Clinical trial NCT03032354: Probiotics in Newly Recognized Type 1 Diabetes
Official title: Effect of Lactobacillus Rhamnosus GG and Bifidobacterium Lactis BB 12 on Beta-cell Function in Children With Newly Diagnosed Type 1 Diabetes - a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 1
Keywords: probiotics
children
remission
Lead sponsor: Medical University of Warsaw
Sponsor class: OTHER
First posted: 2017-01-26
Enrollment: 96
Sex: ALL
Minimum age (years): 8
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: They are major genera of bacteria that make up the colon flora in human, constitute intestinal microbial homeostasis, inhibit growth of pathogens, improve the gut mucosal barrier and modulate local and systemic immune responses. Changes in gut microbiota can influence the immune system by increasing gut permeability, intestinal inflammation, and impaired oral tolerance in type 1 diabetes.Taken together, the data imply that bacteriotherapy may potentially be used as a tool to modulate the immune system for preventing islet destruction. Supplementation of Lactobacillus rhamnosus GG and Bifidobacterium lactis BB12 improved blood glucose control in normoglycaemic pregnant women and reduced the frequency of gestational diabetes mellitus

Aim of the study:

The effect of Lactobacillus rhamnosus GG and Bifidobacterium lactis BB12 on beta-cell function in children with newly diagnosed type 1 diabetes: a randomized, double blind, placebo-controlled trial.

Primary end point:

Area under the curve (AUC) of c-peptide level during during fasting and at 30,60,90,120 min following the start of the meal

Intervention:

Included patients will be randomly assigned to receive a combination of Lactobacillus rhamnosus GG and Bifidobacterium lactis BB12 (Probiotics Group ) or placebo (Placebo Group ) during six months.

The expected results:

Beneficial effect of Lactobacillus rhamnosus GG and Bifidobacterium lactis BB12 on beta-cell function shown in the properly performed, methodologically accurate study would create a rationale for its routine use in patients with newly diagnosed type 1 diabetes.

Detailed description: Intervention:

At the 6-month follow-up visit will be evaluated adherence and occurrence of side effects of the study procedure. The outcome measures will be assessed at the beginning of the study, and at the 6 and 12-month follow-up visit.

Eligibility criteria: Inclusion Criteria:

* Type 1 diabetes confirmed by clinical history and the presence of at least one positive autoantibody: anti-glutamic acid decarboxylase (anti-GAD), islet antigen 2 (IA2), islet cell antibody ( ICA)
* Fasting c-peptide level \>/= 0.4 ng/ml
* The diagnosis of diabetes during the last 60 days
* Consent to participate in the study

Exclusion Criteria:

* Antibiotic-therapy during last 4 weeks
* Taking of probiotics during last 2 weeks
* Intestinal infection during last 2 weeks
* Intestinal chronic diseases

