Diabetes Mellitus, Type 1Phase 2NCT02547519
Pre-POINT-Early Study
A Phase 2 study testing Oral Insulin in people with Diabetes Mellitus, Type 1, run by Technical University of Munich at 1 site in Germany.
Trial summary
Type 1 diabetes (T1D) results from an autoimmune destruction of the insulin-producing beta cells within the pancreatic islets of Langerhans. This process is identified by circulating islet autoantibodies to beta cell antigens, and is mediated by a lack of immunological self-tolerance. Read more about this study
- Who is it for?
- Ages 6 months to 2 yearsHealthy volunteers can take part
- Conditions the study is for
- Diabetes Mellitus, Type 1
- What is being tested?
- Oral Insulin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 44 participants
- Where
- 1 siteGermany
- Study dates
- Aug 2015to Dec 2017
- 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 6 months to 2 years
- All sexes
- Healthy volunteers accepted
- Child
Who may be able to join
- Children aged 6 months to 2 years who have a first degree relative with type 1 diabetes, and have a HLA genotype that includes a HLA DR4-DQB1*0302 or HLA DR4-DQB1*0304 haplotype, and does not include one of the following alleles or haplotypes: DR 11, DR 12, DQB1*0602, DR7-DQB1*0303, DR14-DQB1*0503
- and must be
- Islet autoantibody negative at time of recruitment.
Who cannot join
- Concomitant disease or treatment, which may interfere with assessment or cause immunosuppression, as judged by the investigators.
- Prior or current participation in another intervention trial.
- Any condition that could be associated with poor compliance.
Trial locations and contacts
1 site in 1 country.
Germany1 site
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: Pilot Study Using Oral Insulin at Early Age for Immune Efficacy in Primary Prevention of Type 1 Diabetes
Type 1 diabetes (T1D) results from an autoimmune destruction of the insulin-producing beta cells within the pancreatic islets of Langerhans. This process is identified by circulating islet autoantibodies to beta cell antigens, and is mediated by a lack of immunological self-tolerance. Self-tolerance is achieved by T cell exposure to antigen in the thymus or periphery in a manner that deletes autoreactive effector T cells or induces regulatory T cells. Immunological tolerance can be achieved by administration of antigen under appropriate conditions. Administration of oral 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.
Read the detailed description
The purpose of the Pre-POINT-Early Study is to investigate and consolidate the finding from the preceding Pre-POINT Study, namely safety and immune efficacy at a daily dose of 67.5 mg oral insulin. Since younger children will be tested in Pre-POINT-Early, the 67.5 mg dose will be reached by dose escalation starting at 7.5 mg for 3 months followed by exposure to 22.5 mg for 3 months, and reaching the desired 67.5 mg dose, which is administered for 6 months in 22 children.
The active substance for oral application is human insulin, synthesized in a special non-disease-producing laboratory strain of Escherichia coli bacteria that has been genetically altered by the addition of the gene for human insulin production (Lilly Pharmaceuticals, Indianapolis, Indiana, USA). The physical, chemical and pharmaceutical properties of the human insulin have been well documented by the manufacturer. Oral Insulin will be applied as a capsule containing 7.5; 22.5 and 67.5 mg of the active substance together with filling substance cellulose. After oral administration insulin will be rapidly degraded by gastric acids. Enteric delivery and systemic availability is therefore unlikely and efficacy of active insulin is likely to be restricted to the oral mucosa.
In human studies oral insulin administration was safe and without adverse side effects at doses between 2.5 and 7.5 mg per day. Additionally Bonifacio et al. have conducted and completed the Pre-POINT study, the first primary autoantigen vaccination dose-finding study in which children with high genetic risk for type 1 diabetes were administered insulin orally daily. Oral insulin at all tested doses (2.5 mg; 7.5 mg; 22.5 mg and 67.5 mg) in Pre-POINT was considered safe: None of the children who received study drug or placebo experienced hypoglycaemic episodes after administration of medication, and no allergic reactions were observed.
The Pre-POINT-Early intended doses for oral application are 7.5, 22.5 and 67.5 mg per day. The aim of the study is to determine whether daily administration of oral insulin starting with dose 7.5 mg (3 months), moving to dose 22.5 mg (3 months) and to the highest dose of 67.5 mg (6 months) insulin to young children aged 6 months to 2 years with high genetic risk for T1DM induces immune responses to insulin and/or proinsulin with features of immune regulation.
- Conditions
- Diabetes Mellitus, Type 1
- Being tested
- Oral Insulin, Placebo
- Keywords
- Type 1 diabetes, T1D, diabetes mellitus, oral insulin, oral 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.
Oral InsulinDrug
Total of 12 months treatment; dose escalation scheme: daily treatment with 7.5 mg or placebo for 3 months; increasing to daily treatment with 22.5 mg or placebo for the following 3 months; increasing to daily treatment with 67.5 mg or placebo for the last 6 months of the treatment period.
