A Randomized Double Blinded Study to Examine the Use of N-acetyl Cysteine for the Prevention and Treatment of HAAF in Patients With Type 1 Diabetes
Condition: Type 1 Diabetes; Hypoglycemia Unawareness
MeSH terms: Unconsciousness; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemia
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This is a single center, double blind randomized cross over design trial that will compare
      the impact of N-acetyl cysteine (200 mg) vs. saline infusion during experimental hypoglycemia
      on day one on the responses to experimental hypoglycemia on day two. 18 participants will be
      studied twice, 8 weeks apart. On each occasion they will undergo a 2 hour hypoglycemic clamp
      (target 50 mg/dl) in the morning and in the afternoon on day one and then again on the
      morning of day 2 and day 3. During the morning clamps, samples will be collected for later
      measurement of serum epinephrine levels, plasma and red blood cell NAC, cysteine, and
      glutathione concentrations and GSH/GSSG ratios (redox status), and participants will be asked
      to complete a hypoglycemia symptom questionnaire
    

Detailed description: 
      This study will consist of a screening visit and two 2-day intervention visits separated by
      approximately 8 weeks.

      At the screening visit, informed consent will be obtained, a standardized form will be used
      to ensure subjects meet inclusion/exclusion criteria, and baseline hemoglobin A1c will be
      obtained. On arrival, two IVs will be placed and they will be randomized to receive NAC or
      saline infusion. Baseline blood samples will be drawn for glucose, epinephrine,
      norepinephrine, cortisol, cysteine and glutathione measurements. Subjects will then be given
      25 mg IV diphenhydramine (Benadryl) followed by a 60 minute infusion of NAC (150 mg) or a
      similar volume of saline between 8 am and 9 am, followed by a four hour infusion of 50 mg of
      NAC. Thirty minutes after the start of the NAC infusion, a hyperinsulinemic (2.0 mu/kg/min)
      hypoglycemic (target = 50 mg/dl) clamp protocol will be started. During the morning study,
      blood samples will be collected every 5 minutes for monitoring of blood glucose levels and
      every 15 minutes for later measurement of serum epinephrine, norepinephrine, cortisol. Plasma
      and red blood cells samples will also be collected every 15 minutes for later measurement of
      NAC, cysteine, glutathione, and GSH/GSSG ratios (redox status). During the final 15 minutes
      of the morning clamp, subjects will be asked to quantitate their symptoms using a
      standardized method (13). At the completion of the morning clamp, glucose will be given to
      return the participant to euglycemia. 2 hours after the end of the morning clamp, a second
      hyperinsulinemic (2.0 mu/kg/min) hypoglycemic (target = 50 mg/dl) clamp protocol will be
      followed over two hours. . The afternoon clamp study will proceed as in the morning except
      that no serum or plasma will be collected except for the monitoring of glucose and collection
      of samples for subsequent measurement of NAC, cysteine, glutathione, and GSH/GSSG ratios.
      After the completion of the afternoon clamps, subjects will be returned to euglycemia and fed
      a meal. They will be discharged home.

      At 7 AM the following morning they will under a single 2 hour hyperinsulinemic hypoglycemic
      stepped clamp (75, 65, 55,45 mg/dl targets) during which blood samples will be collected as
      on the morning of day 1. Symptom scores will be collected in the final 15 minutes of each
      step in the clamp.

      At the completion of the study on day 2 of Part 1, they will be scheduled to return for Part
      2 in 8 weeks. This timing is selected to ensure that female participants are studied at the
      same phase of the menstrual cycle. During Part 2 they will receive the treatment not provided
      during Part 1 in a blinded fashion. The rest of the study protocol will be the same as in
      Part 1.
    

Intervention name(s): N-acetyl cysteine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): N-acetyl cysteine (or saline) IV infusion given as a 150 mg/kg loading dose over the first hour and then follow that with a 50 mg/kg maintenance dose infused over the next 4 hours during a controlled hyperinsulinemic hypoglycemic insulin clamp
Other intervention name(s): NAC
Intervention MeSH terms: Acetylcysteine; N-monoacetylcystine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention
Keywords: Diabetes; Hypoglycemia; Unawareness; HAAF