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Effects of Dapagliflozin in Non-diabetic Patients With Proteinuria (DIAMOND)

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ClinicalTrials.gov Identifier: NCT03190694
Recruitment Status : Recruiting
First Posted : June 19, 2017
Last Update Posted : October 5, 2018
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Hiddo Lambers Heerspink, University Medical Center Groningen

Brief Summary:
This study tests the hypothesis that dapagliflozin lowers proteinuria in patients with non-diabetic chronic kidney disease.

Condition or disease Intervention/treatment Phase
Chronic Kidney Diseases Proteinuria Drug: Dapagliflozin 10mg Phase 2

Detailed Description:

Despite optimal treatment with renin-angiotensin-aldosterone-system (RAAS) inhibitors, many patients with non-diabetic kidney disease show progressive kidney function loss, which is associated with high residual proteinuria. Novel treatment strategies are therefore required to further decrease proteinuria and to slow kidney function decline.

Dapagliflozin is a sodium-glucose transport (SGLT2) inhibitor and inhibits the reabsorption of glucose and sodium in the proximal tubule. The increased natriuresis following dapagliflozin administration normalizes tubuloglomerular feedback resulting in a reduction in intra-glomerular hypertension, which is in turn manifested by acute reversible reductions in glomerular filtration rate and albuminuria. Since many etiologies of non-diabetic nephropathy are characterized by intraglomerular hypertension, we hypothesize that dapagliflozin acutely decreases GFR and proteinuria in patients without diabetes at risk of progressive kidney function loss via a glucose independent hemodynamic mechanism.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: A Randomized Double Blind 6-Weeks Cross-over
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: A Study to Assess the Renoprotective Effects of the SGLT2 Inhibitor Dapagliflozin in Non-Diabetic Patients With Proteinuria: a Randomized Double Blind 6-Weeks Cross-Over Trial
Actual Study Start Date : November 12, 2017
Estimated Primary Completion Date : July 16, 2019
Estimated Study Completion Date : December 1, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Diseases

Arm Intervention/treatment
Experimental: Dapagliflozin 10mg Tablet
10 mg Green, plain, diamond shaped, film coated tablet (orally)
Drug: Dapagliflozin 10mg
Tablet
Other Name: Placebo Matching Dapagliflozin 10mg

Placebo Comparator: Placebo Matching Dapagliflozin Tablet
Green, plain, diamond shaped, film coated tablet. Does not contain active ingredient
Drug: Dapagliflozin 10mg
Tablet
Other Name: Placebo Matching Dapagliflozin 10mg




Primary Outcome Measures :
  1. Change in 24-hr proteinuria with dapagliflozin for six weeks relative to placebo in patients with non-diabetic kidney disease and proteinuria 500 mg/day on stable angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker treatment. [ Time Frame: 6 weeks ]
    bioequivalence


Secondary Outcome Measures :
  1. Effect of dapagliflozin 10 mg/d compared to placebo on Glomerular Filtration Rate (GFR) using iohexol clearance [ Time Frame: 6 weeks ]
    bioequivalence

  2. Effect of dapagliflozin 10 mg/d compared to placebo on systolic/diastolic blood pressure [ Time Frame: week 0, 2, 4, 5, 6, 12, 15, 18, 24 ]
    bioequivalence

  3. Effect of dapagliflozin 10 mg/d compared to placebo on body weight [ Time Frame: week 0, 2, 4, 5, 6, 12, 15, 18, 24 ]
    bioequivalence

  4. Effect of dapagliflozin 10 mg/d compared to placebo on selected neurohormones/ biomarkers [ Time Frame: week 0, 3, 6, 12, 15, 18, 24 ]
    bioequivalence

  5. Safety of dapagliflozin vs. placebo - the number of hypoglycemia episodes between groups and serious adverse events [ Time Frame: week 0-26 ]
    safety



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age ≥18 and ≤75 years
  • Urinary protein excretion > 500 mg/g and ≤ 3500 mg/g in a 24-hr urine collection eGFR ≥ 25 mL/min/1.73m2
  • On a stable dose of an ACEi or ARB for at least 4 weeks prior to randomization
  • Willing to sign informed consent
  • Women of Child-Bearing Potential (WOCBP):
  • WOCBP must be using an acceptable method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the last dose of study drug in such a manner that the risk of pregnancy is minimized.
  • WOCBP must have a negative serum or urine pregnancy test result (minimum sensitivity 25 IU/L or equivalent units of HCG) within 0 to 72 hours before the first dose of study drug.
  • Women must not be breast-feeding.

