## Protocol Section
### Identification Module
**NCT ID:** NCT05727579

**Acronym:** DESIGN

**Brief Title:** DiEtary Sodium Intake Effects on Ertugliflozin-induced Changes in GFR, reNal Oxygenation and Systemic Hemodynamics: the DESIGN Study

**Official Title:** DiEtary Sodium Intake Effects on Ertugliflozin-induced Changes in GFR, reNal Oxygenation and Systemic Hemodynamics: the DESIGN Study, a Randomized, Placebo-controlled, Cross-over Study With Ertugliflozin in People With Type 2 Diabetes

#### Organization Study ID Info
**ID:** DC2022ERTU
#### Organization
**Class:** OTHER
**Full Name:** Amsterdam UMC, location VUmc
### Status Module
#### Completion Date
**Date:** 2025-03-01

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2023-05-01

**Type:** ACTUAL

**Last Update Submit Date:** 2023-04-28

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2024-09-01

**Type:** ESTIMATED

#### Start Date
**Date:** 2023-06-01

**Type:** ESTIMATED

**Status Verified Date:** 2023-04

#### Study First Post Date
**Date:** 2023-02-14
**Type:** ACTUAL
**Study First Submit Date:** 2023-01-24
**Study First Submit QC Date:** 2023-02-03
### Sponsor Collaborators Module

#### Collaborators

**Class:** INDUSTRY

**Name:** Merck Sharp & Dohme LLC

**Class:** OTHER

**Name:** University of Colorado, Denver

#### Lead Sponsor

**Class:** OTHER

**Name:** Amsterdam UMC, location VUmc

#### Responsible Party

**Investigator Affiliation:** Amsterdam UMC, location VUmc

**Investigator Full Name:** D van Raalte

**Investigator Title:** Dr.

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** True

**Is US Export:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** SGLT2 inhibitors such as ertugliflozin improve blood pressure and kidney outcomes in people living with diabetes through incompletely understood mechanisms, however, not all patients treated with SGLT2 inhibition have improved outcomes. Changes in kidney sodium handling is among the mechanisms by which SGLT2 inhibition may reduce blood pressure and drive beneficial kidney outcomes. This process is heavily dependent on daily sodium intake by patients receiving SGLT2 inhibitor treatment. In this study, the effect of daily sodium intake on SGLT2-inhibitor induced physiological effect is studied, including blood pressure regulation and kidney physiology.

### Conditions Module

**Conditions:**

- Diabetes Mellitus

- Diabetic Kidney Disease

- Hypertension

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** CROSSOVER

**Intervention Model Description:** While the treatment by ertugliflozin or placebo will be blinded, the sodium interventions are open-label.

##### Masking Info

**Masking:** DOUBLE

**Who Masked:**

- PARTICIPANT

- INVESTIGATOR

**Primary Purpose:** BASIC_SCIENCE

#### Enrollment Info

**Count:** 34

**Type:** ESTIMATED

**Phases:**

- PHASE4

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Intervention Names:**

- Other: Salt-Diet and/or Ertugliflozin

**Label:** low-sodium diet; placebo

**Type:** OTHER

#### Arm Group 2

**Intervention Names:**

- Other: Salt-Diet and/or Ertugliflozin

**Label:** low-sodium diet; ertugliflozin 15 once daily

**Type:** OTHER

#### Arm Group 3

**Intervention Names:**

- Other: Salt-Diet and/or Ertugliflozin

**Label:** high-sodium diet; placebo

**Type:** OTHER

#### Arm Group 4

**Intervention Names:**

- Other: Salt-Diet and/or Ertugliflozin

**Label:** High-sodium diet; ertugliflozin 15 mg once daily

**Type:** OTHER

### Interventions

#### Intervention 1

**Arm Group Labels:**

- High-sodium diet; ertugliflozin 15 mg once daily

- high-sodium diet; placebo

- low-sodium diet; ertugliflozin 15 once daily

- low-sodium diet; placebo

**Description:** The interventions consist of an determined amount of dietary sodium intake in combination with either Ertugliflozin 15mg once daily or placebo

**Name:** Salt-Diet and/or Ertugliflozin

**Type:** OTHER

### Outcomes Module

#### Other Outcomes

**Description:** To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on GFR.

**Measure:** Glomerular filtration rate (GFR)

**Time Frame:** 24 weeks

**Description:** To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on hematocrit.

**Measure:** Hematocrit

**Time Frame:** 24 weeks

**Description:** To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on blood pressure.

**Measure:** Blood pressure

**Time Frame:** 24 weeks

**Description:** To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on kidney oxygenation.

**Measure:** Kidney oxygenation

**Time Frame:** 24 weeks

**Description:** To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on effective renal plasma flow.

**Measure:** Effective renal plasma flow

**Time Frame:** 24 weeks

**Description:** To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on renal vasculare resistance.

**Measure:** Renal vasculare resistance

**Time Frame:** 24 weeks

**Description:** To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on body anthropometrics

**Measure:** Body anthropometrics

**Time Frame:** 24 weeks

**Description:** To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on fasting plasma glucose

**Measure:** Fasting plasma glucose

**Time Frame:** 24 weeks

**Description:** To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on albumin excretion rate

**Measure:** Albumin excretion rate

**Time Frame:** 24 weeks

**Description:** To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on 24hr urinary glucose excretion

**Measure:** Glucose excretion

**Time Frame:** 24 weeks

**Description:** To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on biomarkers

**Measure:** Biomarkers

**Time Frame:** 24 weeks

#### Primary Outcomes

**Description:** To investigate the modifying effects of WHO-recommended sodium intake (90 mmol per day) vs. high sodium intake (targeted at 250 mmol per day) on the effect of ertugliflozin 15 mg daily, versus placebo, on 24-hour blood pressure in overweight/obese adults with type 2 diabetes

**Measure:** To investigate the modifying effect of sodium intake on Ertugliflozin on blood pressure

**Time Frame:** 24 weeks

#### Secondary Outcomes

**Description:** To investigate the efficacy of ertugliflozin 15 mg daily, versus placebo, in overweight/obese adults with type 2 diabetes to reduce the hypertensive effects of a high-sodium diet (250 mmol per day) versus participant's normal diet (170 mmol/per day).

**Measure:** To investigate the effect of Ertugliflozin on the hypertensive effects of high dietary sodium intake

**Time Frame:** 24 weeks

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Adults with previously diagnosed T2DM according to American Diabetes Association (ADA) criteria
* HbA1c 6.5-10%
* Age 35-80 years of age
* Overweight or obese with BMI: \>25 kg/m2
* We will make every effort to enrol participants of all races/ethnicities."
* Both sexes (females must be post-menopausal; no menses \>1 year; in case of doubt, Follicle-Stimulating Hormone (FSH) will be determined with cut-off defined as \>31 U/L)
* Ability to provide signed and dated, written informed consent prior to any study procedures
* Estimated GFR 60-90 ml/min/1.73m2 by CKD-EPI matching the eGFR range of most participants in VERTIS-CV
* Sodium intake at baseline \< 200 mmol/day
* UACR \< 30 mg/mmol
* All participants need to be on a stable dose of Diabetes medication, including Metformin, SU, insulin
* All participants need to be on a stable dose of RAS inhibition

Exclusion Criteria:

History of unstable or rapidly progressing renal disease

* Estimated GFR \<60 mL/min/1.73m2 or eGFR \> 90 mL/min/1.73m2 determined by CKD-EPI
* UACR \> 30 mg/mmol
* Current/chronic use of the following medication: SGLT2 inhibitors, TZD, GLP-1RA, glucocorticoids, immune suppressants, antimicrobial agents, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). Subjects on diuretics will only be excluded when these drugs cannot be stopped for the duration of the study.
* Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) will not be allowed, unless used as incidental medication (1-2 tablets) for non-chronic indications (i.e. sports injury, headache or back ache). However, no such drug can be taken within a timeframe of 2 weeks prior to renal testing
* History of diabetic ketoacidosis (DKA) requiring medical intervention (e.g. emergency room visit and/or hospitalization) within 1 month prior to the Screening visit.
* Current urinary tract infection and active nephritis
* Recent (\<6 months) history of cardiovascular disease, including:

