## Protocol Section
### Identification Module
**NCT ID:** NCT03828279

**Acronym:** HGR

**Brief Title:** Global Registry to Gather Data on Natural History of Patients With Hereditary Angioedema Type I and II

**Official Title:** The Global Registry on Hereditary Angioedema Type I and II

#### Organization Study ID Info
**ID:** HAERegistry
#### Organization
**Class:** OTHER
**Full Name:** HAE Global Registry Foundation
### Status Module
#### Completion Date
**Date:** 2023-12-31

**Type:** ESTIMATED

#### Expanded Access Info
**Last Known Status:** RECRUITING
#### Last Update Post Date
**Date:** 2019-02-05

**Type:** ACTUAL

**Last Update Submit Date:** 2019-02-03

**Overall Status:** UNKNOWN

#### Primary Completion Date
**Date:** 2019-12-31

**Type:** ESTIMATED

#### Start Date
**Date:** 2017-10-01

**Type:** ACTUAL

**Status Verified Date:** 2019-01

#### Study First Post Date
**Date:** 2019-02-04
**Type:** ACTUAL
**Study First Submit Date:** 2019-01-23
**Study First Submit QC Date:** 2019-01-31
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** HAE Global Registry Foundation

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** True

### Description Module

**Brief Summary:** The objective of this international hereditary angioedema (HAE) register is to collect homogeneous clinical and laboratory data on patients with HAE type I and II gathering better information on the natural course of the disease and detecting therapeutic options to manage it.

**Detailed Description:** It is an international multicenter disease registry, the principal investigator at each center is responsible for competent ethic committee/institutional review board approval and for identifying co-investigators, who collect patients' informed consent and insert patients' data. Participating patients own their data. Upon acceptance of the informed consent, the treating physician transfers data of the case report form (CRF) to a specifically designed electronic support (eCRF) and the patients enter data on attacks. Physicians at center fill-in the eCRF with data for demography, diagnosis, prophylaxis and associated diseases. Plasma levels of C1 inhibitor antigen and function and of C4 antigen document laboratory diagnostic criteria. Each patient has a national identifier code. Patients fill-in attack reports that encompass duration, severity and treatment of each angioedema episode. C1 inhibitor coding gene (SERPING1) genotype is entered according to the last Hugo nomenclature. Yearly update of information is recommended, patients with follow up above two years are moved in a separate area and excluded from analysis. Each patient prospectively fills data on attacks. On a specific informed consent, the patient can agree on storing biological material (plasma and nucleic acids) for research purposes.

The data processor is an innovative start-up (Cloud-R s.r.l. Milan, Italy) that manages all data according to a specific contract and in compliance with current regulation on sensitive data security and processing. The Registry, delivered in the mode of Registry-as-a-Service (RaaS), is designed following General Data Protection Regulation (GDPR) guidelines, and issues regular software and infrastructure enhancements as a part of the normal operational mode. The system generates statistics of aggregated anonymized data following the participating centers' hierarchy levels and Global Registry governance rules. Patients supply data on attacks either on paper support or using a Web form or a mobile application. These data will flow into a staging area for physician validation before being considered valid for statistics. For each entry the system updates in real-time all the statistics and dashboards. The platform has configurable functionalities to support data quality management. It provides data format validation, integration to external qualified libraries, alerts, dashboards, automatic index calculations, advanced filters and queries, data change log. This open architecture, allows integration of the system, via standard API's, to external or sub-registries, registries, biobanks and clinical bioinformatics tools, i.e. for specific trial studies leveraging a specific cluster of patients already present in the Global Registry.

An independent non-profit foundation (HGRF) made of representatives of patients' associations is in charge for funding and delegates all the management to the HAE Global Registry Board (HGRB). The HGRB is in charge for operational, assisted by the HAE Global Registry Scientific Committee (HGRSC) for topics of competence. No registry member, center, group or board can access the entire set of data. All registry members, as single or group, can propose studies based on aggregated data by addressing the request to the HGRSC. Analysis and studies of data at local centers can occur at any time. Members of HGRB and HGRSC are elected to be representative of different cultural and geographic backgrounds. Their offices have a two-year term with no more than one consecutive renewal. Angioedema centers can join the Registry upon request to the HGRB . The registry quality control system periodically checks Registry entries and compliance of eCRF with the source data. For each information, the system will grant traceability of time and author.

### Conditions Module

**Conditions:**

- Hereditary Angioedema Type I and II

**Keywords:**

- angioedema

- disease registry

- C1 inhibitor

- anti bradykinin treatments

### Design Module

#### Bio Spec

**Description:** Sodium Citrate samples are collected form patients for testing plasma levels of C1 inhibitor antigen and function and C4 antigen. Cells are collected for DNA extraction and detection of mutations in SERPING1

**Retention:** SAMPLES_WITH_DNA

#### Design Info

**Observational Model:** COHORT

**Time Perspective:** PROSPECTIVE

#### Enrollment Info

**Count:** 220

**Type:** ESTIMATED

**Patient Registry:** True

**Study Type:** OBSERVATIONAL

**Target Duration:** 1 Year

### Arms Interventions Module

#### Arm Group 1

**Description:** Patients were diagnosed as C1 inhibitor HAE type I when functional and antigenic C1 inhibitor were ≤ 50% of normal

**Intervention Names:**

- Diagnostic Test: functional and antigenic C1 inhibitor

**Label:** hereditary angioedema type I

#### Arm Group 2

**Description:** Patients were diagnosed as type II when functional C1 inhibitor was ≤50% and antigenic was \>50% of normal

**Intervention Names:**

- Diagnostic Test: functional and antigenic C1 inhibitor

**Label:** hereditary angioedema type II

### Interventions

#### Intervention 1

**Arm Group Labels:**

- hereditary angioedema type I

- hereditary angioedema type II

**Description:** Diagnosis of HAE is based on personal and/or family history of angioedema and on C1 inhibitor functional or antigenic plasma levels ≤50% of normal.

**Name:** functional and antigenic C1 inhibitor

**Other Names:**

- genetic analysis

**Type:** DIAGNOSTIC_TEST

### Outcomes Module

#### Primary Outcomes

**Description:** Number of angioedema events

**Measure:** Number of angioedema events

**Time Frame:** Through study completion, an average of 5 years

**Description:** Time in hours of presence of angioedema symptoms

**Measure:** Time of angioedema events

**Time Frame:** Through study completion, an average of 5 years

**Description:** Number of severe, moderate, mild angioedema symptoms based on a three point scale patient reported outcome

**Measure:** Severity of angioedema events

**Time Frame:** through study completion, an average of 5 years

#### Secondary Outcomes

**Description:** Number and type of comorbidities recorded according to the International Classification of Diseases 9 codes

**Measure:** Comorbidities

**Time Frame:** Through study completion , an average of 5 years

**Description:** Incidence of comorbidities emerging in patients exposed to specific treatments

**Measure:** Treatment-Emergent comorbidities

**Time Frame:** Through study completion , an average of 5 years

**Description:** Hours of presence of angioedema symptoms during specific long term prophylaxis

**Measure:** Treatment efficacy

**Time Frame:** Through study completion , an average of 5 years

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* patients diagnosed with HAE type I and II with signed informed consent
* laboratory diagnostic criteria documenting plasma levels of C1 inhibitor antigen and function and of C4 antigen

Exclusion Criteria:

* patients without HAE type I and II
* patients without documented laboratory diagnostic criteria
* patients not capable to give informed consent

**Healthy Volunteers:** True

**Sampling Method:** PROBABILITY_SAMPLE

**Sex:** ALL

**Standard Ages:**

- CHILD

- ADULT

- OLDER_ADULT

**Study Population:** patients diagnosed with HAE type I and II and followed by a referral center for angioedema

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** marco.cicardi@unimi.it

**Name:** marco cicardi, MD

**Phone:** +39 0239042516

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Milan

**Contacts:**

***Contact 1:***

- **Email:** marco.cicardi@unimi.it

- **Name:** marco cicardi, M.D.

