Subcutaneous CINRYZE With Recombinant Human Hyaluronidase for Prevention of Angioedema Attacks

• Sponsor: Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01756157
• Collaborator: (none)
• Enrollment: 47
• Locations: 23
• Arms: 2
• Actual Duration (Months): 7.3
• Patients Per Site: 2
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Hereditary Angioedema (HAE)	Biological: CINRYZE with rHuPH20	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 47 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: 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
• Actual Study Start Date: Feb 4, 2013
• Actual Primary Completion Date: Sep 13, 2013
• Actual Study Completion Date: Sep 13, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SC CINRYZE with rHuPH20 Dose Level 1 followed by Dose Level 2 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.	Biological: CINRYZE with rHuPH20; Other Names: C1 esterase inhibitor (human) Recombinant human hyaluronidase
Experimental: SC CINRYZE with rHuPH20 Dose Level 2 followed by Dose Level 1 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.	Biological: CINRYZE with rHuPH20; Other Names: C1 esterase inhibitor (human) Recombinant human hyaluronidase

Outcome Measures

Primary Outcome Measures

1. Normalized Number of Angioedema Attacks During the Treatment Period [From Visit 1 (Week 1) up to Visit 16 (Week 8) 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. 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.

Secondary Outcome Measures

1. Cumulative Attack-severity During the Treatment Period [From Visit 1 (Week 1) up to Visit 16 (Week 8) during each 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.

2. Cumulative Daily-severity During the Treatment Period [From Visit 1 (Week 1) up to Visit 16 (Week 8) during each 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.

3. Cumulative Symptomatic Days During the Treatment Period [From Visit 1 (Week 1) up to Visit 16 (Week 8) during each 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.

4. Number of Angioedema Attacks Requiring Acute Treatment During the Treatment Period [From Visit 1 (Week 1) up to Visit 16 (Week 8) 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. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Be ≥12 years of age.

• Have a confirmed diagnosis of Hereditary Angioedema.

Exclusion Criteria:

• Receipt of any C1 inhibitor (C1 INH) therapy or any blood products for treatment or prevention of an angioedema attack within 7 days before the first dose of study drug.

• Be receiving prophylactic intravenous CINRYZE that exceeds 1000 units every 3 or 4 days (maximum weekly dose 2000 units).

• Have received any androgen therapy (e.g., danazol, oxandrolone, stanozolol, testosterone) within 7 days prior to the first dose of study drug.

• If female, have started taking or changed the dose of any hormonal contraceptive regimen or hormone replacement therapy (i.e., estrogen/progestin containing products) within 3 months prior to the first dose of study drug.

• History of allergic reaction to C1 INH products, including CINRYZE or other blood products.

• History of abnormal blood clotting.

• Have a known allergy to hyaluronidase or any other ingredient in the study formulation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ViroPharma Investigational Site	Birmingham	Alabama	United States	35209
2	ViroPharma Investigational Site	Scottsdale	Arizona	United States	85251
3	ViroPharma Investigational Site	Bentonville	Arkansas	United States	72712
4	ViroPharma Investigational Site	Walnut Creek	California	United States	94598
5	ViroPharma Investigational Site	Colorado Springs	Colorado	United States	80907
6	ViroPharma Investigational Site	Tampa	Florida	United States	33613
7	ViroPharma Investigational Site	Boston	Massachusetts	United States	02114
8	ViroPharma Investigational Site	Las Vegas	Nevada	United States	89106
9	ViroPharma Investigational Site	Mineola	New York	United States	11501
10	ViroPharma Investigational Site	Cincinnati	Ohio	United States	45267
11	ViroPharma Investigational Site	Columbus	Ohio	United States	43235
12	ViroPharma Investigational Site	Lake Oswego	Oregon	United States	97035
13	ViroPharma Investigational Site	Hershey	Pennsylvania	United States	17033
14	ViroPharma Investigational Site	Pittsburgh	Pennsylvania	United States	15241
15	ViroPharma Investigational Site	Knoxville	Tennessee	United States	37909
16	ViroPharma Investigational Site	Dallas	Texas	United States	75231
17	ViroPharma Investigational Site	Spokane	Washington	United States	99204
18	ViroPharma Investigational Site	Berlin		Germany
19	ViroPharma Investigational Site	Essen		Germany
20	ViroPharma Investigational Site	Mainz		Germany
21	ViroPharma Investigational Site	Munchen		Germany
22	ViroPharma Investigational Site	Barcelona		Spain
23	ViroPharma Investigational Site	Jonkoping		Sweden