  * Acute coronary syndrome
  * Chronic heart failure (New York Heart Association grade II-IV)
  * Stroke or transient ischemic neurologic disorder
* Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) \>3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) \>3x ULN
* History of or actual malignancy (except basal cell carcinoma)
* History of or actual severe mental disease
* Substance abuse (alcohol: defined as \>4 units/day)
* Allergy to any of the agents used in the study
* Individuals who are investigator site personnel, directly affiliated with the study, or are immediate (spouse, parent, child, or sibling, whether biological or legally adopted) family of investigator site personnel directly affiliated with the study
* Inability to understand the study protocol or give informed consent

**Maximum Age:** 80 Years

**Minimum Age:** 35 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** d.vanraalte@amsterdamumc.nl

**Name:** Daniel van Raalte, MD PhD

**Phone:** +31204440534

**Role:** CONTACT

### IPD Sharing Statement Module

**IPD Sharing:** UNDECIDED

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000014570

- Term: Urologic Diseases

- ID: D000052776

- Term: Female Urogenital Diseases

- ID: D000005261

- Term: Female Urogenital Diseases and Pregnancy Complications

- ID: D000091642

- Term: Urogenital Diseases

- ID: D000052801

- Term: Male Urogenital Diseases

- ID: D000048909

- Term: Diabetes Complications

- ID: D000003920

- Term: Diabetes Mellitus

- ID: D000004700

- Term: Endocrine System Diseases

### 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

- Abbrev: BXS

- Name: Urinary Tract, Sexual Organs, and Pregnancy Conditions

- Abbrev: BC14

- Name: Heart and Blood Diseases

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M7115

- Name: Diabetes Mellitus

- Relevance: LOW

- As Found: Unknown

- ID: M7119

- Name: Diabetes Mellitus, Type 2

- Relevance: LOW

- As Found: Unknown

- ID: M10698

- Name: Kidney Diseases

- Relevance: HIGH

- As Found: Kidney Disease

- ID: M10024

- Name: Hypertension

- Relevance: LOW

- As Found: Unknown

- ID: M7123

- Name: Diabetic Nephropathies

- Relevance: HIGH

- As Found: Diabetic Kidney Disease

- ID: M17319

- Name: Urologic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M2875

- Name: Urogenital Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M27093

- Name: Female Urogenital Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M14127

- Name: Pregnancy Complications

- Relevance: LOW

- As Found: Unknown

- ID: M8399

- Name: Female Urogenital Diseases and Pregnancy Complications

- Relevance: LOW

- As Found: Unknown

- ID: M27095

- Name: Male Urogenital Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M26004

- Name: Diabetes Complications

- Relevance: LOW

- As Found: Unknown

- ID: M7862

- Name: Endocrine System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T4202

- Name: Oculocerebral Syndrome With Hypopigmentation

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000007674

- Term: Kidney Diseases

- ID: D000003928

- Term: Diabetic Nephropathies

### Intervention Browse Module - Ancestors

- ID: D000077203

- Term: Sodium-Glucose Transporter 2 Inhibitors

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

- ID: D000007004

- Term: Hypoglycemic Agents

- ID: D000045505

- Term: Physiological Effects of Drugs

### Intervention Browse Module - Browse Branches

- Abbrev: Hypo

- Name: Hypoglycemic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M263808

- Name: Ertugliflozin

- Relevance: HIGH

- As Found: Esophagitis

- ID: M1691

- Name: Sodium-Glucose Transporter 2 Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M10054

- Name: Hypoglycemic Agents

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: C000570288

- Term: Ertugliflozin

### Misc Info Module

- Version Holder: 2024-05-24
