Clinical trial NCT02620072: Fr1da Insulin Intervention
Official title: Mechanistic Study Using Oral Insulin for Immune Efficacy in Secondary Prevention of Type 1 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Stage 1 Diabetes Mellitus, Type 1
Keywords: Type 1 diabetes
T1D
diabetes mellitus
oral insulin
oral tolerance
autoantigen
self tolerance
prevention
at risk for developing type 1 diabetes
juvenile diabetes
dysglycemia
Lead sponsor: Technical University of Munich
Sponsor class: OTHER
Collaborators: name: Technische Universität Dresden
name: Ludwig-Maximilians - University of Munich
name: Helmholtz Zentrum München
First posted: 2015-12-02
Enrollment: 220
Sex: ALL
Minimum age (years): 2
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Type 1 diabetes (T1D) results from an autoimmune destruction of the insulin-producing beta cells. The process of autoimmune destruction 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. Evidence is now emerging in humans that these approaches may be effective in chronic inflammatory diseases such as multiple sclerosis and allergy. Administration of oral insulin in multiple islet autoantibody-positive children offers the potential for inducing immunological tolerance to beta cells and thereby protect against further development progression to type 1 diabetes.

Detailed description: Type 1 diabetes (T1D) is a disease that predominantly affects children. T1D is preceded by islet autoimmunity, which often starts in early childhood and which has a peak incidence at around 1 to 2 years of age. Previous studies show that multiple islet autoantibodies indicate a point of limited return in the path to T1D. Every year, around 10% of multiple islet autoantibody positive children progress from islet autoantibody positivity to symptomatic T1D. Thus, therapy and intervention is needed to change the inevitable path to insulin dependence. Treated should be initiated early when most beta cells are still intact and when the autoimmune process is less advanced may be more effective.

Administration of oral insulin in multiple islet autoantibody-positive children offers the potential for immunological tolerance against beta cells and thereby protect against progression to T1D. Previous studies in rodents had indicated that mucosal administration of insulin is effective in inducing regulatory immune responses that can prevent autoimmune diabetes. Mouse studies indicated that the dose of oral insulin is important. In human studies oral insulin administration shows an excellent safety profile, without adverse side effects at doses between 2.5 and 7.5 mg per day (1-3). The administration of oral insulin (7.5 mg per day) to prediabetic ICA and IAA positive first degree relatives of T1D patients within the DPT-1 study showed no significant beneficial effect in the intention to treat analysis. A sub-analysis of the data, however, showed significant benefit in those relatives with higher titer IAA.

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 tested doses (2.5 mg; 7.5 mg; 22.5 mg and 67.5 mg) showed five of six children exposed to a dose of 67.5 mg insulin had evidence of an antibody or T cell response to insulin. The response differed to the typical responses seen in children who develop diabetes in that the antibody responses were of weak affinity and the T cell responses had a preponderance of cells with regulatory T cell phenotypes (37). These results are also encouraging from a safety viewpoint and indicate that oral exposure to insulin at doses that are approximately equivalent to efficacious doses in rodents may promote tolerance in children.

A secondary prevention study using 7.5 mg oral insulin administered daily is currently conducted by the TrialNet Study Group, and includes the Forschergruppe Diabetes, Klinikum rechts der Isar der Technischen Universität München as a study site. Autoantibody, normoglycemic subjects aged 3 to 45 years are treated with oral insulin. In this currently conducted trial there have been no safety issues reported thus far.

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 mg of the active substance together with filling substance cellulose and a dose escalation to 67.5 mg of the active substance together with filling substance cellulose. After ingestion, most of the insulin will be 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.

The Fr1da Insulin Intervention Study intends doses for oral application at 7.5 mg and 67.5 mg per day. The aim of the study is to determine whether daily administration of up to 67.5 mg insulin to young children aged 2 years to 12 years with multiple islet autoantibodies alters the immune responses to insulin over an intervention period of 12 months and whether an altered immune response is associated with protection from developing dysglycemia or diabetes and whether oral insulin treatment reduces the rate of progression to dysglycemia or diabetes.

The immune response to oral insulin treatment has not yet been demonstrated to indicate protection from disease. To address this, the Fr1da Insulin Intervention Study included dysglycemia as a co-primary outcome in the trial, through novel data indicating that dysglycemia is a valid outcome on the path to type 1 diabetes. Once such dysglycemia is present in multiple autoantibody positive subjects, there is an average time of 2 years to clinical symptomatic diabetes.

Eligibility criteria: Inclusion Criteria:

1. Written informed consent signed by either parent(s) or legal guardian(s).
2. Children aged 2 years to 12 years.
3. Positive for at least two islet autoantibodies out of autoantibodies to glutamic acid decarboxylase (GAD65), to insulin (IAA), autoantibodies to IA-2 (IA2A), or autoantibodies to zink transporter 8 (ZnT8A) (time between screening sample collection and randomization must not exceed 90 days).
4. Normoglycemia assessed by oral glucose tolerance test (OGTT).
5. Participation in an observational study that regularly monitors diabetes development

Exclusion Criteria:

Participants meeting any of the following criteria will NOT be eligible for inclusion into the study:

1. dysglycaemia or overt hyperglycemia (diabetes)
2. Concomitant disease or treatment that may interfere with assessment or cause immunosuppression, as judged by the investigators.
3. Current participation in another intervention trial.
4. Any condition that could be associated with poor compliance.

Primary outcomes:
measure: Immune response to insulin
timeFrame: change from baseline (visit 1) to 12 months of treatment
measure: Dysglycemia or diabetes
timeFrame: every 6 months up to at least 24 months after baseline
Secondary outcomes:
measure: Gene expression of single cells.
timeFrame: Gene expression profile measurement on insulin-responsive cells at 12 month visit
measure: The change from baseline in insulin autoantibodies
timeFrame: change from baseline to 3 months, 6, months, and 12 months
measure: Number of circulating Insulin-tetramer positive T cells
timeFrame: comparison at 9 month visit
measure: CD4+ T cell responses to insulin
timeFrame: comparison at 0, 3, 6, and 12 month visit
measure: CD8+ T cell responses to insulin
timeFrame: comparison at 0, 3, 6, and 12 month visit
measure: Microbiome alpha diversity, beta diversity and taxanomic abundance
timeFrame: comparison at 0, 6, and 12 month visits
measure: Monocyte and T cell sub-populations
timeFrame: comparison at 0, 3, 6, 9, and 12 month visits
measure: Plasma inflammatory proteins
timeFrame: comparison at 0, and 12 month visits
measure: Transcriptome of peripheral blood mononuclear cells
timeFrame: comparison at 0, and 12 month visits
measure: Progression to diabetes
timeFrame: Measured at baseline (visit 1) and at each subsequent visit of the treatment phase (visits 2, 3, 4, 5) and observational follow-up of 24 to 54 months after the one year treatment (visits 6, 7, 8, 9, 10, 11, 12, 13, 14)
Other outcomes:
measure: Hypoglycemia
timeFrame: Measured at baseline (visit 1) and at subsequent change in dose (visits 2).
measure: Adverse events
timeFrame: Duration of participation from study visit 1 until the end of the study (min. 36 months, max. 66 months) or drop out
Locations:
city: München
country: Germany
facility: Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes, der Technischen Universität München
state: Deutschland (deu)
Study officials:
affiliation: Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München
name: Anette-G. Ziegler, Prof. Dr., MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Paul Langerhans Institute Dresden (PLID) of the Helmholtz Zentrum München at the Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden
name: Ezio Bonifacio, Prof. Dr., PhD
role: STUDY_CHAIR
affiliation: Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München
name: Peter Achenbach, PD. Dr., MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Forschergruppe Diabetes, Klinikum rechts der Isar, Techn. Universität München and Kinderklinik München Schwabing, Klinik u. Poliklinik f. Kinder- und Jugendmedizin, Klinikum Schwabing, StKM GmbH und Klinikum rechts der Isar der Techn. Universität München
name: Katharina Warncke, Dr., MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München
name: Christiane Winkler, Dr., PhD
role: STUDY_CHAIR
References:
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.