Lisofylline as Continuous Subcutaneous and Intravenous Administration in Subjects With Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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The primary goal of the study is to investigate the safety and tolerability of the investigational drug lisofylline, when administered under the skin or in the vein, in people with type 1 diabetes. A second aim is to determine how much drug is available in the blood after injection under the skin, compared to injection in the vein.

Detailed Description
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This is an open-label, randomized, crossover study in subjects with type 1 diabetes. There are two treatment periods separated by approximately one week. One treatment will consist of a 10 hour subcutaneous infusion of lisofylline, and the other treatment will consist of a 10 hour intravenous infusion of lisofylline. Eligible subjects will be admitted to the Infusion Center the morning of dosing (Day 1, Day 7) during each treatment period, receive their assigned dose of study drug on Day 1 and Day 7, and will remain confined to the Infusion Center until approximately 3 hours following the start of study drug administration for the remaining blood draws. The subjects will then be escorted to the Sleep Center of Eastern Virginia Medical School for an overnight stay during which time their heart rate and oxygen saturation will be monitored by pulse oximetry. The next morning the subjects will return to the Infusion Center for a final blood draw and physical examination. The Infusion Center and the Sleep Disorders Center are both within Sentara Norfolk General Hospital. All subjects will be assigned to a treatment sequence according to a randomization schedule.

Official Title
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A Safety, Tolerability and Bioavailability Study of Lisofylline After Continuous Subcutaneous (12 mg/kg) and Intravenous (9 mg/kg) Administration in Subjects With Type 1 Diabetes Mellitus

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Drug: Lisofylline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female adults between the ages of 18 and 45 years of age Ability to understand and provide written informed consent Ability to complete the study in compliance with the protocol If female, subjects must be non-pregnant and non-lactating, and willing to use appropriate and adequate contraception during the study If male, subjects must be willing to use effective birth control during the study Weight at least 50 kgs (110 lbs) Body mass index between 18.5 and 30 kg/m2 QTc < 450 msec at screening Clinical diagnosis of type 1 diabetes at least 2 years prior to screening Treatment with insulin for at least 1 year and on a stable dose for at least 3 months prior to screening (dose must be < 0.8 units/kg/day) Subjects must self-monitor blood glucose levels at least daily HbA1c 6-9% Serum c-peptide level < 0.6 ng/mL Serum creatinine < 1.5 mg/dL for males and < 1.4 mg/dL for females Negative hepatitis B, hepatitis C and HIV testing at screening or within 3 months of screening Subjects must be free from clinically significant abnormal findings at the time of screening (to include abnormalities on examination, medical history, electrocardiogram, clinical laboratory testing); to be determined by principal investigator Exclusion Criteria: Subjects with significant stomach, liver, kidney or heart disease, including high blood pressure, stroke or other blood vessel disease. Significant eye problems due to diabetes, diabetic nerve disease, or non-healed diabetic foot ulcers Personal or family history of long QTc syndrome History of clinically significant changes in orthostatic blood pressure Clinically significant changes in orthostatic blood pressure at screening History of peptic ulcer disease and/or gastrointestinal bleeding/perforation History or presence of proliferative retinopathy, severe non-proliferative retinopathy, macular edema or presence of untreated diabetic eye disease History of severe peripheral or autonomic neuropathy in the opinion of the study physician History of hypoglycemia unawareness, and/or episodes of severe hypoglycemia within 60 days of screening Diagnosis of type 2 diabetes, based upon subject report Use of oral antihyperglycemic medications, pentoxyifylline, and/or theophylline Use of any drug therapy that directly affects gastrointestinal motility History of any significant drug allergy History of difficulty with phlebotomy Use of any recreational drugs within the past year or a previous history of drug or alcohol abuse Positive results from a screen for alcohol or substances of abuse at screening or upon admission to the study site Current smoker or user of any tobacco products Use of prescription medications is acceptable at the Principal Investigator's discretion if they have been part of a stable drug regimen documented for the last 60 days. Drug therapy should be held the morning of Day 1 and Day 7 at the Principal Investigator's discretion use of any over-the-counter drugs or herbal preparations within 72 hours prior to receiving study drug Consumption of any caffeine-containing foods or beverages within 24 hours prior to receiving study drug Consumption of alcohol within 24 hours prior to admission to the study site Consumption of any grapefruit or grapefruit-containing juices within 72 hours prior to receiving study drug Use of an investigational drug or product, or participation in a drug research study within 30 days prior to receiving drug Prior exposure to lisofylline Donation of blood (1 pint or more) within 30 days or plasma within 7 days of receiving study drug Any condition which in the opinion of the study investigator would interfere with the participant's ability to provide informed consent, comply with study instructions, possibly confound interpretation of study results, or endanger the participant if he or she took part in the trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lisofylline subcutaneous<br>Lisofylline 12mg/kg as a continuous subcutaneous infusion over a 10 hours period | Drug: Lisofylline<br>* Lisofylline single dose of 9 mg/kg continuous intravenous infusion over a 10 hour period, and lisofylline single dose of 12 mg/kg continuous subcutaneous infusion over a 10 hour period during the alternate period 1 week apart.<br>|
| Experimental: Lisofylline intravenous<br>Lisofylline 9 mg/kg as a continuous intravenous infusion over a 10 hours period | Drug: Lisofylline<br>* Lisofylline single dose of 9 mg/kg continuous intravenous infusion over a 10 hour period, and lisofylline single dose of 12 mg/kg continuous subcutaneous infusion over a 10 hour period during the alternate period 1 week apart.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of Study Drug | Subjects will be monitored for adverse events both during and after the study drug infusion and will undergo physical examinations, electrocardiograms and clinical safety laboratory tests. Study staff will contact subjects within 5 days after each dosing period and approximately 30 days after the 2nd dosing period, to review laboratory results and to ask the subject about any changes in health that they have experienced. Should the subject require an in-person evaluation, this will be arranged with the principal or sub-investigator promptly. | 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Study Drug Bioavailability After Subcutaneous and Intravenous Infusion | Blood will be collected for determination of lisofylline concentrations at various predetermined time points during the infusions, and 10 and 24 hours following infusion completion. This will help to determine if subcutaneous infusion over 10 hours results in similar lisofylline plasma concentrations as with intravenous infusion. | 24 hours | 
| Evaluation of Early Efficacy of Study Drug | Blood draws will be performed at predetermined time points during and after the infusions in order to measure serum cytokine and chemokine concentrations, as well as to measure plasma STAT 4 and phosphorylated STAT 4 (markers of lisofylline efficacy). | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lisofylline