Clinical trial NCT02544321
Conditions: Type 1 Diabetes
Sponsor: University of Colorado, Denver
Start date: 2015-09-01; Completion date: 2019-06-01
Enrollment: 108 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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:

Arms: arm 1: 4 weeks of investigational drug Bromocriptine QR arm 2: 4 weeks of placebo
Interventions: intervention 1: Bromocriptine intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
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COMIRB Protocol 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD 
CAMPUS BOX F-490    TELEPHONE:  303-724-1055  Fax:  303-724-0990 
 
 
Protocol #: 15-1309 
Project Title: 
 
Bromocriptine QR as adjunct therapy in Type 1 Diabetes 
 
 
Principal Investigator:  Irene Schauer 
Version Date:  
11/29/2018 
 
 
 
 
  
 
I. Hypotheses and Specific Aims:   
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. A morning DA 
surge normally resets the circadian clock to a more insulin sensitive state, and 
stimulates the transition from fasting to the fed state. This dopaminergic 
signaling is attenuated or absent in T2D1. Morning BCQR is thought to 
mimic/restore this AM dopamine surge in T2D. In T2D, BCQR has been shown 
to cause persistent decreases throughout the day in sympathetic nervous 
system (SNS) activity, glucagon, hepatic glucose production (HGP) and 
lipolysis, which in turn lead to persistent lowering of glucose and fatty acid  
(FFA) levels (Figure 1)1. Increased SNS and renin-angiotensin system (RAS) 
activity likely play a key role in microvascular and macrovascular sequelae and 
both are decreased with BCQR. Thus BCQR may also decrease rates of 
complications independent of glycemic control. An initial study with BCQR, in fact, found a dramatic decrease in CVD 
events in T2D1,2. BCQR has not been studied in T1D, but it’s mechanism of action, mechanistic studies, and our 
preliminary data support our proposed study of possible benefits of BCQR on insulin action, glycemic control, and the 
vasculature in T1D. We hypothesize primarily that BCQR will improve insulin action, thus improving glycemic 
control and/or decreasing insulin requirements in T1D. We further hypothesize that (1) Subject characteristics 
such as age, BMI, sex, HbA1c, residual C-peptide, and/or sleep quality and duration may impact the response to 
BCQR, (2) BCQR will have additional benefits on vascular compliance and function that may translate to 
improved CVD outcomes and support the added cost of BCQR therapy in T1D, and (3) Decreased chronic central 
SNS activation will improve hypoglycemia awareness and thus hypoglycemia frequency and severity.  
Specific Aims:  
SA#1: To test the hypothesis that BCQR will improve clinical parameters of insulin action in T1D (insulin dose, mean 
glucose and glycemic variability by continuous glucose monitoring [CGM], postprandial glucose excursion by glucose and 
insulin area under the curve during MMTT). We further hypothesize that (1) these benefits will incur due to improved 
postprandial suppression of glucagon and lipolysis and (2) the decrease in chronic SNS tone will lead to improved SNS 
responsiveness to hypoglycemia, with beneficial effects on hypoglycemia awareness and counter-regulatory response 
(hypoglycemia awareness questionnaire) and susceptibility to hypoglycemia (CGM). 
SA#2: To investigate clinical parameters that may predict response to BCQR in order to allow targeted use of this 
intervention if appropriate. Subgroup analyses will be performed by age, BMI and estimated insulin sensitivity.  
Multivariate modeling will address other potential predictors including C-peptide, fasting NEFA, baseline HbA1c, sex, 
sleep characteristics, circadian rhythm delay. 
SA#3: To test the hypothesis that BCQR-induced reduction in SNS activation, NEFA levels, and vascular IR will improve 
vascular function (arterial stiffness by Dynapulse and endothelial function by EndoPAT) and decrease blood pressure. 
 
Figure 1 
AM DA surge 
(BCQR)
Improved glycemic 
control
24 hour SNS 
activity
HGP
Lipolysis
NEFA levels
insulin sensitivity


