## Protocol Section
### Identification Module
**NCT ID:** NCT05402579

**Acronym:** DaNGER

**Brief Title:** Diabetic Ketoacidosis From New SGLT2i: Can Genomics Estimate Risk

**Official Title:** Diabetic Ketoacidosis From New SGLT2i: Can Genomics Estimate Risk (DaNGER)

#### Organization Study ID Info
**ID:** CTO 3737
#### Organization
**Class:** OTHER
**Full Name:** Mount Sinai Hospital, Canada
### Status Module
#### Completion Date
**Date:** 2024-06-06

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2023-07-11

**Type:** ACTUAL

**Last Update Submit Date:** 2023-07-07

**Overall Status:** RECRUITING

#### Primary Completion Date
**Date:** 2024-06-06

**Type:** ESTIMATED

#### Start Date
**Date:** 2022-07-29

**Type:** ACTUAL

**Status Verified Date:** 2023-07

#### Study First Post Date
**Date:** 2022-06-02
**Type:** ACTUAL
**Study First Submit Date:** 2022-05-30
**Study First Submit QC Date:** 2022-05-30
### Sponsor Collaborators Module

#### Collaborators

**Class:** OTHER

**Name:** Unity Health Toronto

**Class:** OTHER

**Name:** University Health Network, Toronto

**Class:** OTHER

**Name:** Sault Area Hospital

#### Lead Sponsor

**Class:** OTHER

**Name:** Mount Sinai Hospital, Canada

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** Sodium glucose co-transporter 2 (SGLT2) inhibitors have revolutionized care for people living with type 2 diabetes mellitus (T2DM). They reduce a person's risk of heart failure, renal failure, myocardial infarction, stroke, cardiovascular mortality, and potentially all-cause mortality. Remarkably, some of these benefits also extend to people who do not have T2DM. While the benefits of SGLT2 inhibitors are impressive, there is one life-threatening side effect associated with their use: diabetic ketoacidosis (DKA). The ability to predict which patients are at highest risk of DKA is needed to sufficiently mitigate this risk. Moreover, considering the impressive benefits of SGLT2 inhibitors, identifying patients at the lowest risk of SGLT2 inhibitor-associated DKA is also important so that providers do not overestimate risk in those who stand to benefit most.

Advances in genomic technologies and related analyses have provided unprecedented opportunities to bring genomics-driven precision medicine initiatives to the forefront of clinical research. Leading these developments has been the progress made by genome-wide association studies (GWAS) due to decreasing genotyping costs, and consequently, the ability to routinely study large numbers of patients. These approaches allow for systematic screening of the genome in an unbiased manner and have accelerated the discovery of genetic variants and novel biological processes that contribute to the development of adverse treatment outcomes.

By using innovative approaches, which harness large cohorts of population controls, sample size limitations that are associated with rare adverse drug reactions such as SGLT2 inhibitor-associated DKA can be overcome. The DANGER study represents a highly innovative new direction wherein partnership among basic science researchers and computational biologists will lead to the application of genomic techniques to identify genetic variants that may be associated with SGLT2 inhibitor-associated DKA.

### Conditions Module

**Conditions:**

- Diabetes Type 2

- DKA

- Diabetic Ketoacidosis

**Keywords:**

- DKA

- SGLT2i

- Diabetes Type 2

### Design Module

#### Bio Spec

**Description:** Genetic samples will be collected using a DNA saliva collection kit (Oragene: OG-510) and will be sent for genome-wide genotyping to The Centre for Applied Genomics in The Hospital for Sick Children (SickKids)

**Retention:** NONE_RETAINED

#### Design Info

**Observational Model:** CASE_CONTROL

**Time Perspective:** OTHER

#### Enrollment Info

**Count:** 200

**Type:** ESTIMATED

**Study Type:** OBSERVATIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Patients with type 2 diabetes mellitus who were hospitalized with SGLT2 inhibitor-associated DKA

**Intervention Names:**

- Genetic: Genomic analysis

**Label:** Cases

#### Arm Group 2

**Description:** There are two sources for controls. \[1\] Patients hospitalized at one of the participating hospitals who were on an SGLT2i and do not have DKA. \[2\] Population controls using publicly available data from the Canadian Longitudinal Study on Aging (CLSA) database.

**Intervention Names:**

- Genetic: Genomic analysis

**Label:** Controls

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Cases

- Controls

**Description:** Genetic samples will be collected using a DNA saliva collection kit (Oragene: OG-510) and will be sent for genome-wide genotyping to The Centre for Applied Genomics in The Hospital for Sick Children (SickKids)

**Name:** Genomic analysis

**Type:** GENETIC

### Outcomes Module

#### Primary Outcomes

**Description:** Genetic ancestry will be calculated using principal component analyses and outliers will be removed. GWAS will be performed with SAIGE, including genetic ancestry and the relevant clinical/demographic variables as covariates, to identify genetic variants associated with SGLT2 inhibitor-associated DKA.

**Measure:** Identification of genomic variants associated with an increased risk of SGLT2 inhibitor-associated DKA

**Time Frame:** One year

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

To be considered eligible for participation in this study, a participant must meet each of the following criteria:

1. Be 18 years or older and have a diagnosis of type 2 diabetes mellitus.
2. Have been admitted to hospital with SGLT2 inhibitor-associated DKA (cases) or admitted to hospital on an SGLT2 inhibitor and not have DKA (controls).
3. Be able to provide written consent (or, if patient is unable, have a substitute decision maker \[SDM\] available).

Exclusion Criteria:

A participant will be ineligible for participation in this study if he or she satisfies any one or more of the following criteria:

1. Diagnosis of type 1 diabetes mellitus.
2. Unable to spit 10mL into a vial.
3. A first degree relative has already been recruited into the study.

Our study will not include children or pregnant women because SGLT2 inhibitors are not approved for use in either patient population.

**Maximum Age:** 100 Years

**Minimum Age:** 18 Years

**Sampling Method:** NON_PROBABILITY_SAMPLE

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

**Study Population:** Cases: Patients with type 2 diabetes mellitus who were hospitalized with SGLT2 inhibitor-associated DKA will be eligible for inclusion in our study.

Controls: There are two sources for controls. \[1\] Patients hospitalized at one of the participating hospitals who were on an SGLT2i and do not have DKA. \[2\] Population controls using publicly available data from the Canadian Longitudinal Study on Aging (CLSA) database.

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** mike.fralick@sinaihealth.ca

**Name:** Michael Fralick, MD, PhD

**Phone:** 4165864800

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Toronto

**Contacts:**

***Contact 1:***

- **Email:** mike.fralick@sinaihealth.ca

- **Name:** Michael Fralick

- **Role:** CONTACT

**Country:** Canada

**Facility:** St. Joseph's Health Centre (Unity Health Toronto)

**State:** Ontario

**Status:** RECRUITING

**Location 2:**

**City:** Toronto

**Contacts:**

***Contact 1:***

- **Email:** mike.fralick@sinaihealth.ca

- **Name:** Michael Fralick

- **Role:** CONTACT

**Country:** Canada

**Facility:** Toronto General Hospital (University Health Network)

**State:** Ontario

**Status:** RECRUITING

### IPD Sharing Statement Module

**IPD Sharing:** NO

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000003920

- Term: Diabetes Mellitus

- ID: D000044882

- Term: Glucose Metabolism Disorders

- ID: D000008659

- Term: Metabolic Diseases

- ID: D000004700

- Term: Endocrine System Diseases

- ID: D000000137

- Term: Acid-Base Imbalance

- ID: D000048909

- Term: Diabetes Complications

### Condition Browse Module - Browse Branches

- Abbrev: BC18

- Name: Nutritional and Metabolic Diseases

- Abbrev: BC19

- Name: Gland and Hormone Related Diseases

- Abbrev: All

- Name: All Conditions

### Condition Browse Module - Browse Leaves

- ID: M7115

- Name: Diabetes Mellitus

- Relevance: LOW

- As Found: Unknown

- ID: M7119

- Name: Diabetes Mellitus, Type 2

- Relevance: HIGH

- As Found: Diabetes Type 2

- ID: M10687

- Name: Ketosis

- Relevance: HIGH

- As Found: Ketoacidosis

- ID: M19230

- Name: Diabetic Ketoacidosis

- Relevance: HIGH

- As Found: Diabetic Ketoacidosis

- ID: M3499

- Name: Acidosis

- Relevance: HIGH

- As Found: Ketoacidosis

- ID: M11639

- Name: Metabolic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M25403

- Name: Glucose Metabolism Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M7862

- Name: Endocrine System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M3498

- Name: Acid-Base Imbalance

- Relevance: LOW

- As Found: Unknown

- ID: M26004

- Name: Diabetes Complications

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000003924

- Term: Diabetes Mellitus, Type 2

- ID: D000007662

- Term: Ketosis

- ID: D000000138

- Term: Acidosis

- ID: D000016883

- Term: Diabetic Ketoacidosis

### Intervention Browse Module - Browse Branches

- Abbrev: Hypo

- Name: Hypoglycemic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M1691

- Name: Sodium-Glucose Transporter 2 Inhibitors

- Relevance: LOW

- As Found: Unknown

### Misc Info Module

- Version Holder: 2024-05-24
