Probiotics in Newly Recognized Type 1 Diabetes

Diabetes Mellitus, Type 1 Clinical Trial

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03032354
• Other study ID #: AgaLidka
• Status: Not yet recruiting
• Phase: Phase 4
• First received: January 5, 2017
• Last updated: July 6, 2017
• Start date: July 15, 2017
• Est. completion date: December 2018

Study information

• Verified date: January 2017
• Source: Medical University of Warsaw
• Contact: Agnieszka Szypowska, Assoc. Prof.
• Phone: +48 509928617
• Email: agnieszka.szypowska[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 96
• Est. completion date: December 2018
• Est. primary completion date: December 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 8 Years to 17 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1

Intervention

Drug:
• Lactobacillus rhamnosus GG and Bifidobacterium lactis BB12
Combination therapy of probiotics during 6 months

Other:
• Placebo, (Placebo group)
Placebo during 6 months

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Medical University of Warsaw

References & Publications (25)

American Diabetes Association. Standards of medical care in diabetes--2014. Diabetes Care. 2014 Jan;37 Suppl 1:S14-80. doi: 10.2337/dc14-S014. — View 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; — View Citation

Brown CT, Davis-Richardson AG, Giongo A, Gano KA, Crabb DB, Mukherjee N, Casella G, Drew JC, Ilonen J, Knip M, Hyöty H, Veijola R, Simell T, Simell O, Neu J, Wasserfall CH, Schatz D, Atkinson MA, Triplett EW. Gut microbiome metagenomics analysis suggests — View Citation

de Goffau MC, Luopajärvi K, Knip M, Ilonen J, Ruohtula T, Härkönen T, Orivuori L, Hakala S, Welling GW, Harmsen HJ, Vaarala O. Fecal microbiota composition differs between children with ß-cell autoimmunity and those without. Diabetes. 2013 Apr;62(4):1238- — View 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. — View 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. Epub 2012 Jun 11. — View 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. Review. — View 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. Review. — View 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. — View 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. — View 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. — View Citation

Ludvigsson J, Faresjö M, Hjorth M, Axelsson S, Chéramy 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 — View Citation

Luopajärvi 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.1399-5 — View 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. — View Citation

Mejía-León ME, Petrosino JF, Ajami NJ, Domínguez-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. — View Citation

Murri M, Leiva I, Gomez-Zumaquero JM, Tinahones FJ, Cardona F, Soriguer F, Queipo-Ortuño 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 — View Citation

Oikarinen M, Tauriainen S, Oikarinen S, Honkanen T, Collin P, Rantala I, Mäki M, Kaukinen K, Hyöty 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. — View 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):5 — View 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.109.104 — View 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 M — View 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. — View 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. Epub 2005 Nov 29. — View 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. Review. — View 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. Review. — View 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. — View Citation

* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area under the curve (AUC) during fasting and at 30,60,90,120 min following the start of the meal		120 min responses to a mixed meal
Secondary	Insulin requirement (U / kg body mass )		up 60 days from diabetes recognition, at 3th, 6th, 12th month
Secondary	HbA1c		up to 60 days from diabetes recognition, at 3th, 6th, 12th month
Secondary	Weight in kilograms		up to 60 days from diabetes recognition, and at 3th, 6th, 12th month
Secondary	Number of participants with abnormal laboratory values and/or adverse events that are related to treatment ( eg.abdominal pain, diarrhea , constipation , vomiting,flatulence)		at 3th, 6th, 12th month
Secondary	Occurrence of other autoimmune diseases		at 12th month
Secondary	Height in meters		up to 60 days from diabetes recognition, and at 3th, 6th, 12th month
Secondary	BMI in kg/m2		up to 60 days from diabetes recognition, and at 3th, 6th, 12th month
Secondary	BMI score		up to 60 days from diabetes recognition, and at 3th, 6th, 12th month
Secondary	severe hypoglycemia		up to 60 days from diabetes recognition, at 3th, 6th, 12th month
Secondary	ketoacidosis		up to 60 days from diabetes recognition, at 3th, 6th, 12th month
Secondary	Fasting c- peptide concentrations in ng/ml		up to 60 days from diabetes recognition, and in: 6th, 12th month