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II. Background and Significance:  
Novel approaches to the management of T1D are urgently needed to address the ongoing gap in therapeutic 
efficacy, to minimize complication risk and improve morbidity and mortality in T1D. For instance, only 25% of youth 
in our multi-center T1D EXCHANGE Registry were able to reach target A1c despite advances in insulin-based options3.  
Although T1D is primarily a disease of insulin deficiency, we and others have demonstrated IR in adolescents and adults 
with T1D4-7 (preliminary data), even among subjects with normal body mass index (BMI). IR is associated with increased 
risk of CVD in type 2 diabetes (T2D), obesity, and metabolic syndrome8-12. In the Pittsburgh Epidemiology of Diabetes 
Complications (EDIC) and the Diabetes Control and Complications Trial (DCCT) adult T1D studies, IR estimated by non-
clamp surrogate measures was worse than expected13,14. Moreover, in a study by Martin et al, IR predicted the 
progression of vascular disease in T1D adults, and in EDIC, estimated IR, not glycemia, predicted CVD events and 
mortality13,15.  Further, a subset of participants in the DCCT with better glucose control experienced greater weight gain 
and worse CVD profiles, which suggests that lowering HbA1c with insulin alone may not decrease CVD risk16. In our 
recent study of 87 adults in the NIH Coronary Artery Calcification in T1D (CACTI) study, the T1D subjects were 
consistently and significantly more IR than the nondiabetic (nonDM) control group (preliminary data), and IR predicted 
increased coronary artery calcification17,18. In our recent adolescent JDRF-funded T1D studies, obese and normal weight 
T1D youth were more IR than control youth, which correlated with reduced exercise capacity, vascular dysfunction and 
more CVD risk factors (preliminary data) 18-20. Moreover, obesity is increasingly seen in youth and adults with T1D (40% of 
T1D adolescents in the T1D EXCHANGE are overweight or obese3), and obesity super-imposed on T1D is likely to 
worsen IR and CVD complications. Thus, IR is consistently present in T1D, and IR and its consequences present 
novel therapeutic targets to improve glycemic control and reduce complications.  
BromocriptineQR: Bromocriptine, a dopamine (DA) agonist, has long been widely used for treating Parkinson’s disease 
and by endocrinologists for treating prolactinoma. Its recent approval in a quick release formulation, bromocriptine quick 
release (BCQR), for T2D is an exciting development, representing a novel mechanism for improving glycemic control and 
the metabolic disturbances associated with IR1. The normal physiological morning dopamine surge resets the circadian 
clock, and triggers the transition from the fasting to the fed state. This dopaminergic signaling is attenuated or absent in in 
insulin resistant states, including T2D1. Morning BCQR mimics/restores the AM dopamine surge in T2D, resulting in 
persistent improvements throughout the day including decreased sympathetic nervous system (SNS) activity and 
suppression of glucagon release, hepatic glucose production (HGP) and lipolysis (Fig 1). These changes then lead to the 
beneficial effects of persistent lowering of glucose and non-esterified fatty acid (NEFA) levels throughout the day, 
particularly postprandially, resulting in improved glucose tolerance1 . In addition, BCQR results in persistently decreased 
SNS tone and decreased activation of the renin angiotensin system (RAS)1,2. The latter known effects likely explain the 
benefits of bromocriptine in congestive heart failure, an approach that has since been replaced by more specific 
adrenergic and RAS-targeted medications21,22. Finally, a randomized placebo-controlled clinical trial of BCQR in 3,070 
adults with T2D found a significant 40% risk reduction in the pre-specified primary cardiovascular endpoint (ischemic and 
nonischemic events). A post-hoc analysis of the “hard” clinical CVD composite endpoint of MI, CVD death, and stroke also 
showed a significant 52% risk reduction23.  
BCQR in T1D: BCQR has not yet been studied in T1D, and its mechanism of action and recent literature support our 
proposed physiological studies of possible benefits of BCQR in T1D on insulin action and vascular function. For example, 
studies in streptozotocin-induced diabetes in rats also implicate dopamine in the defects in central regulation of SNS 
activity in T1D24.  Furthermore, BCQR reduces SNS activity in lean non-DM subjects, suggesting that its effect is not 
exclusive to obesity, and that BCQR could be expected to decrease SNS-triggered lipolysis and glucagon release in 
T1D25,26. Moreover, chronic SNS activation is known to occur in T1D and contributes to hypoglycemic unawareness, 
causing dangerous unrecognized hypoglycemia. We have demonstrated a significant degree of adipose, hepatic and 
muscle IR in normal weight and obese adolescents and adults with T1D18,19, resulting in unchecked lipolysis, HGP and 
hyperglycemia similar to T2D. IR in T1D appears to involve the artificial nature of peripheral insulin delivery, a mechanism 
that cannot currently be directly targeted. This mechanism is supported by studies showing that IR is present early 
following diagnosis of T1D, but resolves transiently during a non-insulin-requiring “honeymoon” period7. Furthermore, 
pancreatic transplant improves IR27,28 but only normalizes IR when the transplant is integrated into the portal 
circulation29,30. Non-physiological insulin delivery results in relative hepatic insulin deficiency and potentially glucagon 
dysregulation, both resulting in abnormal HGP27-29,31. Hepatic insulin deficiency may also lower insulin-like growth factor-1 


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(IGF-1), which subsequently increases pituitary growth hormone secretion, further inducing IR at multiple tissues31. New 
data from our fatty-acid targeted intervention demonstrate that IR in T1D correlates with NEFA levels and thus should 
improve with decreased SNS-triggered lipolysis. BCQR’s effects of reducing both HGP and NEFA levels would thus be 
expected to improve overall glycemia and postprandial glucose excursions, lower insulin dose by improving IR, and also 
reset the SNS system to respond more appropriately to hypoglycemia. In addition, SNS dysregulation likely also plays a 
key role in the macrovascular sequelae of diabetes. Our preliminary data show vascular dysfunction in T1D and increased 
CVD-risk markers associated with IR. The dramatic benefits in terms of CVD risk reduction in T2D are potentially related 
to decreased SNS activity and/or improvements in IR and therefore may translate to T1D1,2.  
T1D and sleep: Poor sleep may contribute to the development of IR, either directly due to effects on glucose regulation or 
indirectly via dysregulation of appetite leading to weight gain. Alterations in sleep (time, disruption, architecture, and 
quality) are associated with neuroendocrine changes in appetite 32-34, SNS arousal35, and metabolic dysregulation35,36.  
Reports of reduced sleep times of up to 64%37 have been documented for children and adolescents with T1D. In adults 
with T1D, short sleep duration was associated with reduced insulin sensitivity38, increased HbA1c and a greater 
prevalence of non-dipping BP patterns39,40.  Additionally, two  polysomnography studies revealed that those with T1D 
spent more sleep time in lighter stages of sleep (stages 1 and 2) and less time in restorative slow-wave sleep (stage 3) 
compared to healthy control subjects41,42.  In one observational study in youth with T1D43, the T1D cohort spent 
significantly more time in stage 2 and less time in stage 3 sleep than a matched control group.  Within the T1D cohort, 
those who spent the most time in stage 2 sleep also had higher daily glucose and HbA1c levels suggesting metabolic 
dysregulation with lighter sleep43.  Conversely, fluctuations in glucose levels (>25 mg/dl/hr), even when the blood glucose 
level remained within normal ranges, have been associated with sleep disruption44.  Thus improving glycemic variability 
may help improve sleep and subsequently metabolic and CVD outcomes. In addition, all adolescents have a delayed 
phase circadian rhythm characterized by delayed melatonin release with later sleep onset and delayed melatonin offset 
with later waking45,46. As a result of this natural adolescent pattern, but artificially imposed early wake times for school, 
chronic short sleep is endemic in adolescence and sleep patterns and circadian rhythms are most likely to be abnormal in 
adolescents, arguing for their ultimate inclusion in our study 47. By providing an AM dopamine surge, BCQR may help 
improve the circadian rhythm abnormalities expected in individuals with T1D, contributing to improved glycemic control 
and insulin action. Conversely, sleep quality and/or duration may help to determine and predict response to BCQR 
treatment. This background supports our proposed inclusion of sleep duration, quality, and efficacy outcomes.   
Thus, the literature and our published studies support an expectation of improved insulin action, reduced insulin 
requirement, improved glycemic control and variability, and improved hypoglycemia awareness with BCQR 
treatment in T1D. In addition, the potential for reduction in macrovascular complications, even independent of 
glycemic control, and ease of administration makes BCQR a competitive candidate for adjunct oral therapy in 
T1D. We are singularly well positioned to perform this study with our large T1D population, existing pediatric and 
adult cohorts, and expertise in all proposed methods. 
III. Preliminary Studies/Progress Report:   
T1D subjects are markedly IR: Despite a lack of 
metabolic syndrome characteristics, hyperinsulinemic 
euglycemic clamps in our Coronary Artery Calcification in 
T1D (CACTI) study cohort reveal that T1D adults are 
significantly more IR than nonDM controls, with a mean 
glucose infusion rate (GIR) of only 44% of nonDM 
controls (GIR 5.8 ± 3.5 vs. 13.2 ± 5.7 mg/min/kgFFM, 
p<0.0001). Multiple adjustments, including age, fasting 
glucose, final clamp glucose and insulin, and BMI or 
visceral fat area attenuate the difference in IR only very 
slightly such that mean GIR for T1D remains 49% of that 
of nonDM18. T1D adults also fail to suppress HGP in 
response to insulin, evidence of significant hepatic IR48. 
Similarly, our JDRF-funded studies in T1D youth found a GIR that is 67% of age, BMI and pubertal stage-matched nonDM 
youth (13.3 ± 4.2 vs. 19.8 ± 4.6 mg/min/kgFFM, p<0.01)19(Fig 2). T1D youth (pink bar) were even more IR than obese 
Figure 1: Whole Body Insulin Sensitivity
Figure 1: Whole Body Insulin Sensitivity
2:


