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Adaptive Study of IL-2 Dose Frequency on Regulatory T Cells in Type 1 Diabetes (DILfrequency)

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ClinicalTrials.gov Identifier: NCT02265809
Recruitment Status : Completed
First Posted : October 16, 2014
Last Update Posted : August 21, 2018
Sponsor:
Collaborators:
University of Cambridge
Sir Jules Thorn Charitable Trust
Juvenile Diabetes Research Foundation
Wellcome Trust
National Institute for Health Research, United Kingdom
Information provided by (Responsible Party):
Dr Frank Waldron-Lynch, Cambridge University Hospitals NHS Foundation Trust

Brief Summary:

Type 1 diabetes (T1D) is the most common severe autoimmune disease worldwide and is caused by the body's immune destruction of its own insulin producing pancreatic beta cells leading to insulin deficiency and development of elevated blood sugars. Currently, medical management of T1D focuses on intensive insulin replacement therapy to limit complications (retinopathy, nephropathy, neuropathy); nevertheless clinical outcomes remain suboptimal. There are intensive efforts to design novel immunotherapies that can arrest the autoimmune process and thereby preserve residual insulin production leading to fewer complications and better clinical outcomes.

Genetics are in part the cause of T1D and the majority of genes contributing to T1D produce proteins involved in immune regulation (called "tolerance"). A key player in immune tolerance is a molecule called interleukin-2 (IL-2) which enhances the ability of cells called T regulatory (Treg) cells to suppress the destruction the insulin producing beta cells. Aldesleukin is a human recombinant IL-2 product produced by recombinant DNA technology using a genetically engineered E. coli strain expressing an analogue of the human IL-2 gene. There is substantial data to suggest that ultra-low doses (ULD) of IL-2 (aldesleukin) can arrest the autoimmune mediated destruction of pancreatic beta cells by the induction of functional Treg cells.

The former study "Adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes" (DILT1D) (NCT 01827735) was a single dose mechanistic study designed to establish the doses of IL-2 (aldesleukin) required to induce a minimal Treg increase (0.1 fold from baseline) or to induce a slightly larger Treg increase (0.2 fold from baseline) (maximal increase). Following on from the DILT1D study, the goal of the DILfrequency study is to use an adaptive design to determine the optimal dose and frequency of ULD IL-2 (aldesleukin) to maximize Treg function by frequently injecting ultra-low doses of IL-2 (aldesleukin). The responsiveness of each T1D participant to a particular frequency of IL-2 (aldesleukin) administration informs the frequency of dosing given to the next patient. This strategy focuses on improving the function of regulatory T cells that are exquisitely sensitive to IL-2 (aldesleukin).


Condition or disease Intervention/treatment Phase
Type 1 Diabetes Drug: Aldesleukin Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 41 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Adaptive Study of IL-2 Dose Frequency on Regulatory T Cells in Type 1 Diabetes (DILfrequency)
Actual Study Start Date : October 3, 2014
Actual Primary Completion Date : May 26, 2016
Actual Study Completion Date : May 26, 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diabetes Type 1
Drug Information available for: Aldesleukin

Arm Intervention/treatment
Experimental: Aldesleukin
Aldesleukin will be administered subcutaneously at varying doses and frequencies for a period of up to 98 days from first administration depending on the treatment assignment. The maximum dose allowed is 0.6 X 10^6 IU/m2.
Drug: Aldesleukin
Other Names:
  • Proleukin
  • IL-2




Primary Outcome Measures :
  1. Change from baseline of CD4 T regulatory cells, CD4 T effector cells and CD25 expression on T regulatory cells during treatment with ultra low dose IL-2 [ Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment) ]
    Fluorescence-activated cell sorting


Secondary Outcome Measures :
  1. T regulatory cell number, phenotype and proliferation [ Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment) ]
    Measured by fluorescence-activated cell sorting

  2. T effector cell number, phenotype and proliferation [ Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment) ]
    Measured by fluorescence-activated cell sorting

  3. Natural Killer cell number, phenotype and proliferation [ Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment) ]
    Measured by fluorescence-activated cell sorting

  4. B lymphocyte cell number, phenotype and proliferation [ Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment) ]
    Measured by fluorescence-activated cell sorting

  5. T cell and Natural killer cell intracellular signalling [ Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment) ]
    Measured by fluorescence-activated cell sorting

  6. Full blood count [ Time Frame: Visits 1-12 (between day -30 and day -1 up to a maximum of approximately day 98 depending on treatment assignment) ]
    Measured by automatic analyser

  7. Blood levels of IL-2, IL-6, IL-10, TNF-alpha, soluble CD25, IP-10, soluble rIL-6, and CRP [ Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment) ]
    Measured by enzyme-linked immunosorbent assay

  8. Change in metabolic control [ Time Frame: Visits 1-12 (between day -30 and day -1 up to a maximum of approximately day 98 depending on treatment assignment) ]
    Blood glucose, HbA1c, C-peptide, insulin use and autoantibody status

  9. Safety and tolerability [ Time Frame: Visits 1-12 (between day -30 and day -1 up to a maximum of approximately day 98 depending on treatment assignment) ]
    Assessed by clinical history, physical examination, temperature, blood pressure, heart rate, 12-Lead electrocardiogram (ECGs), clinical laboratory tests, and adverse event recording


Other Outcome Measures:
  1. Genotype of T1D associated loci [ Time Frame: Visit 1 (between day -30 and day -1) ]
    Measured by immunochip

  2. Gene expression analysis of purified lymphocyte subsets and peripheral blood mononucleated cells [ Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment) ]
    Measured by RNA sequencing

  3. IL-2 sensitivity of T regulatory, T effector and NK subsets [ Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment) ]
    Measured by fluorescence-activated cell sorting

  4. Treg suppression and T effector proliferation assays [ Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment) ]
    Measured by radioactive thymidine assay and/or fluorescence-activated cell sorting

  5. Antigen specific T cell assays [ Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment) ]
    Measured fluorescence-activated cell sorting and/or Enzyme-Linked ImmunoSpot (ELISPOT) assay

  6. Sysmex® analysis of whole blood [ Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment) ]
    Measured by automatic analyser

  7. Epigenetic analysis of analysis of purified lymphocyte subsets and peripheral blood [ Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment) ]
    Measured by Bisulphite sequencing of DNA

  8. Serum/plasma level of cytokines, soluble receptors and inflammatory markers [ Time Frame: Visits 2-12 (day 0 up to a maximum of approximately day 98 depending on treatment assignment) ]
    Measured by enzyme-linked immunosorbent assay

  9. Serum/plasma and cellular metabolites [ Time Frame: Visits 1-12 (between day -30 and day -1 up to a maximum of approximately day 98 depending on treatment assignment) ]
    Mass spectrometry

  10. Recruitment analysis [ Time Frame: Visit 1 (between day -30 and day -1) ]
    Analysis of DILfrequency recruitment database



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Type 1 diabetes
  • 18-70 years of age
  • Duration of diabetes less than 60 months from diagnosis
  • Written informed consent to participate

Exclusion Criteria:

  • Hypersensitivity to aldesleukin or any of the excipients
  • History of severe cardiac disease
  • History of malignancy within the past 5 years (with the exception of localized carcinoma of the skin that had been resected for cure or cervical carcinoma in situ)
  • History or concurrent use of immunosuppressive agents or steroids
  • History of unstable diabetes with recurrent hypoglycaemia
  • History of live vaccination two weeks prior to first treatment
  • Active autoimmune hyper or hypothyroidism
  • Active clinical infection
  • Major pre-existing organ dysfunction or previous organ allograft
  • Females who are pregnant, lactating or intend to get pregnant during the study
  • Males who intend to father a pregnancy during the study
  • Donation of more than 500 ml of blood within 2 months prior to aldesleukin administration
  • Participation in a previous therapeutic clinical trial within 2 months prior to aldesleukin administration
  • Abnormal ECG
  • Abnormal full blood count, chronic renal failure (Stage 3,4,5) and/or evidence of severely impaired liver function (ALT/AST > 3xULN at screening; alkaline phosphatase and bilirubin 2xULN at screening (isolated bilirubin >2xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%))

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02265809


Locations
United Kingdom
Wellcome Trust Clinical Research Facility, Addenbrookes Hospital
Cambridge, Cambridgeshire, United Kingdom, CB2 0QQ
Sponsors and Collaborators
Cambridge University Hospitals NHS Foundation Trust
University of Cambridge
Sir Jules Thorn Charitable Trust
Juvenile Diabetes Research Foundation
Wellcome Trust
National Institute for Health Research, United Kingdom
Investigators
Principal Investigator: Frank Waldron-Lynch, MB BChir PhD University of Cambridge
Study Chair: Kevin M O'Shaughnessy, BM BCh DPhil University of Cambridge

Additional Information:
Publications:
Responsible Party: Dr Frank Waldron-Lynch, Academic Consultant Endocrinologist, Cambridge University Hospitals NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT02265809     History of Changes
Other Study ID Numbers: DILfrequency
First Posted: October 16, 2014    Key Record Dates
Last Update Posted: August 21, 2018
Last Verified: August 2018

Keywords provided by Dr Frank Waldron-Lynch, Cambridge University Hospitals NHS Foundation Trust:
Interleukin 2
Type 1 diabetes
T regulatory cells
Adaptive trial

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Aldesleukin
Interleukin-2
Antineoplastic Agents
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs