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Trial of Intranasal Insulin in Children and Young Adults at Risk of Type 1 Diabetes (INITII)

Primary Purpose

Type 1 Diabetes

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Intranasal insulin
Placebo
Sponsored by
Melbourne Health
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Type 1 Diabetes focused on measuring Type 1 diabetes

Eligibility Criteria

4 Years - 30 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: First-degree or second-degree relative of a person with Type 1 diabetes (T1D) diagnosed before age 40. Age 4-30 years if first-degree relative; age 4-20 years if second-degree relative. Confirmed serum antibodies to two or more islet antigens. Normal oral glucose tolerance test (OGTT). First phase insulin response (FPIR) at or above threshold - Primary Stratum - greater than or equal to 10th percentile for siblings, offspring and second-degree relatives of person with T1D (greater than or equal to 100uU/ml if aged 8 or more years OR greater than or equal to 60 uU/ml if aged less than 8) and greater than or equal to the 1st percentile for parents of someone with T1D (greater than ore equal to 60uU/ml). Secondary Stratum: Greater than or equal 1st percentile, less than 10th percentile for siblings, offspring and second-degree relatives of someone with T1D (greater than or equal to 50uU/ml less than 100 uU/ml if aged greater than or equal to 8 years or greater than or equal to 20 uU/ml less than 60uU/ml if aged less than 8 years) Provision of written consent. - Exclusion Criteria: History of treatment with insulin or oral hypoglycemic agents Known diabetes by ADA/WHO criteria Pregnant or lactating or of child-bearing potential not using an adequate method of contraception Concomitant disease or treatment which may interfere with assessment or cause immunosuppression, as judged by the investigators. Uncorrected vitamin D deficiency Known alcohol or drug abuse, psychiatric or other condition that could be associated with poor compliance. Known liver disease, or persisting elevation of plasma Aspartate transaminase (AST) or Alanine transaminase (ALT) levels. Impaired renal function Any defect or pathology of nasal passage which would preclude application of the intranasal spray. -

Sites / Locations

  • The Children's Hospital at Westmead
  • Mater Children's Hospital
  • Womens and Childrens Hospital
  • Royal Melbourne Hospital
  • Princess Margaret Hospital
  • University of Auckland

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

DV001

Placebo

Arm Description

Recombinant human intranasal insulin formulation in a buffered solution of benzalkonium chloride and glycerol presented in multi-dose nasal spray devices with actuators (Pfeiffer) designed to deliver 100ul spray doses to nasal mucosa. The product is formulated at a dose strength of 1100 IU / mL (40mg/mL) manufacturing formulation. The product will be self administered by eligible participants as two 100 microlitre spray doses per nostril. Treatment will be administered daily for 7 consecutive days then on one day each week for 12 months. Participants will be followed until they develop diabetes or until 5 years after the last participant has been randomised (maximum period of follow up is expected to be 10 years.

Placebo insulin carrier solution of benzalkonium chloride and glycerol presented in multi-dose nasal spray devices with actuators (Pfeiffer) designed to deliver 100ul spray doses to nasal mucosa. The product will be self administered by participants as two 100 microlitre spray doses per nostril. Treatment will be administered daily for 7 consecutive days then on one day each week for 12 months. Participants will be followed until they develop diabetes or until 5 years after the last participant has been randomised (maximum period of follow up is expected to be 10 years.

Outcomes

Primary Outcome Measures

Diagnosis of Diabetes AT 5 years according to American Diabetes Association / World Health Organization (ADA/WHO) criteria.
Defined as the presence of 2 or more of the following diagnostic criteria including diabetic fasting blood glucose level, diabetic 2 hour postprandial blood glucose level, diabetic HbA1c and symptoms

Secondary Outcome Measures

B cell function
Measured as glucose and insulin responses in Oral glucose tolerance test (OGTT) 6 monthly
Insulin Action
Insulin resistance measured by Homeostasis of model assessment - resistance (HOMA-R) 6 monthly
Immune function
Measured by levels of circulating antibodies to insulin, Glutamic acid decarboxylase (GAD) and Tyrosine phosphatase - like insulinoma antigen (IA-2) and T cell responses to proinsulin, denatured insulin, GAD and tetanus at 5 years

Full Information

First Posted
June 12, 2006
Last Updated
October 5, 2020
Sponsor
Melbourne Health
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1. Study Identification

Unique Protocol Identification Number
NCT00336674
Brief Title
Trial of Intranasal Insulin in Children and Young Adults at Risk of Type 1 Diabetes
Acronym
INITII
Official Title
A Randomised, Double-blind, Placebo-controlled Trial of Intranasal Insulin (440 IU) in Children and Young Adults at Risk of Type 1 Diabetes: Intranasal Insulin Trial II
Study Type
Interventional

2. Study Status

Record Verification Date
October 2020
Overall Recruitment Status
Completed
Study Start Date
December 2006 (undefined)
Primary Completion Date
November 13, 2019 (Actual)
Study Completion Date
November 13, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Melbourne Health

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
In people with type 1 diabetes the beta cells of the pancreas no longer make insulin because the body's immune system has attacked and destroyed the beta cells. It is thought that exposure of the mucous membranes to insulin may cause act like a vaccine effect whereby protective immune cells are stimulated and these then counteract the "bad" immune cells that damage the beta cells. This study aims to determine if intranasal insulin can protect beta cells and stop progression to diabetes in individuals who are at risk.
Detailed Description
Autoimmune diseases are the outcome of dysregulated immune responses to self-antigens. Type 1 diabetes (T1D), previously known as insulin-dependent or juvenile diabetes, is an autoimmune disease in which the body's immune system reacts against and destroys the insulin-producing β cells in the islets of the pancreas. T1D classically affects children and young adults. Approximately 15% of people with diabetes have this form of the disease and no treatment is currently available to prevent it. Asymptomatic individuals in the pre-clinical stage of T1D can be identified by the presence of circulating antibodies to the islet autoantigens (pro)insulin, glutamic acid decarboxylase (GAD) and tyrosine phosphatase-like insulinoma antigen 2 (IA2). (Pro)insulin is the only autoantigen that is specific for β cells and several lines of evidence demonstrate that it plays a key role in driving autoimmune β-cell destruction. The ability to use self-antigens as tools to induce protective immunity, free from the side effects of conventional non-specific immunosuppression, is the 'Holy Grail' of autoimmune disease therapy. Animal models provide proof-of-concept for such antigen-specific therapy. For example, in the non-obese diabetic (NOD) mouse, a model of spontaneous T1D, transgenic over-expression of proinsulin in antigen-presenting cells in the immune system during development or in transferred bone marrow stem cells completely prevented diabetes. On a more practical and translatable level, immune tolerance to an antigen can be achieved by administering antigen to the mucosal immune system. Thus, immune responses to antigen are suppressed by feeding antigen ('oral tolerance') or by administering antigen to the naso-respiratory mucosa .

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 1 Diabetes
Keywords
Type 1 diabetes

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
110 (Actual)