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nonDM (black bar). IR remained despite 
adjustment for BMI, age, pubertal stage, 
% body fat, activity, and post-clamp in-
sulin levels. T1D youth also fail to 
suppress HGP (Glucose Ra), even at the 
highest dose of insulin (Fig 3A)49. These 
data demonstrate muscle and hepatic IR 
across the lifespan in T1D and support 
the possibility of IR as a novel 
therapeutic target in T1D. 
IR in TID includes adipocyte IR: Low-
dose insulin infusion reveals the novel 
finding of adipocyte IR in T1D relative to nonDM 
subjects18,48,50. At 8mU/m2/min of insulin, glycerol rate 
of appearance (RA) and NEFA levels were more 
suppressed in nonDM than T1D adults (NEFA: 193 ± 
24 vs 370 ± 26 μM, p<0.0001) (Fig 4). Similarly, 
NEFA levels and glycerol Ra failed to suppress in 
response to 10 mU/m2/min in our JDRF-funded youth 
T1D studies, and even high dose insulin failed to 
completely suppress glycerol Ra (Fig 3B). NEFA’s 
also correlate negatively with GIR (p=0.01) in our T1D 
youth, arguing that FFA’s also impact systemic IR in 
T1D (ADA 2012).  Finally, we found endothelial 
dysfunction in our T1D youth that correlated with 
NEFA’s19.  
IR in T1D is improved with NEFA lowering: In an ongoing ADA-funded, 
double-blind, random order, placebo-controlled crossover IND-based pilot 
study, we are investigating the effects of acute NEFA lowering with acipimox in 
T1D. Acipimox inhibits lipolysis, lowers NEFA levels and improves IR acutely 
in T2D and in lean and obese nonDM controls51,52. Acipimox is not a viable 
clinical option for insulin sensitization because of tachyphylaxis and rebound. 
However, this proof of concept study examines whether NEFA lowering 
improves IR and vascular function in T1D.  In 4 T1D and 2 controls to-date, 
lower pre-clamp NEFA levels were associated with lower IR (Fig 5).These 
results suggest that failure to suppress lipolysis is a potential mechanism for IR 
and CVD in T1D, and support an intervention like BCQR that targets lipolysis 
will improve IR in T1D.  
IR in T1D is not solely due to poor glycemic control: Analyses of the role of 
glycemic control in IR in T1D suggest that residual hyperglycemia is not the 
sole cause of IR in T1D18,53,54. We found no correlation between fasting 
glucose, HbA1c or CGM measures of hyperglycemia, hypoglycemia or 
glycemic variability and GIR or failure of NEFA suppression in adolescents or adults. These results suggest that in 
moderately well controlled T1D, level of glycemic control does not affect IR, arguing for additional therapies to specifically 
address the IR of T1D.  
Vasculopathy in T1D correlates with IR: Measurement of augmentation index (AI), a measure of arterial stiffness, was 
performed in a large subset of our CACTI population (n=385). After adjustment for age and sex, AI remains signi-ficantly 
greater in T1D than nonDM subjects (mean, 95% confidence interval: 19.5, 18.2 - 20.7 vs. 16.6, 15.4 - 17.7; p=0.0011). 
When estimated IR5 is added to the model, the effect of T1D is completely lost indicating that AI is directly related to IR. 
We also found evidence of vascular stiffness in T1D youth in the SEARCH study using Brachial distensability (BrachD) by 
Figure 3A HGP in T1D youth
Figure 3B Adipose IR in T1D youth 
Figure 5: Insulin sensitivity (GIR) 
increases with lower fatty acid levels. 
X = nonDM; closed symbols = T1D.
KgFFM/min 
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Figure 1: §Least square m eans adjusted for age, BMI (kg/m 2), 
gender, starting glucose concentration, and tim e point insulin 
level. * p < 0.05 for difference by diabetes in m en; # by diabetes 
in wom en;  † p < 0.05 for sex difference in DM ; ‡ in nonDM. 
*#
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Figure 4


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Dynapulse55,56 and endothelial dysfunction by venous plethysmography19, both of which correlated with IR. We are 
currently assessing endothelial dysfunction with EndoPAT and arterial stiffness with Dynapulse in our JDRF- and ADA-
funded metformin trials in lean and obese adolescents with T1D, and to-date approximately 60% of T1D adolescents 
overall (and 70% of obese) have endothelial dysfunction (AFMR/SPR abstract submitted). Thus, we are experienced with 
the use and interpretation of these measures and they are feasible in youth and adults. In particular, arterial stiffness and 
endothelial dysfunction seem to present early and persist57, arguing for pediatric studies where prevention may still be 
possible. Moreover, three months of metformin was recently shown to improve arterial stiffness and endothelial function in 
30 young women with IR related to PCOS58, showing that short-term interventions are sufficient to impact these 
outcomes.  The associations with IR suggest that the increased arterial stiffness and endothelial dysfunction seen in T1D 
may be explained by IR and may improve with BCQR treatment.     
CAC presence and progression correlate with IR 
in T1D: In CACTI, presence and progression of CAC 
correlated inversely with GIR and directly with NEFA 
levels during clamp stage 2 for both T1D and 
nonDM adults after adjustment for age18.  By logistic 
regression analysis the odds ratio for existence of 
CAC was 0.45 for every 1 SD increase in GIR and 
2.4 for every 1 SD increase in stage 2 NEFA levels 
(Table 1)18. These data suggest that BCQR may 
have benefit beyond glycemic control in T1D and 
support our proposed studies of vascular stiffness 
and function. CVD benefit would provide a powerful 
additional rationale to justify the cost of this 
additional intervention in T1D. 
Estimation of IR in T1D: We used the gold-standard hyperinsulinemic euglycemic clamp from our JDRF-funded study 
along with simple clinical variables (age, sex, race/ethnicity, BMI, WC, Tanner stage, HbA1c, lipids, blood pressure (BP) 
and %fat) in T1D and T2D adolescents to develop an estimate of IR59,60 61. Estimated IR correlated well with GIR from our 
hyperinsulinemic euglycemic clamps (R2=0.74).  We then applied this estimate of IR to a cohort of 290 T1D adolescents, 
and found that estimated IR was inversely related to CV risk factors (BP, LDL, hsCRP, p<0.0001). Our CACTI study 
similarly developed a predictive equation for T1D adults (eIS-CACTI)18,62,63 which includes waist circumference, daily 
insulin dose per kg body weight, triglycerides and DBP:  exp[4.1075 – 0.01299*waist(cm)–1.05819*insulin dose (daily 
units per kg) - 0.00354*triglycerides (mg/dL) - 0.00802*DBP (mm Hg)]. The eIS-CACTI explains 63% of the variance in 
the GDR in hyperinsulinemic-euglycemic clamp studies, and has now been validated in adolescent and adult cohorts with 
and without T1D18,62,63. We therefore can now make use of these equations to estimate IR in both youth and adults in the 
proposed study rather than performing clamps, saving cost and reducing subject burden.  
 
IV. Research Methods 
 
A. Outcome Measure(s):   
Primary outcome measures are mean CGM glucose and insulin dose (SA#1), impact of age and BMI on response to 
therapy (SA#2) and improvement in brachial artery distensibilty and RH-PAT (SA#3). Insulin dose was chosen as a 
clinical primary outcome because of the short treatment duration and to allow insulin dose adjustments as needed to 
avoid hypoglycemia. Secondary outcomes (see detailed methods below) include measures of (1) glycemic control (CGM 
parameters (SD, %hyperglycemic)); (2) baseline/postprandial metabolic labs [area under the curve (AUC) for MMTT 
glucose, insulin, NEFA, triglycerides, glucagon, and glucagon-like peptide1 (GLP1); (3) hypoglycemia frequency and 
awareness (CGM %hypoglycemic, hypoglycemia symptoms scores (Gold method, Clarke method, and the McAuley 
score64-67); (4) SNS activity (heart rate variability); (5) other metabolic markers (HDL, LDL); (6) circadian rhythm/sleep 
effects (sleep quality scores, measured sleep with actiwatch sleep monitor); (7) CVD measures (arterial stiffness by 
Dynapulse, endothelial function by EndoPAT, and blood pressure), and (8), blood storage for future  inflammatory (IL-6, 
TNF-α, hsCRP, adiponectin), and vascular (endothelin 1, PAI-1, ICAM, renin, angiotensin, aldosterone) markers.  


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B. Description of Population to be Enrolled:   
Study population: Initially our goal is to enroll 60 T1D subjects (50% male) with the goal of completing 40 in the adult 
cohort. Ultimately, if the study drug is tolerated and safe in our adult cohort, we plan to amend the protocol to include 
adolescents, with involvement of Dr. Nadeau, the co-PI on the JDRF award.  With the addition of the adolescent cohort, 
we plan to recruit 133 T1D subjects with the goal of completing 80. Submission of this amendment will occur in late year 1 
ONLY IF there is no concerning safety signal in the adult cohort. Inclusion criteria: (1) T1D of >9 months 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) and (3) age 12-60 years of age. Exclusion criteria include (1) any comorbid 
condition associated with inflammation, IR, or dyslipidemia including cancer(with the exception of skin cancer), heart 
failure, active or end stage liver disease, end stage kidney disease, 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 or ergot-related medications, or triptan medications for migraine, (6) 
diagnosis or history of psychosis and (7) diabetes of other cause such as MODY or cystic fibrosis-related diabetes. BMI 
will not be restricted in order allow secondary analysis for effects of BMI on responsiveness to BCQR. Postmenarchal 
premenopausal females will be tested in the early follicular phase (cycle d2-10) where possible.   
C. Study Design and Research Methods   
 
Research Design and Methods: We propose to address the study hypotheses and aims with a double-blinded, random-
order, placebo-controlled cross-over design study in T1D. The intervention will consist of 4 weeks of treatment with BCQR 
(CyclosetTM) and 4 weeks of placebo separated by a ≥ 4 week washout. Interventions of this duration have been found to 
be adequate for detecting changes in vascular function, cardiac autonomic function, and glucose control for other anti-
diabetic and fatty acid lowering agents (eg68-72).  Most studies with BCQR in T2D have longer in duration. However, two 
studies demonstrated improved glucose and/or insulin levels after administration of a single dose73 or 4-8 weeks of daily 
dosing74. In addition, the mechanism predicts acute changes in glucose control and vascular parameters. The shorter 
duration is proposed here to minimize the cost and subject burden in this pilot study. 
Recruitment: Ultimately 133 T1D subjects (50% male, 50% adolescent) will be enrolled with the goal of having 100 
eligible and completing 80 (see power analysis). Recruitment will begin year 1 for the adult cohort and an adolescent 
cohort will be added in year 2. We will begin with a mass mailing to the established CACTI cohort of >600 adults with T1D 
mailing list established through Dr. Schauer’s clinical relationship. In addition, a co-investigator from the Barbara Davis 
Center adult T1D clinic (Dr. Polsky) is included specifically for recruitment purposes. Through these approaches we hope 
to have the full adult cohort recruited, but not completed, by the end of year 1. Late in year 1, any adverse events will be 
thoroughly reviewed by the safety officer to assess for any safety concerns (in particular hypoglycemia) prior to submitting 
an amendment to broaden the age range to add the adolescent cohort. However, we do not expect to encounter 
significant safety issues since higher doses and much longer durations of standard release bromocriptine are widely used 
in adults and children for other medical conditions. Beginning year 2, adolescent recruitment will consist of patients from 
the Barbara Davis Center for Childhood Diabetes (BDC) where co-investigator Dr. Nadeau is a medical provider and has 
a weekly clinic. Dr. Nadeau has excelled when recruiting adolescent T1D patients as she currently recruits for multiple 
protocols researching the abnormalities associated with T1D. Furthermore, Dr. Nadeau holds a weekly Endocrine Clinic 
and is a provider in the Lifestyle Medicine Clinic at the Children’s Hospital of Colorado where she has a clinical 
relationship with many patients with T1D and other endocrine disorders. Co-investigator Dr. Paul Wadwa is also a 
physician at the BDC and holds multiple weekly clinics with T1D patients. IRB approved flyers will be placed in private 
Endocrine clinics in the Denver Metro area. Through these approaches we hope to have the full adolescent cohort 
recruited.  We include both lean and obese participants as BMI and age-based differences in IR, glycemic control, 
hormone levels, sleep patterns and diabetes duration may impact response to BCQR. This recruitment strategy has been 
used successfully for our similarly powered individual ongoing studies. 
Investigational product: Bromocriptine Quick Release (Cycloset™): Bromocriptine itself has been available and widely 
used for Parkinson’s disease and prolactinoma for decades. It was also used for a time for congestive heart failure. BCQR 
is FDA approved for adult and T2D is currently undergoing safety and efficacy trials in T2D adolescents. BCQR has a 
similar side effect profile to standard formulations of bromocriptine. Common side effects include mild hypotension, mild 
fatigue/somnolence, headache, depressed mood, insomnia, nausea, and diarrhea. Less common and more serious side 
effects have been seen with BCQR including hypersensitivity reactions, hypoglycemia and syncope. Bromocriptine is 


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standardly used in young children, adolescents, and adults of all ages with hyperprolactinemia at higher does than 
proposed in our study and should be well tolerated. To assess the hypotensive side effect of Bromocriptine, blood 
pressure measurements, as outlined by the CDC to access orthostatic hypotension, will be collected at every study visit 
for the adolescent cohort only. Continuous glucose monitoring and contact with study staff will help avoid hypo- or 
hyperglycemia. Potential benefits include improved glycemic control and decreased insulin requirement, as well as 
metabolic and vascular benefits related to decreased chronic SNS activity, decreased renin angiotensin system activation, 
and resetting of the circadian rhythm. 
Study design: Eligible subjects will be randomized to order of treatment (placebo followed by BCQR vs. BCQR followed 
by placebo). Belmar Pharmacy will be supplying the study drug (BCQR 0.8 mg and identical placebo tablets). The study 
timeline for Phase 1 is illustrated in Fig 6. Phase 2 consists of visits identical to Phase 1 numbered 5-7. 
  
Visit 1: Screening visit: 
Prescreening will be 
done by phone or in 
conjunction with a 
clinical diabetes visit. 
The full screening visit 
will include the consent 
process, history, 
physical exam, and 
screening labs (HbA1c, 
comprehensive 
metabolic panel, TSH (adult participants only), urine microalbumin, lipids).  All females will also have a pregnancy test and 
detailed menstrual history. Adult females will have FSH and estradiol to determine pre- or postmenopausal status.  
Visit 2: Medication Start Visit: Qualifying subjects will return for a medication start visit and DEXA scan for body composi-
tion and estimation of daily caloric needs. Subjects will be trained in the use of a CGM system (Dexcom G4 Platinum). 
The monitor will be in real time unblinded mode throughout the uptitration portion of each study phase for safety purposes 
by guarding against hypoglycemia due to insulin sensitization and allowing informed insulin dose adjustment with 
assistance from study personnel if needed.  Baseline insulin dosing totals and average blood glucose will be recorded by 
subjects 3 days prior to starting the study medication. Subjects will also complete hypoglycemia and sleep questionnaires 
to assess frequency and awareness of lows, sleep patterns and sleep adequacy. Medication will be dispensed by the 
UCH or CHCO pharmacy to blind subjects and study personnel. Subjects will uptitrate study medication as follows: BCQR 
(0.8 mg) or placebo- 1 pill QAM for one week, then 2 pills QAM for one week, then 4 pills QAM for the remainder of the 4 
weeks. If an uptitration step is not tolerated, subjects will be returned to the last tolerated dose for a few days and 
uptitration will be attempted again. If again not tolerated, subjects will remain at the last tolerated dose as long as this is at 
least 1.6 mg QAM. If unable to reach minimum acceptable dose, subjects will be withdrawn from the study.  
Visit 3: Pre-MMTT Visit: Subjects will return for provision of Actiwatch and review of CGM data from the past 3 weeks. 
There will be continued data collection regarding glycemic control, variability, frequency of hypoglycemia, physical activity, 
and sleep duration and quality. Detailed 7-day sleep and insulin diaries will again be provided for the last week. Prior to 
each post-medication metabolic study day, subjects will also be provided with a 1-day standardized, macronutrient-
controlled, weight maintenance diet (45% carbohydrate, 20% protein, 35% fat) with caloric content based on prior DEXA 
lean body mass and an activity factor as in our previous studies. Depending on scheduling conflicts and the ability to pick 
up study diet, study staff may provide participants with food recommendations to eat 1 day prior to MMTT with the same 
macronutrient distribution listed above. 
Optional combined Visit 1, 2, and 3: For subjects that might have long distances to travel or scheduling conflicts, a 
combined visit will be provided as an option. For adolescents, a point of care A1c will be completed at screening to satisfy 
inclusion/exclusion criteria in addition to the other procedures outlined under visit 1. If participant is eligible and enrolled, 
IDS pharmacy will dispense medication to the study team. The sleep and insulin diaries along with the Actiwatch will be 
given to the subject at Visit 1 or 2. A phone call from the study doctor will be made to the subject during week 3 of the 
Figure 6: Study timeline (for each medication phase)
Stage day: 0                                          
14                       ~21               ~25             ~28  
Visit 2
•Urine pregnancy test 
(females)
•DEXA
•Start real-time CGMS 
•Pick up supplies, 
medication, 
questionnaires
•2 week 
uptitration of 
study drug
•Regular PI 
contact re 
glycemic 
control
Pick 
up 3d 
study 
diet 
Visit 4
•Turn in CGMS, 
Actiwatch, extra 
med, diaries, 
questionaires, 
•Vascular testing
•IV/Baseline labs
•MMTT 
Visit 3
•Download and 
blind CGMS 
•Pick up 
Actiwatch, 
insulin/sleep 
diaries, 
questionnaires
~26
1d


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phase to review CGM data as well as discuss any issues that may have come up. Subjects will also be reminded at this 
time to complete the insulin and sleep diaries and wear the Actiwatch during the last week. 
Visit 4: Mixed Meal Tolerance Test (MMTT) Visit: Subjects will present in the AM fasting following the 1-day study diet. 
Fasting Dynapulse measurements of vascular stiffness and central and peripheral blood pressure, EndoPAT 
measurements of endothelial function and augmentation index, and measurement of heart rate variability for autonomic 
tone will be performed. An IV will then be placed and baseline labs will be drawn, including hormonal and metabolic 
markers (described in MMTT detailed methods below).  Additional blood will be drawn and stored for future vascular and 
inflammatory markers. Next, an MMTT will be performed as described below. Pills will be counted to assess compliance, 
and the hypoglycemic and sleep questionnaires will be repeated. An optional MRI will be performed of the chest and 
abdomen.  
After at least a four week washout period, the full cycle will be repeated with the second blinded intervention, starting with 
Visit 5 (medication start visit as above, but without DEXA). Measurements following the placebo phase will serve as the 
untreated baseline. 
Optional combined visits 5, 6 and 7 (adolescents only): For subjects that might have long distances to travel or 
scheduling conflicts a combined visit will be provided as an option. Activity watch, questionnaires, CGM and study 
medication will be mailed to participant following the 4-week washout period. In the event a participant does not feel 
comfortable placing CGM at home, they will be able to come to the CTRC for CGM placement assistance. 
Methods:  
Mixed Meal Tolerance Test75: A standardized mixed meal (Boost +®, 45 grams of carbohydrate) meal tolerance test 
(MMTT) will take place at the end of each medication cycle as in our previous studies61. The subject will be confirmed to 
have arrived fasting, caffeine-free, and having taken the AM dose of the study medication.  Daily insulin pump basal rate 
or basal long acting insulin injections should continue as usual. The subject will be instructed not to exercise throughout 
the MMTT.  A point of care fasting glucose will be done prior to the MMTT.  The MMTT may be cancelled and 
rescheduled at the investigator’s discretion if this blood glucose measurement is below 50 mg/dl or above 300 mg/dl. An 
intravenous catheter (IV) will be inserted for multiple blood draws.  At approximately -30 minutes, a fasting blood draw will 
occur, including the timed labs below, plus a fasting lipid panel, HbA1c, adiponectin, and progesterone (female only to 
document state of menstrual cycle). A urine sample will be collected for urine microalbumin:Cr ratio. At approximately -5 
minutes, the “time 0” blood draw will occur. Immediately after the blood draw, the subject will subcutaneously inject a 
standard bolus of their usual short-acting mealtime insulin with their standard correction factor (CF) and 
carbohydrate:insulin ratio for ingestion of the liquid meal containing 45 grams of carbohydrate, 14 grams of fat, and 14 
grams of protein. The phase 2 MMTT will be completed with the same bolus dose as the phase 1 MMTT unless the 
starting blood glucose requires a different CF dose. Immediately after bolusing with insulin, as close to the true “time 0” as 
possible, and to be completed within 5 minutes, the participant will drink the meal (Boost +®). Actual blood draw times will 
be recorded, as well as insulin dose and all glucose measurements taken throughout the MMTT. During the MMTT, blood 
is drawn for glucose, insulin, C-peptide, triglycerides, NEFA, GLP-1, glucagon levels at -30(approximately), 0, 30, 60, 120, 
180 and 240 minutes and serum creatinine and cystatin C (adolescents only). If a subject experiences a hypoglycemic 
event or any other event compromising safety, the MMTT will be stopped at investigator discretion.  
Dynapulse: Brachial artery distensibility (BrachD) will be measured with the DynaPulsePathway (PulseMetric, Inc., San 
Diego California) as in our previous studies. The Dynapulse is a noninvasive portable system utilizing a standard sphyg-
momanometer cuff inflated in the same fashion as used to obtain blood pressure. The instrument derives BrachD using 
the technique of pulse waveform analysis of arterial pressure signals obtained from the sphygmomanometer. Brachial 
artery waveforms are uploaded to an online analysis site and analyzed for measures of vascular stiffness. 
EndoPAT: Reactive hyperemia–peripheral artery tonometry (RH-PAT) by the EndoPat device (Itamar Medical Ltd., 
Caesarea, Israel) is a non-invasive technique that combines the traditional flow-mediated dilatation with pneumatic 
fingertip probes to measure arterial pulse wave amplitude and provide an objective measure of endothelial function 
(Reactive Hyperemia Index, RHI) and vascular stiffness (Augmentation index, AI). RH-PAT in T1D adolescents found 
endothelial dysfunction (lower mean RHI) (1.63 ± 0.5) when compared with children without diabetes (1.95 ± 0.3, p= 0.01) 
compared to nondiabetic controls 76. Children with T1D underwent a second RH-PAT study 4 weeks after their initial study 
to determine the intrapatient variability of the technique and repeat RH-PAT scores were predicted by initial RH-PAT 
scores (p= 0.0025, mean intrapatient RHI SD=0.261, and coefficient of variation=14.8).  


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Briefly, the patient sits in a reclining chair with the hands at heart level and propped in a comfortable position such that the 
fingers are hanging freely. Fingertip probes are placed on both index fingers and pulse wave amplitudes are recorded for 
the duration of the study. After 5-6 min of baseline measurement, arterial flow to the nondominant arm is occluded for 5 
min using a BP cuff inflated to 40 mmHg above systolic pressure. After the 5-min occlusion, the cuff is rapidly deflated to 
allow for reactive or flow-mediated hyperemia. Pulse wave amplitudes are recorded for at least 5 min after the cuff is 
deflated. An integrated software program compares the ratio of arterial pressure in the two fingers before and after the 
occlusion to calculate the RH-PAT score. The RH-PAT score is calculated as the ratio of the average pulse wave 
amplitude measured over 60 s starting 1 min after cuff deflation to the average pulse wave amplitude measured at 
baseline. This ratio is normalized to the concurrent signal from the contralateral finger to correct for changes in systemic 
vascular tone. 
Heart Rate Variability: Heart rate variability (HRV) assessment provides a non-invasive and objective method for 
investigating autonomic input into the heart and measuring cardiac autonomic neuropathy (CAN). We have previously 
shown it is associated with subclinical atherosclerosis77-79. In addition, studies in T1D youth demonstrated reduction in 
HRV80, mostly with vagal withdrawal early81 and sympathetic dysfunction later in the disease process82. However, our 
large study found overall HRV reduction suggesting a more advanced state of cardiac autonomic neuropathy77,78. 
Therefore HRV analysis is expected to find abnormalities already occurring in T1D youth. The measurement quantifies the 
amount by which the R–R interval or heart rate changes from one cardiac cycle to the next, and can be assessed either 
by time-domain analysis or by spectral analysis (frequency-domain analysis) of ECG recordings. HRV will be assessed in 
supine subjects over a 5 minute period of rest, and then during 5 minutes of deep breathing.  Following another 5 minute 
baseline period before each session, responses to standing and Valsalva breathing will be measured. Tachycardic and 
bradycardic extremes are identified and the difference used as a measure of CAN.  
MRI: The MRI will be obtained during visits 4 and 7 at the UCD Brain Imaging Center on the Anschutz campus or at the 
CHC Radiology Department.  The purpose of the thorax MRI is to obtain phase contrast imaging through several levels of 
the aorta, including the ascending aorta, the transverse arch, and the descending aorta and renal vessels, as well as the 
heart. MRI images will be taken supine of the thorax during normal breathing, as well as during inhalation and exhalation. 
These dicom images will be transferred from the MRI to an off-line processing system, MatLab, where the contours of the 
PC images will be carried out in order to determine the flow pattern and wall shear stress. 
DEXA: Body composition will be measured using the DEXA technique on the adult and pediatric CTRCs and will be used 
to derive fat-free mass and % body fat.  This technique relies on the absorption of dual electron wavelengths for the 
assessment of body fat, lean tissue, and bone mineral density.  
Indirect calorimetry: For measurement of RQ fasting and during low infusion rate to assess insulin response of shift from 
fat to carbohydrate metabolism.  
Waist Circumference: Measurements from phase 1 and 2 will be used in an insulin sensitivity prediction equation.90 
Sleep questionnaires: The Epworth sleepiness scale for adults83 and the adult Sleep Hygiene Scale84,85 will be 
completed by adult participants to obtain information on behavioral sleep variables as in our ongoing sleep study in 
PCOS. Adolescent participants will complete the Cleveland Adolescent Sleepiness Questionnaire, the Sleep Disturbances 
Scale for Children, the Adolescent Sleep Hygiene Scale and the Behavioral Sleep Medicine Clinic Sleep Questionnaire. 
Through this study we will also collaborate with Ann Hallbower, MD, Pediatric Sleep expert (University of Colorado, 
Denver) who has extensive experience with these questionnaires and the Actiwatch sleep monitor, and is available for 
consultation on the proposed project as needed.  
Sleep/wake and activity monitoring: Typical home sleep and activity patterns will be monitored for one week using 
actigraphy86,87. The Actiwatch Spectrum Plus (Philips Respironics, OR) will be worn on the non-dominant wrist and will 
collect data on movements and light exposure in 1-min bins. A concurrent sleep diary will be completed by participants to 
allow for removal of artifacts (e.g., failure to wear the actigraphy during a portion of the night). Average sleep start and end 
time, sleep duration, and sleep efficiency will be examined.  Participants will be asked to refrain from caffeine, non-
steroidal anti-inflammatory drugs, and alcohol during the sleep monitoring period.  
Hypoglycemia questionnaires: Hypoglycemia awareness will be assessed using the Gold method (Question: “Do you 
know when your hypos are starting?” response on 7 point Likert scale), Clarke method (8 question questionnaire), and the 
McAuley score (list of symptoms with a 7 point Likert scale for each)64-67. 
 
