EASSI - Evaluation of the Safety of Self-Administration With Icatibant

• Sponsor: Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00997204
• Collaborator: Jerini AG (Industry)
• Enrollment: 151
• Locations: 26
• Arms: 2
• Actual Duration (Months): 20.9
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study is being conducted to explore the clinical safety, local tolerability, convenience and effectiveness of self-treatment of hereditary angioedema (HAE) attacks with subcutaneous injections of icatibant.

Condition or Disease	Intervention/Treatment	Phase
Hereditary Angioedema	Drug: Icatibant	Phase 3

Detailed Description

This Phase IIIb study was multi-center and open-label with a single dose level. Subjects with a documented diagnosis of HAE Type I or II were eligible to participate in this trial. Eligible subjects included those who had received treatment for HAE with icatibant in previous clinical trials, or subjects who had been previously treated with the marketed product Firazyr® and subjects who were naïve to icatibant treatment.

All subjects were trained on the method of self-administration at their enrollment visit (Visit 1).For the training sessions, a syringe pre-filled with 3 mL placebo solution was used in place of icatibant. Comprehensive educational material and instructions including pictograms were developed for the subjects to illustrate the method of self-administration and use of the Patient Diary. The training material provided additional information on how to self-diagnose an HAE attack and how to decide on the necessity to treat.In addition, instructions were provided on what to do in case of a laryngeal attack.

Study Design

• Study Type: Interventional
• Actual Enrollment: 151 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open Label, Multicenter Study to Evaluate Safety, Local Tolerability, Convenience, and Efficacy of a Self-Administered Subcutaneous Formulation of Icatibant for the Treatment of Acute Attacks of Hereditary Angioedema
• Actual Study Start Date: Sep 25, 2009
• Actual Primary Completion Date: Jun 22, 2011
• Actual Study Completion Date: Jun 22, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Icatibant- Naive Treatment Phase Single subcutaneous injection of icatibant, 30 mg	Drug: Icatibant; Single subcutaneous injection of icatibant, 30 mg; Other Names: Brand name, Firazyr®
Experimental: icatibant- Self administration Phase Single subcutaneous injection of icatibant, 30 mg	Drug: Icatibant; Single subcutaneous injection of icatibant, 30 mg; Other Names: Brand name, Firazyr®

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events in Self-treatment of Acute HAE Attacks With s.c. Injections of Icatibant [7 days from the beginning of each phase]

   Clinical safety of self-treatment of acute HAE attacks with s.c. injections of icatibant was assessed by calculating the number of AEs occurred during the study. Only those adverse events occurring up to the earlier of 7 days from the start of the naive phase, study discontinuation and start of the self-administration phase are assessed. The Local Tolerability Assessment tool was used. Subjects and Investigators graded erythema/reddening, swelling, burning, pruritus/itching, warm sensation, and skin pain on a 0 to 3 severity scale.

Secondary Outcome Measures

1. Clinical Efficacy of Self-treatment of Acute HAE Attacks With s.c. Injections of Icatibant, Time to Symptom Relief Using VAS Score for a Single Primary Symptom by Patient Cohort [48 hours post-dose]

   Subjects assessed angioedema attack symptoms using the visual analogue scale (VAS) for skin pain, skin swelling and abdominal pain. The VAS is a continuous scale comprised of a 100 mm in length line, anchored by 2 verbal descriptors, one for each symptom extreme 0 (no pain) and 100 (worst pain). The respondent is asked to place a mark on the VAS line (any where between 0 and 100 mm) at the point that represents their pain intensity. The score is determined by measuring the distance (mm) on the line between the "no pain" anchor and the patient's mark, providing a range of scores from 0-100. A higher score indicates greater pain intensity. Score interpretation is: no pain (0-4 mm), mild pain (5-44 mm), moderate pain (45-74 mm), and severe pain (75-100 mm). Symptom relief is defined as at least a 50% reduction in a pre-dose VAS score of 30 mm or greater. The time to onset of symptom relief is defined as the first of 3 consecutive assessments at which symptom relief was observed.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Each patient must meet the following criteria to be enrolled in this study.

1. Males and females 18 years of age at the time of informed consent

2. Documented diagnosis of HAE Type I or II based on ALL of the following criteria:

• Family and/or medical history

• Characteristic attack manifestations, recurrent attacks

• Historical functional C1-INH <50% normal values

1. Women of childbearing potential must use consistently and correctly a highly effective, adequate method of birth control (failure rate less than 1% per year) - sexual abstinence or have a vasectomised partner during the duration of the study. Hormonal contraception can be continued if verified by a physician that it doesn't affect the course of HAE attacks.

2. Mental and physical condition allowing patients to complete baseline assessment, to self-administer icatibant and to follow other study procedures.

3. Ability to provide signed written informed consent after all aspects of the study have been explained and discussed with the patient.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from the study.

1. Participation in a clinical trial of another investigational medicinal product within the past month (except a previous icatibant study).

2. Diagnosis of angioedema other than Type I or Type II HAE.

3. Evidence of symptomatic coronary artery disease based on medical history, in particular, unstable angina pectoris or severe coronary heart disease.

4. Congestive heart failure (NYHA Class 3 and 4).

5. Stroke within the past 6 months.

6. Treatment with angiotensin converting enzyme (ACE) inhibitor.

7. Pregnancy and/or breast-feeding.

8. In the opinion of the investigator: mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study.

9. In the opinion of the investigator: unlikely to comply with the protocol, for example, uncooperative attitude, inability to return for follow-up visits, or unlikely to complete the study for any reason.

10. In the opinion of the investigator: inability to manage study medication or self-administration of an injection.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital Britanico Unidad de Alergia	Buenos Aires		Argentina	C1035AAT
2	Universitätsklinik für Dermatologie und Venerologie	Graz		Austria	8036
3	Odense Universitetshospital-OUH	Odense	I Og Alergicentret	Denmark
4	Centre Hospitalier Universitaire/ Service de Dermatologie	Angers	Angers Cedex 09	France	49933
5	Hospital Edouaed Herriot	Lyon	Cedex 03	France	69437
6	Clinique Universitaire de Medicine/ Centre National de reference	Grenoble	Grenoble Cedex 09	France	38043
7	Hopital Claude Huriex/ Service de medicine interne	Lille	Lille Cedex	France	59037
8	Hopital Europeen Georges Pompidou Immunologie Clinique	Paris	Paris Cedex 15	France	75015
9	Universitätsmedizin Berlin, Klinik für Dermatologie, Venerologie und Allergologie, Charité	Berlin		Germany	10117
10	Universitäts-Hals-Nasen-Ohren-Klinik Essen, Universität Duisburg-Essen	Essen		Germany	45127
11	Klinkum der Johann Wolfgang Goethe-Universitat	Frankfurt am Main		Germany	60590
12	Hautklinik und Poliklinik, Universitätsmedizin der Johannes Gutenberg-Universität	Mainz		Germany	55101
13	Bnai-Zion M.C. Clinical Immunology and Allergy Division	Haifa		Israel	31048
14	Tel Aviv Sourasky Medical Center - Allergy Unit	Tel Aviv		Israel	64239
15	The Chaim Sheba Medical Center, The Allergy and Clinical Immunology Unit	Tel Hashomer		Israel	52621
16	Ospedale Luigi Sacco	Milano		Italy	20157
17	Universita degli Studi di Napoli 'Federico II'	Napoli,		Italy	80131
18	Hospital Universitario Vall de Hebrón / Sección de Alergia, Escola Infermeria	Barcelona		Spain	08035
19	Hospital General Universitario Gregorio Maranon	Madrid		Spain	28007
20	Hospital Universitario La Paz, Servicio de Alergia	Madrid		Spain	28046
21	Hospital Universitario La Fe, Servicio de Alergia	Valencia		Spain	46009
22	Luzerner Kantonsspital	Luzern		Switzerland
23	Universitätsspital Zürich / Dermatologische Klinik	Zurich		Switzerland	8091
24	Southmead Hospital, Department of Immunology	Bristol		United Kingdom	BS10 5NB
25	Barts & The London NHS Trust, Pathology and Pharmacy Building	London		United Kingdom	E1 2ES
26	Derriford Combined Laboratory, Department of Clinical Immunology & Allergy	Plymouth		United Kingdom	PL6 8DH

