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 (NAC for HAAF)

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

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

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes; Hypoglycemia Unawareness
• Intervention / Treatment: Drug: Placebo; Drug: N-acetyl cysteine

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.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Department of Medicine, Division of Diabetes, Endocrinology and Metabolism

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy controls
• Age 18 - 65 years
• Baseline hemoglobin A1C <6.0%

Exclusion Criteria:

• History of stroke, seizures (other than those related to hypoglycemia), arrhythmias, active cardiac disease (all of which could be associated with adverse cardiac or neurological events during hypoglycemia)
• Pregnancy or plan to become pregnant during the study period
• Diagnosis of asthma (increases risk of hypersensitivity reactions to NAC)
• Use of anti-oxidants or drugs that can alter glucose metabolism
• Concomitant medical problems that may prevent the subject from successfully completing the protocol
• Unwillingness to avoid exercise during the 7 days before each part of the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Normal Saline IV infusion given during a controlled hyperinsulinemic hypoglycemic insulin clamp	Drug: Placebo
Experimental: Treatment with N-Acetyl Cysteine; N-acetyl cysteine 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	Drug: N-acetyl cysteine; 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 Names: NAC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in Epinephrine Secretion During the Morning Episodes of Hypoglycemia on Days One and Two Under the Two Treatment Conditions	Epinephrine secretion during hypoglycemia is assessed by collecting blood samples for measurement of epinephrine concentrations at baseline and every 15 minutes during the period of hypoglycemia (starting at point where blood glucose is first < 55 mg/dl) in the clamp studies done in the mornings of days 1 and 2 of both parts 1 and 2. .	8-10 weeks

Collaborators and Investigators

• Sponsor: University of Minnesota

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2015
• Primary Completion (Actual): December 1, 2017
• Study Completion (Actual): December 1, 2017

Study Registration Dates

• First Submitted: May 23, 2014
• First Submitted That Met QC Criteria: July 31, 2014
• First Posted (Estimate): August 1, 2014

Study Record Updates

• Last Update Posted (Actual): January 31, 2020
• Last Update Submitted That Met QC Criteria: January 21, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: Diabetes; Hypoglycemia; Unawareness; HAAF
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Nervous System Diseases; Immune System Diseases; Autoimmune Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Endocrine System Diseases; Consciousness Disorders; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemia; Unconsciousness; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: Protocol 22498

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No