Propranolol in Treating Hypoglycemia Unawareness

NCT03161964 | Terminated Phase 2 Results FDA Drug

• 1 other identifier: IRB #101995
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

Brief Summary

Impaired awareness of hypoglycemia is common in type 1 diabetes (T1DM) patients. Impaired hypoglycemia awareness increases severe hypoglycemia risk by six-fold. Severe hypoglycemia compromises quality of life and can potentially cause death. The long-term goal of this pilot study is to lead to the development of novel therapeutic approaches to improve hypoglycemia awareness and thus prevent severe hypoglycemia development in T1DM population with impaired awareness of hypoglycemia. It is hypothesized that propranolol will improve hypoglycemia recognition in T1DM. The specific aims of the study are to determine whether propranolol treatment improves subjects' recognition of hypoglycemic episodes, and improves hypoglycemic awareness scores; whether propranolol favorably increases hypoglycemia blood glucose nadir, decreases onset-to-treatment/recovery time (i.e. hypoglycemia duration), and reduces hypoglycemia/severe hypoglycemia frequency; and, whether propranolol reduces fear of hypoglycemia and improves overall blood glucose control.

Conditions

Type 1 Diabetes Mellitus

Keywords

Hypoglycemia; Impaired Awareness of Hypoglycemia; Propranolol

Outcome Measures

Primary Outcomes (1)

• Ratio of Self-reported Hypoglycemic Episodes to Total Hypoglycemic Episodes Determined by Continuous Glucose Monitoring (CGM)

  A subject's self-reported hypoglycemic episode is defined by a hypoglycemic symptom record on the hypoglycemia diary with a confirmatory glucose value (glucometer value \< 70 mg/dL), or an incidental glucometer value \< 70 mg/dL if no hypoglycemia symptom develops. A single CGM hypoglycemic episode is defined by any CGM readings \< 70 mg/dL, followed by at least one reading ≥ 70 mg/dL from the Dexcom Professional Mobile CGM system. Self-reported and CGM assessment of hypoglycemic episodes will be conducted for two weeks before study drug intervention and two weeks after study drug intervention. The average change in the ratio of self-reported hypoglycemic episodes to total (CGM) episodes will be compared between the propranolol and placebo treatment arms

  2 weeks

Secondary Outcomes (15)

• Gold Questionnaire Score for Hypoglycemia Awareness

  4 weeks

• Clarke Questionnaire Score for Hypoglycemia Awareness

  4 weeks

• Pederson-Bjergaard Questionnaire Score for Hypoglycemia Awareness

  4 weeks

• Nadir Glucose Level

  2 weeks

• Nadir Glucose Level in Categories

  2 weeks

Study Arms (2)

Propranolol

EXPERIMENTAL

After enrollment and the initial two-week continuous glucose monitoring assessment, study subjects randomized to the Propranolol Arm will be treated with Propranolol 80 Mg Oral Capsule, Extended Release daily for four weeks.

Drug: Propranolol 80 Mg Oral Capsule, Extended Release

Placebo

EXPERIMENTAL

After enrollment and the initial two-week continuous glucose monitoring assessment, study subjects randomized to the Placebo Arm will be treated with matching placebo oral capsule daily for four weeks.

Drug: Placebo oral capsule

Interventions

Propranolol 80 Mg Oral Capsule, Extended Release DRUG

Propranolol capsule over-encapsulated to match placebo for blinding

Also known as: propranolol Long Acting (LA)

Propranolol

Placebo oral capsule DRUG

Placebo capsule over-encapsulated to match propranolol for blinding

Also known as: placebo

Placebo

Eligibility Criteria

• Age: 21 Years - 59 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Subjects with Type 1 diabetes mellitus for more than 5 years with impaired awareness of hypoglycemia
• Age between 21 to 59 years old
• Hemoglobin A1c ≤ 9%; most recent value within 3 months
• No beta-blocker use history in the last 6 months
• Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines

You may not qualify if:

• History of coronary, cerebral or peripheral vascular disease
• History of cardiac conduction abnormality or heart failure
• History of advanced liver disease
• Active malignancy
• Major Central or Peripheral Nervous System disease
• History of human immunodeficiency virus infection
• Contraindication to beta-blockers, including hypersensitivity to beta-blocker and bronchospastic disease
• Female in pregnancy or not able to practice effective contraception during the study period
• Concomitant acetaminophen use
• Currently utilizing unblinded real-time continuous glucose monitoring
• Advanced diabetic microvascular complications including retinopathy, neuropathy and nephropathy
• Inability to understand or cooperate with study procedure, including performing glucometer glucose assessment a minimum of four times a day, carrying glucose tablets and following standardized hypoglycemia treatment, completing hypoglycemia diary, wearing continuous glucose monitoring, and using a single glucometer
• Recent or current use or involvement in clinical studies of other therapies (e.g. opioid antagonist, SSRI, behavioral modification, relaxation of glycemic control) that may improve hypoglycemia awareness or prevent impaired hypoglycemia awareness development

Sponsors & Collaborators

• Anu Sharma: lead

Study Sites (1)

University of Utah

Salt Lake City, Utah, 84132, United States

Location

Related Publications (20)

• Diabetes Control and Complications Trial Research Group; Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, Rand L, Siebert C. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993 Sep 30;329(14):977-86. doi: 10.1056/NEJM199309303291401.

  PMID: 8366922 BACKGROUND

• Hypoglycemia in the Diabetes Control and Complications Trial. The Diabetes Control and Complications Trial Research Group. Diabetes. 1997 Feb;46(2):271-86.

  PMID: 9000705 BACKGROUND

• Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes. 2008 Dec;57(12):3169-76. doi: 10.2337/db08-1084. No abstract available.

  PMID: 19033403 BACKGROUND

• Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med. 2013 Jul 25;369(4):362-72. doi: 10.1056/NEJMra1215228. No abstract available.

  PMID: 23883381 BACKGROUND

• Geddes J, Schopman JE, Zammitt NN, Frier BM. Prevalence of impaired awareness of hypoglycaemia in adults with Type 1 diabetes. Diabet Med. 2008 Apr;25(4):501-4. doi: 10.1111/j.1464-5491.2008.02413.x.

  PMID: 18387080 BACKGROUND

• Cranston I, Lomas J, Maran A, Macdonald I, Amiel SA. Restoration of hypoglycaemia awareness in patients with long-duration insulin-dependent diabetes. Lancet. 1994 Jul 30;344(8918):283-7. doi: 10.1016/s0140-6736(94)91336-6.

  PMID: 7914259 BACKGROUND

• Dagogo-Jack S, Rattarasarn C, Cryer PE. Reversal of hypoglycemia unawareness, but not defective glucose counterregulation, in IDDM. Diabetes. 1994 Dec;43(12):1426-34. doi: 10.2337/diab.43.12.1426.

  PMID: 7958494 BACKGROUND

• Rickels MR, Peleckis AJ, Markmann E, Dalton-Bakes C, Kong SM, Teff KL, Naji A. Long-Term Improvement in Glucose Control and Counterregulation by Islet Transplantation for Type 1 Diabetes. J Clin Endocrinol Metab. 2016 Nov;101(11):4421-4430. doi: 10.1210/jc.2016-1649. Epub 2016 Aug 29.

  PMID: 27571180 BACKGROUND

• Szepietowska B, Zhu W, Chan O, Horblitt A, Dziura J, Sherwin RS. Modulation of beta-adrenergic receptors in the ventromedial hypothalamus influences counterregulatory responses to hypoglycemia. Diabetes. 2011 Dec;60(12):3154-8. doi: 10.2337/db11-0432. Epub 2011 Oct 19.

  PMID: 22013013 BACKGROUND

• Chan O, Sherwin R. Influence of VMH fuel sensing on hypoglycemic responses. Trends Endocrinol Metab. 2013 Dec;24(12):616-24. doi: 10.1016/j.tem.2013.08.005. Epub 2013 Sep 21.

