United States |
| ViroPharma Investigational Site | Knoxville | Tennessee | 37909 | United States |
| ViroPharma Investigational Site | Dallas | Texas | 75231 | United States |
| ViroPharma Investigational Site | Spokane | Washington | 99204 | United States |
| ViroPharma Investigational Site | Berlin | Germany |
| ViroPharma Investigational Site | Essen | Germany |
| ViroPharma Investigational Site | Mainz | Germany |
| ViroPharma Investigational Site | München | Germany |
| ViroPharma Investigational Site | Barcelona | Spain |
| ViroPharma Investigational Site | Jönköping | Sweden |
| Beard N, Frese M, Smertina E, Mere P, Katelaris C, Mills K. Interventions for the long-term prevention of hereditary angioedema attacks. Cochrane Database Syst Rev. 2022 Nov 3;11(11):CD013403. doi: 10.1002/14651858.CD013403.pub2. |
| FG001 | Treatment Sequence B/A | Participants received Treatment B in Period 1 and Treatment A in Period 2; for 8 weeks each as a single 20 mL SC injection per dose. 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. 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. |
| COMPLETED |
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| NOT COMPLETED |
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| Washout Period (at Least 7 Days) |
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| Second Intervention Period |
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Intent-to-treat safety (ITT-S) population included all participants who received any amount of study drug.
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| ID | Title | Description |
|---|---|---|
| BG000 | Entire Study Population | Included participants who received 1000 U CINRYZE with 24,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks (Treatment A) first and 2000 U CINRYZE with 48,000 U rHuPH20 twice weekly (every 3 or 4 days) for 8 weeks (Treatment B) first. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Normalized Number of Angioedema Attacks During the 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. Participants 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 participants participated in a given period and expressed as the monthly frequency. | Intent-to-treat efficacy (ITT-E) population included all participants who completed both randomized treatment periods and fulfilled a priori defined evaluability criteria. | Posted | Mean | 95% Confidence Interval | angioedema attacks | From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period |
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| Secondary | Cumulative Attack-severity During the Treatment Period | Cumulative Attack-severity score was the sum of maximum symptom severity recorded for each angioedema attack, 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 participant 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 participant's ability to attend work/school or participate in family life and social activities. Cumulative attack-severity was normalized for the number of days participants participated in a given period and expressed as the monthly frequency. The scores ranged from 0 to 168 and higher scores represent worse symptoms. | ITT-E population | Posted | Mean | Standard Deviation | Score on a scale | From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period |
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| Secondary | Cumulative Daily-severity During the Treatment Period | 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 participant 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 participant's ability to attend work/school or participate in family life and social activities. Cumulative daily severity was normalized for the number of days participants participated in a given period and expressed as the monthly frequency. The scores ranged from 0 to 168 and higher scores represent worse symptoms. | ITT-E population | Posted | Mean | Standard Deviation | Score on a scale | From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period |
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| Secondary | Cumulative Symptomatic Days During the Treatment Period | Cumulative symptomatic days was defined as the sum of the symptomatic days of each angioedema attack reported during the treatment period. Participants 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 participants participated in a given period and expressed as the monthly frequency. | ITT-E population | Posted | Mean | Standard Deviation | days | From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period |
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| Secondary | Number of Angioedema Attacks Requiring Acute Treatment During the 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. Participants 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 participants participated in a given period and expressed as the monthly frequency. | ITT-E population | Posted | Mean | Standard Deviation | angioedema attacks | From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period |
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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)
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Treatment A (1000 U CINRYZE + 24000 U rHuPH20) | Participants 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. | 0 | 44 | 42 | 44 | ||
| EG001 | Treatment B (2000 U CINRYZE + 48000 U rHuPH20) | Participants 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. | 0 | 46 | 46 | 46 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Contusion | Injury, poisoning and procedural complications | MedDRA 16.0 | Non-systematic Assessment |
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| Hereditary angioedema | Congenital, familial and genetic disorders | MedDRA 16.0 | Non-systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 16.0 | Non-systematic Assessment |
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| Injection site reactions | General disorders | MedDRA 16.0 | Non-systematic Assessment |
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| Injection site extravasation | General disorders | MedDRA 16.0 | Non-systematic Assessment |
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| Fatigue | General disorders | MedDRA 16.0 | Non-systematic Assessment |
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| Chest discomfort | General disorders | MedDRA 16.0 | Non-systematic Assessment |
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| Injury associated with device | General disorders | MedDRA 16.0 | Non-systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA 16.0 | Non-systematic Assessment |
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| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
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| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 16.0 | Non-systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA 16.0 | Non-systematic Assessment |
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Results of efficacy endpoints (time to first angioedema attack, effects of C1 inhibitor and C4 levels on clinical outcome during treatment period) were not reported due to early termination of the study but later completed for safety data.
If a multicentre publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicentre Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Shire | +1 866 842 5335 | ClinicalTransparency@shire.com |
| ID | Term |
|---|---|
| D054179 | Angioedemas, Hereditary |
| ID | Term |
|---|---|
| D000799 | Angioedema |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D000081208 | Hereditary Complement Deficiency Diseases |
| D000081207 | Primary Immunodeficiency Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D014581 | Urticaria |
| D017445 | Skin Diseases, Vascular |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D006969 | Hypersensitivity, Immediate |
| D006967 | Hypersensitivity |
| D007154 | Immune System Diseases |
| D007153 | Immunologic Deficiency Syndromes |
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| ID | Term |
|---|---|
| C469952 | SERPING1 protein, human |
| D050718 | Complement C1 Inhibitor Protein |
| ID | Term |
|---|---|
| D006023 | Glycoproteins |
| D006001 | Glycoconjugates |
| D002241 | Carbohydrates |
| D003174 | Complement C1 Inactivator Proteins |
| D015843 | Serpins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D003169 | Complement Inactivator Proteins |
| D003165 | Complement System Proteins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
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Participants 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.
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