Clinical trial NCT04635670: Effects of Probiotics and Fibers on Albuminuria in Persons With Type 1 Diabetes
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
Overall status: COMPLETED
Phase: NA
Conditions: Type 1 Diabetes
Nephropathy
Albuminuria
Diabetic Kidney Disease
Keywords: probiotics, dietary fibers
Lead sponsor: Steno Diabetes Center Copenhagen
Sponsor class: OTHER
Collaborators: name: DSM Nutritional Products, Inc.
First posted: 2020-11-19
Enrollment: 41
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. 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)
2. Albuminuria: UACR \> 30 mg/g (in ≥2 out 3 morning spot urine collections prior to randomization)
3. Participants must be on stable renin-angiotensin system blocking treatment 4 weeks before start of study drug and throughout study duration.
4. 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

Primary outcomes:
measure: Change in albuminuria based on urinary albumin-creatinine ratio (UACR)
timeFrame: 30 weeks. Samples will be collected before and after each og te two treatment periods.
Secondary outcomes:
measure: Change in kidney function (GFR as plasma clearance of 99mTc-DTPA)
timeFrame: 30 weeks. 99mTc-DTPA GFR will be performed after each of the two treatment periods.
measure: Change in 24-hour blood pressure
timeFrame: 30 weeks. 24h BP will be performed after each of the two treatment periods.
measure: Change in microcirculation evaluated by the GlycoCheck device
timeFrame: 30 weeks. GlycoCheck will be performed before and after each of the two treatment periods.
measure: Change in endothelial dysfunction (von Willebrand factor, endothelin-1, ADMA, ICAM-1, VCAM-1 and E-selectin)
timeFrame: 30 weeks. Blood tests will be performed before and after each of the two treatment periods.
measure: Change in urinary markers of oxidative stress F2-isoprostanes and 8-oxodG
timeFrame: 30 weeks. Urine samples will be collected before and after each of the two treatment periods.
measure: Change in intestinal inflammation measured by fecal calprotectin
timeFrame: 30 weeks. Fecal samples will be collected before and after each of the two treatment periods.
measure: Change in biomarkers of intestinal permeability (LPS and zonulin)
timeFrame: 30 weeks. Blood tests will be performed before and after each of the two treatment periods.
measure: Change in systemic inflammation (hs-TNT, TNF-alfa, IL6, IL8, IL1-beta, SAA, sICAM1, sICAM3 and suPAR)
timeFrame: 30 weeks. Blood tests will be performed before and after each of the two treatment periods.
measure: Change in tubular function (NGAL, KIM-1, Beta2microglobulin, hepatocellular growth factor and adiponectin)
timeFrame: 30 weeks. Urine samples will be collected before and after each of the two treatment periods.
measure: Change in autonomous neuropathy evaluated by VagusTM
timeFrame: 30 weeks. Vagus test will be performed before and after each of the two treatment periods.
Other outcomes:
measure: Change in concentration of microbial uremic toxins in the blood; hippuric acid, kynurenic acid, indoxyl sulfate and p-cresol sulfate
timeFrame: 30 weeks. Blood tests will be performed before and after each of the two treatment periods.
measure: Change in Gut microbiome characterization assessed by 16S RNA sequencing
timeFrame: 30 weeks. Fecal samples will be collected before and after each of the two treatment periods.
Locations:
city: Gentofte
country: Denmark
facility: Steno Diabetes Center Copenhagen
Study officials:
affiliation: Steno Diabetes Center Copenhagen
name: Peter Rossing, Proff, MD
role: PRINCIPAL_INVESTIGATOR
References: