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

Phase 2

Completed

Conditions: Type 1 Diabetes

Interventions: Other: Placebo
Drug: Bromocriptine

Registration Number: NCT02544321

Lead Sponsor: University of Colorado, Denver

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 108

Inclusion Criteria

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

Exclusion Criteria

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;
Tobacco or marijuana use;
Pregnancy;
Regular or frequent oral steroid use;
Current use of insulin sensitizing medications, neuroleptics, ergot-related medications, or triptan medications for migraine,
Diagnosis or history of psychosis,
Diabetes of other cause such as Maturity Onset Diabetes of the Young or cystic fibrosis-related diabetes.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	4 weeks of placebo
Bromocriptine QR	Bromocriptine	4 weeks of investigational drug Bromocriptine QR

Primary Outcome Measures

Name	Time	Method
Hyperemia Peripheral Arterial Tonometry (RH-PAT): Reactive Hyperemia Index (RHI)	4 weeks	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.
Brachial Artery Distensibility	4 weeks	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).
Mean Glucose	4 weeks	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
Insulin Dosing	4 weeks	At the end of each 4 week intervention period, we will measure the effect of BCQR on insulin dosing (units//kg/day)

Secondary Outcome Measures

Name	Time	Method
Mean Glycemic Variability	4 weeks	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.
Hypoglycemia Awareness	4 weeks	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.
Heart Rate Variability (Adolescents)	4 weeks	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.
Metabolic Markers - Insulin	4 weeks	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.
Sleep Duration	4 weeks	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.
Sleep Quality	4 weeks	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.
Metabolic Markers-fatty Acids	4 weeks	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.
Augmentation Index	4 weeks	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).
Heart Rate Variability (Adults)	4 weeks	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.
Metabolic Markers-glucose and Triglycerides	4 weeks	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.
Metabolic Markers - GLP1	4 weeks	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.
Metabolic Markers-glucagon	4 weeks	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.