  PMID: 24063974 BACKGROUND

• Barnes MB, Lawson MA, Beverly JL. Rate of fall in blood glucose and recurrent hypoglycemia affect glucose dynamics and noradrenergic activation in the ventromedial hypothalamus. Am J Physiol Regul Integr Comp Physiol. 2011 Dec;301(6):R1815-20. doi: 10.1152/ajpregu.00171.2011. Epub 2011 Sep 28.

  PMID: 21957162 BACKGROUND

• Ramanathan R, Cryer PE. Adrenergic mediation of hypoglycemia-associated autonomic failure. Diabetes. 2011 Feb;60(2):602-6. doi: 10.2337/db10-1374.

  PMID: 21270270 BACKGROUND

• UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ. 1998 Sep 12;317(7160):713-20.

  PMID: 9732338 BACKGROUND

• Barnett AH, Leslie D, Watkins PJ. Can insulin-treated diabetics be given beta-adrenergic blocking drugs? Br Med J. 1980 Apr 5;280(6219):976-8. doi: 10.1136/bmj.280.6219.976.

  PMID: 6106521 BACKGROUND

• Shorr RI, Ray WA, Daugherty JR, Griffin MR. Antihypertensives and the risk of serious hypoglycemia in older persons using insulin or sulfonylureas. JAMA. 1997 Jul 2;278(1):40-3.

  PMID: 9207336 BACKGROUND

• Kerr D, MacDonald IA, Heller SR, Tattersall RB. Beta-adrenoceptor blockade and hypoglycaemia. A randomised, double-blind, placebo controlled comparison of metoprolol CR, atenolol and propranolol LA in normal subjects. Br J Clin Pharmacol. 1990 Jun;29(6):685-93. doi: 10.1111/j.1365-2125.1990.tb03689.x.

  PMID: 1974143 BACKGROUND

• Viberti GC, Keen H, Bloom SR. Beta blockade and diabetes mellitus: effect of oxprenolol and metoprolol on the metabolic, cardiovascular, and hormonal response to insulin-induced hypoglycemia in normal subjects. Metabolism. 1980 Sep;29(9):866-72. doi: 10.1016/0026-0495(80)90126-2.

  PMID: 6106148 BACKGROUND

• Marengo C, Marena S, Renzetti A, Mossino M, Pagano G. Beta-blockers in hypertensive non-insulin-dependent diabetics: comparison between penbutolol and propranolol on metabolic control and response to insulin-induced hypoglycemia. Acta Diabetol Lat. 1988 Apr-Jun;25(2):141-8. doi: 10.1007/BF02581378.

  PMID: 3066086 BACKGROUND

• Clausen-Sjobom N, Lins PE, Adamson U, Curstedt T, Hamberger B. Effects of metoprolol on the counter-regulation and recognition of prolonged hypoglycemia in insulin-dependent diabetics. Acta Med Scand. 1987;222(1):57-63. doi: 10.1111/j.0954-6820.1987.tb09929.x.

  PMID: 3307308 BACKGROUND

• Odugbesan O, Toop M, Barnett AH. Beta-and alpha-adrenergic blockade and metabolic responses to insulin induced hypoglycaemia in diabetics. Diabetes Res. 1987 Jul;5(3):135-8.

  PMID: 2822334 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Hypoglycemia

Interventions

Propranolol; Capsules

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Dosage Forms; Pharmaceutical Preparations

Results Point of Contact

• Title: Dr. Anu Sharma
• Organization: University of Utah

Anu.Sharma@hsc.utah.edu

(801) 581-7761

Study Officials

• Anu Sharma, MD

  University of Utah

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator; Assistant Professor (Clinical)

Study Record Dates

• First Submitted: May 17, 2017
• First Posted: May 22, 2017
• Study Start: October 19, 2017
• Primary Completion: December 19, 2019
• Study Completion: December 19, 2019
• Last Updated: August 24, 2020
• Results First Posted: August 24, 2020

Record last verified: 2020-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)