Propranolol in Treating Hypoglycemia Unawareness

NCT ID: NCT03161964

Last Updated: 2020-08-24

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 2 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-10-19
• Study Completion Date: 2019-12-19

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.

Detailed Description

Type 1 diabetes mellitus (T1DM) can lead to serious and devastating complications, including microvascular (retinopathy, neuropathy and nephropathy) and cardiovascular disease. Both diabetic microvascular and cardiovascular complications can be reduced with intensive insulin therapy and strict blood glucose control which target hemoglobin A1C to less than 7%. However, tighter glycemic control correlates with a higher incidence of hypoglycemia and severe hypoglycemia. Recurring exposure to hypoglycemia leads to an attenuated sympathoadrenal response to hypoglycemia (which is termed hypoglycemia-associated autonomic failure), and thus a loss or decrease in neurogenic hypoglycemic symptoms (i.e. impaired awareness of hypoglycemia). Impaired awareness of hypoglycemia is associated with a six-fold increased risk of severe hypoglycemia and physician or patient-directed higher glycemic goals. Impaired awareness of hypoglycemia is therefore a major barrier in diabetes management, by precluding optimal glycemic control and realization of its full benefits.

Several therapeutic strategies have been proposed to improve hypoglycemia awareness in T1DM patients. A temporal increase in glycemic goal only sustains hypoglycemia awareness recovery for a short-term. Islet transplantation is invasive, extremely expensive and requires life-long use of immunosuppressants. A widely available and affordable treatment with sustained efficacy for improving hypoglycemia awareness is therefore in urgent need. Pharmaceutical agents targeting potential mechanisms that contribute to the development of impaired hypoglycemia awareness have been proposed, including beta-blockers, opioid receptor antagonists and selective serotonin uptake inhibitors (SSRIs). However, none of these agents has been approved for the treatment of impaired hypoglycemia awareness.

The current pilot study will examine the clinical use of beta-blockers, specifically propranolol, for the treatment of impaired hypoglycemia awareness. In a physiological condition, hypoglycemia leads to counterregulatory hormone responses, including catecholamines. Catecholamine elevation mediates the development of neurogenic symptoms, including palpitation, anxiety and diaphoresis, and patient's recognition of a hypoglycemic episode. Previous study suggests that recurring hypoglycemic events, potentially through repeated ventromedial hypothalamus (VMH) noradrenergic system activation, dampen the counterregulatory hormone response to hypoglycemia. In addition, carvedilol (a non-specific beta-blocker) prevented hypoglycemia-associated autonomic failure development in rats made recurrently hypoglycemic. Consistent with these findings, propranolol, which crosses blood brain barrier and blocks beta-2 adrenergic receptors, has been shown to prevent hypoglycemia-associated autonomic failure in healthy human subjects. Thus, an intervention which can block the propagating mechanism(s) (i.e. repeated activation of beta2-adrenergic receptors) will likely lead to sympathoadrenal function improvement, and thus increase hypoglycemic symptoms and hypoglycemia awareness.

Beta-blocker is one of the most extensively used medication classes in the United States, and has been commonly utilized in diabetes patients for cardiac diseases. Although beta-blocker may theoretically attenuate hypoglycemic symptoms or lead to worsening of hypoglycemia, multiple studies have proven that beta-blockers increase hypoglycemic symptoms and can be safely used in insulin-dependent diabetes patients. In particular, a retrospective study included more than 13,000 patients and examined the relationship between antihypertensive use and hypoglycemia, and this study supported that beta-blocker use was not associated with an increase in severe hypoglycemia. As well, in a recent post-hoc analysis of a large type 2 diabetes intensive insulin therapy study (ACCORD), the group receiving beta-blocker and intensive insulin therapy had fewer cardiovascular events and comparable all-cause and cardiovascular death events compared to the group receiving beta-blocker and conventional therapy; this is thus evident for the safety of beta-blocker usage in patients undergoing intensive insulin therapy. With the safety data and previous basic/clinical observations, it is therefore proposed that propranolol is a strong testing candidate for potential hypoglycemia-associated autonomic failure treatment.

Conditions

Type 1 Diabetes Mellitus

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Propranolol

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.

Group Type: EXPERIMENTAL

Propranolol 80 Mg Oral Capsule, Extended Release

Intervention Type: DRUG

Propranolol capsule over-encapsulated to match placebo for blinding

Placebo

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.

Group Type: EXPERIMENTAL

Placebo oral capsule

Intervention Type: DRUG

Placebo capsule over-encapsulated to match propranolol for blinding

Interventions

Propranolol 80 Mg Oral Capsule, Extended Release

Propranolol capsule over-encapsulated to match placebo for blinding

Intervention Type: DRUG

Placebo oral capsule

Placebo capsule over-encapsulated to match propranolol for blinding

Intervention Type: DRUG

Other Intervention Names

propranolol Long Acting (LA); placebo

Eligibility Criteria

Inclusion Criteria

• 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

Exclusion Criteria

• 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

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 59 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Anu Sharma

OTHER

Sponsor Role: lead

Responsible Party

Anu Sharma

Principal Investigator; Assistant Professor (Clinical)

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Anu Sharma, MD

Role: PRINCIPAL_INVESTIGATOR

University of Utah

Locations

University of Utah

Salt Lake City, Utah, United States

Countries

United States

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Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

IRB #101995

Identifier Type: -

Identifier Source: org_study_id