Diabetes Mellitus, Type 1Phase 2NCT03182322
PINIT Study: Primary Intranasal Insulin Trial
A Phase 2 study testing intranasal insulin in people with Diabetes Mellitus, Type 1, run by Technical University of Munich at 2 sites in Germany.
Trial summary
Type 1 diabetes (T1D) results from an autoimmune destruction of the insulin-producing beta cells. Administration of mucosal insulin in islet autoantibody-negative children who are genetically predisposed for T1D offers the potential for inducing immunological tolerance to beta cells and thereby protect against the… Read more about this study
- Who is it for?
- Ages 1 year to 7 yearsHealthy volunteers can take part
- Conditions the study is for
- Diabetes Mellitus, Type 1
- What is being tested?
- intranasal insulin
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 38 participants
- Where
- 2 sitesGermany
- Study dates
- 25 May 2018to 7 Jun 2021
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 7 years
- All sexes
- Healthy volunteers accepted
- Child
Who may be able to join
- Children aged 1 year to 7 years (randomization must be performed prior to 8th birthday) who
- have the HLA DR3-DQB1*0201/DR4-DQB1*0302 or the HLA DR3-DQB1*0201/DR4-DQB1*0304 genotype or
- have a first degree relative with type 1 diabetes, and have a HLA genotype that includes the HLA DR4-DQB1*0302 or HLA DR4-DQB1*0304 haplotype, and does not include one of the following alleles DR 11, DR 12, DQB1*0602, or haplotypes DR7-DQB1*0303, DR14-DQB1*0503, DR13-DQB1*0603 and must be
- Islet autoantibody negative (autoantibodies against insulin, GAD, IA-2 and ZnT8) at time of screening.
Who cannot join
- Concomitant disease or treatment, which may interfere with assessment or cause immunosuppression, as judged by the investigators.
- Any condition that could be associated with poor compliance.
- Any defect or pathology of nasal passage, which would preclude application of the intranasal spray.
- Any moderate to severe intolerance to ingredients of the investigational medicinal product.
Trial locations and contacts
2 sites in 1 country.
Germany2 sites
Klinik und Poliklinik für Kinder und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany
Dresden, 01307
Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes der Technischen Universität München
München, 80804
About this study
Official title: An Immune Efficacy Study for Primary Prevention Using Intranasal Insulin Therapy in Islet Autoantibody Negative Children at High Genetic Risk for Type 1 Diabetes
Type 1 diabetes (T1D) results from an autoimmune destruction of the insulin-producing beta cells. Administration of mucosal insulin in islet autoantibody-negative children who are genetically predisposed for T1D offers the potential for inducing immunological tolerance to beta cells and thereby protect against the development of islet autoimmunity and T1D. Intranasal insulin has the advantage that whole protein will be exposed at the mucosa. Therefore, the available dose of insulin when administered intranasally is likely to be consistent between individuals. On this basis, the investigators aim to conduct a placebo-controlled, double-blind/double-masked primary intervention pilot trial (PINIT Study) of intranasal insulin treatment in islet autoantibody negative children to test immune efficacy and safety in the primary prevention setting. This pilot will help to develop and design a Phase III study aiming to test efficacy of preventing islet autoimmunity and T1D.
Read the detailed description
Hypothesis: The hypothesis is that intranasal administration of insulin will induce protective immune responses and prevent T1D-autoimmunity, and the development of T1D.
Objectives: To determine whether intranasal administration of 440 IU insulin to children with high genetic risk for T1D will induce likely protective IgG or IgA antibody responses to insulin, and/or T-cell responses to insulin and/or proinsulin.
Intranasal insulin will be applied as a fine aerosol spray to the back of the nose. The insulin formulation and method of administration of intranasal insulin is designed to stimulate local mucosal immunity to insulin as an antigenic protein. Without an absorption enhancer, such as a surfactant, intranasal insulin is not anticipated to have systemic hormonal effects. The presentation is a multi-dose spray device with nasal actuator in a brown glass vial designed to deliver 50 μl spray doses to the nasal mucosa.
