A phase I, open-label study of anti-inflammatory therapy with rilonacept in adolescents and adults with type 1 diabetes mellitus
Concise Summary of Project:
1. Study design
Phase I safety study; single center, open label, no placebo group (comparison with baseline and with historical controls). This non-randomized trial consists of 6 months of rilonacept treatment in adolescent and adult patients with type 1 diabetes and measurable residual C-peptide secretion (such secretion indicates remaining insulin secretory capacity that might be preserved and thus, the possibility of benefit from the study drug). This study has been mandated by the FDA, which is requiring 6 months of safety data on patients older than 16 years before allowing us to enroll younger children, as would be required for an adequately powered randomized controlled trial with an efficacy endpoint. There will be a follow-up telephone call to each subject one month after completing study drug. Thus the duration of each subject[AND]amp;apos;s participation is 7 months.
2. Outcome variables
The primary outcome variable is all-cause infection (i.e., infections from all causes, including by way of illustration but not limitation, upper respiratory tract infections including nasopharyngitis and sinusitis; urinary tract infections; lower respiratory tract and lung infections including bronchitis viral gastroenteritis).
Secondary endpoints are not powered and, in this Phase I trial, corrections for multiple comparisons will not be made. Secondary outcome measures will include:
Incidence and severity of other adverse effects including hypoglycemia, local site reactions and dyslipidemia.
How rilonacept affects :
a. HgA1c levels over time
b. Insulin dose (units/kg/day) over time
c. Changes in sex steroids (testosterone and estradiol).
d. Preservation of beta cell function as measured by baseline-adjusted C-peptide secretory capacity (mean area under the stimulated C-peptide curve [AUC] over a 2-hour mixed meal tolerance test) conducted after 6 months of treatment.
3. Number of subjects
The FDA requires us to have 6 months of safety data on 10 subjects with type 1 diabetes older than 16 years before allowing us to enroll younger children, as would be required for an adequately powered randomized controlled trial with an efficacy endpoint. To allow for a 33% early withdrawal rate, we will need start 15 subjects on the study drug. We do not have a good estimate of the rate of screen failures for this study; we will assume a 40% screen failure rate, thus requiring us to consent 25 subjects. Because the study design has a wide recruitment window (within 5 years of diagnosis with measurable C-peptide) there are a large number of potential subjects at Children[AND]amp;apos;s Medical Center Dallas, Parkland Hospital and the University Hospital.
We estimate a 6 month accrual period, so that the study will last 13 months total from the beginning of recruitment to the last study measurement on the final subject.
* T1D (by American Diabetes Association criteria) within 5 years of diagnosis.
o The limitation in time since diagnosis is intended to maximize the likelihood that patients will retain measurable insulin secretory capacity.
* Age 16-45 years (males and females will be recruited).
o The minimum age is mandated by the FDA for this phase I study. Onset of type 1 diabetes is rare above 45 years of age.
* Must have detectable titers of at least one diabetesxrelated autoantibody at any time after diagnosis: (GAD65) or (IA2). IAA will be checked as part of a panel but will not be used as a basis for inclusion or exclusion since levels of this antibody may rise in any patient on chronic insulin therapy.
* Patients should have an insulin-dose adjusted hemoglobin A1c (IDAA1c)(30) <10.8. IDAA1c= A1c + 4*(insulin dose [units/kg/24h]). For patients on basal-bolus insulin regimens who are using carbohydrate-insulin ratios to calculate their bolus (short-acting) insulin doses, the total daily dose will be estimated as twice the basal (glargine or detemir) insulin dose.
o The threshold value of this parameter is correlated with a stimulated C-peptide level >0.2 nmol/l and will minimize the number of screening mixed meal tolerance tests that must be performed.
* Mean C-peptide level > 0.2 nmol/l on a mixed meal tolerance test (MMTT).
* Diabetes of sufficient severity to require insulin therapy.
* Ethical x Before any study-specific procedure, written informed consent will be obtained from the subject. The written informed consent document will be prepared in the language(s) of the potential patient population (both English and Spanish speaking patients will be eligible).