TreatIng Microalbuminuria Over 24 Weeks in Subjects With or Without Type 2 Diabetes or HYpertension (TIMOTHY)

Rationale:

Increased albuminuria has a relatively high prevalence in the general population (5-9%) People with increased albuminuria are more likely to develop progressive kidney and cardiovascular disease compared to persons with no albuminuria. ACE-inhibitors or Angiotensin Receptor Blockers are recommended by clinical practice guidelines to lower albuminuria in patients with hypertension and diabetes. However, despite these drugs decrease albuminuria by approximately 30%, elevated albuminuria remains present in the substantial proportion of persons in the general population.

SGLT2 inhibitors are a relatively new class of drugs. Originally they were developed as oral antihyperglycemic drugs. SGLT2 inhibitors have been demonstrated to lower albuminuria and protect the kidney in patients with established chronic kidney disease (CKD) with or without diabetes. Whether the efficacy of SGTL2 inhibitors to lower albuminuria (and possibly confer kidney protection) to persons in the general population (with or without diabetes or hypertension) with persistent albuminuria who generally are at early stages of CKD is unknown.

Objective:

To assess the albuminuria lowering effects of dapagliflozin in subjects with and without diabetes or hypertension and persistent elevated albuminuria.

Study design:

Randomized placebo-controlled double blind clinical trial of 24 weeks in duration followed by a 4 weeks wash-out period

Study Overview

• Status: Terminated
• Conditions: Albuminuria
• Intervention / Treatment: Drug: Placebo; Drug: Dapagliflozin 10Mg Tab

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands
    • UMCG

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 45 to 80 years
• Persistent urinary albumin:creatinine ratio (UACR) ≥ 2.5 mg/mmol (~25 mg/g)
• Willing to sign informed consent

Exclusion Criteria:

Diagnosis of type 1 diabetes mellitus

• eGFR < 25 ml/min/1.73m2
• UACR > 3500 mg/g
• Concurrent treatment with SGLT2 inhibitor
• Receiving immunosuppressive therapy within 6 months prior to enrolment
• History of diabetic ketoacidosis
• Active malignancy aside from treated squamous cell or basal cell carcinoma of the skin.
• Initiation or changes in the dose of interventions in the renin-angiotensinaldosterone- system, diuretics, GLP-1 receptor agonists within 6 weeks of screening will not be allowed.

• Any medication, surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of medications including, but not limited to any of the following:

  • History of active inflammatory bowel disease within the last six months;
  • Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection;
  • Gastro-intestinal ulcers and/or gastrointestinal or rectal bleeding within last six months;
  • Pancreatic injury or pancreatitis within the last six months;
  • Evidence of hepatic disease as determined by any one of the following: ALT or AST values exceeding 3x ULN at the screening visit, a history of hepatic encephalopathy, a history of esophageal varices, or a history of portocaval shunt;
  • Evidence of urinary obstruction or difficulty in voiding at screening
• History of severe hypersensitivity or contraindications to dapagliflozin
• Subjects who, in the assessment of the investigator, may be at risk for dehydration or volume depletion that may affect the interpretation of efficacy or safety data
• Participation in any clinical intervention study within 3 months prior to initial dosing.
• History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during the screening.
• History of noncompliance to medical regimens or unwillingness to comply with the study protocol.
• Any surgical or medical condition, which in the opinion of the investigator, may place the patient at higher risk from his/her participation in the study, or is likely to prevent the patient from complying with the requirements of the study or completing the study.
• Pregnancy or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo
Active Comparator: Dapagliflozin 10mg/day	Drug: Dapagliflozin 10Mg Tab; dapagliflozin 10 mg/d or matched placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
urinary albumin/creatinine ratio	Change in albuminuria defined as urinary albumin/creatinine ratio: UACR) with dapagliflozin 10mg/d for 24 weeks relative to placebo	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
systolic and diastolic blood pressure	Change in systolic and diastolic blood pressure: effect of dapagliflozin 10mg/d compared to placebo on change in systolic and diastolic blood pressure	24 weeks
body weight	change in body weight: effect of dapagliflozin 10mg/d compared to placebo on change in body	24 weeks
HbA1c	change in HbA1c: effect of dapagliflozin 10mg/day compared to placebo on change in HbA1c	24 weeks
eGFR	change in eGFR: effect of dapagliflozin 10mg/day compared to placebo on change in eGFR	24 weeks
change in UACR	difference in proportion of patients with ≥30%, 40%, 50% change in UACR from baseline at week 24.: effect of dapagliflozin 10mg/day compared to placebo on the proportion of patients with ≥30%, 40%, 50% change in UACR	24 weeks
number of SAE's and AE's	Safety of dapagliflozin vs Placebo: number of SAE's and AE's reported by the subject or investigator if qualified as: reason for discontinuation, volume depletion, fracture, diabetic ketoacidosis, amputation and adverse events leading to amputation, urinary tract infection, genital infections and hypoglycemia	24 weeks

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Collaborators: AstraZeneca

Study record dates

Study Major Dates

• Study Start (Actual): February 3, 2022
• Primary Completion (Actual): February 2, 2023
• Study Completion (Actual): February 2, 2023

Study Registration Dates

• First Submitted: December 2, 2021
• First Submitted That Met QC Criteria: February 24, 2022
• First Posted (Actual): March 7, 2022

Study Record Updates

• Last Update Posted (Actual): April 17, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Urologic Diseases; Urological Manifestations; Urination Disorders; Proteinuria; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Hypertension; Albuminuria; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: 2021/1001; 2021-004073-31 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No