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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02544321

Enrollment

108

Registered

2015-09-09

Start date

2015-09-30

Completion date

2019-06-30

Last updated

2021-09-13

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Type 1 Diabetes

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.

Interventions

DRUGBromocriptine

OTHERPlacebo

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

12 Years to 60 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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)
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).
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.

Secondary

Measure	Time frame	Description
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.
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-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.
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.
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.
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 - 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.
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.
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.
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.

Countries

United States

Participant flow

Pre-assignment details

Some participants screen failed or withdrew from the study after enrollment, but prior to starting the study.

Participants by arm

Arm	Count
Bromocriptine QR, Then Placebo 4 weeks of investigational drug Bromocriptine QR, then 4 weeks of placebo.	43
Placebo, Then Bromocriptine QR 4 weeks of placebo, then 4 weeks of investigational drug Bromocriptine QR	41
Total	84

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	1	1
Overall Study	Protocol Violation	0	1
Overall Study	Withdrawal by Subject	1	2

Baseline characteristics

Characteristic	Bromocriptine QR, Then Placebo	Placebo, Then Bromocriptine QR	Total
Age, Continuous Adolescents	16.5 years STANDARD_DEVIATION 2.8	15.6 years STANDARD_DEVIATION 2.7	16.1 years STANDARD_DEVIATION 2.8
Age, Continuous Adults	44.1 years STANDARD_DEVIATION 9	38 years STANDARD_DEVIATION 10	41.1 years STANDARD_DEVIATION 9.9
Ethnicity (NIH/OMB) Adolescents Hispanic or Latino	1 Participants	2 Participants	3 Participants
Ethnicity (NIH/OMB) Adolescents Not Hispanic or Latino	21 Participants	18 Participants	39 Participants
Ethnicity (NIH/OMB) Adolescents Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Adults Hispanic or Latino	0 Participants	1 Participants	1 Participants
Ethnicity (NIH/OMB) Adults Not Hispanic or Latino	21 Participants	20 Participants	41 Participants
Ethnicity (NIH/OMB) Adults Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Adolescents American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Adolescents Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Adolescents Black or African American	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) Adolescents More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Adolescents Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Adolescents Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Adolescents White	22 Participants	19 Participants	41 Participants
Race (NIH/OMB) Adults American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Adults Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Adults Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Adults More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Adults Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Adults Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Adults White	21 Participants	21 Participants	42 Participants
Region of Enrollment United States	43 participants	41 participants	84 participants
Sex: Female, Male Adolescents Female	15 Participants	9 Participants	24 Participants
Sex: Female, Male Adolescents Male	7 Participants	11 Participants	18 Participants
Sex: Female, Male Adults Female	12 Participants	11 Participants	23 Participants
Sex: Female, Male Adults Male	9 Participants	10 Participants	19 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	1 / 42	1 / 42	0 / 42	0 / 42
other Total, other adverse events	13 / 42	17 / 42	1 / 42	3 / 42
serious Total, serious adverse events	1 / 42	1 / 42	0 / 42	0 / 42

Outcome results

Primary

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).

Time frame: 4 weeks

Population: Compared for placebo versus BCQR after 4 weeks of treatment.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Bromocriptine QR (Adolescents)	Brachial Artery Distensibility	6.35 %/mmHg	Standard Error 0.19
Bromocriptine QR (Adults)	Brachial Artery Distensibility	6.2 %/mmHg	Standard Error 0.2
Placebo (Adolescents)	Brachial Artery Distensibility	6.14 %/mmHg	Standard Error 0.19
Placebo (Adults)	Brachial Artery Distensibility	6.4 %/mmHg	Standard Error 0.2

Primary

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.

Time frame: 4 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Bromocriptine QR (Adolescents)	Hyperemia Peripheral Arterial Tonometry (RH-PAT): Reactive Hyperemia Index (RHI)	1.95 score on a scale	Standard Error 0.09
Bromocriptine QR (Adults)	Hyperemia Peripheral Arterial Tonometry (RH-PAT): Reactive Hyperemia Index (RHI)	2.1 score on a scale	Standard Error 0.1
Placebo (Adolescents)	Hyperemia Peripheral Arterial Tonometry (RH-PAT): Reactive Hyperemia Index (RHI)	2.24 score on a scale	Standard Error 0.09
Placebo (Adults)	Hyperemia Peripheral Arterial Tonometry (RH-PAT): Reactive Hyperemia Index (RHI)	2.2 score on a scale	Standard Error 0.1

Primary

Insulin Dosing

At the end of each 4 week intervention period, we will measure the effect of BCQR on insulin dosing (units//kg/day)

Time frame: 4 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Bromocriptine QR (Adolescents)	Insulin Dosing	0.9 units//kg/day	Standard Error 0.03
Bromocriptine QR (Adults)	Insulin Dosing	0.54 units//kg/day	Standard Error 0.02
Placebo (Adolescents)	Insulin Dosing	0.88 units//kg/day	Standard Error 0.03
Placebo (Adults)	Insulin Dosing	0.56 units//kg/day	Standard Error 0.02

Primary

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

Time frame: 4 weeks

Population: Data reflects average glucose levels.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Bromocriptine QR (Adolescents)	Mean Glucose	182 mg/dl	Standard Error 5
Bromocriptine QR (Adults)	Mean Glucose	165 mg/dl	Standard Error 5
Placebo (Adolescents)	Mean Glucose	181 mg/dl	Standard Error 5
Placebo (Adults)	Mean Glucose	165 mg/dl	Standard Error 5

Secondary

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).

Time frame: 4 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Bromocriptine QR (Adolescents)	Augmentation Index	10.42 Percentage of pressure wave	Standard Error 1.71
Bromocriptine QR (Adults)	Augmentation Index	-2.0 Percentage of pressure wave	Standard Error 1.8
Placebo (Adolescents)	Augmentation Index	12.52 Percentage of pressure wave	Standard Error 1.72
Placebo (Adults)	Augmentation Index	-2.5 Percentage of pressure wave	Standard Error 1.8

Secondary

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.

Time frame: 4 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Bromocriptine QR (Adolescents)	Heart Rate Variability (Adolescents)	73 milliseconds	Standard Error 5
Bromocriptine QR (Adults)	Heart Rate Variability (Adolescents)	76.4 milliseconds	Standard Error 4.9

Secondary

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.

Time frame: 4 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Bromocriptine QR (Adolescents)	Heart Rate Variability (Adults)	1.09 ratio	Standard Error 0.05
Bromocriptine QR (Adults)	Heart Rate Variability (Adults)	1.14 ratio	Standard Error 0.05

Secondary

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.

Time frame: 4 weeks

Population: Unadjusted least square means by mixed procedure.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Bromocriptine QR (Adolescents)	Hypoglycemia Awareness	Clarke method scores	1.36 score on a scale	Standard Error 1.23
Bromocriptine QR (Adolescents)	Hypoglycemia Awareness	Gold method scores	2.15 score on a scale	Standard Error 1.31
Bromocriptine QR (Adolescents)	Hypoglycemia Awareness	McAuley score	3.25 score on a scale	Standard Error 0.22
Bromocriptine QR (Adults)	Hypoglycemia Awareness	McAuley score	3.40 score on a scale	Standard Error 0.31
Bromocriptine QR (Adults)	Hypoglycemia Awareness	Gold method scores	3.02 score on a scale	Standard Error 1.67
Bromocriptine QR (Adults)	Hypoglycemia Awareness	Clarke method scores	2.33 score on a scale	Standard Error 1.9
Placebo (Adolescents)	Hypoglycemia Awareness	Clarke method scores	1.33 score on a scale	Standard Error 1.2
Placebo (Adolescents)	Hypoglycemia Awareness	McAuley score	3.21 score on a scale	Standard Error 0.22
Placebo (Adolescents)	Hypoglycemia Awareness	Gold method scores	2.00 score on a scale	Standard Error 1.18
Placebo (Adults)	Hypoglycemia Awareness	Clarke method scores	2.67 score on a scale	Standard Error 1.84
Placebo (Adults)	Hypoglycemia Awareness	Gold method scores	3.15 score on a scale	Standard Error 1.59
Placebo (Adults)	Hypoglycemia Awareness	McAuley score	2.90 score on a scale	Standard Error 0.29

Secondary

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.

Time frame: 4 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Bromocriptine QR (Adolescents)	Mean Glycemic Variability	71 mg/dl	Standard Error 2.1
Bromocriptine QR (Adults)	Mean Glycemic Variability	61 mg/dl	Standard Error 2.5
Placebo (Adolescents)	Mean Glycemic Variability	73 mg/dl	Standard Error 2.1
Placebo (Adults)	Mean Glycemic Variability	63 mg/dl	Standard Error 2.5

Secondary