Firazyr® Patient Registry (Icatibant Outcome Survey - IOS)

• ClinicalTrials.gov Identifier: NCT01034969
• Recruitment Status: Recruiting
• First Posted: December 18, 2009
• Last Update Posted: July 7, 2020
• Sponsor: Shire
• Collaborator: Takeda Development Center Americas, Inc.
• Information provided by (Responsible Party): Shire

Tracking Information

• First Submitted Date: December 17, 2009
• First Posted Date: December 18, 2009
• Last Update Posted Date: July 7, 2020
• Actual Study Start Date: July 10, 2009
• Estimated Primary Completion Date: May 24, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 31, 2018)

• Incidence of Cardiac Ischemia Events in Participants Predisposed to Cardiac Ischemia Events With Concomitant Firazyr (Icatibant) Administration [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  Incidence of cardiac ischemia events in participants predisposed to cardiac ischemia events with concomitant Firazyr (Icatibant) administration will be assessed.
• Incidence of Hypotension for Firazyr (Icatibant) [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  Incidence of hypotension for Firazyr (Icatibant) will be assessed.
• Incidence of Swelling of Mucous Membranes for Firazyr (Icatibant) [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  Incidence of swelling of mucous membranes for Firazyr (Icatibant) will be assessed.
• Incidence of Bronchoconstriction for Firazyr (Icatibant) [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  Incidence of bronchoconstriction for Firazyr (Icatibant) will be assessed.
• Incidence of Aggravation of Pain for Firazyr (Icatibant) [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  Incidence of aggravation of pain for Firazyr (Icatibant) will be assessed.
• Sexual Hormones Level Measurements- Tanner Staging for Firazyr (Icatibant) [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  Effects on sexual maturation in pubertal adolescents will be measured using Tanner staging (pubic hair stage and genital breast stage) for Firazyr (Icatibant).
• Time to Complete Resolution of the Firazyr (Icatibant)-Treated Laryngeal Attacks [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  Time to complete resolution of the laryngeal attacks will be assessed. It is defined as the time between the first injection of treatment and the complete resolution of all symptoms.
• Incidence of Adverse Events (AE) Related to Firazyr (Icatibant)-Treated Laryngeal Attacks [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  An AE is defined as any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in the registry, whether or not considered product-related. This includes an exacerbation of a pre-existing condition.
• Incidence of Adverse Drug Reactions (ADR) for Firazyr (Icatibant) [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  An ADR is a response to a medicinal product that is noxious and unintended and that occurs at doses normally used in man for prophylaxis, diagnosis, and treatment of disease or for the restoration, correction, or modification of physiological function.
• Incidence of Serious Adverse Events (SAE) for Firazyr (Icatibant) [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  An AE or ADR that meets 1 or more of the following criteria or outcomes is classified as an SAE whether considered to be related to the pharmaceutical product or not: death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; a persistent or significant disability or incapacity; a congenital anomaly or birth defect; important medical events.
• Incidence of Pregnancy and Lactation Events During Firazyr (Icatibant) Exposure [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  The incidence of pregnancy or lactation events coinciding with exposure to Firazyr (Icatibant) will be summarized by angioedema treatment and subgroup.
• Incidence of Adverse Events (AE) for Cinryze (C1 Inhibitor [Human]) [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  An AE is defined as any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in the registry, whether or not considered product-related. This includes an exacerbation of a pre-existing condition.
• Incidence of Adverse Drug Reactions (ADR) for Cinryze (C1 Inhibitor [Human]) [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  An ADR is a response to a medicinal product that is noxious and unintended and that occurs at doses normally used in man for prophylaxis, diagnosis, and treatment of disease or for the restoration, correction, or modification of physiological function.
• Incidence of Serious Adverse Events (SAE) for Cinryze (C1 Inhibitor [Human]) [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  An AE or ADR that meets 1 or more of the following criteria or outcomes is classified as an SAE whether considered to be related to the pharmaceutical product or not: death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; a persistent or significant disability or incapacity; a congenital anomaly or birth defect; important medical events.
• Incidence of Thrombotic or Thromboembolic Events for Cinryze (C1 Inhibitor [Human]) [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  Thrombotic or thromboembolic events will be reported as SAEs and will include, but are not limited to, established diagnoses of any of the following: renal allograft arterial or venous thrombosis; deep vein thrombosis; myocardial infarction; pulmonary embolism; Ischemic cerebrovascular accident (stroke)- cerebrovascular accident exclusive of cerebrovascular hemorrhage (subarachnoid or subdural hemorrhage); any large vessel thrombosis; thrombophlebitis; catheter-related thrombotic events (including clotted dialysis access grafts) will be assessed.
• Incidence of Pregnancy and Lactation Events During Cinryze (C1 Inhibitor [Human]) Exposure [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  The incidence of pregnancy or lactation events coinciding with exposure to Cinryze (C1 inhibitor [human]) will be summarized by angioedema treatment and subgroup.
• Drug Exposure Data for Cinryze (C1 Inhibitor [Human]) [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  Drug exposure data for Cinryze (C1 inhibitor [human]) for prophylaxis, pre-procedural, and acute treatments will be reported.
• Frequency of Hereditary Angioedema (HAE) Attacks in Participants Treated With Cinryze (C1 Inhibitor [Human]) [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  Frequency of HAE attacks in participants treated with Cinryze (C1 inhibitor [human]) will be assessed.
• Severity of Hereditary Angioedema Attacks in Participants Treated With Cinryze (C1 Inhibitor [Human]) [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  Severity of HAE attacks in participants treated with Cinryze (C1 inhibitor [human]) will be assessed.
• Anatomic Location of Hereditary Angioedema Attacks in Participants Treated With Cinryze (C1 Inhibitor [Human]) [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  Anatomic location of HAE attacks in participants treated with Cinryze (C1 inhibitor [human]) will be assessed.
• Outcome of Severe or Laryngeal Hereditary Angioedema Attacks in Participants Treated With Cinryze (C1 Inhibitor [Human]) [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  Outcome of severe or laryngeal HAE attacks in participants treated with Cinryze (C1 inhibitor [human]) will be assessed.
• Outcome of Hereditary Angioedema Attacks for Treatment With Cinryze (C1 Inhibitor [Human]) [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  Outcome of HAE attacks for treatment with Cinryze (C1 inhibitor [human]) which was initiated more than 4 hours after onset of the attack will be reported.