Primary outcomes:
measure: Area under the curve (AUC) during fasting and at 30,60,90,120 min following the start of the meal
timeFrame: 120 min responses to a mixed meal
Secondary outcomes:
measure: Insulin requirement (U / kg body mass )
timeFrame: up 60 days from diabetes recognition, at 3th, 6th, 12th month
measure: HbA1c
timeFrame: up to 60 days from diabetes recognition, at 3th, 6th, 12th month
measure: Weight in kilograms
timeFrame: up to 60 days from diabetes recognition, and at 3th, 6th, 12th month
measure: Number of participants with abnormal laboratory values and/or adverse events that are related to treatment ( eg.abdominal pain, diarrhea , constipation , vomiting,flatulence)
timeFrame: at 3th, 6th, 12th month
measure: Occurrence of other autoimmune diseases
timeFrame: at 12th month
measure: Height in meters
timeFrame: up to 60 days from diabetes recognition, and at 3th, 6th, 12th month
measure: BMI in kg/m2
timeFrame: up to 60 days from diabetes recognition, and at 3th, 6th, 12th month
measure: BMI score
timeFrame: up to 60 days from diabetes recognition, and at 3th, 6th, 12th month
measure: severe hypoglycemia
timeFrame: up to 60 days from diabetes recognition, at 3th, 6th, 12th month
measure: ketoacidosis
timeFrame: up to 60 days from diabetes recognition, at 3th, 6th, 12th month
measure: Fasting c- peptide concentrations in ng/ml
timeFrame: up to 60 days from diabetes recognition, and in: 6th, 12th month
Other outcomes:
Locations:
Study officials:
affiliation: Medical University of Warsaw
name: Agnieszka Szypowska, Assoc. Prof.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kriegel MA, Sefik E, Hill JA, Wu HJ, Benoist C, Mathis D. Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11548-53. doi: 10.1073/pnas.1108924108. Epub 2011 Jun 27.
citation: Greenbaum CJ, Beam CA, Boulware D, Gitelman SE, Gottlieb PA, Herold KC, Lachin JM, McGee P, Palmer JP, Pescovitz MD, Krause-Steinrauf H, Skyler JS, Sosenko JM; Type 1 Diabetes TrialNet Study Group. Fall in C-peptide during first 2 years from diagnosis: evidence of at least two distinct phases from composite Type 1 Diabetes TrialNet data. Diabetes. 2012 Aug;61(8):2066-73. doi: 10.2337/db11-1538. Epub 2012 Jun 11.
citation: Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial. A randomized, controlled trial. The Diabetes Control and Complications Trial Research Group. Ann Intern Med. 1998 Apr 1;128(7):517-23. doi: 10.7326/0003-4819-128-7-199804010-00001.
citation: Shapiro AM, Ricordi C, Hering BJ, Auchincloss H, Lindblad R, Robertson RP, Secchi A, Brendel MD, Berney T, Brennan DC, Cagliero E, Alejandro R, Ryan EA, DiMercurio B, Morel P, Polonsky KS, Reems JA, Bretzel RG, Bertuzzi F, Froud T, Kandaswamy R, Sutherland DE, Eisenbarth G, Segal M, Preiksaitis J, Korbutt GS, Barton FB, Viviano L, Seyfert-Margolis V, Bluestone J, Lakey JR. International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006 Sep 28;355(13):1318-30. doi: 10.1056/NEJMoa061267.
citation: Laitinen K, Poussa T, Isolauri E; Nutrition, Allergy, Mucosal Immunology and Intestinal Microbiota Group. Probiotics and dietary counselling contribute to glucose regulation during and after pregnancy: a randomised controlled trial. Br J Nutr. 2009 Jun;101(11):1679-87. doi: 10.1017/S0007114508111461. Epub 2008 Nov 19.
citation: Luoto R, Laitinen K, Nermes M, Isolauri E. Impact of maternal probiotic-supplemented dietary counselling on pregnancy outcome and prenatal and postnatal growth: a double-blind, placebo-controlled study. Br J Nutr. 2010 Jun;103(12):1792-9. doi: 10.1017/S0007114509993898. Epub 2010 Feb 4.
citation: Badami E, Sorini C, Coccia M, Usuelli V, Molteni L, Bolla AM, Scavini M, Mariani A, King C, Bosi E, Falcone M. Defective differentiation of regulatory FoxP3+ T cells by small-intestinal dendritic cells in patients with type 1 diabetes. Diabetes. 2011 Aug;60(8):2120-4. doi: 10.2337/db10-1201. Epub 2011 Jun 6.
citation: Hara N, Alkanani AK, Ir D, Robertson CE, Wagner BD, Frank DN, Zipris D. The role of the intestinal microbiota in type 1 diabetes. Clin Immunol. 2013 Feb;146(2):112-9. doi: 10.1016/j.clim.2012.12.001. Epub 2012 Dec 11.
citation: Ludvigsson J, Faresjo M, Hjorth M, Axelsson S, Cheramy M, Pihl M, Vaarala O, Forsander G, Ivarsson S, Johansson C, Lindh A, Nilsson NO, Aman J, Ortqvist E, Zerhouni P, Casas R. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N Engl J Med. 2008 Oct 30;359(18):1909-20. doi: 10.1056/NEJMoa0804328. Epub 2008 Oct 8.
citation: American Diabetes Association. Standards of medical care in diabetes--2014. Diabetes Care. 2014 Jan;37 Suppl 1:S14-80. doi: 10.2337/dc14-S014. No abstract available.
