Phase 1 Study to Explore the Safety and Pharmacokinetics of DAPAglifozin in Adolescents and Adults With Type 1 Diabetes
Condition: Type 1 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 1

Summary: 
      Dapagliflozin has been effective at lowering glucose and hemoglobin A1c (HbA1C) in subjects
      with tpye 2 diabetes (T2DM), when studied as monotherapy as well as in combination with
      insulin or oral anti-diabetic medications.This lead to investigations if this therapy would
      also be of benefit in type 1 diabetes as intensive insulin therapy is associated with glucose
      fluctuations, hypoglycemia, weight gain, and subsequent insulin resistance, all of which may
      reduce efficacy.

      The purpose of the pilot study is to collect clinical data on the HbA1c-dependent effect of a
      single-dose of 10mg dapagliflozin on the insulin dose administered intravenously during a
      glucose-infusion and an oral mixed-meal for the ensuing 24 hours with blood glucose kept
      between 160 - 220 mg/dl.

      The first objective is to investigate the degree of insulin dose reduction 24 hours after a
      single dose of 10mg dapagliflozin in patients with type 1 diabetes Further objectives are to
      investigate

        -  the effect on urinary glucose excretion

        -  if this effect is influenced by baseline glycemic control

        -  if dapagliflozin influences postprandial insulin need

        -  if dapagliflozin is associated with elevated ß-hydroxybutyrate levels

        -  PK after oral administration of 10mg dapagliflozin
    

Detailed description: 
      The purpose of the study is to evaluate the safety profile and tolerability, particularly
      with regard to hypoglycemia and ketone development, following once daily oral dose of 10 mg
      of dapagliflozin administered in subjects with type 1 diabetes (T1DM) as a single dose as
      well as pharmacokinetics (PK) for 18 hours of treatment.

      The study aimed to patients who have different degrees of inadequate glycemic control despite
      insulin use. Approximately 36 subjects will be screened in order to randomize 10 patients in
      each different HbA1C category.

      The trial will consist of six visits: a screening visit (Visit 1), two dosing visits (Visit 2
      and Visit 4), two phone visits (Visit 3 and Visit 5) and a follow-up visit (Visit 6).
      Furthermore, an information visit will take place prior to the screening visit in order to
      obtain patient's informed consent. Screening will take place 2-21 days prior to Visit 2 and
      the follow-up visit will take place 5-21 days after the end of Visit 4. The dosing visits
      will be separated by a wash-out period (5-30 days between the end of Visit 2 and begin of
      Visit 4) during which the subjects will resume their normal insulin treatment. Each phone
      visit (Visit 3 and Visit 5) will take place 3-5 days after the end of dosing Visits 2 and 4.
      The planned total duration of the trial is 18-78 days per subject (rescheduled visits
      excluded). Each subject will be randomised to a treatment sequence consisting of two
      treatment periods in which the subjects will receive dapagliflozin and placebo on two
      separate dosing visits.

      Subjects metabolic control will be achieved by a variable i.v. infusion of human insulin by
      an infusion pump. The procedure will be used in order to aim and maintain blood glucose
      levels between 160 and 220 mg/dl thereby being in the range of the urinary threshold of
      glucose.

      The fluid infusion and insulin dosing scheme will depend on body weight (BW) and blood
      glucose (BG) levels.

      Two standardized mixed-meals will be given 6 hours and 12 hours after dosing. Blood glucose
      measurements will be performed every 15min for 120min after the mixed-meal.

      Blood samples for determination of dapagliflozin concentration in serum will be taken 18times
      in 24hours as well as every urine sample will be collected for 24 hours after dosing for the
      determination of 24hour urinary glucose and creatinine for efficacy measurement.

      After conclusion of the trial the documented insulin doses over time will be summed up for
      calculation of the total insulin dose and the insulin dose per kg body weight per 24 hours.
      Separate calculations will be done for the overnight period pre-dosing, six hours after
      dosing, two hours prior and after the first and second Standard Meal and until the end of the
      visit.
    

Intervention name(s): dapagliflozin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): one administration in the morning; one administration in the morning
Other intervention name(s): Forxiga; Control
Intervention MeSH terms: Dapagliflozin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment