Study to Explore the Effects of Probiotics on Endotoxin Levels in Type 2 Diabetes Mellitus Patients
|First Received Date ICMJE||January 1, 2013|
|Last Updated Date||January 8, 2013|
|Start Date ICMJE||March 2013|
|Estimated Primary Completion Date||March 2015 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||effects of probiotics on endotoxin levels in patients with T2DM [ Time Frame: 1 year ] [ Designated as safety issue: No ]
Exploration of baseline characteristics and determination of associations between nutritional habits, gut flora and levels of endotoxin/inflammatory markers at baseline and subsequent follow ups
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT01765517 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||effects of probiotics on gut microflora [ Time Frame: 1 year ] [ Designated as safety issue: No ]
Determine changes from baseline in the amount of probiotics, all anaerobic bacteria and short-chain fatty acids (e.g., propionate and butyrate) present in fecal samples.
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE
||Effects of probiotics on insulin resistance [ Time Frame: 1 year ] [ Designated as safety issue: No ]
Determine changes from baseline in serum levels of glucose, HbA1C, insulin and C-peptide
|Original Other Outcome Measures ICMJE||Same as current|
|Brief Title ICMJE||Study to Explore the Effects of Probiotics on Endotoxin Levels in Type 2 Diabetes Mellitus Patients|
|Official Title ICMJE||A 26-week, Randomized, Double-blind, Placebo-controlled Study to Explore the Effects of Probiotics on Endotoxin Levels in Patients With Type 2 Diabetes Mellitus|
Probiotics, which are believed to be health promoting live microorganisms, have been reported to influence circulating endotoxin levels. Ingestion of the live cultures may alter gut mircobiota in a beneficial manner to reduce inflammation; although their mechanism and influence to reduce inflammation in T2DM is not established for this disease state. Therefore, the aim of this study is to (1) characterize the beneficial effects of probiotics on circulating endotoxin levels and other biomarkers related to systemic low-grade inflammation in patients with T2DM; (2) Compare circulating endotoxin levels and inflammatory cytokine levels between patients treated with probiotics or placebo to examine the beneficial effects of probiotics on reducing the inflammatory status, through assessment of systemic markers (adipokines, endotoxin, cytokines); (3) to examine the effects of probiotics on gut microflora in order to understand the mechanism for such change in inflammatory status. To achieve this, 120 consenting adult Saudis, naïve or newly diagnosed 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. Glycemic inflammatory markers will be measured and fecal samples analysed, interventions will be done at baseline, 4, 8, 12 and 26 weeks. It is envisaged that probiotics will induce beneficial changes in gut mircobiota, reduce the systemic inflammatory state through altering systemic endotoxin levels and, as such, reduce the systemic inflammatory response observed in T2DM subjects. This will have a fundamental impact on how we should treat the inflammatory component of T2DM, particularly once the results are verified in a larger cohort of patients, as this could have very dramatic effects on how we treat patients with T2DM. Reducing the pathogenesis of T2DM by dampening the inflammatory response, which may also impact on insulin resistance status and health of the individual, will have clear benefits. This could have profound effects on preventative T2DM management, as well as current T2DM care without excessive cost for the wider Saudi health economy.
In this 26-week, single-center, double-blind, randomized, placebo-controlled study, 60 patients with T2DM will be treated with probiotics and 60 will be treated with placebo. Interventions will be done at weeks 0, 4, 8, 12 and 26 from all subjects. Patients allocated to the probiotics group will receive capsules containing four strains of freeze-dried bacteria, namely Lactobacillus acidophilus, Lactobacillus bulgaricus, Bifidobacterium bifidum, and Streptococcus thermophiles (Bio-plus®, Supherb, Israel), at a daily dose of 2 × 1010 CFU. Participants in the placebo group will receive capsules containing wheat-based non-fermentable fibers, as used in another clinical trial [Pereg et al, 2011].
Recruitment of Patients
Recruitment of patients to this study will be made possible by collaboration with primary care centers throughout Riyadh and the Biomarkers Research Program, College of Science, King Saud University.
Allocation to Treatment
After confirmation of eligibility and obtaining written informed consent, the patients will be given a unique subject number by the probiotics company, who also will perform the randomization (stratified for gender), The patients and clinicians at the primary care center will be blinded to the treatment received. The eligible patients will be allocated (1:1) to treatment for 26 weeks with either the probiotics supplement or placebo. Subjects will be instructed to
Data Handling and Record Keeping
Case report form (CRF) will be used to record data for all participants, and will be completed by the research nurse, who will also enter the data into an electronic database.
Study schedule and location
After inclusion, all further treatments will be managed at the primary care center where the subject was recruited (see appendix C for scheduled visits). A research nurse and a research dietician will be responsible for all contact with patients. Doctors associated with the research team will be available if problems arise.
Acquisition of Clinical Data and Assessment of Compliance
Acquisition of Routine Biochemical Data and Biological Samples
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. The subjects will also be withdrawn from the study in case of:
Adverse events (AEs) are undesirable signs or symptoms that occur during the study and may or may not be causally related to the treatment. All AEs considered possibly, probably or definitely related to the test product will be recorded on CRFs.
Serious Adverse Events
Serious adverse events (SAEs) are defined as events that are fatal, life-threatening, disabling, incapacitating or result in hospitalization or prolong hospital stay, or result in malformation. All SAEs will be recorded in the CRF, whether they are related to the test product or not. According to previous studies (9), probiotics are very safe, and any SAE that might be possibly, probably or definitely related to the test product will be regarded as unexpected. All unexpected SAEs will be reported immediately to the Medicines and Healthcare products Regulatory Agency (MHRA). Any SAE that might be related to the test will immediately lead to discontinuation of the test product.
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. These documents state that the informed consent of subjects is an essential precondition for participation in the clinical study. The study will commence only after obtaining approval from the local ethical review board of the College of Medicine Research Center, King Saud University.
Plan for Data Analyses
As this trial is designed to assess the physiological effects rather than support clinical indications for treatment with probiotics in T2DM, we plan to perform per protocol analyses. 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.
Raw data will be entered in a statistical software (Statistical Package for the Social Sciences), SPSS version 16.5 (Chicago, IL, USA). Preparation of data set will be done prior to analyses. Descriptive statistics will be done; frequencies will be presented in percentage (%). Continuous variables will be presented as mean ± standard deviation. Variables exhibiting non-Gaussian variables will be transformed prior to analyses. Repeated measures analysis of co-variance (ANCOVA) will be used to compare groups, which will represent a combination of analysis of variance (ANOVA) and linear regression. Confounding and fixed variables such as age and gender, as well as BMI will be taken if proper matching has not been achieved prior to repeated measures. Post-hoc Banjamini-Hohberg corrections will be done for multiple comparisons. For comparison of 2 groups, independent T-test will be done for continuous variables and Mann-Whitney for non-continuous variables. Analysis of adverse events (if any) will be done using Chi-Square test and Fisher's exact test following assumptions of randomness, independence and size. Significance will be set at p < 0.05.
|Study Type ICMJE||Interventional|
|Study Phase||Not Provided|
|Study Design ICMJE||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Supportive Care
|Condition ICMJE||Diabetes Mellitus Type 2|
|Study Arm (s)||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Not yet recruiting|
|Estimated Enrollment ICMJE||120|
|Estimated Completion Date||March 2015|
|Estimated Primary Completion Date||March 2015 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||20 Years to 75 Years|
|Accepts Healthy Volunteers||No|
|Location Countries ICMJE||Saudi Arabia|
|NCT Number ICMJE||NCT01765517|
|Other Study ID Numbers ICMJE||11-MED2114-02, NPST_Alokail|
|Has Data Monitoring Committee||Yes|
|Responsible Party||Nasser Al-Daghri, King Saud University|
|Study Sponsor ICMJE||King Saud University|
|Information Provided By||King Saud University|
|Verification Date||January 2013|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP