Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT02605564 |
| Other study ID # |
5140361 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
January 19, 2016 |
| Est. completion date |
August 2, 2022 |
Study information
| Verified date |
October 2022 |
| Source |
Loma Linda University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The central hypothesis of this proposal is that a gluten-free diet introduced shortly after
diagnosis can reverse or arrest islet destruction in children and adolescents with type 1
diabetes mellitus (T1DM). The specific aims are to determine the effects of a gluten-free
diet on 1) endogenous insulin production and 2) the corresponding gut flora of children with
new-onset type 1 diabetes. This is a randomized placebo controlled clinical trial testing the
effect of altering the gut microbiome via a gluten-free diet on endogenous insulin production
as a measure of the pace and severity of islet destruction at the time of diagnosis of type 1
diabetes. The project entails eliminating gluten from the diet of the intervention group and
comparing bacterial gut flora and endogenous insulin response with those in a control group
up to one year following the diagnosis of type 1 diabetes. The proposal introduces a new
potential etiology for type 1 diabetes in humans: the Bacterial Hypothesis. The short term
goal is to identify specific islet-preserving microbiome changes induced by eliminating
gluten from the diet of patients recently diagnosed with type 1 diabetes. The long term goal
is to develop these changes into effective and safe strategies that can allow patients with
type 1 diabetes to achieve permanent insulin-independence.
Description:
Research Strategy A. SPECIFIC AIMS
The continuing rise in incidence of type 1 diabetes mellitus (T1DM) globally has not been
matched by successful efforts for prevention or amelioration of the disease. Additionally, a
huge gap exists in our understanding of the adjacent gastrointestinal milieu in which the
pancreatic islet destructive process occurs and leads to insulin-dependence in T1DM. The
largest increase in incidence of type 1 diabetes over the past decade has occurred in
children under 5 years of age, a group particularly susceptible to diabetes related morbidity
and mortality. Invasive methodologies via finger pricking for glucose monitoring and
subcutaneous insulin injection remain the standard of care required for patient survival.
Many intervention studies have been conducted based on inadequately substantiated knowledge
of the mechanisms (presumed to be exclusively autoimmune) causing permanent beta-cell
destruction in type 1 diabetes. Almost all intervention trials in new-onset type 1 diabetes
show only transient improvement of insulin production (up to 6 months) with subsequent
decline to levels similar to the control arms. Moreover, there are scientific arguments and
data which suggest that non autoimmune pathogenic mechanisms may be involved, perhaps in a
more toxic and generalized affliction of the pancreas. Recent evidence that beta-cells
continue to regenerate in the pancreas of patients with long-standing type 1 diabetes offers
hope that the disease process leading to insulin-dependence may be reversed if islet
destruction is arrested at a critical window of time.
The link between type 1 diabetes and the gut microbiome is actively being explored. Emerging
evidence suggests a role of the gut microbiome in the destruction and protection of islets in
type 1 diabetes-prone experimental models. In addition, type 1 diabetes was prevented in
genetically established murine models of the disease when these animals were restricted to a
gluten-free diet. The specific hypothesis addressed in this application is that a gluten-free
diet introduced shortly after diagnosis can reverse or halt the progression of type 1
diabetes in children and adolescents. Our proposed mechanism is that a gluten-free diet
preserves endogenous insulin production via altering the gut microbiota towards strains that
are inherently less toxic to islets. The study is designed for a comprehensive assessment of
the role of a gluten-free diet in children with T1DM. A specific objective is to reduce or
modify patients' gut microbiota early in the disease process as a possible means of arresting
islet destruction. The specific measurable aims of the current application outline an
innovative approach to begin the identification of beta-cell protective effects of specific
changes in gut flora that can be therapeutically developed to ameliorate type 1 diabetes.
Specific Aim 1: To determine the effect of a gluten-free diet on endogenous insulin secretion
and pancreatic morphology in children and adolescents with new-onset type 1 diabetes.