WOCBP comprises women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who are not post-menopausal.

Exclusion Criteria:

  • Diagnosis of type 1 or type 2 diabetes mellitus
  • Urinary protein excretion > 3500 mg/day
  • Autosomal dominant polycystic kidney disease or autosomal recessive polycystic kidney disease, lupus nephritis, or ANCA-associated vasculitis
  • Indication for immunosuppressants as per the treating physician's judgment.
  • Receiving cytotoxic therapy, immunosuppressive therapy, or other immunotherapy for primary or secondary renal disease within 6 months prior to enrolment.
  • Active malignancy aside from treated squamous cell or basal cell carcinoma of the skin.
  • 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 of difficulty in voiding at screening
  • History of severe hypersensitivity or contraindications to dapagliflozin
  • Subject 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 investigation within 3 months prior to initial dosing.
  • Donation or loss of 400 ml or more of blood within 8 weeks 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
  • WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and up to 4 weeks after the last dose of study drug.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03190694


Contacts
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Contact: Hiddo J Lambers Heerspink, Prof.Dr. +31-50-3617859 h.j.lambers.heerspink@umcg.nl
Contact: David Cherney, Prof.Dr.MD +1-416-340-4151 david.cherney@uhn.ca

Locations
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Canada, British Columbia
Nephrology Dept., Vancouver Coastal Health Research Institute Recruiting
Vancouver, British Columbia, Canada, V5Z 1M9
Contact: Sean Barbour, MD    +1-604-875-5950    Sean.Barbour@vch.ca   
Canada, Ontario
Division of Nephrology University Health Network, University of Toronto Recruiting
Toronto, Ontario, Canada, M5G 2C4
Contact: David Cherney, Prof.MD    +1-416-340-4151    david.cherney@uhn.ca   
Malaysia
Nephrology Unit, University Kebangsaan Malaysia Recruiting
Kuala Lumpur, Malaysia, 5600
Contact: Halim Gafor, Prof.MD       halimgafor@gmail.com   
University Malaya Medical Centre, Ward 8TE Recruiting
Kuala Lumpur, Malaysia, 59100
Contact: Lim Soo Kun, Prof.MD    603-79494422    sookun_73@yahoo.com   
Netherlands
Dept Internal Medicine, division of Nephrology Hospital Group Twente Not yet recruiting
Almelo, Netherlands, 7609 PP
Contact: Gozewijn D Laverman, MD    +31-887084350    g.laverman@zgt.nl   
Dept.of Nephrology, VU University Medical Center Recruiting
Amsterdam, Netherlands, 1081 HV
Contact: Marcus G Vervloet, MD    +31-9032129301    m.vervloet@vumc.nl   
Dept. Nephrology, University Medical Center Groningen Recruiting
Groningen, Netherlands, 9713 GZ
Contact: Ron T Gansevoort, MD    +31-50-3616161    R.T.Gansevoort@umcg.nl   
Sponsors and Collaborators
Hiddo Lambers Heerspink
AstraZeneca

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Responsible Party: Hiddo Lambers Heerspink, Clinical Pharmacologist, University Medical Center Groningen
ClinicalTrials.gov Identifier: NCT03190694     History of Changes
Other Study ID Numbers: 2017003001
2017-001090-16 ( EudraCT Number )
First Posted: June 19, 2017    Key Record Dates
Last Update Posted: October 5, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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

Keywords provided by Hiddo Lambers Heerspink, University Medical Center Groningen:
chronic kidney disease
non diabetic

Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency, Chronic
Proteinuria
Urologic Diseases
Renal Insufficiency
Urination Disorders
Urological Manifestations
Signs and Symptoms
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs