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Effects of Probiotics and Fibers on Albuminuria in Persons With Type 1 Diabetes (ProFOS)

Primary Purpose

Type 1 Diabetes, Nephropathy, Albuminuria

Status

Recruiting

Phase

Not Applicable

Locations

Denmark

Study Type

Interventional

Intervention

Pro-/prebiotic Mix

Placebo

About this trial

This is an interventional treatment trial for Type 1 Diabetes focused on measuring probiotics, dietary fibers

Eligibility Criteria

18 Years - 100 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Persons ≥ 18 years of age with a diagnosis of type 1 diabetes (age at onset <40 years; permanent insulin treatment initiated within 1 year of diagnosis)
Albuminuria: UACR > 30 mg/g (in ≥2 out 3 morning spot urine collections prior to randomization)
Participants must be on stable renin-angiotensin system blocking treatment 4 weeks before start of study drug and throughout study duration.
Able to understand the written participant information and give informed consent

Exclusion Criteria:

1. Non-diabetic kidney disease indicated by medical history and/or laboratory findings 2. Known inflammatory bowel disease (IBD) 3. IBD symptoms due to investigator's opinion 4. Known celiac disease 5. Existing ostomy, malabsorption, history of bowel resection or bariatric surgery.
6. Heart valve replacement or history of endocarditis 7. Known rheumatic disorders treated with anti-inflammatory agents 8. Known hyperthyroidism or hypothyroidism 9. Active immunosuppressant therapy with systemic effect due to investigator's opinion 10. Current cancer treatment or within five years from baseline (except basal cell skin cancer or squamous cell skin cancer) 11. eGFR<15 ml/min/1.73m2, dialysis or kidney transplantation 12. Active antibiotic therapy until 30 days ahead of screening 13. Dietary supplements containing fibers (e.g. psyllium), probiotics or carotenoids until 30 days ahead of screening 14. The receipt of any investigational product 90 days prior to this trial 15. Unable to participate in study procedures 16. Any clinically significant disorder, except for conditions associated with type 1 diabetes, which in the Investigators opinion could interfere with the results of the trial 17. Pregnancy or lactation 18. Participation in another intervention study

Sites / Locations

Steno Diabetes Center CopenhagenRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Active Comparator

Arm Label

Placebo

Active

Arm Description

Soluble powder for oral use twice daily

The investigational product is soluble powder for oral use of pre-/probiotic mix 3.0 g twice daily.

Outcomes

Primary Outcome Measures

Change in albuminuria based on urinary albumin-creatinine ratio (UACR)

Three morning urine samples will be collected for assessment of UACR. The geometric mean of the 3 samples will be calculated.

Secondary Outcome Measures

Change in kidney function (GFR as plasma clearance of 99mTc-DTPA)

Renal function (GFR) and extracellular volume (ECV) will be assessed during 4 hours with the measurement plasma clearance of 99mTc-DTPA to provide accurate GFR measurement. A bolus of 0.5 mL Technetium-99m DTPA (approximately 10 MBq) is injected and blood samples are drawn at 0, 180, 200, 220 and 240 minutes after the injection. Urine is collected during the investigation. Plasma concentrations of 99mTc-DTPA at these time points are measured and used to calculate the plasma clearance of 99mTc-DTPA which approximates GFR.

Change in 24-hour blood pressure

24-hours blood pressure will be measured using a standard cuff-based device (boso TM-2430 PC2) that measures the blood pressure every 15 minutes between 07 in the morning and 23 in the evening and every 30 minutes during the night.

Change in microcirculation evaluated by the GlycoCheck device

GlycoCheck is a handheld video capillary microscope that measure glycocalyx thickness and sublingual capillary density under the tongue. The measurement will be performed by investigator and is a measure of the microcirculation damage. The distribution of the red blood cell column width at each capillary segment is used to calculate the perfused boundary region, which is the distance between the median and the outer edge of the red blood cell perfused lumen. The perfused boundary region reflects the thickness of the endothelial glycocalyx, based on the idea that loss of its integrity allows deeper penetration of the red blood cells into the gel-like layer covering the endothelial lining. Higher perfused boundary region, therefore, indicates thinner glycocalyx. The software also returns total and perfused capillary density in segments per millimeter square.

Change in endothelial dysfunction (von Willebrand factor, endothelin-1, ADMA, ICAM-1, VCAM-1 and E-selectin)

Biomarkers drawn from blood will include markers of endothelial dysfunction (von Willebrand factor, endothelin-1, ADMA, ICAM-1, VCAM-1 and E-selectin),

Change in urinary markers of oxidative stress F2-isoprostanes and 8-oxodG

Markers of oxidative stress (F2-isoprostanes and 8-oxodG) will be measured in urine by ELISA and multiplexing methods.

Change in intestinal inflammation measured by fecal calprotectin

Fecal samples will be collected for calprotectin analyses.

Change in biomarkers of intestinal permeability (LPS and zonulin)

Biomarkers drawn from blood will include markers of intestinal permeability (LPS and zonulin)

Change in systemic inflammation (hs-TNT, TNF-alfa, IL6, IL8, IL1-beta, SAA, sICAM1, sICAM3 and suPAR)

Biomarkers drawn from blood will include markers of inflammation (hs-TNT, TNF-alfa, IL6, IL8, IL1-beta, SAA, sICAM1, sICAM3, suPAR)

Change in tubular function (NGAL, KIM-1, Beta2microglobulin, hepatocellular growth factor and adiponectin)

Markers of tubular kidney injury (NGAL, KIM-1, Beta2microglobulin, hepatocellular growth factor (HGF) and adiponectin) will be measured in urine by ELISA and multiplexing methods.

Change in autonomous neuropathy evaluated by VagusTM

Autonomic nervous system function will be evaluated with the VagusTM device. The heart rate will be measured by 5-minute resting measures and in response to deep breathing, position change from lying to standing position and by exhaling through a mouthpiece against 40 mmHg of pressure (Valsalva maneuver).

Full Information

NCT ID

NCT04635670

First Posted

October 20, 2020

Last Updated

February 9, 2022

Sponsor

Steno Diabetes Center Copenhagen

Collaborators

DSM Nutritional Products, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT04635670

Brief Title

Effects of Probiotics and Fibers on Albuminuria in Persons With Type 1 Diabetes

Acronym

ProFOS

Official Title

Effects of Probiotics and Fibers on Markers of Nephropathy, Inflammation and Endothelial Dysfunction in Persons With Type 1 Diabetes and Albuminuria

Study Type

Interventional

2. Study Status

Record Verification Date

February 2022

Overall Recruitment Status

Recruiting

Study Start Date

June 29, 2020 (Actual)

Primary Completion Date

September 2022 (Anticipated)

Study Completion Date

December 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Steno Diabetes Center Copenhagen

Collaborators

DSM Nutritional Products, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The primary objective is to assess the impact of three months' treatment with pre-/probiotic mix on markers of nephropathy and other comorbidity related to diabetes. A double blinded, randomized, placebo-controlled crossover, single-centre study including 46 patients with type 1 diabetes and albuminuria. The treatment period is 2 x 12 weeks with 6 weeks washout. The primary outcome is to evaluate the effect of pre-/probiotic mix on albuminuria.

Detailed Description

Recent data has pointed towards a link between gut microbiota and chronic kidney disease (CKD). It is hypothesized that defects in the intestinal barrier due to intestinal dysbiosis, a microbial imbalance in the intestines, allow bacterial toxins and other proinflammatory substances to pass and cause systemic inflammation that damages the endothelium. To reestablish the microbial symbiosis and thereby strengthening the gut barrier different treatments have been investigated. Fibers serve as substrate for the beneficial bacterial strains and probiotics are selected bacteria that exert a beneficial effect on the gut environment. It is hypothesized that a supplement of fructo-oligosaccharides and probiotics (Pre-/probiotic mix) will strengthen the gut barrier and thereby protect the endothelium and kidneys. The aim of this study is to test whether af Pre-/probiotic mix, will have a beneficial impact on albuminuria in persons with type 1 diabetes and albuminuria. 46 patients with type 1 diabetes and albuminuria will be recruited from Steno Diabetes Center Copenhagen (SDCC) in accordance with the study in- and exclusion criteria.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Type 1 Diabetes, Nephropathy, Albuminuria, Diabetic Kidney Disease

