Reduction of Peritoneal Glucose Uptake With Use of SGLT2 in Humans Undergoing Peritoneal Dialysis Treatment (PRESERVE)

Reduction of Peritoneal Glucose Uptake With Use of SGLT2 in Humans Undergoing Peritoneal Dialysis Treatment. A Proof of Concept Phase 2a Clinical Trial.

End stage renal disease is annually diagnosed in about one thousand patients in Denmark, and one of the treatment modalities in renal replacement therapy is peritoneal dialysis with about 25 % of patients assigned to this treatment (Hommel2010). Peritoneal dialysis is based on the principle of filtering waste products to peritoneal fluid and by exchange of peritoneal fluid eliminate waste products from the body.

In peritoneal dialysis commonly used fluids contain glucose. Exposure to high glucose levels in peritoneal fluid during peritoneal dialysis has several side effects. Primarily, as glucose passes over and into the peritoneal membrane it causes local inflammation which leads to fibrosis over time (Zhou2016). Fibrosis limits the capacity of the exchange of water and waste products over the peritoneal membrane. The decrease of peritoneal exchange capacity is most commonly the reason for termination of peritoneal dialysis.

SGLT2-channels are identified in peritoneal mesothelial cells of rats (Debray-Carcia 2016), and most recently also in humans (Shentu2021). An in vitro model of human peritoneal mesothelial cells incubated with the SGLT2-inhibitor (empagliflozin) has shown significantly decrease in glucose uptake (Zhou2019). Exposure to intraperitoneal empagliflozin in rats, reduced the uptake of glucose over the peritoneal membrane significantly by 78 % and the ultrafiltration was increased (Zhou2019).

Currently, to our knowledge, no clinical trials have been conducted in humans attending peritoneal dialysis with the aim of investigating either the effect or safety of SGLT2i, as it is indeed the first of its kind, with the aim of including participants in peritoneal dialysis.

Study Overview

• Status: Enrolling by invitation
• Conditions: End Stage Renal Disease; Peritoneal Dialysis Complication
• Intervention / Treatment: Drug: Dapagliflozin 10 MG [Farxiga]

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Zealand
    • Holbæk, Zealand, Denmark, 4300
      • University Hospital Copenhagen - Holbaek

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Written informed consent
2. Age above 18 years of age
3. In stable peritoneal dialysis for more than 14 days.

Exclusion Criteria:

1. In treatment with SGLT2i currently or within the last 90 days.
2. Treatment for peritoneal infection within the last 30 days.
3. Any hospitalization within the last 30 days.
4. Anaphylaxis to the IMP.
5. Impaired lever function with ALAT above normal range within the last 6 month.
6. Sever efflux problems during peritoneal dialysis for the last 14 days, judged by the investigator.
7. Non-menopausal defined as menstruation within the last 12 month without any other medical cause. Only applicable for female participants.
8. Substance abuse, judged by the investigator.
9. Incapable to follow study protocol, judged by the investigator.
10. Previously included in this clinical trial and exposed to the IMP.
11. Included in another clinical trial with exposure to any IMP within the last 30 days.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: On treatment; Assigned to oral treatment with dapagliflozin 10 mg for three consecutive days.	Drug: Dapagliflozin 10 MG [Farxiga]; Primary end-points are measure before (day 0), on treatment (day 1 and day 3) and after treatment (day 21)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peritoneal glucose uptake (mg/ dL)	Glucose level in peritoneal fluid during a four hour standardized peritoneal dialysis. Change in total glucose uptake before and after treatment (treatment periode of three days)	Day 0 (baseline), Day 3 (max dose of treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fluid volume (ml)	Fluid volume ultra-filtrated during peritoneal dialysis.	Measured at end of each peritoneal dialysis. Peritoneal dialysis done af Day 0, Day 1 (first day of treatment) and day 3 (max dose of treatment)
Plasma glucose level (mg/ dL)	Glucose levels in blood and peritoneal-fluid during peritoneal dialysis. Comparaison of maximal plasma level.	Measured at end of each peritoneal dialysis. Peritoneal dialysis done af Day 0, Day 1 (first day of treatment) and day 3 (max dose of treatment).
Pharmacokinetics (nmol)	Dapagliflozin and its metabolites levels in blood and peritoneal-fluid	Samples for biobank - samples drawn at end of each peritoneal dialysis. Peritoneal dialysis done af Day 0, Day 1 (first day of treatment) and day 3 (max dose of treatment). Samples are drawn every 30 minuttes during each peritoneal dialysis.
Adverse events (events)	Safety in terms of AE and/or SAE	At day 1 (first day of treatment), day 3 (max dose of treatment) and day 30 (four weeks after treatment)

Collaborators and Investigators

• Sponsor: Holbaek Sygehus
• Investigators: Principal Investigator: Morten Lindhardt, MD, PhD, Copenhagen University Hospital - Holbaek

Study record dates

Study Major Dates

• Study Start (Actual): November 18, 2021
• Primary Completion (Anticipated): February 27, 2022
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: January 13, 2022
• First Submitted That Met QC Criteria: February 11, 2022
• First Posted (Actual): February 22, 2022

Study Record Updates

• Last Update Posted (Actual): February 22, 2022
• Last Update Submitted That Met QC Criteria: February 11, 2022
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: dapagliflozin; SGLT2-inhibition
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Renal Insufficiency, Chronic; Kidney Failure, Chronic; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: HOL-MED-01-2021

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The data material used in this study are available from the corresponding author on reasonable request which will not conflict with the anonymity and confidentiality of the data.
• IPD Sharing Time Frame: Depended on the request - Days to weeks
• IPD Sharing Access Criteria: Not conflict with the anonymity and confidentiality of the data and a signed contract for data sharing.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

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