PlaceboDrug
Total of 12 months treatment; daily treatment with insulin or placebo capsules containing filling substance (microcrystalline cellulose).
| Study group | Role | What they receive |
|---|---|---|
| oral insulin capsule (dose escalation using 3 dose strengths) | Experimental | Dose 1 is 7.5 mg rH-insulin crystals; dose 2 is 22.5 mg rH-insulin crystals; dose 3 is 67.5 mg rH-insulin crystals. The insulin crystals are formulated together with filling substance (microcrystalline cellulose to a total weight of 200 mg) and contained in hard gelatine capsules. The study treatment will be given orally. Receives: Drug: Oral Insulin |
| Placebo capsule | Placebo comparator | Daily treatment with placebo capsules containing filling substance (microcrystalline cellulose). Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
The activation of a CD4+ T cell immune response against insulin
The primary outcome for immune efficacy is the activation of an immune response (antibody or CD4+ T cell) against insulin. Each participant will be categorized as reaching a response or not. A response is defined as a >2-fold increase that reaches a stimulation index of >3.0.
Measured: change from baseline (visit 1) in CD4+ T cell response measured as a stimulation index at 12 months of treatment
The activation of an antibody response against insulin.
An antibody response is defined as an increase from baseline of >10 cpm in serum IgG binding to insulin from baseline to 12 months, or a positive salivary IgA binding to insulin at 12 months.
Measured: change from baseline (visit 1) in antibodies measured as serum IgG binding to insulin (unit of measure, cpm) and salivary IgA binding to insulin (unit of measure, cpm) at 12 months of treatment
Secondary outcomes (5)
Gene expression of CD4+ T cell response to insulin.
The number of responders in the insulin treated group will be compared with the number of responders in the placebo treated group. As secondary outcomes, responder status in individual measures of antibody response to insulin, CD4+ T cells response to insulin, and CD4+ T cell response to proinsulin will be compared between insulin treated and placebo treated groups. For a mechanistic secondary outcome, the proportion of insulin responsive and of proinsulin responsive CD4+ T cells that have a Treg gene expression profile, an IFNg profile, and the Treg/IFNg cell ratio will be compared between the insulin treated and placebo treated groups.
Measured: gene expression profile measurement on insulin-responsive CD4+ T cells at 12 months visit.
Hypoglycemia
Metabolic changes within two hours after receiving study drug. This will be performed at the first administration of oral insulin or placebo at each new dose (visit 1, visit 2, and visit 3). At these visits, blood glucose concentrations will be measured at 0 minutes, 30 minutes, 60 minutes, and 120 minutes after receiving study drug to determine whether the treatment induces hypoglycaemia which is defined as <50 mg/dl (<2.8 mmol/L).
Measured: Measured at baseline (visit 1) and at each subsequent change in dose (visits 2 and 3)
change in total IgE concentration
The purpose is to detect an unexpected allergy to study drug. Total IgE will be measured at visit 1 and at the end of each dose or oral insulin or placebo. The change in concentration from baseline will be reported and compared between placebo and the study drug treated participants for each of the three doses.
Measured: A change from baseline (visit 1) in total IgE concentration at 3 months of treatment,change from baseline (visit 1) in total IgE concentration at 6 months of treatment,change from baseline (visit 1) in total IgE concentration at 12 months of treatment
Study drug specific IgE
The purpose is to detect an unexpected allergy to study drug. Insulin-specific IgE (cpm) will be measured using a radiobinding immunoprecipitation assay at visit 1 and at the end of treatment. Each child will be classified as positive or negative for the appearance of IgE antibodies against insulin after 12 months, and the number of children with IgE antibodies against insulin will be reported in the placebo and study drug treated groups.
Measured: Baseline (visit 1) and end of treatment (12 months).
GAD and IA-2 autoantibodies
The purpose is to detect seroconversion to islet autoantibody positive. Measurements are performed using a radiobinding immunoprecipitation assay. Children who become positive on two occasions during follow-up will stop treatment. The number of children who develop autoantibodies to GAD or IA-2 in he placebo and study drug treated groups will be compared.
Measured: Measured at baseline where they must be negative, and at 3 months, 6 months, 9 months, and 12 months.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Sep 2015 (estimated)
- Study startAug 2015
- Primary completionDec 2017
- Study completionDec 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Diabetes Mellitus, Type 1Studies of the same condition, open and under way.
- 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
- 44 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, German Center for Diabetes Research
- Responsible party
- Sponsor
- Investigators
- Anette-G. Ziegler, Prof. Dr., MD, Principal investigator, Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes, der Technischen Universität MünchenEzio Bonifacio, Prof. Dr., PhD, Principal investigator, DFG-Center for Regenerative Therapies Dresden, Dresden University of TechnologyPeter Achenbach, PD Dr., MD, Principal investigator, Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes, der Technischen Universität München
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02547519
- Sponsor's protocol ID
- 808040017
- Status last verified
- Feb 2018
- First submitted
- 29 Aug 2015
- Last updated
- 13 Feb 2018
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Assfalg R, Knoop J, Hoffman KL, Pfirrmann M, Zapardiel-Gonzalo JM, Hofelich A, Eugster A, Weigelt M, Matzke C, Reinhardt J, Fuchs Y, Bunk M, Weiss A, Hippich M, Halfter K, Hauck SM, Hasford J, Petrosino JF, Achenbach P, Bonifacio E, Ziegler AG. Oral insulin immunotherapy in children at risk for type 1 diabetes in a randomised controlled trial. Diabetologia. 2021 May;64(5):1079-1092. doi: 10.1007/s00125-020-05376-1. Epub 2021 Jan 30.
PubMed 33515070
Study at a glance
From the registry record, last updated by the sponsor on 13 Feb 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pilot Study Using Oral Insulin at Early Age for Immune Efficacy in Primary Prevention of Type 1 Diabetes
- ClinicalTrials.gov ID
- NCT02547519
- Acronym / sponsor ID
- 808040017
- Conditions
- Diabetes Mellitus, Type 1
- Keywords
- Type 1 diabetes, T1D, diabetes mellitus, oral insulin, oral tolerance, autoantigen, self tolerance, prevention
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 44 participants (actual)
- Lead sponsor
- Technical University of MunichUniversity, hospital or other
- Collaborators
- Technische Universität Dresden, Ludwig-Maximilians - University of Munich, Helmholtz Zentrum München, German Center for Diabetes Research
- Study start
- Aug 2015
- Primary completion
- Dec 2017 (actual)
- Study completion
- Dec 2017 (actual)
- First posted
- 11 Sep 2015 (estimated)
- 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 within the pancreatic islets of Langerhans. This process is identified by circulating islet autoantibodies to beta cell antigens, and is mediated by a lack of immunological self-tolerance. Self-tolerance is achieved by T cell exposure to antigen in the thymus or periphery in a manner that deletes autoreactive effector T cells or induces regulatory T cells. Immunological tolerance can be achieved by administration of antigen under appropriate conditions. Administration of oral 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.
Detailed description
The purpose of the Pre-POINT-Early Study is to investigate and consolidate the finding from the preceding Pre-POINT Study, namely safety and immune efficacy at a daily dose of 67.5 mg oral insulin. Since younger children will be tested in Pre-POINT-Early, the 67.5 mg dose will be reached by dose escalation starting at 7.5 mg for 3 months followed by exposure to 22.5 mg for 3 months, and reaching the desired 67.5 mg dose, which is administered for 6 months in 22 children.
The active substance for oral application is human insulin, synthesized in a special non-disease-producing laboratory strain of Escherichia coli bacteria that has been genetically altered by the addition of the gene for human insulin production (Lilly Pharmaceuticals, Indianapolis, Indiana, USA). The physical, chemical and pharmaceutical properties of the human insulin have been well documented by the manufacturer. Oral Insulin will be applied as a capsule containing 7.5; 22.5 and 67.5 mg of the active substance together with filling substance cellulose. After oral administration insulin will be rapidly degraded by gastric acids. Enteric delivery and systemic availability is therefore unlikely and efficacy of active insulin is likely to be restricted to the oral mucosa.
In human studies oral insulin administration was safe and without adverse side effects at doses between 2.5 and 7.5 mg per day. Additionally Bonifacio et al. have conducted and completed the Pre-POINT study, the first primary autoantigen vaccination dose-finding study in which children with high genetic risk for type 1 diabetes were administered insulin orally daily. Oral insulin at all tested doses (2.5 mg; 7.5 mg; 22.5 mg and 67.5 mg) in Pre-POINT was considered safe: None of the children who received study drug or placebo experienced hypoglycaemic episodes after administration of medication, and no allergic reactions were observed.
The Pre-POINT-Early intended doses for oral application are 7.5, 22.5 and 67.5 mg per day. The aim of the study is to determine whether daily administration of oral insulin starting with dose 7.5 mg (3 months), moving to dose 22.5 mg (3 months) and to the highest dose of 67.5 mg (6 months) insulin to young children aged 6 months to 2 years with high genetic risk for T1DM induces immune responses to insulin and/or proinsulin with features of immune regulation.