Keywords

probiotics, dietary fibers

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Crossover Assignment

Model Description

Randomised, double blinded, placebo controlled, crossover, single-centre study. A total of 46 participants will be randomly assigned into two groups of 23 to a sequence of treatment (active followed by placebo or vice versa). Allocation will be masked for both participants and investigators.

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

Allocation will be masked for both participants and investigators. Only after completion of all study visits by all participants and after database lock the randomization code will be opened.

Allocation

Randomized

Enrollment

46 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Soluble powder for oral use twice daily

Arm Title

Active

Arm Type

Active Comparator

Arm Description

The investigational product is soluble powder for oral use of pre-/probiotic mix 3.0 g twice daily.

Intervention Type

Dietary Supplement

Intervention Name(s)

Pro-/prebiotic Mix

Intervention Description

Soluble powder for oral use of pre-/probiotic mix 3.0 g twice daily.

Intervention Type

Dietary Supplement

Intervention Name(s)

Placebo

Intervention Description

Soluble powder for oral use twice daily.

Primary Outcome Measure Information:

Title

Change in albuminuria based on urinary albumin-creatinine ratio (UACR)

Description

Three morning urine samples will be collected for assessment of UACR. The geometric mean of the 3 samples will be calculated.

Time Frame

30 weeks. Samples will be collected before and after each og te two treatment periods.

Secondary Outcome Measure Information:

Title

Change in kidney function (GFR as plasma clearance of 99mTc-DTPA)

Description

Time Frame

30 weeks. 99mTc-DTPA GFR will be performed after each of the two treatment periods.

Title

Change in 24-hour blood pressure

Description

Time Frame

30 weeks. 24h BP will be performed after each of the two treatment periods.

Title

Change in microcirculation evaluated by the GlycoCheck device

Description

Time Frame

30 weeks. GlycoCheck will be performed before and after each of the two treatment periods.

Title

Change in endothelial dysfunction (von Willebrand factor, endothelin-1, ADMA, ICAM-1, VCAM-1 and E-selectin)

Description

Biomarkers drawn from blood will include markers of endothelial dysfunction (von Willebrand factor, endothelin-1, ADMA, ICAM-1, VCAM-1 and E-selectin),

Time Frame

30 weeks. Blood tests will be performed before and after each of the two treatment periods.

Title

Change in urinary markers of oxidative stress F2-isoprostanes and 8-oxodG

Description

Markers of oxidative stress (F2-isoprostanes and 8-oxodG) will be measured in urine by ELISA and multiplexing methods.

Time Frame

30 weeks. Urine samples will be collected before and after each of the two treatment periods.

Title

Change in intestinal inflammation measured by fecal calprotectin

Description

Fecal samples will be collected for calprotectin analyses.

Time Frame

30 weeks. Fecal samples will be collected before and after each of the two treatment periods.

Title

Change in biomarkers of intestinal permeability (LPS and zonulin)

Description

Biomarkers drawn from blood will include markers of intestinal permeability (LPS and zonulin)

Time Frame

30 weeks. Blood tests will be performed before and after each of the two treatment periods.

Title

Change in systemic inflammation (hs-TNT, TNF-alfa, IL6, IL8, IL1-beta, SAA, sICAM1, sICAM3 and suPAR)

Description

Biomarkers drawn from blood will include markers of inflammation (hs-TNT, TNF-alfa, IL6, IL8, IL1-beta, SAA, sICAM1, sICAM3, suPAR)

Time Frame

30 weeks. Blood tests will be performed before and after each of the two treatment periods.

Title

Change in tubular function (NGAL, KIM-1, Beta2microglobulin, hepatocellular growth factor and adiponectin)

Description

Markers of tubular kidney injury (NGAL, KIM-1, Beta2microglobulin, hepatocellular growth factor (HGF) and adiponectin) will be measured in urine by ELISA and multiplexing methods.

Time Frame

30 weeks. Urine samples will be collected before and after each of the two treatment periods.

Title

Change in autonomous neuropathy evaluated by VagusTM

Description

Time Frame

30 weeks. Vagus test will be performed before and after each of the two treatment periods.

Other Pre-specified Outcome Measures:

Title

Change in concentration of microbial uremic toxins in the blood; hippuric acid, kynurenic acid, indoxyl sulfate and p-cresol sulfate

Description

Biomarkers will include markers of bacterial uremic toxins (hippuric acid, kynurenic acid, indoxyl sulfate and p-cresol sulfate).

Time Frame

30 weeks. Blood tests will be performed before and after each of the two treatment periods.

Title

Change in Gut microbiome characterization assessed by 16S RNA sequencing

Description

Fecal samples will be collected at visit 2, 3, 4 and 5 for calprotectin and gut microbiome analyses. Feces is collected according to current standard operation procedures in order to characterize the gut microbiome. The fecal samples should be stored at -20 °C in the participants' freezer and be delivered to SDCC in the provided cooling bag no more than 48 hours after collection. At SDCC the samples will be stored at -80°C. The gut microbiome characterization is based on 16S rRNA gene sequencing. After standardized microbial DNA extraction, the microbial DNA will be subjected to sequencing, microbial gene analyses, taxonomy analyses including enterotypes known species and unknown meta-species and functional annotation.

Time Frame

30 weeks. Fecal samples will be collected before and after each of the two treatment periods.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

100 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Persons ≥ 18 years of age with a diagnosis of type 1 diabetes (age at onset <40 years; permanent insulin treatment initiated within 1 year of diagnosis) Albuminuria: UACR > 30 mg/g (in ≥2 out 3 morning spot urine collections prior to randomization) Participants must be on stable renin-angiotensin system blocking treatment 4 weeks before start of study drug and throughout study duration. Able to understand the written participant information and give informed consent Exclusion Criteria: 1. Non-diabetic kidney disease indicated by medical history and/or laboratory findings 2. Known inflammatory bowel disease (IBD) 3. IBD symptoms due to investigator's opinion 4. Known celiac disease 5. Existing ostomy, malabsorption, history of bowel resection or bariatric surgery. 6. Heart valve replacement or history of endocarditis 7. Known rheumatic disorders treated with anti-inflammatory agents 8. Known hyperthyroidism or hypothyroidism 9. Active immunosuppressant therapy with systemic effect due to investigator's opinion 10. Current cancer treatment or within five years from baseline (except basal cell skin cancer or squamous cell skin cancer) 11. eGFR<15 ml/min/1.73m2, dialysis or kidney transplantation 12. Active antibiotic therapy until 30 days ahead of screening 13. Dietary supplements containing fibers (e.g. psyllium), probiotics or carotenoids until 30 days ahead of screening 14. The receipt of any investigational product 90 days prior to this trial 15. Unable to participate in study procedures 16. Any clinically significant disorder, except for conditions associated with type 1 diabetes, which in the Investigators opinion could interfere with the results of the trial 17. Pregnancy or lactation 18. Participation in another intervention study

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Elisabeth Buur Stougaard, MD

Phone

+45 21125957

elisabeth.buur.stougaard@regionh.dk

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Peter Rossing, Proff, MD

Organizational Affiliation

Steno Diabetes Center Copenhagen

Official's Role

Principal Investigator

Facility Information:

Facility Name

Steno Diabetes Center Copenhagen

City

Gentofte

ZIP/Postal Code

2820

Country

Denmark

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Elisabeth Buur Stougaard, MD

Phone

+45 21125957

elisabeth.buur.stougaard@regionh.dk

First Name & Middle Initial & Last Name & Degree

Ninna Hahn Tougaard, MD

Phone

+45 29399798

ninna.hahn.tougaard.01@regionh.dk

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Effects of Probiotics and Fibers on Albuminuria in Persons With Type 1 Diabetes

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