Sponsors and Collaborators

• Shire

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT01756157
• Other Study ID Numbers: 0624-206; 2012-000083-24
• First Posted: Dec 25, 2012
• Last Update Posted: Jun 3, 2021
• Last Verified: May 1, 2021

• Keywords provided by Shire: Crossover; C1 esterase inhibitor; Prevention; C1 inhibitor; Hereditary Angioedema; Subcutaneous; Recombinant human hyaluronidase
• Additional relevant MeSH terms: Angioedema; Angioedemas, Hereditary; Complement C1s; Complement C1 Inhibitor Protein; Complement C1 Inactivator Proteins

Study Results

Participant Flow

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 Detail	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
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
Period Title: First Intervention Period
STARTED	22	22
COMPLETED	22	22
NOT COMPLETED	0	0
Period Title: First Intervention Period
STARTED	22	22
COMPLETED	22	22
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Entire Study Population
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 Participants	47
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.0 (14.6)
Sex: Female, Male (Count of Participants)
Female	33 70.2%
Male	14 29.8%

Outcome Measures

1. Primary Outcome

Title	Normalized Number of Angioedema Attacks During the Treatment Period
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

Outcome Measure Data

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)
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.
Measure Participants	22	22
Mean (95% Confidence Interval) [angioedema attacks]	1.58	0.97

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
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0523
	Comments
	Method	Paired t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean difference
	Estimated Value	-0.61
	Confidence Interval	(2-Sided) 95%; -1.23 to 0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Cumulative Attack-severity During the Treatment Period
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

Outcome Measure Data

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)
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.
Measure Participants	22	22
Mean (Standard Deviation) [Score on a scale]	3.14 (3.79)	1.81 (2.55)

3. Secondary Outcome

Title	Cumulative Daily-severity During the Treatment Period
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

Outcome Measure Data

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)
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.
Measure Participants	22	22
Mean (Standard Deviation) [Score on a scale]	4.63 (5.79)	2.81 (4.42)

4. Secondary Outcome

Title	Cumulative Symptomatic Days During the Treatment Period
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

Outcome Measure Data

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)
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.
Measure Participants	22	22
Mean (Standard Deviation) [days]	3.06 (3.51)	2.14 (3.30)

5. Secondary Outcome

Title	Number of Angioedema Attacks Requiring Acute Treatment During the Treatment Period
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

Outcome Measure Data

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)
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.
Measure Participants	22	22
Mean (Standard Deviation) [angioedema attacks]	0.99 (1.51)	0.43 (0.89)

Adverse Events

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)
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 (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
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%)		0/46 (0%)
Other (Not Including 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	42/44 (95.5%)		46/46 (100%)
Congenital, familial and genetic disorders
Hereditary angioedema	32/44 (72.7%)	108	28/46 (60.9%)	69
Gastrointestinal disorders
Nausea	2/44 (4.5%)	2	1/46 (2.2%)	1
General disorders
Injection site reactions	37/44 (84.1%)	1113	40/46 (87%)	1212
Injection site extravasation	4/44 (9.1%)	15	9/46 (19.6%)	32
Fatigue	4/44 (9.1%)	5	1/46 (2.2%)	1
Chest discomfort	2/44 (4.5%)	2	0/46 (0%)	0
Injury associated with device	2/44 (4.5%)	2	0/46 (0%)	0
Infections and infestations
Nasopharyngitis	4/44 (9.1%)	4	1/46 (2.2%)	1
Injury, poisoning and procedural complications
Contusion	2/44 (4.5%)	2	0/46 (0%)	0
Musculoskeletal and connective tissue disorders
Muscle spasms	3/44 (6.8%)	3	2/46 (4.3%)	2
Back pain	2/44 (4.5%)	2	0/46 (0%)	0
Pain in extremity	2/44 (4.5%)	2	0/46 (0%)	0
Nervous system disorders
Headache	2/44 (4.5%)	2	3/46 (6.5%)	3

Limitations/Caveats

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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.