• Original Primary Outcome Measures (submitted: December 17, 2009): To monitor the safety of Firazyr® during long-term treatment [ Time Frame: Non-interventional patient registry ]

Current Secondary Outcome Measures (submitted: July 31, 2018)

• Time to Treatment For Attack [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  Time to treatment for attack will be assessed. It is defined as the time between the onset of the attack and the first injection of treatment.
• Time to Complete Resolution of Attack [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  Time to complete resolution of attack will be assessed. It is defined as the time between the first injection of treatment and the complete resolution of all symptoms.
• Total Duration of Attack [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  Total duration of attack will be assessed. It is defined as the time between the onset of the attack and the complete resolution of all symptoms
• Hereditary Angioedema-Treated Attacks [ Time Frame: From enrollment through study participation (Approximately 13 years) ]
  The frequency, severity, and affected sites of HAE-treated attacks will be reported.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Firazyr® Patient Registry (Icatibant Outcome Survey - IOS)
• Official Title: Icatibant Outcome Survey (IOS) Registry
• Brief Summary: The Icatibant Outcome Survey (IOS) is a prospective, observational disease registry designed to document the routine clinical outcomes over time in participants with angioedema treated with Firazyr® (icatibant) and/or Cinryze® (C1 inhibitor [human]) in countries where it is currently approved. The data collected will be used to evaluate the safety of Firazyr (icatibant) and Cinryze (C1 inhibitor [human]) in routine clinical practice and as a data source for post-marketing investigations.
• Detailed Description: The Icatibant Outcome Survey (IOS) is a multicenter, prospective, observational study for participants treated with Firazyr (icatibant) and/or Cinryze (C1 inhibitor [human]) in countries where it is currently approved. The entry of participants in the Icatibant Outcome Survey (IOS) is at the discretion of the physician and the participant and is not a pre-requisite for prescribing Firazyr (icatibant) or Cinryze (C1 inhibitor [human]).
• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided
• Biospecimen: Not Provided
• Sampling Method: Non-Probability Sample
• Study Population: Participants with Type I or II HAE, and, where applicable, with angiotensin-converting enzyme inhibitor (ACE-I)-induced angioedema, non-histaminergic idiopathic angioedema, or acquired angioedema, irrespective of treatment and/or other treatments and also participants who have taken at least 1 dose of Firazyr (Icatibant) or Cinryze (C1 inhibitor [human]) will be included in this study.
• Condition: Hereditary Angioedema (HAE)
• Intervention: Not Provided

Study Groups/Cohorts

Participants with hereditary angioedema (HAE)

All participants with hereditary angioedema (HAE) who are administered Cinryze (C1 inhibitor [human]) or Firazyr (Icatibant) for the treatment or prevention of angioedema attacks in routine clinical practice will be included into the study.

Publications *

• Longhurst HJ, Dempster J, Lorenzo L, Buckland M, Grigoriadou S, Symons C, Bethune C, Fabien V, Bangs C, Garcez T. Real-world outcomes in hereditary angioedema: first experience from the Icatibant Outcome Survey in the United Kingdom. Allergy Asthma Clin Immunol. 2018 Aug 6;14:28. doi: 10.1186/s13223-018-0253-x. eCollection 2018.
• Caballero T, Zanichelli A, Aberer W, Maurer M, Longhurst HJ, Bouillet L, Andresen I; IOS Study Group. Effectiveness of icatibant for treatment of hereditary angioedema attacks is not affected by body weight: findings from the Icatibant Outcome Survey, a cohort observational study. Clin Transl Allergy. 2018 Mar 23;8:11. doi: 10.1186/s13601-018-0195-x. eCollection 2018.
• Aberer W, Maurer M, Bouillet L, Zanichelli A, Caballero T, Longhurst HJ, Perrin A, Andresen I; IOS Study Group. Breakthrough attacks in patients with hereditary angioedema receiving long-term prophylaxis are responsive to icatibant: findings from the Icatibant Outcome Survey. Allergy Asthma Clin Immunol. 2017 Jul 5;13:31. doi: 10.1186/s13223-017-0203-z. eCollection 2017.
• Zanichelli A, Longhurst HJ, Maurer M, Bouillet L, Aberer W, Fabien V, Andresen I, Caballero T; IOS Study Group. Misdiagnosis trends in patients with hereditary angioedema from the real-world clinical setting. Ann Allergy Asthma Immunol. 2016 Oct;117(4):394-398. doi: 10.1016/j.anai.2016.08.014.
• Longhurst HJ, Aberer W, Bouillet L, Caballero T, Maurer M, Fabien V, Zanichelli A; IOS Study Group. The Icatibant Outcome Survey: treatment of laryngeal angioedema attacks. Eur J Emerg Med. 2016 Jun;23(3):224-7. doi: 10.1097/MEJ.0000000000000292.
• Longhurst HJ, Aberer W, Bouillet L, Caballero T, Fabien V, Zanichelli A, Maurer M; IOS Investigators. Analysis of characteristics associated with reinjection of icatibant: Results from the icatibant outcome survey. Allergy Asthma Proc. 2015 Sep-Oct;36(5):399-406. doi: 10.2500/aap.2015.36.3892. Erratum in: Allergy Asthma Proc. 2015 Nov-Dec;36(6):511.
• Hernández Fernandez de Rojas D, Ibañez E, Longhurst H, Maurer M, Fabien V, Aberer W, Bouillet L, Zanichelli A, Caballero T; IOS Study Group. Treatment of HAE Attacks in the Icatibant Outcome Survey: An Analysis of Icatibant Self-Administration versus Administration by Health Care Professionals. Int Arch Allergy Immunol. 2015;167(1):21-8. doi: 10.1159/000430864. Epub 2015 Jun 25.
• Maurer M, Longhurst HJ, Fabien V, Li HH, Lumry WR. Treatment of hereditary angioedema with icatibant: efficacy in clinical trials versus effectiveness in the real-world setting. Allergy Asthma Proc. 2014 Sep-Oct;35(5):377-81. doi: 10.2500/aap.2014.35.3780. Epub 2014 Aug 6.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 19, 2016): 3000
• Original Estimated Enrollment (submitted: December 17, 2009): 100
• Estimated Study Completion Date: May 24, 2023
• Estimated Primary Completion Date: May 24, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Diagnosis of at least 1 of the following:

   • Hereditary angioedema (HAE) type I or II
   • HAE with normal C1 inhibitor
   • ACE-I-induced angioedema
   • Non-histaminergic idiopathic angioedema
   • Acquired angioedema.
2. Signed and dated written informed consent from the participant or, for participants aged less than(<)18 years (or as per local regulation, such as <16 years in the United Kingdom [UK]), parent and/or participants legally authorized representative (LAR), and assent of the minor where applicable.
3. At sites only participating in the drug registry, participants must have taken at least 1 dose of Firazyr (Icatibant) or Cinryze (C1 inhibitor [human]).
4. Enrolled participants in Germany taking Firazyr (Icatibant) or Cinryze (C1 inhibitor [human]) will only use the respective product in accordance with the product label.

Exclusion Criteria:

1. Participants enrolled in clinical trials where the product is blinded or where the product under investigation is for the treatment of HAE, ACE-I-induced angioedema, non-histaminergic idiopathic angioedema, or acquired angioedema.
2. Participants enrolled in another Shire-sponsored registry involving products for the treatment of HAE, ACE-I-induced angioedema, non-histaminergic idiopathic angioedema, or acquired angioedema. An exception applies to participants enrolled in the Shire lanadelumab ENABLE study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No

Contacts

Contact: Takeda Development Center Americas Contact; +1 866 842 5335; ClinicalTransparency@takeda.com

• Listed Location Countries: Australia, Austria, Brazil, Czechia, Denmark, France, Germany, Greece, Ireland, Israel, Italy, Spain, Sweden, United Kingdom
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01034969
• Other Study ID Numbers: JE049-5134
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Shire provides access to the de-identified individual participant data for eligible studies to aid qualified researchers in addressing legitimate scientific objectives. These IPDs will be provided following approval of a data sharing request, and under the terms of a data sharing agreement.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described in the Data Sharing section of the www.shiretrials.com website. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• URL: https://www.shiretrials.com/en/our-commitment-to-transparency/data-sharing-with-researchers

• Responsible Party: Shire
• Study Sponsor: Shire
• Collaborators: Takeda Development Center Americas, Inc.

Investigators

• Study Director: Study Director; Takeda Development Center Americas

• PRS Account: Shire
• Verification Date: July 2020