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Trial record 5 of 40 for:    cinryze | Hereditary Angioedema

Subcutaneous CINRYZE With Recombinant Human Hyaluronidase for Prevention of Angioedema Attacks

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01756157
Recruitment Status : Completed
First Posted : December 25, 2012
Results First Posted : June 12, 2015
Last Update Posted : December 13, 2018
Sponsor:
Information provided by (Responsible Party):
Shire

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Prevention
Condition Hereditary Angioedema (HAE)
Intervention Biological: CINRYZE with rHuPH20
Enrollment 47
Recruitment Details 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 Screen failure reasons were consent withdrawn by 1 participant and violation of eligibility criteria by 4 participants.
Pre-assignment 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.
Arm/Group Title Treatment Sequence A/B Treatment Sequence B/A
Hide Arm/Group Description

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.

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.

Period Title: First Intervention Period
Started 23 24
Completed 22 22
Not Completed 1 2
Reason Not Completed
Withdrawal by Subject             1             0
Lost to Follow-up             0             2
Period Title: Washout Period (at Least 7 Days)
Started 22 22
Completed 22 22
Not Completed 0 0
Period Title: Second Intervention Period
Started 22 22
Completed 22 22
Not Completed 0 0
Arm/Group Title Entire Study Population
Hide Arm/Group Description 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.
Overall Number of Baseline Participants 47
Hide Baseline Analysis Population Description
Intent-to-treat safety (ITT-S) population included all participants who received any amount of study drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 47 participants
39.0  (14.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 47 participants
Female
33
  70.2%
Male
14
  29.8%
1.Primary Outcome
Title Normalized Number of Angioedema Attacks During the Treatment Period
Hide Description 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.
Time Frame From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat efficacy (ITT-E) population included all participants who completed both randomized treatment periods and fulfilled a priori defined evaluability criteria.
Arm/Group Title Treatment A (1000 U CINRYZE + 24000 U rHuPH20) Treatment B (2000 U CINRYZE + 48000 U rHuPH20)
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 22 22
Mean (95% Confidence Interval)
Unit of Measure: angioedema attacks
1.58
(0.88 to 2.29)
0.97
(0.41 to 1.53)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Treatment A (1000 U CINRYZE + 24000 U rHuPH20), Treatment B (2000 U CINRYZE + 48000 U rHuPH20)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0523
Comments [Not Specified]
Method Paired t-test, 2 sided
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean difference
Estimated Value -0.61
Confidence Interval (2-Sided) 95%
-1.23 to 0.01
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Cumulative Attack-severity During the Treatment Period
Hide Description

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.

Time Frame From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period
Hide Outcome Measure Data
Hide Analysis Population Description
ITT-E population
Arm/Group Title Treatment A (1000 U CINRYZE + 24000 U rHuPH20) Treatment B (2000 U CINRYZE + 48000 U rHuPH20)
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 22 22
Mean (Standard Deviation)
Unit of Measure: Score on a scale
3.14  (3.79) 1.81  (2.55)
3.Secondary Outcome
Title Cumulative Daily-severity During the Treatment Period
Hide 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 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.

Time Frame From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period
Hide Outcome Measure Data
Hide Analysis Population Description
ITT-E population
Arm/Group Title Treatment A (1000 U CINRYZE + 24000 U rHuPH20) Treatment B (2000 U CINRYZE + 48000 U rHuPH20)
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 22 22
Mean (Standard Deviation)
Unit of Measure: Score on a scale
4.63  (5.79) 2.81  (4.42)
4.Secondary Outcome
Title Cumulative Symptomatic Days During the Treatment Period
Hide Description 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.
Time Frame From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period
Hide Outcome Measure Data
Hide Analysis Population Description
ITT-E population
Arm/Group Title Treatment A (1000 U CINRYZE + 24000 U rHuPH20) Treatment B (2000 U CINRYZE + 48000 U rHuPH20)
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 22 22
Mean (Standard Deviation)
Unit of Measure: days
3.06  (3.51) 2.14  (3.30)
5.Secondary Outcome
Title Number of Angioedema Attacks Requiring Acute Treatment During the Treatment Period
Hide Description 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.
Time Frame From Visit 1 (Week 1) up to Visit 16 (Week 8) during each treatment period
Hide Outcome Measure Data
Hide Analysis Population Description
ITT-E population
Arm/Group Title Treatment A (1000 U CINRYZE + 24000 U rHuPH20) Treatment B (2000 U CINRYZE + 48000 U rHuPH20)
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 22 22
Mean (Standard Deviation)
Unit of Measure: angioedema attacks
0.99  (1.51) 0.43  (0.89)
Time Frame 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 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.

 
Arm/Group Title Treatment A (1000 U CINRYZE + 24000 U rHuPH20) Treatment B (2000 U CINRYZE + 48000 U rHuPH20)
Hide Arm/Group Description 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. 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.
All-Cause Mortality
Treatment A (1000 U CINRYZE + 24000 U rHuPH20) Treatment B (2000 U CINRYZE + 48000 U rHuPH20)
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Hide Serious Adverse Events
Treatment A (1000 U CINRYZE + 24000 U rHuPH20) Treatment B (2000 U CINRYZE + 48000 U rHuPH20)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/44 (0.00%)      0/46 (0.00%)    
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Treatment A (1000 U CINRYZE + 24000 U rHuPH20) Treatment B (2000 U CINRYZE + 48000 U rHuPH20)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   42/44 (95.45%)      46/46 (100.00%)    
Congenital, familial and genetic disorders     
Hereditary angioedema * 1  32/44 (72.73%)  108 28/46 (60.87%)  69
Gastrointestinal disorders     
Nausea * 1  2/44 (4.55%)  2 1/46 (2.17%)  1
General disorders     
Injection site reactions * 1  37/44 (84.09%)  1113 40/46 (86.96%)  1212
Injection site extravasation * 1  4/44 (9.09%)  15 9/46 (19.57%)  32
Fatigue * 1  4/44 (9.09%)  5 1/46 (2.17%)  1
Chest discomfort * 1  2/44 (4.55%)  2 0/46 (0.00%)  0
Injury associated with device * 1  2/44 (4.55%)  2 0/46 (0.00%)  0
Infections and infestations     
Nasopharyngitis * 1  4/44 (9.09%)  4 1/46 (2.17%)  1
Injury, poisoning and procedural complications     
Contusion * 1  2/44 (4.55%)  2 0/46 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Muscle spasms * 1  3/44 (6.82%)  3 2/46 (4.35%)  2
Back pain * 1  2/44 (4.55%)  2 0/46 (0.00%)  0
Pain in extremity * 1  2/44 (4.55%)  2 0/46 (0.00%)  0
Nervous system disorders     
Headache * 1  2/44 (4.55%)  2 3/46 (6.52%)  3
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 16.0
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.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Study Physician
Organization: Shire
Phone: 1866-842-5335
Layout table for additonal information
Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT01756157    
Other Study ID Numbers: 0624-206
2012-000083-24 ( EudraCT Number )
First Submitted: June 29, 2012
First Posted: December 25, 2012
Results First Submitted: May 29, 2015
Results First Posted: June 12, 2015
Last Update Posted: December 13, 2018