Bromocriptine Quick Release (BCQR) as Adjunct Therapy in Type 1 Diabetes

Bromocriptine Quick Release (QR) as Adjunct Therapy in Type 1 Diabetes

Type 1 diabetes (T1D) continues to be a disease plagued by hyperglycemia, insulin resistance (IR), and increased cardiovascular disease (CVD) despite advances in insulin delivery and glucose monitoring. Therefore new approaches are needed. Bromocriptine (BC), a dopamine (DA) agonist, has long been widely used for treating Parkinson's disease and prolactinoma. Its recent approval in a quick release formulation, BCQR, for type 2 diabetes (T2D) is an exciting development, representing a novel mechanism for improving IR. BCQR has not been studied in T1D, but it's mechanism of action, mechanistic studies, and preliminary data support the proposed study of possible benefits of BCQR on insulin action, glycemic control, and the vasculature in T1D. This study has received an exemption from the FDA to study BCQR in adults with T1D and an IND approval (131360) to study BCQR in adolescents with T1D. This is a random-order, double-blind, placebo-controlled study of a 4 week intervention. Outcomes will include fasting and postprandial glucose, glycemic variability, insulin dosing, hypoglycemia frequency and awareness, sleep quality, and metabolic hormone levels.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Other: Placebo; Drug: Bromocriptine

• Study Type: Interventional
• Enrollment (Actual): 108
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado-Denver, Anshutz Medical Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 60 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Type 1 Diabetes (T1D) of >1 year duration based on a clinical course consistent with T1D and rapid conversion to insulin requirement after diagnosis.
2. HbA1c 6.5-10% (adults) or any HbA1c up to 12% (pediatrics)
3. age 12-60 years of age

Exclusion Criteria:

1. Any comorbid condition associated with inflammation, insulin resistance, or dyslipidemia including cancer, heart failure, active or end stage liver disease, kidney disease (except microalbuminuria), inadequately treated thyroid disease, or rheumatologic disease;
2. Tobacco or marijuana use;
3. Pregnancy;
4. Regular or frequent oral steroid use;
5. Current use of insulin sensitizing medications, neuroleptics, ergot-related medications, or triptan medications for migraine,
6. Diagnosis or history of psychosis,
7. Diabetes of other cause such as Maturity Onset Diabetes of the Young or cystic fibrosis-related diabetes.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Bromocriptine QR; 4 weeks of investigational drug Bromocriptine QR	Drug: Bromocriptine; Other Names: Bromocriptine Quick Release (BCQR)
Placebo Comparator: Placebo; 4 weeks of placebo	Other: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Glucose	At the end of each 4 week intervention period, we will measure the effect of Bromocriptine Quick Release on average glucose levels (mg/dl) by continuous glucose monitoring	4 weeks
Insulin Dosing	At the end of each 4 week intervention period, we will measure the effect of BCQR on insulin dosing (units//kg/day)	4 weeks
Brachial Artery Distensibility	At the end of each 4 week intervention period, we will measure the brachial artery distensibility as a measure of vascular stiffness by Dynapulse (%/mmHg). A larger number indicates less stiffness (ie greater compliance).	4 weeks
Hyperemia Peripheral Arterial Tonometry (RH-PAT): Reactive Hyperemia Index (RHI)	At the end of each 4 week intervention period, we will measure the reactive hyperemia Index (RHI). The Reactive Hyperemia Index (RHI) measures increased bloodflow after vascular occlusion. Higher scores indicate lower CVD risk and a better outcome, Scores of less than 1.67 may be considered abnormal. Scores of 1.67 1.67-2.09 may be considered borderline, and scores of 2.10 or higher my be considered normal.	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Glycemic Variability	At the end of each 4 week intervention period, we will measure the effect of Bromocriptine Quick Release on glycemic variability throughout the day (mg/dl), measured as SD of all glucose values throughout the last 7 days of intervention. Incorrectly initially entered as primary outcome. per protocol this has always been a secondary outcome.	4 weeks
Hypoglycemia Awareness	At the end of each 4 week intervention period, we will measure Hypoglycemia Awareness using the Gold method (7 point Likert scale: Possible scores range from 1 to 7. higher scores indicate more impaired awareness of hypoglycemia, and a worse outcome), Clarke method (8 question questionnaire characterizing hypoglycemia awareness. Possible scores range from 0-7, with higher scores indicating less awareness and a worse outcome), and the McAuley score (list of symptoms with a 7 point Likert scale for each. Possible scores range from 1-7 for each item, and are averaged across all symptoms, for a total possible score range of 1-7, with higher scores indicating more symptom awareness, and a better outcome). Incorrectly initially entered as primary outcome. per protocol this has always been a secondary outcome.	4 weeks
Augmentation Index	At the end of each 4 week intervention period, the % will be measured by SyphgmoCor. The Augmentation Index measures vascular stiffness by comparing pulse pressure of the reflected wave to the primary wave. HIGHER scores indicate greater vascular stiffness and higher cardiovascular risk, but a normal range has not been clearly defined. Presented as AI normalized to a heart rate of 75 (AI75).	4 weeks
Heart Rate Variability (Adults)	At the end of each 4 week intervention period we will measure the autonomic function by ECG. Ratio of maximum heart rate/minimum heartrate during a valsalva maneuver.	4 weeks
Heart Rate Variability (Adolescents)	At the end of each 4 week intervention period we will measure the autonomic function by HRV measured by endopat and reported using the single gold standard measure of SDNN (standard deviation of beat to beat time interval). Normal is >100, 50-100 indicates compromised autonomic function.	4 weeks
Sleep Duration	At the end of each 4 week intervention period, measurements of sleep duration on weekdays and weekends (minutes) by a Philips Spectrum Plus sleep monitor will be obtained.	4 weeks
Sleep Quality	At the end of each 4 week intervention period, measurements of sleep efficiency (percent of time in bed spent asleep) during the week and on weekends by a Philips Spectrum Plus sleep monitor will be obtained.	4 weeks
Metabolic Markers-glucose and Triglycerides	At the end of each 4 week intervention period, glucose, insulin, triglycerides, NEFA, GLP-1, and glucagon area under the curve will be measured during Mixed Meal Tolerance Test.	4 weeks
Metabolic Markers-fatty Acids	At the end of each 4 week intervention period, glucose, insulin, triglycerides, NEFA, GLP-1, and glucagon area under the curve will be measured during Mixed Meal Tolerance Test.	4 weeks
Metabolic Markers-glucagon	At the end of each 4 week intervention period, glucose, insulin, triglycerides, NEFA, GLP-1, and glucagon area under the curve will be measured during Mixed Meal Tolerance Test.	4 weeks
Metabolic Markers - GLP1	At the end of each 4 week intervention period, glucose, insulin, triglycerides, NEFA, GLP-1, and glucagon area under the curve will be measured during Mixed Meal Tolerance Test.	4 weeks
Metabolic Markers - Insulin	At the end of each 4 week intervention period, glucose, insulin, triglycerides, NEFA, GLP-1, and glucagon area under the curve will be measured during Mixed Meal Tolerance Test.	4 weeks

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: Juvenile Diabetes Research Foundation
• Investigators: Principal Investigator: Irene Schauer, MD, PhD, University of Colorado, Denver; Principal Investigator: Kristen Nadeau, MD, MS, Children's Hospital Colorado/University of Colorado

Publications and helpful links

General Publications

• Tell SS, Schafer M, Vigers T, Baumgartner AD, Lyon E, Gross S, Polsky S, Snell-Bergeon JK, Schauer IE, Nadeau KJ. Bromocriptine quick-release as adjunct therapy in youth and adults with type 1 diabetes: A randomized, placebo-controlled crossover study. Diabetes Obes Metab. 2022 Nov;24(11):2148-2158. doi: 10.1111/dom.14800. Epub 2022 Jul 25.

Study record dates

Study Major Dates

• Study Start: September 1, 2015
• Primary Completion (Actual): June 1, 2019
• Study Completion (Actual): June 1, 2019

Study Registration Dates

• First Submitted: August 26, 2015
• First Submitted That Met QC Criteria: September 8, 2015
• First Posted (Estimate): September 9, 2015

Study Record Updates

• Last Update Posted (Actual): September 13, 2021
• Last Update Submitted That Met QC Criteria: August 16, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Dopamine Agonists; Dopamine Agents; Hormone Antagonists; Antiparkinson Agents; Anti-Dyskinesia Agents; Bromocriptine
• Other Study ID Numbers: 15-1309; UL1TR001082 (U.S. NIH Grant/Contract)