Effects of Probiotics in Patients with Diabetes Mellitus Type 2: Study Protocol for a Randomized, Double-Blind, Placebo-Controlled Trial
This Research brief is summarized from a published clinical study. All the information and statistics cited below were taken directly from the original publication piloted by Alokail, et at.1 NutraScience Labs has restructured or paraphrased some sections of this brief in an attempt to more succinctly summarize the research.
The human gastrointestinal tract contains bacteria, archaea ,and eukarya. Bacteria living in the gut have the highest cell density. Gut microbiota interacts at several levels in the functions of the body.
Studies have shown that a reduction in circulating endotoxin leads to a reduction in inflammatory cytokines and inflammatory response. Also, abnormal alterations in diet have a profound influence on human endotoxin circulation, but more so for patients with type 2 diabetes mellitus (T2DM).
The present study proposes to test the hypothesis that probiotics will alter the gut microbiota sufficiently to reduce systemic endotoxins and the resulting inflammation in subjects with T2DM.
To achieve this, 120 consenting adult Saudi T2DM patients without co-morbidities will be enrolled in this clinical trial and randomized to receive twice-daily placebo or probiotics for 26 weeks in a double-blind manner. The study will specifically explore the effects of probiotics on endotoxin levels in patients with DMT2 and relate them to the circulating levels of inflammatory cytokines.
In this 26- week study, 60 patients with T2DM will be treated with probiotics and 60 will be given a placebo.Interventions will be performed at weeks 0, 4, 8, 12 and 26 in all subjects.
Both samples are indistinguishable in color, smell and taste.
Recruitment of Patients
Recruitment was done by collaboration with primary care centers throughout Riyadh and the Biomarkers Research Program, College of Science, King Saud University.
The study protocol has been approved by the ethics committee.
The sample includes stable and well controlled T2DM patients aged 20 to 75 years who provided written informed consent.
Chronic gastrointestinal disease (except irritable bowel syndrome), systemic antibiotics within 6 weeks before inclusion, use of probiotics within 3 months before inclusion, regular intake of insulin or insulin analogs, antibiotics or probiotics, antacids, H2-receptor blockers, proton pump inhibitors, loperamide, cholestryramine, ω3-unsaturated fatty acid supplements, fibrates, corticosteroids or sex steroids, daily alcohol consumption greater than 30 g, significant immunodeficiency, known cardio-vascular disease, breast-feeding or pregnancy, non-Arab ethnicity, participation in another clinical trial within the last 6 months, legal incapability or mental incapacity to give consent.
Allocation to Treatment
Each participant will be given a unique subject number. They will be allocated to treatment for 26 weeks with either the probiotics supplement or the placebo.
The subjects will be asked to ingest one sachet before breakfast and one before going to bed by combining the contents with lukewarm water and drinking the mixture.
Data Handling and Record Keeping
Case report forms (CRF) will be used to record data for all participants, filled in by a research nurse and digitized later.
Study Schedule and Location
A research nurse and a research dietician will be responsible for all contacts with patients. Doctors associated with the research team will be available if problems arise.
Acquisition of Clinical Data and Assessment of Compliance
- Thorough medical history
- Nutritional habits well assessed
- Changes in medication
- Anthropometric measurements will be made using standardized methods
- Height will be measured at the start of treatment.
- Weight, waist circumferenceand hip circumferencewill be measured at the start and end of the treatment.
- Liver ultrasonography will be performed either at screening or at the start of treatment
- Compliance will be monitored at weeks 4, 8, 12 and 26.
Acquisition of Routine Biochemical Data and Biological Samples
- Blood samples obtained will be analyzed at the Biomarkers Research Program
- Fasting blood samples will be collected at weeks 0, 8 and 26.
- Stool samples will be obtained at the same time points as blood samples and stored in a plastic sealable bag to be handed over to the clinic.
Subjects may withdraw from the trial at any time at their own request, or they may be withdrawn at any time at the discretion of the investigator for safety, behavioral or administrative reasons.
Adverse events are undesirable signs or symptoms that occur during the study and may or may not be causally related to the treatment.
Serious Adverse Events
Serious adverse events are defined as events that are fatal, life-threatening, disabling, incapacitating or result in hospitalization or prolonged hospital stay, or result in malformation.
According to previous studies, probiotics are safe, and any serious adverse event that might be possibly, probably or definitely related to the test product will be regarded as unexpected.
Ethical and Regulatory Aspects
The study will be performed in accordance with the protocol and the ethical principles that have their origin in the Declaration of Helsinki as well as with the International Council for Harmonization Guidance on Good Clinical Practice.
The sample size was calculated based on the estimated mean change during treatment (Δ-values) and corresponding standard deviation (SD) of the change.
Plan for Data Analysis
Only subjects treated with at least 80% of the planned doses for at least 80% of the time will be considered as treated per protocol.Preparation of the dataset will be done prior to analysis and descriptive statistics will be performed where frequencies will be presented as a percentage.
Probiotics have been previously shown to affect lipopolysaccharide levels which may still have long-term beneficial effects that will have a trend effect on inflammatory or insulin resistance markers.
The strongest evidence for the use of probiotics has been in the management of diarrhea.
Studies in obesity have also shown altered gut microbial compositions in human subjects and in mice. Differences in the gut composition between obese and lean individuals are related to dietary factors independent of obesity.
Trials have also documented favorable effects of probiotics in other gastrointestinal diseases (for example, irritable bowel syndrome, pouchitis and necrotizing enterocolitis in premature infants).
However, not all studies have shown beneficial effects of probiotics, and thus caution should be taken in terms of the dosage and strains to be used, as these may have important ramifications on the effects observed.
To date, relatively few studies have examined the effects of endotoxin in metabolic diseases using probiotics.
To summarize, it is expected that the findings of the study will show that probiotics alter gut microbiota in T2DM and that, in theory, the alterations will be metabolically favorable with continued probiotic use.
This study will be the first to address this issue beyond classical inflammatory conditions.
- Estimated Enrollment: 120
- Study start date: October 2013
- Estimated study completion date: October 2015
- Estimated primary completion date: October 2015
1. Alokail et al. Trials 2013, 14:195 http://www.trialsjournal.com/content/14/1/195.