Specific Aim 2: To determine the effect of a gluten-free diet on the gut flora of patients
with new-onset type 1 diabetes.
Resultant data will allow determination of the relation between gut flora and beta- cell
function in patients with new-onset diabetes.
Collectively, the proposed studies are innovative for new-onset T1DM in children. A large
population of these patients currently receive care at the Pediatric Diabetes Clinics of Loma
Linda University (LLU) which currently provide care to approximately 2000 patients with T1DM.
On average, three to five patients with new-onset T1DM are diagnosed at LLU Children's
Hospital every week. This proposal is consistent with the research theme of the university
which is focused on diet and health, and is very much in line with the 'Wholeness' mission of
the institution. In collaboration with the new Genomic Center at LLU, we have a unique
opportunity to evaluate a novel mechanism of T1DM. In the future, this can lead to a
sustained research program on diet as therapy for type 1 diabetes, allow our site to design
and pioneer multi-center trials in this field, and optimize our chances to attract generous
extramural funding.
The preliminary data from this study will form the basis for an RO1 application.
B. Significance Type 1 diabetes mellitus is the most common metabolic disease of childhood.
Every year, approximately twenty thousand children are diagnosed with type 1 diabetes
mellitus (T1DM) in the United States alone according to the Centers for Disease Control and
Prevention. The incidence of T1DM continues to increase worldwide. The largest increase in
global incidence of T1DM over the past two decades has occurred in children under 5 years of
age, a group particularly susceptible to diabetes-related morbidity and mortality. As one of
the most common chronic illnesses in children, T1DM has been extensively studied and
concluded to be a consequence of autoimmune destruction of the insulin-producing pancreatic
islet beta-cells in genetically susceptible individuals. Despite the increasing prevalence of
type 2 diabetes, T1DM remains the most common form of diabetes in childhood, accounting for
approximately two-thirds of new diagnoses of diabetes in patients under 19 years of age in
the United States. The acute complications of T1DM include hypoglycemia, ketoacidosis, and
severe psychopathology, all of which are potentially fatal. The origins of profoundly
disabling long-term complications such as blindness, kidney failure and amputations can be
significantly obliterated if glycemic control is maintained early at the onset of the
disease.
A large body of data is emerging on the role of the gut microbiome in health and disease.
Recent studies have provided some evidence for a role for structural modulation of gut
microbiota in the pathogenesis of type 2 diabetes, the type of diabetes that is more common
in adults. Similar evidence has been observed in other disorders such as obesity and
cardiovascular disease. These studies have suggested that alteration in the composition of
intestinal microbiota may be linked to the development of several diseases, but this is not
yet clearly implicated in patients with type 1 diabetes.
More recently, special focus was directed to the role of gut bacteria in the destruction
versus protection of pancreatic islets. This has first been studied in T1DM-prone
experimental models. Since a type-1 diabetes-related protein was identified in wheat , T1DM
murine models showed a reduction in diabetes-associated cell subsets when put on a wheat-free
diet. Moreover, type 1 diabetes was prevented in genetically established murine models of the
disease when they were restricted to a gluten-free diet.
In young children who are genetically susceptible to T1DM, gut bacteria were notably less
diverse and less stable in the group which progressed to develop type 1 diabetes
autoimmunity. Of interest are reports of increased incidence of type 1 diabetes in children
who, on retrospective review, had received proton pump inhibitor therapy (NIH, personal
communication). Additionally, there is a published report of remission of T1DM in a 6 year
old child maintained by strictly adhering to a gluten-free diet without any insulin therapy.
This triggered a multicenter pilot study currently taking place in Northern Europe with
preliminary data suggesting that a gluten-free diet can preserve insulin secretion in adults
with type 1 diabetes. To our knowledge, none of the patients maintained on a gluten free diet
have undergone studies of the gut microbiome to date.