- **Phone:** +3950319829

- **Role:** CONTACT

**Country:** Italy

**Facility:** ASST FBF Sacco

**Status:** RECRUITING

**Zip:** 20157

#### Overall Officials

**Official 1:**

**Affiliation:** HAE Global Registry Foundation

**Name:** marco cicardi, MD

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**Access Criteria:** to be a member of the HAERegistry and have the approval of the HGRSC to analyze data

**Description:** All registry members, as single or group, can propose studies based on aggregated anonymized data by addressing the request to the HAE Global Registry Scientific Committee (HGRSC)

**Info Types:**

- STUDY_PROTOCOL

- SAP

- ICF

- CSR

**IPD Sharing:** YES

**Time Frame:** entire study period

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000014652

- Term: Vascular Diseases

- ID: D000002318

- Term: Cardiovascular Diseases

- ID: D000014581

- Term: Urticaria

- ID: D000017445

- Term: Skin Diseases, Vascular

- ID: D000012871

- Term: Skin Diseases

- ID: D000006969

- Term: Hypersensitivity, Immediate

- ID: D000006967

- Term: Hypersensitivity

- ID: D000007154

- Term: Immune System Diseases

- ID: D000081208

- Term: Hereditary Complement Deficiency Diseases

- ID: D000081207

- Term: Primary Immunodeficiency Diseases

- ID: D000030342

- Term: Genetic Diseases, Inborn

- ID: D000007153

- Term: Immunologic Deficiency Syndromes

### Condition Browse Module - Browse Branches

- Abbrev: BC14

- Name: Heart and Blood Diseases

- Abbrev: BC17

- Name: Skin and Connective Tissue Diseases

- Abbrev: BC20

- Name: Immune System Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BC16

- Name: Diseases and Abnormalities at or Before Birth

- Abbrev: BC18

- Name: Nutritional and Metabolic Diseases

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M4127

- Name: Angioedema

- Relevance: HIGH

- As Found: Angioedema

- ID: M27584

- Name: Angioedemas, Hereditary

- Relevance: HIGH

- As Found: Hereditary Angioedema

- ID: M28606

- Name: Hereditary Angioedema Types I and II

- Relevance: HIGH

- As Found: Hereditary Angioedema Types I and II

- ID: M17400

- Name: Vascular Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M17330

- Name: Urticaria

- Relevance: LOW

- As Found: Unknown

- ID: M15674

- Name: Skin Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M19714

- Name: Skin Diseases, Vascular

- Relevance: LOW

- As Found: Unknown

- ID: M10018

- Name: Hypersensitivity

- Relevance: LOW

- As Found: Unknown

- ID: M10020

- Name: Hypersensitivity, Immediate

- Relevance: LOW

- As Found: Unknown

- ID: M10200

- Name: Immune System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M6879

- Name: Deficiency Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M2286

- Name: Hereditary Complement Deficiency Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M10199

- Name: Immunologic Deficiency Syndromes

- Relevance: LOW

- As Found: Unknown

- ID: M2285

- Name: Primary Immunodeficiency Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M23686

- Name: Genetic Diseases, Inborn

- Relevance: LOW

- As Found: Unknown

- ID: M16355

- Name: Syndrome

- Relevance: LOW

- As Found: Unknown

- ID: T2734

- Name: Hereditary Angioedema

- Relevance: HIGH

- As Found: Hereditary Angioedema

### Condition Browse Module - Meshes

- ID: D000000799

- Term: Angioedema

- ID: D000054179

- Term: Angioedemas, Hereditary

- ID: D000056829

- Term: Hereditary Angioedema Types I and II

### Intervention Browse Module - Ancestors

- ID: D000051056

- Term: Complement Inactivating Agents

- ID: D000007166

- Term: Immunosuppressive Agents

- ID: D000007155

- Term: Immunologic Factors

- ID: D000045505

- Term: Physiological Effects of Drugs

### Intervention Browse Module - Browse Branches

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: VaDiAg

- Name: Vasodilator Agents

### Intervention Browse Module - Browse Leaves

- ID: M26365

- Name: Complement C1 Inhibitor Protein

- Relevance: HIGH

- As Found: Biometry

- ID: M5197

- Name: Bradykinin

- Relevance: LOW

- As Found: Unknown

- ID: M10725

- Name: Kininogens

- Relevance: LOW

- As Found: Unknown

- ID: M6392

- Name: Complement System Proteins

- Relevance: LOW

- As Found: Unknown

- ID: M6401

- Name: Complement C1 Inactivator Proteins

- Relevance: LOW

- As Found: Unknown

- ID: M10212

- Name: Immunosuppressive Agents

- Relevance: LOW

- As Found: Unknown

- ID: M10201

- Name: Immunologic Factors

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000050718

- Term: Complement C1 Inhibitor Protein

### Misc Info Module

- Version Holder: 2024-05-24
