Safety Study to Assess Whether Proinsulin Peptide Injections Can Slow or Stop the Body Damaging Its Own Insulin-making Cells in the Pancreas in Patients Newly Diagnosed With Type 1 Diabetes (MonoPepT1De)

• Allergy and hypersensitivity [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
  To confirm that PI peptide treatment does not induce allergy or hypersensitivity and has a good safety profile in new−onset type 1 diabetes patients.
• Safety of frequent dosing [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
  To explore the safety of extending peptide treatment to more frequent dosing (2−weekly) and for a longer time period (6 months)
• Protective effects of insulin preservation [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  To provide preliminary data on any protective effect on preservation of insulin production after 1 year of treatment
• T cell (immune) response to islet cell antigens [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  To provide preliminary data on changes in the T cell (immune) response to islet cell antigens in newly−diagnosed patients following PI peptide treatment.

The purpose of this study is to address the safety issue of whether, in patients with newly−diagnosed diabetes who still make some insulin, proinsulin peptide therapy adversely affects the rate of damage to the insulin making cells.

Type 1 Diabetes (also known as insulin−dependent diabetes) is caused by destruction of the insulin producing cells (Beta Cells) in the pancreas. Our group is interested in how this destruction could be stopped or reversed, as this may lead to development of a new generation of diabetes treatments which can prevent or slow down the damage, reducing or possibly even removing there need for insulin injections.

In a previous study we examined the safety of our novel approach to this problem, proinsulin (PI) peptide immunotherapy, in longstanding diabetes patients (diagnosed more than 5 years before), and found it to be well tolerated and free of major hypersensitivity reactions. However, it remains theoretically possible that this form of immunotherapy could make the immune reaction to the insulin making cells worse rather than better.

This cannot be studied directly in longstanding patients as they have no or almost no insulin making cells left.

So,the principle objective of the current study is to address the safety issue of whether, in patients with newly−diagnosed diabetes who still make some insulin, proinsulin peptide therapy adversely affects the rate of damage to the insulin making cells.

• Drug: Pro insulin peptide
  Patients will receive 10 micro gr of the peptide every 2 weeks (12 doses).
• Drug: Pro insulin peptide
  Patients will receive 10 micro gr of the peptide monthly (ever 4 weeks, 6 doses) and saline injections monthly alternating with the peptide (2 weeks interval between the drug and saline).
• Drug: Saline
  Patients will receive 0 micro gr of peptide, but have saline injections every 2 weeks (controls).

• Experimental: Pro insulin peptide
  Patients will receive 10 micro gr of the peptide every 2 weeks (12 doses).
  Intervention: Drug: Pro insulin peptide
• Active Comparator: Pro insulin peptide & saline
  Patients will receive 10 micro gr of the peptide monthly (ever 4 weeks, 6 doses) and saline injections monthly alternating with the peptide (2 weeks interval between the drug and saline).
  Intervention: Drug: Pro insulin peptide
• Placebo Comparator: Saline
  Patients will receive 0 micro gr of peptide, but have saline injections every 2 weeks (controls)
  Intervention: Drug: Saline

Inclusion Criteria:

1. Age 18-40 years.

2. If female, must be (as documented in patient notes):

   • postmenopausal (at least 1 year without spontaneous menses)
   • surgically sterile (tubal ligation or hysterectomy at least 6 months prior to enrolment)
   • using acceptable contraception (e.g., oral, intramuscular, or implanted hormonal contraception) at least 3 months prior to enrolment
   • have a sexual partner with non-reversed vasectomy (with confirmed azoospermia)
   • be using 1 barrier method with the use of a spermicide(e.g., condom, diaphragm or cap)
   • have placement of a intra-uterine device

3. If male, must be:

   • using a barrier method of contraception (condom) with the use of a spermicide
   • have a sexual partner using one of the methods in point 2 above or
   • have a non-reversed vasectomy (with confirmed azoospermia),
4. Diagnosis of Type 1 diabetes within the last 100 days (dated from the first insulin injection).
5. Possession of *0401 allele at the HLA-DRB1 gene locus
6. At least one positive islet cell autoantibody (ie anti-GAD65, antibodies to insulinoma-associated antigen-2 (IA-2) or zinc transporter 8 (ZnT8)).
7. Peak insulin C-peptide >200 pmol/L (at any time point after stimulation with Mixed Meal Tolerance Test).
8. Written and witnessed informed consent to participate.

Exclusion Criteria:

1. Females who are pregnant, breast-feeding or not using adequate forms of contraception.
2. Use of immunosuppressive or immunomodulatory therapies, including systemic steroids within 1 month prior to randomisation and any monoclonal antibody therapy given for any indication.
3. Any other medical condition which, in the opinion of investigators, could affect the safety of the subject's participation.
4. Recent subject's involvement in other research studies which, in the opinion of investigators, may adversely affect the safety of the subjects or the results of the study.
5. Subjects should not have had immunisations with live or killed vaccines or allergic desensitisation procedures less than 1 month prior to their first treatment.

• Diabetes Vaccine Development Centre
• Juvenile Diabetes Research Foundation