The PINIT Study is designed as a randomized, placebo-controlled, double-blind, multicenter, primary intervention pilot phase II study, in which intranasal insulin will be administered daily for the first seven days and once per week thereafter. The study will include 38 islet autoantibody negative children with the HLA DR3/4-DQ8 genotype or with a first degree relative with T1D and at least one HLA DR4-DQ8 haplotype and no protective HLA DR-DQ alleles or haplotypes. These 38 children will be randomized to either insulin or placebo in a 1:1 ratio. The study will be monitored by an external Data Safety Monitoring Committee (DSMB).
Recruitment will be carried out German wide and will be organized by clinical centers in Munich and Dresden. PINIT will determine the immune bioavailability of mucosal insulin to the immune system in the age group of 1 year to 7 years and assess safety of treatment with intranasal insulin at a single dose (440 IU).
Primary outcome - immune efficacy: The primary outcome is immune efficacy measured by the activation of an immune response (antibody or CD4+ T cell) against insulin.
Additional outcomes are:
- safety assessed by blood glucose concentrations in the first 2 hours after receiving study drug to determine whether the treatment induces hypoglycaemia, and the development of islet autoantibodies to GAD and IA-2 and ZnT8 is assessed at 3 and 6 months after commencing treatment.
- mechanistic T cell studies to determine the characteristics of any T cell response to insulin.
- Flow cytometry to measure T cell and monocyte subpopulations
- RNA seq on peripheral blood mononuclear cells
- Serum inflammatory markers
Comparisons between treatment groups will be performed on the whole cohort and also separately on the participants by the type 1 diabetes susceptible INS genotype, and after stratification for age and SIGLEC1 (CD169) positivity of monocytes.
Time schedule: The recruitment phase will run over a period of 12 months. Enrolled participants will be treated for 6 months. First patient first visit (FPFV) occured in May 2018 and the last patient last visit (LPLV) occured on 18. August 2020. The overall end of trial time point is defined as the time when all mechanistic assays and measurement of lab values including T-cell stimulation tests have been completed. This is expected by end of February 2021.
- Conditions
- Diabetes Mellitus, Type 1
- Being tested
- intranasal insulin, Placebo
- Keywords
- Type 1 diabetes, T1D, diabetes mellitus, intranasal insulin, mucosal tolerance, autoantigen, self tolerance, prevention, at risk for developing type 1 diabetes, juvenile diabetes
- Medical subject headings
- Diabetes Mellitus, Type 1, Diabetes Mellitus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
intranasal insulinDrug
Total of 6 months treatment; daily for the first 7 intervention days and one day per week thereafter (formulation containing rH-insulin, benzalkonium chloride, glycerol and water)
PlaceboOther
Total of 6 months treatment; daily for the first 7 intervention days and one day per week thereafter placebo (formulation containing benzalkonium chloride, glycerol and water)
| Study group | Role | What they receive |
|---|---|---|
| intranasal insulin | Experimental | rH-insulin formulation and for a dose of 440 IU insulin to the nasal mucosa. Treatment will be administered daily for the first 7 intervention days, and one day per week thereafter for 6 months. Receives: Drug: intranasal insulin |
| intranasal placebo | Placebo comparator | Treatment with placebo nasal spray daily for the first 7 intervention days and one day per week thereafter for 6 months. Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
The activation of an immune response (antibody or CD4+ T cell) against insulin.
The responses are as previously defined in the Pre-POINT study (JAMA 313:1541-9). An antibody response is defined as serum IAA positivity in the competitive immuno-precipitation assay, an increase from baseline (>10 cpm) in serum IgG binding to insulin, or a positive salivary IgA binding to insulin. A CD4+ T cell response is defined as a stimulation index >3 and a >2-fold increase from stimulation index at baseline. A positive response (responder) will be defined as a child with an antibody or T cell response to insulin at any time point during treatment. The number of responders in the insulin treated group will be compared with the number of responders in the placebo treated group.
Measured: change from baseline (visit 1) in CD4+ T cell response measured as a stimulation index at 3 months (visit 2) and 6 months (visit 3) of treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jun 2017
- Study start25 May 2018
- Primary completion7 Jun 2021
- Study completion7 Jun 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Diabetes Mellitus, Type 1Studies of the same condition, open and under way.