citation: Mejia-Leon ME, Petrosino JF, Ajami NJ, Dominguez-Bello MG, de la Barca AM. Fecal microbiota imbalance in Mexican children with type 1 diabetes. Sci Rep. 2014 Jan 22;4:3814. doi: 10.1038/srep03814.
citation: Patelarou E, Girvalaki C, Brokalaki H, Patelarou A, Androulaki Z, Vardavas C. Current evidence on the associations of breastfeeding, infant formula, and cow's milk introduction with type 1 diabetes mellitus: a systematic review. Nutr Rev. 2012 Sep;70(9):509-19. doi: 10.1111/j.1753-4887.2012.00513.x.
citation: Murri M, Leiva I, Gomez-Zumaquero JM, Tinahones FJ, Cardona F, Soriguer F, Queipo-Ortuno MI. Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case-control study. BMC Med. 2013 Feb 21;11:46. doi: 10.1186/1741-7015-11-46.
citation: Vaarala O. Human intestinal microbiota and type 1 diabetes. Curr Diab Rep. 2013 Oct;13(5):601-7. doi: 10.1007/s11892-013-0409-5.
citation: Vaarala O, Atkinson MA, Neu J. The "perfect storm" for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity. Diabetes. 2008 Oct;57(10):2555-62. doi: 10.2337/db08-0331.
citation: de Goffau MC, Luopajarvi K, Knip M, Ilonen J, Ruohtula T, Harkonen T, Orivuori L, Hakala S, Welling GW, Harmsen HJ, Vaarala O. Fecal microbiota composition differs between children with beta-cell autoimmunity and those without. Diabetes. 2013 Apr;62(4):1238-44. doi: 10.2337/db12-0526. Epub 2012 Dec 28.
citation: Hague A, Butt AJ, Paraskeva C. The role of butyrate in human colonic epithelial cells: an energy source or inducer of differentiation and apoptosis? Proc Nutr Soc. 1996 Nov;55(3):937-43. doi: 10.1079/pns19960090. No abstract available.
citation: Peng L, Li ZR, Green RS, Holzman IR, Lin J. Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J Nutr. 2009 Sep;139(9):1619-25. doi: 10.3945/jn.109.104638. Epub 2009 Jul 22.
citation: Brown CT, Davis-Richardson AG, Giongo A, Gano KA, Crabb DB, Mukherjee N, Casella G, Drew JC, Ilonen J, Knip M, Hyoty H, Veijola R, Simell T, Simell O, Neu J, Wasserfall CH, Schatz D, Atkinson MA, Triplett EW. Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS One. 2011;6(10):e25792. doi: 10.1371/journal.pone.0025792. Epub 2011 Oct 17.
citation: Luopajarvi K, Savilahti E, Virtanen SM, Ilonen J, Knip M, Akerblom HK, Vaarala O. Enhanced levels of cow's milk antibodies in infancy in children who develop type 1 diabetes later in childhood. Pediatr Diabetes. 2008 Oct;9(5):434-41. doi: 10.1111/j.1399-5448.2008.00413.x. Epub 2008 May 21.
citation: Turley SJ, Lee JW, Dutton-Swain N, Mathis D, Benoist C. Endocrine self and gut non-self intersect in the pancreatic lymph nodes. Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17729-33. doi: 10.1073/pnas.0509006102. Epub 2005 Nov 29.
citation: Oikarinen M, Tauriainen S, Oikarinen S, Honkanen T, Collin P, Rantala I, Maki M, Kaukinen K, Hyoty H. Type 1 diabetes is associated with enterovirus infection in gut mucosa. Diabetes. 2012 Mar;61(3):687-91. doi: 10.2337/db11-1157. Epub 2012 Feb 7.
citation: King C, Sarvetnick N. The incidence of type-1 diabetes in NOD mice is modulated by restricted flora not germ-free conditions. PLoS One. 2011 Feb 25;6(2):e17049. doi: 10.1371/journal.pone.0017049.
citation: Roesch LF, Lorca GL, Casella G, Giongo A, Naranjo A, Pionzio AM, Li N, Mai V, Wasserfall CH, Schatz D, Atkinson MA, Neu J, Triplett EW. Culture-independent identification of gut bacteria correlated with the onset of diabetes in a rat model. ISME J. 2009 May;3(5):536-48. doi: 10.1038/ismej.2009.5. Epub 2009 Feb 19.
citation: Valladares R, Sankar D, Li N, Williams E, Lai KK, Abdelgeliel AS, Gonzalez CF, Wasserfall CH, Larkin J, Schatz D, Atkinson MA, Triplett EW, Neu J, Lorca GL. Lactobacillus johnsonii N6.2 mitigates the development of type 1 diabetes in BB-DP rats. PLoS One. 2010 May 6;5(5):e10507. doi: 10.1371/journal.pone.0010507.
citation: Groele L, Szajewska H, Szalecki M, Swiderska J, Wysocka-Mincewicz M, Ochocinska A, Stelmaszczyk-Emmel A, Demkow U, Szypowska A. Lack of effect of Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 on beta-cell function in children with newly diagnosed type 1 diabetes: a randomised controlled trial. BMJ Open Diabetes Res Care. 2021 Mar;9(1):e001523. doi: 10.1136/bmjdrc-2020-001523.
citation: Groele L, Szajewska H, Szypowska A. Effects of Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 on beta-cell function in children with newly diagnosed type 1 diabetes: protocol of a randomised controlled trial. BMJ Open. 2017 Oct 11;7(10):e017178. doi: 10.1136/bmjopen-2017-017178.