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)
Primary Purpose
Type 1 Diabetes, Hypoglycemia Unawareness
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
N-acetyl cysteine
Placebo
Sponsored by
About this trial
This is an interventional prevention trial for Type 1 Diabetes focused on measuring Diabetes, Hypoglycemia, Unawareness, HAAF
Eligibility Criteria
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
Sites / Locations
- University of Minnesota Department of Medicine, Division of Diabetes, Endocrinology and Metabolism
Arms of the Study
Arm 1
Arm 2
Arm Type
Placebo Comparator
Experimental
Arm Label
Placebo
Treatment with N-Acetyl Cysteine
Arm Description
Normal Saline IV infusion given during a controlled hyperinsulinemic hypoglycemic insulin clamp
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
Outcomes
Primary Outcome Measures
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. .
Secondary Outcome Measures
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02206152
Brief Title
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
Acronym
NAC for HAAF
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
January 2020
Overall Recruitment Status
Completed
Study Start Date
February 2015 (Actual)
Primary Completion Date
December 2017 (Actual)
Study Completion Date
December 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Minnesota
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 1 Diabetes, Hypoglycemia Unawareness
Keywords
Diabetes, Hypoglycemia, Unawareness, HAAF
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 1, Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
22 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Normal Saline IV infusion given during a controlled hyperinsulinemic hypoglycemic insulin clamp
Arm Title
Treatment with N-Acetyl Cysteine
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
N-acetyl cysteine
Other Intervention Name(s)
NAC
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Difference in Epinephrine Secretion During the Morning Episodes of Hypoglycemia on Days One and Two Under the Two Treatment Conditions
Description
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. .
Time Frame
8-10 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Elizabeth Seaquist, MD
Organizational Affiliation
University of Minnesota
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Minnesota Department of Medicine, Division of Diabetes, Endocrinology and Metabolism
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
12. IPD Sharing Statement
Learn more about this trial
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
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