The Diabetes Virus Detection and Intervention Trial

Study Overview
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Brief Summary
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A randomized, double-blind, placebo-controlled study in 96 children and adolescents age 6-15 newly diagnosed with type 1 diabetes to describe the influence of antiviral treatment (Pleconaril and Ribavirin) on progression of disease and residual insulin secretion.

Detailed Description
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If antiviral treatment is efficient in halting the disease progression, it will be to great benefit for the participating patients. Maintenance or even an increase in beta cell mass due to regeneration will lead to improved endogenous insulin production and give a milder course of the disease with improved glycemic control. This will in a substantial way improve the long-term prognosis with less severe long term vascular complications.Some patients may have close to complete remission and be able to stop insulin treatment. If antiviral treatment is effective, it would add proof to the concept that type 1 diabetes in its origin is a viral disease. This would be an important milestone in medical research and a breakthrough in the understanding of the etiopathogenesis of autoimmune diseases. It may promote the development of vaccines to prevent the disease. T1D seems more aggressive in children than in adults, and the beta cell function decline rapidly compared to adults. As a consequence, the effect of antiviral treatment will potentially be more significant in children than in adults. Children have higher HbA1c which increases the risk of complications. Thus, T1D is a more aggressive disease in children than in adults and hence it's important to do this study in children. Pharmaceuticals are usually studied in different age intervals, commonly 1-6 years, 6-12 years and 12-15 years. For safety reasons and simplicity, the investigators want to start with the two older groups. The investigators will treat the participants with two antiviral medications (Pleconaril and ribavirin) or placebo in a double blind, randomized, placebo controlled, parallel group study. Pleconaril has previously been given in doses of 5-10mg/kg x 2-3 in clinical trials in children, thus achieving serum levels high enough for killing the majority of the viruses. The investigators have, due to the long treatment period, reduced the doses to 5 mg/kg x 2. Ribavirin will be given in dosages according to Summariy of product characteristics (SmPC). The investigators have chosen to administer Investigational Medicinal Product (IMPs) as an oral solution as this will make it easier to give the medication according to weight.

Official Title
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The Diabetes Virus Detection and Intervention Trial

Conditions
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Type1 Diabetes Mellitus, Enterovirus

Intervention / Treatment
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* Drug: Ribavirin + Pleconaril
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed type 1 Diabetes (E10.9). First injection of insulin maximum three weeks prior to inclusion. Must be willing and capable of taking the study drugs and meet for tests and follow up as described. Signed informed consent and expected cooperation of the patients for the treatment and follow up must be obtained and documented according to International Conference on Harmonization Good Clinical Practice (ICH GCP), and national/local regulations. Aged 6.00-15.99 years at inclusion Exclusion Criteria: Treatment with any oral or injected anti-diabetic medications other than insulin. A history of haemolytic anaemia or significantly abnormal haematology results at screening. History of severe cardiac disease previous six months. Impaired renal function Patients taking ethinyl estradiol Participation in other clinical trials with a new chemical entity within the previous 3 months. Inability or unwillingness to comply with the provisions of this protocol Females who are lactating or pregnant. Males or females (after menarche) not willing to use highly effective contraception (progesterone-only hormonal anticonception with inhibition of ovulation or sexual abstinence) and barrier contraception (condoms), if sexually active during the treatment period and in the following 7 months Presence of serious disease or condition, which in the opinion of the investigator makes the patient non-eligible for the study.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A double-blind, placebo controlled, prospective, randomized trial examining the effect of antiviral treatment given for 6months on residual insulin secretion
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active treatment<br>Pleconaril: 5 mg/kg x2 times a day for 26 weeks up to 40 kg. Max dose 300mg x2. Ribavirin:15 (7.5) mg/kg/day divided in two doses daily for 26 weeks: Max dose 1000mg/24h if body weight<75kg and 1200mg if body weight>75kg. | Drug: Ribavirin + Pleconaril<br>* Randomized to treatment with study drugs (ribavirin and pleconaril)<br>|
| Placebo Comparator: Placebo<br>Receives placebo, on a double blind basis | Drug: Placebos<br>* Randomized to treatment with placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin secretion | Change in mean residual insulin secretion in the Insulin tolerance test (ITT)-population measured by Mixed Meal Tolerance Test (MMTT) stimulated C-peptide two-hour area under the curve profile from visit 1 to12 months after initiation of study treatment. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin secretion | Change in mean residual insulin secretion in the ITT-population measured by Mixed Meal Tolerance Test (MMTT) stimulated C-peptide two-hour area under the curve profile from visit 1 to 3 months after initiation of study treatment. | 3 months | 
| Insulin secretion | Change in mean residual insulin secretion in the ITT-population measured by Mixed Meal Tolerance Test (MMTT) stimulated C-peptide two-hour area under the curve profile from visit 1 to 6 months after initiation of study treatment. | 6 months | 
| Insulin secretion | Change in mean residual insulin secretion in the ITT-population measured by Mixed Meal Tolerance Test (MMTT) stimulated C-peptide two-hour area under the curve profile from visit 1 to 24 months after initiation of study treatment. | 24 months | 
| Insulin secretion | Change in mean residual insulin secretion in the ITT-population measured by Mixed Meal Tolerance Test (MMTT) stimulated C-peptide two-hour area under the curve profile from visit 1 to 36 months after initiation of study treatment. | 36 months | 
| Stimulated c-peptide | Proportion of patients with peak residual insulin secretion measured by MMTT: stimulated C-peptide >0.2 pmol/L | 36 months | 
| C-peptide filter paper | Fasting and meal stimulated C-peptide from blood sampled on filter paper at home at 4 weekly intervals throughout the study period | 36 months | 
| Insulin dose | Mean Insulin dosage per kilo bodyweight per 24 hours | 36 months | 
| HbA1c | HbA1c at every control | 36 months | 
| Hypoglycemic events | Number of severe hypoglycaemic events and less severe events requiring assistance from others with blood glucose values ≤ 3.9 mmol/L will be registered at each control | 36 months | 
| Insulin-dose-adjusted HbA1c (IDAA1c) | HbA1c adjusted to insulin dose | 36 months | 
| Proinsulin/c-peptide ratio in serum | Proinsulin/c-peptide ratio in serum as a measure of beta cell stress | 36 months | 
| Presence of enterovirus | Presence of enterovirus and rhinovirus and/or neutralizing antibodies against those viruses in nose, blood, saliva and stool | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 1 diabetes, Children, Enterovirus, Recent onset