Sponsors and Collaborators

• Shire
• Jerini AG

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT00997204
• Other Study ID Numbers: JE049-3101; 2008-000071-25
• First Posted: Oct 19, 2009
• Last Update Posted: Jun 11, 2021
• Last Verified: May 1, 2021

• Keywords provided by Shire: HAE; Type I HAE; Type II HAE
• Additional relevant MeSH terms: Angioedema; Angioedemas, Hereditary; Icatibant

Study Results

Participant Flow

Pre-assignment Detail	Patients were screened for entry based on their known medical histories (HAE attacks) and previous exposure to a treatment (naïve or not). 151 were enrolled and trained in the self-administration. 47 of these subjects did not have an acute attack of HAE treated with icatibant during this study and were included in the untreated population.

Arm/Group Title	Naive Subjects/ Naive Treatment Phase	Non-Naive Subjects/ Self-administration Phase
Arm/Group Description	Patients who had never received icatibant before this phase, got treatment of Acute HAE Attack with SC icatibant (30 mg)Administered at Site by Health Care Provider.	Subjects who had received treatment for HAE with icatibant in previous clinical trials or had been previously treated with the marketed product Firazyr®, got Treatment of Acute HAE Attack with SC icatibant (30 mg)Self-Administered.
Period Title: Naive Treatment Phase
STARTED	25	79
COMPLETED	19	0
NOT COMPLETED	6	79
Period Title: Naive Treatment Phase
STARTED	19	78
COMPLETED	19	77
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Non-Naive Patients	Naive Patients	Total
Arm/Group Description	Patients who previously treated with icatibant in clinical studies or with commercial Firazyr® and got the treatment during the self-administered phase	Patients who had never received icatibant and treated in both the Naive treatment phase and the Self-administered phase	Total of all reporting groups
Overall Participants	79	25	104
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.607 (13.044)	44.68 (16.53)	41.58 (13.98)
Sex: Female, Male (Count of Participants)
Female	52 65.8%	16 64%	68 65.4%
Male	27 34.2%	9 36%	36 34.6%
Region of Enrollment (Count of Participants)
France	6 7.6%	0 0%	6 5.8%
Argentina	18 22.8%	5 20%	23 22.1%
Spain	9 11.4%	2 8%	11 10.6%
Denmark	5 6.3%	0 0%	5 4.8%
Austria	9 11.4%	5 20%	14 13.5%
Israel	15 19%	0 0%	15 14.4%
Germany	9 11.4%	5 20%	14 13.5%
Italy	1 1.3%	1 4%	2 1.9%
Switzerland	1 1.3%	1 4%	2 1.9%
United Kingdom	6 7.6%	6 24%	12 11.5%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events in Self-treatment of Acute HAE Attacks With s.c. Injections of Icatibant
Description	Clinical safety of self-treatment of acute HAE attacks with s.c. injections of icatibant was assessed by calculating the number of AEs occurred during the study. Only those adverse events occurring up to the earlier of 7 days from the start of the naive phase, study discontinuation and start of the self-administration phase are assessed. The Local Tolerability Assessment tool was used. Subjects and Investigators graded erythema/reddening, swelling, burning, pruritus/itching, warm sensation, and skin pain on a 0 to 3 severity scale.
Time Frame	7 days from the beginning of each phase

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Naive Subjects Administered Icatibant by Health Care Provider	Subjects Who Self-administered Icatibant (Naive)	Subjects Who Self-administered Icatibant (Non-naive)
Arm/Group Description	The first HAE attack of naïve subjects enrolled in the study was treated at the study site, where a Health Care Provider administered icatibant to the subject. 3 subjects (of the original 25 enrolled in the naive treatment phase)self-administered icatibant while observed bu HCP, as opposed to having the HCP perform the injection. these data were not included in the naive treatment safety analyses.	Naive subjects self-administered the study drug at home or other site convenient to the subject, but not at the investigational site, nor under HCP-supervision.	Non-Naive subjects self-administered the study drug at home or other site convenient to the subject, but not at the investigational site, nor under HCP-supervision.
Measure Participants	22	19	78
Number [participants]	11 13.9%	6 24%	27 26%

2. Secondary Outcome

Title	Clinical Efficacy of Self-treatment of Acute HAE Attacks With s.c. Injections of Icatibant, Time to Symptom Relief Using VAS Score for a Single Primary Symptom by Patient Cohort
Description	Subjects assessed angioedema attack symptoms using the visual analogue scale (VAS) for skin pain, skin swelling and abdominal pain. The VAS is a continuous scale comprised of a 100 mm in length line, anchored by 2 verbal descriptors, one for each symptom extreme 0 (no pain) and 100 (worst pain). The respondent is asked to place a mark on the VAS line (any where between 0 and 100 mm) at the point that represents their pain intensity. The score is determined by measuring the distance (mm) on the line between the "no pain" anchor and the patient's mark, providing a range of scores from 0-100. A higher score indicates greater pain intensity. Score interpretation is: no pain (0-4 mm), mild pain (5-44 mm), moderate pain (45-74 mm), and severe pain (75-100 mm). Symptom relief is defined as at least a 50% reduction in a pre-dose VAS score of 30 mm or greater. The time to onset of symptom relief is defined as the first of 3 consecutive assessments at which symptom relief was observed.
Time Frame	48 hours post-dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Naive Subjects Administered Icatibant by Health Care Provider	Subjects Who Self-administered Icatibant (Naive)	Subjects Who Self-administered Icatibant (Non-naive)
Arm/Group Description	The first HAE attack of naïve subjects enrolled in the study was treated at the study site, where a Health Care Provider administered icatibant to the subject.	Naive subjects self-administered the study drug at home or other site convenient to the subject, but not at the investigational site, nor under HCP-supervision.	Non-naive subjects self-administered the study drug at home or other site convenient to the subject, but not at the investigational site, nor under HCP-supervision.
Measure Participants	22	19	78
Median (Inter-Quartile Range) [Hours]	2.0	3.1	2.0

Adverse Events

Time Frame	7 days from the beginning of each phase
Arm/Group Title	Naive Subjects Administered Icatibant by Health Care Provider		Subjects Who Self-administered Icatibant (Naive)		Subjects Who Self-administered Icatibant (Non-naive)
Arm/Group Description	The first HAE attack of naïve subjects enrolled in the study was treated at the study site, where a Health Care Provider administered icatibant to the subject.		Naive subjects self-administered the study drug at home or other site convenient to the subject, but not at the investigational site, nor under HCP-supervision.		Non-naive subjects self-administered the study drug at home or other site convenient to the subject, but not at the investigational site, nor under HCP-supervision.
All Cause Mortality
	Naive Subjects Administered Icatibant by Health Care Provider		Subjects Who Self-administered Icatibant (Naive)		Subjects Who Self-administered Icatibant (Non-naive)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Naive Subjects Administered Icatibant by Health Care Provider		Subjects Who Self-administered Icatibant (Naive)		Subjects Who Self-administered Icatibant (Non-naive)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/19 (0%)		0/78 (0%)
Other (Not Including Serious) Adverse Events
	Naive Subjects Administered Icatibant by Health Care Provider		Subjects Who Self-administered Icatibant (Naive)		Subjects Who Self-administered Icatibant (Non-naive)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/22 (31.8%)		6/19 (31.6%)		21/78 (26.9%)
Congenital, familial and genetic disorders
Hereditary Angioedema	6/22 (27.3%)		3/19 (15.8%)		19/78 (24.4%)
General disorders
Feeling Hot	0/22 (0%)		1/19 (5.3%)		0/78 (0%)
Local Swelling	0/22 (0%)		1/19 (5.3%)		0/78 (0%)
Edema Peripheral	0/22 (0%)		1/19 (5.3%)		0/78 (0%)
Localized edema	0/22 (0%)		1/19 (5.3%)		0/78 (0%)
Investigations
Blood pressure increased	0/22 (0%)		1/19 (5.3%)		0/78 (0%)
Nervous system disorders
Headache	1/22 (4.5%)		1/19 (5.3%)		2/78 (2.6%)
Respiratory, thoracic and mediastinal disorders
Pharyngeal erythema	0/22 (0%)		1/19 (5.3%)		0/78 (0%)
Laryngeal edema	0/22 (0%)		1/19 (5.3%)		0/78 (0%)
Skin and subcutaneous tissue disorders
Skin Lesion	0/22 (0%)		1/19 (5.3%)		0/78 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.