Subcutaneous Administration of Lisofylline to Healthy Normal Subjects and Subjects With Type 1 Diabetes
Condition: Healthy; Type 1 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Type 1 diabetes mellitus (T1DM) is an autoimmune disease. Autoimmune diseases happen when the
      immune system does not identify part of the body as belonging to it. The immune system then
      destroys that part as if it were an unknown tissue in the body. In T1DM, the body kills the
      cells in the pancreas that produce insulin. Insulin is the hormone that "unlocks" the cells
      of the body. It allows glucose to enter and fuel them. Special cells in the body called
      islets make the insulin. Since glucose cannot enter the cells, it builds up in the blood. The
      body's cells literally starve to death. Children are at risk of developing T1DM and the risk
      is much higher than other severe, chronic childhood diseases. The only treatments are a
      careful diet, planned physical activity, and testing blood sugar levels several times a day.
      The patient must also inject insulin each day or use an insulin pump. There is no cure for
      T1DM. Insulin injections are considered life support, because going without insulin for just
      a few days causes the blood to have too much acid in it and that can lead to death. On the
      other hand, taking too much insulin makes blood sugar levels go too low, and if untreated,
      can lead to death as well.

      DiaKine is developing Lisofylline to treat the failed immune system. This is what caused T1DM
      in the first place and it does not go away. The purpose of this study is to see how safe the
      study drug is. The study is also going to compare the levels of study drug in the blood and
      to measure the effect of the study drug on other substances in the blood that are linked to
      type 1 diabetes. These levels will be measured after the study drug is given as an injection
      under the skin and an injection into the vein. To date, Lisofylline has been tested when
      given as an injection in the vein.

      The investigators hypothesize that Lisofylline will be safe when given as an injection under
      the skin and in the vein and that levels of study drug will be very similar when given as an
      injection under the skin and in the vein.

      The investigators also hypothesize that Lisofylline will have a positive effect on the
      substances in the blood that are linked to type 1 diabetes.
    

Detailed description: 
      Compound: Lisofylline

      Protocol Number and Title: DT-002: A Safety, Tolerability and Bioavailability Study of
      Lisofylline After Continuous Subcutaneous (12 mg/kg) and Intravenous (12 mg/kg)
      Administration in Healthy Subjects and in Subjects With Type 1 Diabetes Mellitus

      Clinical Trial Phase: Phase 1 / Phase 2A

      Study Objectives: The primary objective of this study is to assess safety and tolerability of
      Lisofylline (LSF) in healthy adult subjects and in adult subjects with type 1 diabetes
      mellitus (DM) following a single dose of LSF 12 mg/kg administered as a continuous
      subcutaneous (s.c.) infusion over 24 hours, versus a single dose of LSF 12 mg/kg administered
      as a continuous intravenous (i.v.) infusion over 24 hours.

      The secondary objectives of this study are (1) to determine the bioavailability of a single
      dose of LSF 12 mg/kg administered as a continuous s.c. infusion over 24 hours compared to
      that of a single dose of LSF 12 mg/kg administered as a continuous i.v. infusion over 24
      hours; and (2) an exploratory evaluation of the early efficacy of LSF based upon evaluation
      of pharmacodynamic (PD) data.

      Principal Investigator and Study Site:

      Benno G. Roesch, MD Advanced Biomedical Research, Inc. Clinical Research Center 241 Main
      Street Hackensack, New Jersey 07601 USA

      Number of Subjects and Subject Population:

      Up to 8 male or female subjects (up to 4 healthy adult male or female subjects and up to 4
      male or female subjects with type 1 DM) will be enrolled as two separate cohorts into the
      study to ensure a total of at least 6 evaluable subjects.

      Healthy male or female subjects between 18-45 years of age, inclusive, and male or female
      subjects, 18-45 years of age, inclusive, with a clinical diagnosis of type 1 DM for a minimum
      of 2 years, requiring treatment with insulin, and no other clinically significant
      exclusionary disease or conditions, are eligible to participate in the study.

      Study Design: This is an open-label, single-dose, randomized, two-period, two-treatment,
      crossover study in healthy subjects and in subjects with type 1 DM.

      Eligible subjects will be admitted to the Clinic the evening prior to dosing (Day -1, Day 6)
      during each treatment period, receive their assigned dose of study drug on Day 1 and Day 7,
      and will remain confined to the Clinic until approximately 48 h following the start of study
      drug administration (Day 3, Day 9). A washout period of three days will separate the two
      treatment periods. All subjects will receive a single dose of LSF 12 mg/kg administered via
      continuous i.v. infusion over a 24-hour period during one treatment period and a single dose
      of LSF 12 mg/kg administered via continuous s.c. infusion over a 24-hour period during the
      alternate treatment period.

      Healthy subjects and subjects with type 1 DM will comprise two separate cohorts. All subjects
      will be assigned a treatment sequence according to a randomization schedule that will balance
      sequence assignments within the two cohorts.

      Study Duration: The overall duration of the study for each subject is approximately 30 days.
      This includes a 21-day screening period, two active treatment periods of three days each
      separated by a 3-day washout period.

      Study Drug: The drug product, LSF for injection, will be supplied by the Sponsor or designee
      as a 120 mg/mL sterile solution (600 mg LSF/5 mL) in USP type 1 molded clear glass vials.
      Each subject will receive a single dose of LSF 12 mg/kg as a continuous s.c. infusion over 24
      hours during one period, and a single dose of LSF 12 mg/kg as a continuous i.v. infusion over
      24 hours during the alternate period in a randomized fashion.

      Treatment Groups: There will be two treatment groups: LSF 12 mg/kg as a continuous s.c.
      infusion over 24 hours and LSF 12 mg/kg as a continuous i.v. infusion over 24 hours.

      Study Procedures: After providing written informed consent, subjects will undergo a complete
      medical history, medication history, physical examination, vital signs evaluation, resting 12
      lead electrocardiogram (ECG), clinical laboratory tests [chemistry, hematology, urinalysis,
      HIV, Hepatitis B & C diagnostic profile and urine drug, alcohol and pregnancy (females only)
      screen,] within 21 days prior to receiving the first dose of study drug.

      On Days 1 and 7, eligible subjects will receive a single dose of LSF 12 mg/kg administered
      via continuous i.v. infusion over a 24-hour period during one treatment period and a single
      dose of LSF 12 mg/kg administered via continuous s.c. infusion over a 24-hour period during
      the alternate treatment period.

      Seated blood pressure and pulse rate will be measured on Days 1-3 and 7-9 within 15 min prior
      to the start of infusion and 1, 4, 12, 24, 36 and 48 h following the start of infusion. A
      resting 12-lead ECG will be performed on Days 1-2 and Days 7-8 at 1, 8 and 24 h following the
      start of infusion, and prior to discharge from the Clinic on Day 9. An abbreviated physical
      examination will be performed on Day 3, prior to discharge from the Clinic and a complete
      physical examination will be performed on Day 9, prior to discharge from the study. Adverse
      events (AEs) will be monitored by nursing and medical observations and spontaneous reporting
      throughout the study. In addition, skin irritation assessments will be performed on Days 1-2
      and Days 7-8 within 15 min prior to the start of infusion and 2, 4, 8, 12 and 24 h following
      the start of infusion.

      Blood will be collected for determination of plasma LSF concentration on Days 1-2 and Days
      7-8 within 0.5 h prior to the start of infusion (time 0) and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6,
      8, 10, 12, 18 and 24 h following the start of infusion. On Day 2 and Day 8, blood samples
      will be collected 5, 10, 15 and 30 min and 1, 2, 3, 4, 6, 8, 10, 12 and 16 h following
      completion of the 24-h infusion period.

      Blood will be collected for evaluation of cytokine, chemokine, insulin and free fatty acid
      (FFA) serum levels, and for evaluation of STAT4 phosphorylation status of monocytes, on Days
      1-2 and Days 7-8 within 0.5 h prior to the start of infusion (time 0) and 24 h following the
      start of infusion.

      Study Endpoints Plasma LSF concentrations and PK assessments: Blood will be collected for
      determination of plasma LSF concentration at time points noted previously. PK parameters will
      include AUC0-t, AUC0-inf, Cmax, Tmax, t1/2, kel, CL, Vdss and F.

      PD assessments: Blood will be collected for determination of serum cytokine, chemokine,
      insulin and FFA levels at time points noted previously.

      Safety outcome measures: Safety will be based on AEs, vital signs assessments, resting
      12-lead ECG evaluations, physical examination findings and clinical laboratory test results.
    

Intervention name(s): Lisofylline
Intervention type(s): Drug
Intervention description(s): Lisofylline via i.v. administration vs Lisofylline vs s.c. administration
Intervention MeSH terms: Lisofylline
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Keywords: healthy subjects