8. Arms, Groups, and Interventions

Arm Title
DV001
Arm Type
Active Comparator
Arm Description
Recombinant human intranasal insulin formulation in a buffered solution of benzalkonium chloride and glycerol presented in multi-dose nasal spray devices with actuators (Pfeiffer) designed to deliver 100ul spray doses to nasal mucosa. The product is formulated at a dose strength of 1100 IU / mL (40mg/mL) manufacturing formulation. The product will be self administered by eligible participants as two 100 microlitre spray doses per nostril. Treatment will be administered daily for 7 consecutive days then on one day each week for 12 months. Participants will be followed until they develop diabetes or until 5 years after the last participant has been randomised (maximum period of follow up is expected to be 10 years.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo insulin carrier solution of benzalkonium chloride and glycerol presented in multi-dose nasal spray devices with actuators (Pfeiffer) designed to deliver 100ul spray doses to nasal mucosa. The product will be self administered by participants as two 100 microlitre spray doses per nostril. Treatment will be administered daily for 7 consecutive days then on one day each week for 12 months. Participants will be followed until they develop diabetes or until 5 years after the last participant has been randomised (maximum period of follow up is expected to be 10 years.
Intervention Type
Biological
Intervention Name(s)
Intranasal insulin
Intervention Description
440IU Insulin
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Placebo insulin carrier solution containing benzalkonium chloride and glycerol
Primary Outcome Measure Information:
Title
Diagnosis of Diabetes AT 5 years according to American Diabetes Association / World Health Organization (ADA/WHO) criteria.
Description
Defined as the presence of 2 or more of the following diagnostic criteria including diabetic fasting blood glucose level, diabetic 2 hour postprandial blood glucose level, diabetic HbA1c and symptoms
Time Frame
1 year of treatment 9 years follow up
Secondary Outcome Measure Information:
Title
B cell function
Description
Measured as glucose and insulin responses in Oral glucose tolerance test (OGTT) 6 monthly
Time Frame
1 year of treatment 9 years follow up
Title
Insulin Action
Description
Insulin resistance measured by Homeostasis of model assessment - resistance (HOMA-R) 6 monthly
Time Frame
1 year of treatment 9 years follow up
Title
Immune function
Description
Measured by levels of circulating antibodies to insulin, Glutamic acid decarboxylase (GAD) and Tyrosine phosphatase - like insulinoma antigen (IA-2) and T cell responses to proinsulin, denatured insulin, GAD and tetanus at 5 years
Time Frame
1 year of treatment 9 years follow up

10. Eligibility

Sex
All
Minimum Age & Unit of Time
4 Years
Maximum Age & Unit of Time
30 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: First-degree or second-degree relative of a person with Type 1 diabetes (T1D) diagnosed before age 40. Age 4-30 years if first-degree relative; age 4-20 years if second-degree relative. Confirmed serum antibodies to two or more islet antigens. Normal oral glucose tolerance test (OGTT). First phase insulin response (FPIR) at or above threshold - Primary Stratum - greater than or equal to 10th percentile for siblings, offspring and second-degree relatives of person with T1D (greater than or equal to 100uU/ml if aged 8 or more years OR greater than or equal to 60 uU/ml if aged less than 8) and greater than or equal to the 1st percentile for parents of someone with T1D (greater than ore equal to 60uU/ml). Secondary Stratum: Greater than or equal 1st percentile, less than 10th percentile for siblings, offspring and second-degree relatives of someone with T1D (greater than or equal to 50uU/ml less than 100 uU/ml if aged greater than or equal to 8 years or greater than or equal to 20 uU/ml less than 60uU/ml if aged less than 8 years) Provision of written consent. - Exclusion Criteria: History of treatment with insulin or oral hypoglycemic agents Known diabetes by ADA/WHO criteria Pregnant or lactating or of child-bearing potential not using an adequate method of contraception Concomitant disease or treatment which may interfere with assessment or cause immunosuppression, as judged by the investigators. Uncorrected vitamin D deficiency Known alcohol or drug abuse, psychiatric or other condition that could be associated with poor compliance. Known liver disease, or persisting elevation of plasma Aspartate transaminase (AST) or Alanine transaminase (ALT) levels. Impaired renal function Any defect or pathology of nasal passage which would preclude application of the intranasal spray. -
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Leonard C Harrison, MBBS MD DSc
Organizational Affiliation
Melbourne Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Children's Hospital at Westmead
City
Westmead
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
Facility Name
Mater Children's Hospital
City
Brisbane
State/Province
Queensland
ZIP/Postal Code
4101
Country
Australia
Facility Name
Womens and Childrens Hospital
City
North Adelaide
State/Province
South Australia
ZIP/Postal Code
5006
Country
Australia
Facility Name
Royal Melbourne Hospital
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3050
Country
Australia
Facility Name
Princess Margaret Hospital
City
Subiaco
State/Province
Western Australia
ZIP/Postal Code
6840
Country
Australia
Facility Name
University of Auckland
City
Auckland
Country
New Zealand

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34091488
Citation
Jacobsen LM, Schatz DA. Insulin immunotherapy for pretype 1 diabetes. Curr Opin Endocrinol Diabetes Obes. 2021 Aug 1;28(4):390-396. doi: 10.1097/MED.0000000000000648.
Results Reference
derived

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Trial of Intranasal Insulin in Children and Young Adults at Risk of Type 1 Diabetes

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