At LLU, three years following diagnosis of type 1 diabetes, one 17-year old patient at Loma
Linda University pediatric diabetes clinics has maintained excellent glycemic control despite
unusually low insulin requirements (a so called prolonged honeymoon phase) by adhering to a
gluten free diet. Two other patients at LLU, ages 3 and 4 years, experienced a significant
decline in insulin requirements (to honeymoon doses, i.e. total daily insulin less than 0.5
units per kg), necessitating discontinuation of an insulin pump in one case, following six
months of a gluten-free diet.
Taken together, the above data and cases suggested to us that altering the gut microbiota at
onset of the disease via a gluten-free diet may significantly preserve endogenous insulin
production, thereby minimizing the need for insulin injections and optimizing long-term
health in patients with type 1 diabetes.
Access to a large T1DM patient population at Loma Linda University Children's Hospital and
clinics offers a unique opportunity for the exploration of this novel dietary approach that
may contribute to tipping the balance within the pancreas towards islet function and
regeneration. When optimized, this will pave the way for patients with T1DM to achieve
insulin independence.
C. Innovation This proposal challenges the traditional and widely accepted autoimmune
mechanism for the development of T1DM, and adds to our previous data on the role of ambient
direct toxic factors in the development of T1DM in children. In a large case-control study,
we previously described a novel significant association between type 1 diabetes and
cumulative ambient ozone exposure birth to the time of diagnosis. Additionally, we have
already shown that patients under 5 years of age, the group with the largest increase in
incidence globally, frequently lack evidence of known type 1 diabetes autoimmune markers.
Moreover, the rapid rate of increase in incidence and decline in age of T1DM suggests that
aggressive toxic elements rather than a slow autoimmune process play a pivotal role in the
pathogenesis of the disease in children.
The project introduces a new potential etiology for type 1 diabetes in humans: the Bacterial
Hypothesis. Here, we investigate a novel, outstandingly safe, and potentially curative
approach to T1DM, consisting of merely dietary modification to change the gut microbiota
towards a more permissive milieu for insulin secretion. Most intervention trials in new-onset
T1DM have had an open design, and in many trials the investigational agent's side-effects
allowed the participating subjects to know whether or not they received active drug. Thus,
interpretation of results of most intervention studies to date cannot be deemed accurate
given a probable placebo effect. The current study design incorporates the placebo effect in
both study and control subjects. To our knowledge, this is the first randomized placebo
controlled trial testing the effect of dietary modification on the gut flora and the glycemic
control of children with newly diagnosed type 1 diabetes.
D. Approach
This is a randomized controlled clinical trial testing the effect of altering gut bacteria
via a gluten-free diet on the pace and severity of islet destruction in T1DM within six
months of diagnosis. The project entails modifying meal content, frequency and rate of
consumption, and assessing bacterial gut flora and endogenous insulin production up to one
year following enrollment. The current proposal is based on our current level of knowledge of
the T1DM disease process, caveats in current intervention studies, and the desirability of
interventions with minimum side effects in children.
The objective of the current proposal is to change the gut flora to reduce the bacterial
escape in the stomach and duodenum in a way which may have direct detoxification effects on
the adjacent pancreas and its insulin producing islet cells. The proposal tests the effect of
eliminating gluten from the diet on reducing or changing the gut flora in a manner conducive
to insulin secretion by beta cells. As the amount of bacteria entering the duodenum is
extremely dependent on the type of food, as well as on the volume of each meal, the
established benefit of eating small frequent meals may prove to be particularly useful in
patients type 1 DM. The proposed dietary intervention is likely to substantially influence
the bacterial flora in the duodenum without inflicting any significant harm to children's
health, growth or development.
D1. Specific Aim 1: To determine the effect of a gluten-free diet on endogenous insulin
secretion in children and adolescents with new-onset type 1 diabetes.
Subject Recruitment and Sample Size. Subjects diagnosed with type 1 diabetes will be
recruited from LLU Children's Hospitals and clinics within the first six months of diagnosis.
Participating subjects will be randomized to one of two study groups, each consisting of 25
to 30 subjects to provide 80% power to detect a significant difference in endogenous insulin
production (Area under the C-peptide curve in a mixed meal tolerance test).
Inclusion criteria: Ages: 1-17 years; diagnosis of type 1 diabetes within 6 months of
enrollment; parent or guardian willing to sign informed consent to comply with basal bolus
insulin treatment as well as study procedures and diet guidelines.
Exclusion criteria: Diabetes diagnosed under one year of age; patients with known
malabsorption or malnutrition; glycosylated hemoglobin HbA1C value over 9% at three months
following diagnosis (a general screen for noncompliance with treatment guidelines).
Study assessment time points are: enrollment, 3 months, 6 months, 9 months, and 12 months.
The only procedures to be conducted beyond the scope of routine care for type 1 diabetes are:
stool sample collections at enrollment and at 3, 6, 9 and 12 months; and mixed meal tolerance
tests (MMTT) at enrollment, and at 6 and 12 months. MMTT is a standard research tool to
assess islet functional reserve by measuring basal and stimulated blood glucose and C-peptide
at 30 minute intervals over two hours before (time zero) and after a standard high caloric
formula.
At diagnosis, all subjects will undergo routine institutional diabetes protocol laboratory
testing which includes diabetes autoimmune antibodies: Glutamic acid decarboxylase, Islet
Cell Antibodies, Insulin Autoantibodies, Zinc transporter 8 antibodies, as well as thyroid
and celiac antibodies. A fasting lipid panel and thyroid stimulating hormone (TSH) will also
be measured at initial evaluation. The level of 25 hydroxyvitamin D will be measured at
baseline to screen for malabsorption and nutritional deficiency particularly in view of a
suspected role for vitamin D in T1DM.
The standard of care for type 1 diabetes includes quarterly encounters with a diabetes team
including physicians, nurses, dietitians, together with quarterly assessment of glucose
profile, glycosylated hemoglobin (HbA1C), and appropriateness of insulin treatment regimens
with adjustments as needed.
Study subjects will be divided into two groups as follows:
Study group A subjects will receive standard T1DM basal bolus insulin regimens guided by
physicians, nurses, and a nutritional consult to ensure adequate knowledge of diabetes diet
recommendations and carbohydrate- based insulin dosing. In addition, subjects will receive
instructions to consume a "gluten-free" diet (e.g. replace white bread and potatoes with
rice, gluten-free bread and other foods). Group A will also be encouraged to increase the
time of consumption of each meal and to reduce the volume of meals including the volume of
liquids (i.e. a subject can eat the same volume of food desired but in smaller more frequent
meals).
Study group B will receive standard T1DM basal bolus insulin regimen guidelines by the same
physicians, nurses, and nutritionist but will be given the normal meal recommendations for
subjects with T1DM without any gluten intake or volume restrictions. Caloric and carbohydrate
daily recommendations will be tailored to age and will not be different between the two study
groups.
Subjects who show strong serologic evidence of gluten hypersensitivity will be excluded from
the two main study groups and started on a gluten-free diet. Their data will be tracked
retrospectively for any significant outcome differences which may be attributable to
pre-existing gluten hypersensitivity alone.
Gut bacteria will be studied at every assessment time-point via stool sampling in both study
groups.
Glycosylated hemoglobin A1C (HbA1C) will be measured at diagnosis and every three months
together with a dietitian's assessment to ensure compliance with designated diet
instructions.
Mixed meal tolerance testing for basal and stimulated C-peptide measurements will be done at
enrollment, and at 6 months and one year post-enrollment. Peak levels and areas under the
curve for stimulated C-peptide will be compared between the intervention and control group.
Every assessment time-point will include stool sampling for characterization of the bacterial
flora of the gut over time. Stool testing at each time-point will include regular bacterial
strain identification as well as genomic assessment.
