Study design
This phase IV trial is monocentric, randomized and double-blinded with one additional open-label treatment arm serving as the positive control. Two randomizations are performed. In the first randomization, participants are randomized in a 2:1 ratio to either the double-blind part or open-label metformin part. This open randomization is performed via the web-based randomization service “Randomizer” (Randomizer; Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Austria; available at: The patients who are randomized to the double-blind part are further randomized in a 1:1 ratio to either the probiotic group or the placebo group. The second randomization as well as the allocation concealment is performed by Winclove Probiotics B.V, Netherlands. To ensure that the 30 participants undergoing endoscopic procedures are balanced over the three groups, both randomizations are stratified for endoscopy (yes/no). Both randomizations are performed at visit 1.The study takes place at Graz University Hospital, Department of Internal Medicine, Division of Endocrinology and Diabetology, Endocrinology Outpatient Clinic.The treatment arms are the following:
Probiotic (number n = 60).Probiotic placebo (n = 60).Open-label metformin (500 mg twice daily, n = 60).The framework of the study is to show that the effects of the probiotic intervention are superior to the placebo arm. The metformin arm serves as a standard benchmark treatment arm and positive control. The study design is outlined in Fig. 
Study design of the ProPCO-RCT study; First, the participants´ inclusion/exclusion criteria are determined with detailed patient histories, questionnaires and blood analysis at the screening visit. Then, 30 out of the total 180 participants voluntarily submit to an endoscopy in order to obtain gut biopsy samples for detailed microbiome analysis. Next, all participants perform a soy challenge test and a gut permeability test at home and collect stool and urine samples, which they return at visit (1) There they will be randomized into either the open-label metformin arm or the double-blinded probiotic-placebo arms, with the 30 endoscopy participants being allocated equally across the three groups. If they are randomized into the probiotic or placebo groups, they receive a randomized package containing the blinded trial substances. They then take the study medication for 6 months, before repeating both the endoscopies and the tests at home and returning for visit (2) There all assessments from the screening visit are repeated. Participants of the probiotic and placebo arms may prolong their participation by taking the probiotic product in a 6-months follow-up period, before returning for the final follow-up visit, which is identical to the visit 2; w endo: with a scheduled endoscopy visit; wo endo: without a scheduled endoscopy visit;