- More trials run by Technical University of MunichThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 38 participants (actual)
Sponsor and investigators
- Lead sponsor
- Technical University of Munich
- Sponsor type
- University, hospital or other
- Collaborators
- Technische Universität Dresden, Ludwig-Maximilians - University of Munich, Helmholtz Zentrum München, University Hospital Carl Gustav Carus
- Responsible party
- Sponsor
- Investigators
- Peter Achenbach, PD Dr., Principal investigator, Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes, der Technischen Universität München, Kölner Platz 1, 80804 München, GermanyAnette-G. Ziegler, Prof. Dr., Principal investigator, Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes, der Technischen Universität München, Kölner Platz 1, 80804 München, Germany
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03182322
- Sponsor's protocol ID
- 808040015
- Status last verified
- Jun 2021
- First submitted
- 8 Mar 2017
- Last updated
- 22 Jun 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 22 Jun 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Immune Efficacy Study for Primary Prevention Using Intranasal Insulin Therapy in Islet Autoantibody Negative Children at High Genetic Risk for Type 1 Diabetes
- ClinicalTrials.gov ID
- NCT03182322
- Acronym / sponsor ID
- 808040015
- Conditions
- Diabetes Mellitus, Type 1
- Keywords
- Type 1 diabetes, T1D, diabetes mellitus, intranasal insulin, mucosal tolerance, autoantigen, self tolerance, prevention
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 38 participants (actual)
- Lead sponsor
- Technical University of MunichUniversity, hospital or other
- Collaborators
- Technische Universität Dresden, Ludwig-Maximilians - University of Munich, Helmholtz Zentrum München, University Hospital Carl Gustav Carus
- Study start
- 25 May 2018 (actual)
- Primary completion
- 7 Jun 2021 (actual)
- Study completion
- 7 Jun 2021 (actual)
- First posted
- 9 Jun 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Type 1 diabetes (T1D) results from an autoimmune destruction of the insulin-producing beta cells. Administration of mucosal insulin in islet autoantibody-negative children who are genetically predisposed for T1D offers the potential for inducing immunological tolerance to beta cells and thereby protect against the development of islet autoimmunity and T1D. Intranasal insulin has the advantage that whole protein will be exposed at the mucosa. Therefore, the available dose of insulin when administered intranasally is likely to be consistent between individuals. On this basis, the investigators aim to conduct a placebo-controlled, double-blind/double-masked primary intervention pilot trial (PINIT Study) of intranasal insulin treatment in islet autoantibody negative children to test immune efficacy and safety in the primary prevention setting. This pilot will help to develop and design a Phase III study aiming to test efficacy of preventing islet autoimmunity and T1D.
Detailed description
Hypothesis: The hypothesis is that intranasal administration of insulin will induce protective immune responses and prevent T1D-autoimmunity, and the development of T1D.
Objectives: To determine whether intranasal administration of 440 IU insulin to children with high genetic risk for T1D will induce likely protective IgG or IgA antibody responses to insulin, and/or T-cell responses to insulin and/or proinsulin.
Intranasal insulin will be applied as a fine aerosol spray to the back of the nose. The insulin formulation and method of administration of intranasal insulin is designed to stimulate local mucosal immunity to insulin as an antigenic protein. Without an absorption enhancer, such as a surfactant, intranasal insulin is not anticipated to have systemic hormonal effects. The presentation is a multi-dose spray device with nasal actuator in a brown glass vial designed to deliver 50 μl spray doses to the nasal mucosa.
The PINIT Study is designed as a randomized, placebo-controlled, double-blind, multicenter, primary intervention pilot phase II study, in which intranasal insulin will be administered daily for the first seven days and once per week thereafter. The study will include 38 islet autoantibody negative children with the HLA DR3/4-DQ8 genotype or with a first degree relative with T1D and at least one HLA DR4-DQ8 haplotype and no protective HLA DR-DQ alleles or haplotypes. These 38 children will be randomized to either insulin or placebo in a 1:1 ratio. The study will be monitored by an external Data Safety Monitoring Committee (DSMB).
Recruitment will be carried out German wide and will be organized by clinical centers in Munich and Dresden. PINIT will determine the immune bioavailability of mucosal insulin to the immune system in the age group of 1 year to 7 years and assess safety of treatment with intranasal insulin at a single dose (440 IU).
Primary outcome - immune efficacy: The primary outcome is immune efficacy measured by the activation of an immune response (antibody or CD4+ T cell) against insulin.
Additional outcomes are:
- safety assessed by blood glucose concentrations in the first 2 hours after receiving study drug to determine whether the treatment induces hypoglycaemia, and the development of islet autoantibodies to GAD and IA-2 and ZnT8 is assessed at 3 and 6 months after commencing treatment.
- mechanistic T cell studies to determine the characteristics of any T cell response to insulin.
- Flow cytometry to measure T cell and monocyte subpopulations
- RNA seq on peripheral blood mononuclear cells
- Serum inflammatory markers
Comparisons between treatment groups will be performed on the whole cohort and also separately on the participants by the type 1 diabetes susceptible INS genotype, and after stratification for age and SIGLEC1 (CD169) positivity of monocytes.
Time schedule: The recruitment phase will run over a period of 12 months. Enrolled participants will be treated for 6 months. First patient first visit (FPFV) occured in May 2018 and the last patient last visit (LPLV) occured on 18. August 2020. The overall end of trial time point is defined as the time when all mechanistic assays and measurement of lab values including T-cell stimulation tests have been completed. This is expected by end of February 2021.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| intranasal insulin | Experimental | Drug: intranasal insulinrH-insulin formulation and for a dose of 440 IU insulin to the nasal mucosa. Treatment will be administered daily for the first 7 intervention days, and one day per week thereafter for 6 months. |
| intranasal placebo | Placebo comparator | Other: PlaceboTreatment with placebo nasal spray daily for the first 7 intervention days and one day per week thereafter for 6 months. |
Who may qualify
- Ages
- 1 year to 7 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child
Key inclusion criteria (4 listed)
- Children aged 1 year to 7 years (randomization must be performed prior to 8th birthday) who
- Islet autoantibody negative (autoantibodies against insulin, GAD, IA-2 and ZnT8) at time of screening.
Key exclusion criteria (4 listed)
- Concomitant disease or treatment, which may interfere with assessment or cause immunosuppression, as judged by the investigators.
- Any condition that could be associated with poor compliance.
- Any defect or pathology of nasal passage, which would preclude application of the intranasal spray.
- Any moderate to severe intolerance to ingredients of the investigational medicinal product.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| intranasal insulinTotal of 6 months treatment; daily for the first 7 intervention days and one day per week thereafter (formulation containing rH-insulin, benzalkonium chloride, glycerol and water) | Drug | intranasal insulin |
| PlaceboTotal of 6 months treatment; daily for the first 7 intervention days and one day per week thereafter placebo (formulation containing benzalkonium chloride, glycerol and water) | Other | intranasal placebo |
Primary outcome
The activation of an immune response (antibody or CD4+ T cell) against insulin.
Time frame: change from baseline (visit 1) in CD4+ T cell response measured as a stimulation index at 3 months (visit 2) and 6 months (visit 3) of treatment
The responses are as previously defined in the Pre-POINT study (JAMA 313:1541-9). An antibody response is defined as serum IAA positivity in the competitive immuno-precipitation assay, an increase from baseline (>10 cpm) in serum IgG binding to insulin, or a positive salivary IgA binding to insulin. A CD4+ T cell response is defined as a stimulation index >3 and a >2-fold increase from stimulation index at baseline. A positive response (responder) will be defined as a child with an antibody or T cell response to insulin at any time point during treatment. The number of responders in the insulin treated group will be compared with the number of responders in the placebo treated group.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Jun 2021.
- Related InfoLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Peter Achenbach, PD Dr. principal investigator
Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes, der Technischen Universität München, Kölner Platz 1, 80804 München, Germany
Anette-G. Ziegler, Prof. Dr. principal investigator
Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes, der Technischen Universität München, Kölner Platz 1, 80804 München, Germany
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing intranasal insulin in people with Diabetes Mellitus, Type 1, run by Technical University of Munich at 2 sites in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Jun 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The activation of an immune response (antibody or CD4+ T cell) against insulin. (time frame: change from baseline (visit 1) in CD4+ T cell response measured as a stimulation index at 3 months (visit 2) and 6 months (visit 3) of treatment). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Jun 2021.