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 |
|---|---|---|
| oral insulin capsule (dose escalation using 3 dose strengths) | Experimental | Drug: Oral InsulinDose 1 is 7.5 mg rH-insulin crystals; dose 2 is 22.5 mg rH-insulin crystals; dose 3 is 67.5 mg rH-insulin crystals. The insulin crystals are formulated together with filling substance (microcrystalline cellulose to a total weight of 200 mg) and contained in hard gelatine capsules. The study treatment will be given orally. |
| Placebo capsule | Placebo comparator | Drug: PlaceboDaily treatment with placebo capsules containing filling substance (microcrystalline cellulose). |
Who may qualify
- Ages
- 6 months to 2 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child
Key inclusion criteria (3 listed)
- Children aged 6 months to 2 years who have a first degree relative with type 1 diabetes, and have a HLA genotype that includes a HLA DR4-DQB1*0302 or HLA DR4-DQB1*0304 haplotype, and does not include one of the following alleles or haplotypes: DR 11, DR 12, DQB1*0602, DR7-DQB1*0303, DR14-DQB1*0503
- and must be
- Islet autoantibody negative at time of recruitment.
Key exclusion criteria (3 listed)
- Concomitant disease or treatment, which may interfere with assessment or cause immunosuppression, as judged by the investigators.
- Prior or current participation in another intervention trial.
- Any condition that could be associated with poor compliance.
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 |
|---|---|---|
| Oral InsulinTotal of 12 months treatment; dose escalation scheme: daily treatment with 7.5 mg or placebo for 3 months; increasing to daily treatment with 22.5 mg or placebo for the following 3 months; increasing to daily treatment with 67.5 mg or placebo for the last 6 months of the treatment period. | Drug | oral insulin capsule (dose escalation using 3 dose strengths) |
| PlaceboTotal of 12 months treatment; daily treatment with insulin or placebo capsules containing filling substance (microcrystalline cellulose). | Drug | Placebo capsule |
Primary outcome
The activation of a CD4+ T cell immune response against insulin
Time frame: change from baseline (visit 1) in CD4+ T cell response measured as a stimulation index at 12 months of treatment
The primary outcome for immune efficacy is the activation of an immune response (antibody or CD4+ T cell) against insulin. Each participant will be categorized as reaching a response or not. A response is defined as a >2-fold increase that reaches a stimulation index of >3.0.
The activation of an antibody response against insulin.
Time frame: change from baseline (visit 1) in antibodies measured as serum IgG binding to insulin (unit of measure, cpm) and salivary IgA binding to insulin (unit of measure, cpm) at 12 months of treatment
An antibody response is defined as an increase from baseline of >10 cpm in serum IgG binding to insulin from baseline to 12 months, or a positive salivary IgA binding to insulin at 12 months.
5 secondary outcomes
Gene expression of CD4+ T cell response to insulin.
Time frame: gene expression profile measurement on insulin-responsive CD4+ T cells at 12 months visit.
Hypoglycemia
Time frame: Measured at baseline (visit 1) and at each subsequent change in dose (visits 2 and 3)
change in total IgE concentration
Time frame: A change from baseline (visit 1) in total IgE concentration at 3 months of treatment,change from baseline (visit 1) in total IgE concentration at 6 months of treatment,change from baseline (visit 1) in total IgE concentration at 12 months of treatment
Study drug specific IgE
Time frame: Baseline (visit 1) and end of treatment (12 months).
GAD and IA-2 autoantibodies
Time frame: Measured at baseline where they must be negative, and at 3 months, 6 months, 9 months, and 12 months.
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 13 Feb 2018.
- Derived from this study: PubMed 33515070Assfalg R, Knoop J, Hoffman KL, Pfirrmann M, Zapardiel-Gonzalo JM, Hofelich A, Eugster A, Weigelt M, Matzke C, Reinhardt J, Fuchs Y, Bunk M, Weiss A, Hippich M, Halfter K, Hauck SM, Hasford J, Petrosino JF, Achenbach P, Bonifacio E, Ziegler AG. Oral insulin immunotherapy in children at risk for type 1 diabetes in a randomised controlled trial. Diabetologia. 2021 May;64(5):1079-1092. doi: 10.1007/s00125-020-05376-1. Epub 2021 Jan 30.
- Related InfoLink provided by the sponsor.
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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.
Anette-G. Ziegler, Prof. Dr., MD principal investigator
Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes, der Technischen Universität München
Ezio Bonifacio, Prof. Dr., PhD principal investigator
DFG-Center for Regenerative Therapies Dresden, Dresden University of Technology
Peter Achenbach, PD Dr., MD principal investigator
Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes, der Technischen Universität München
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Oral Insulin in people with Diabetes Mellitus, Type 1, run by Technical University of Munich at 1 site 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 3 inclusion and 3 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 13 Feb 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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 a CD4+ T cell immune response against insulin (time frame: change from baseline (visit 1) in CD4+ T cell response measured as a stimulation index at 12 months of treatment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02547519, which also lists 1 linked publication.
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 13 Feb 2018.