D. Description, Risks and Justification of Procedures and Data Collection Tools:  


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Potential risks: 
BCQR intervention: Bromocriptine itself has been available and widely used for Parkinson’s Disease and prolactinoma for 
decades. It was also used for a time for congestive heart failure. The quick release formulation is so far apparently similar 
in safety and tolerability. Common side effects include mild hypotension, mild fatigue/somnolence, headache, depressed 
mood, insomnia, nausea, and diarrhea. Less common and more serious side effects have been seen with BCQR 
including hypersensitivity reactions, hypoglycemia and syncope. There is no increase in CVD. In fact studies so far 
indicate a protective effect. Bromocriptine is standardly used in young children, adolescents, and adults of all ages with 
hyperprolactinemia at higher does than proposed in our study and should be well tolerated. Frequent blood sugar 
monitoring and contact with study staff will help avoid hypo- or hyperglycemia. Potential benefits include improved 
glycemic control and decreased insulin requirement, as well as metabolic and vascular benefits related to decreased 
chronic SNS activity, decreased renin angiotensin system activation, and resetting of the circadian rhythm. Subjects will 
be withdrawn if they are unable to tolerate the minimum acceptable dose of BCQR (1.6mg QD) or if they experience a 
predefined serious adverse event (infection related to blood draw or IV placement; severe hypoglycemia during the mixed 
meal tolerance test (blood glucose < 45 mg/dl), more than one episode of severe hypoglycemia requiring assistance or 
diabetic ketoacidosis (DKA) while on study drug or other severe reactions possibly or probably related to the study drug). 
No further data will be collected from withdrawn subjects. All SAEs will be followed until resolution.  
Blood Samples: The collection of blood samples may result in temporary discomfort, bruising, bleeding, and on rare 
occasions, infection. EMLA cream helps to prevent discomfort, and sterile technique helps to minimize these risks.  
IV risks: There is temporary discomfort when the needle goes in and 10% of the time there is a small amount of bleeding 
under the skin that may produce a bruise. Rarely, there is a risk of a blood clot forming or infection. EMLA cream helps to 
prevent discomfort and sterile technique by experienced CTRC nurses helps to minimize these risks.  
Study Diet: There is a small risk that blood sugars will be higher or lower than normal at home while eating the study diet 
as it may differ from the subject’s usual diet. To avoid this risk, subjects will be asked to monitor their blood sugars at least 
four times a day while on the study diets and following procedures. Carbohydrate content will also be provided for each 
food item to assist with carbohydrate counting.  
Continuous Glucose Monitoring (CGM): A continuous glucose sensor will be placed (Dexcom G4 Platinum, Dexcom, Inc., 
San Diego, CA) to assess home blood glucose values. The sensor is well tolerated with the only side effects being mild to 
moderate site irritation in 2% of patients, and in rare cases, skin infection. 
DEXA Scan: There is no pain with this procedure. For females, a urine pregnancy test will be checked prior to the test to 
avoid any x-ray exposure to a pregnant person. This procedure involves the use of X-rays. The amount of radiation 
exposure during the DEXA test is approximately 15 mSv which is 7 times the level of background radiation in Colorado or 
approximately equal to the amount of radiation a subject would receive being outdoors in Denver for two days.  
Mixed meal tolerance test: There is a small risk that blood sugars will be higher or lower than normal at home while eating 
the study diet and with the mixed meal tolerance test (MMTT) as it may differ from the subject’s usual diet. To avoid this 
risk, blood sugars will be checked before and after the meal and additional carbohydrate or insulin given as indicated.  
Ansar Heat rate variability, Endopat and Dynapulse: There are no significant risks associated with these procedures. 
There may be slight discomfort when the blood pressure cuff is inflated.  
MRI: The MRI is a non-invasive scan. MRI uses a magnet and there is no radiation and no risk involved with the MRI. The 
scan may be loud, therefore participants may be provided with audio protection and optional television. Metal cannot enter 
the MRI area. Participants will be screened to assure no metal is present prior to MRI. 
Indirect Calorimetry: The subject may feel claustrophobic. 
Waist Circumference: There is no risk associated with measuring waist circumference 
Data handling: Data will be examined for completeness and errors during data cleaning, in order to remove any spurious 
or incorrect data and complete any missing data in the database where possible. Protocol deviations will be reported to 
COMIRB and the study Safety Officer within 30 days of the deviation. Deviations from the original statistical analysis plan 
will be reported to COMIRB with the next continuing review and disclosed in any publication resulting from this study. 
Assessment of Safety: Safety parameters will include monitoring of any adverse events (AEs) or serious adverse events 
(SAEs), including number of hypoglycemic episodes and percentage of time spent hypoglycemic during the last week of 
CGM data. Safety parameters will be obtained by questionnaire at each visit, and will include reports of any AEs or SAEs. 


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At each visit, study subjects will be asked if they have had any AE, including illness, injury or hospitalization since the last 
visit. If so, the onset date, resolution date, severity and outcome will be recorded.  All AEs will be reviewed by the PIs and 
a determination of SAE or AE status will be made.  All SAEs will be reported to the IRB, safety officer, and sponsor 
following regulations. Bromocriptine is less well studied in adolescents and therefore further assessment of 
Bromocriptine’s hypotensive effect will be monitored at each visit for adolescents aged 12-17 via orthostatic 
measurements. Assessment of intercurrent illnesses will be made by asking study participants of any illnesses or 
symptoms they have had since the prior visit, onset date and resolution date, severity and outcome of the illness. Subjects 
with SAEs will be followed until resolution of the event. All other subjects with AEs will be followed until the end of the 
study.  
Study stopping and subject discontinuation criteria: The trial will be stopped if >2 subjects meet criteria for individual 
subject discontinuation [≥2 hypoglycemic events requiring assistance or diabetic ketoacidosis (DKA) during a study 
phase] or if >2 subjects experience a serious adverse event (SAE) possibly or probably related to the study drug. Subjects 
will be withdrawn if they are unable to tolerate the minimum acceptable dose of BCQR (1.6mg QD) or if they experience a 
predefined SAE [infection related to blood draw or IV placement; severe hypoglycemia during the MMTT (blood glucose < 
45 mg/dl), more than one episode of severe hypoglycemia requiring assistance or DKA while on study drug or other 
severe reactions possibly or probably related to the study drug]. No further data will be collected from withdrawn subjects. 
As some withdrawals are accounted for in the recruitment plan, there will be no specific replacement of withdrawn 
subjects. SAEs will be followed until resolution. Otherwise, withdrawn subjects will follow up with their care providers.  
    
E. Potential Scientific Problems:   
 
Interpretation of results: Based on the basic and clinical literature for BCQR, we expect that BCQR will reduce HGP and 
lipolysis throughout the day, effectively improving insulin action and reducing glycemic variability, improving glucose 
tolerance and control as evidenced by lower CGM-glucose and glucose AUC during MMTT, and/or decreasing insulin 
dose. Any of these results would support the use of BCQR as adjunct therapy in T1D. In addition, the presumed 
mechanism of BCQR supports an expectation of decreased vascular stiffness and improved endothelial function. These 
results would further support use of BCQR in T1D, even independent of glycemic benefits, as CVD risk reduction is an 
important goal in T1D with long term benefits in health outcomes, quality of life, and lifetime medical costs. We further 
speculate that the effects on sympathetic activation and circadian rhythm may improve sleep quality (thus further 
improving insulin sensitivity), blood pressure, hypoglycemia awareness, and thus hypoglycemia frequency and/or severity. 
Pitfalls and limitations: This is a fairly ambitious study with a large planned cohort to allow subgroup analyses for 
potential targeting of this novel intervention. However, we have been successful individually and in collaborations in 
recruiting for T1D studies with far more burdensome and invasive outcomes, including OGTT, echocardiograms, exercise 
testing, 1-2 day overnight admission, overnight insulin drip (DM subjects), hyperinsulinemic insulin clamp with muscle 
biopsy, multiple study diets, medication interventions, brachial artery and carotid ultrasound, and hepatic MRI paired with 
muscle lipid MRS. Our preliminary studies used adolescents and adults and techniques similar to the proposed protocol, 
establishing the necessary complex procedures and collaborations to complete this study: (1) The PI’s are experienced in 
randomized, double blinded clinical trials in T1D adolescents and adults. This depth of experience makes the 
interventional component likely to be highly successful. (2) The University of Colorado’s recently re-funded Clinical and 
Translational Research Center has the facilities needed for all of the visits and the investigators own the equipment 
required. (3) Our preliminary data demonstrate the feasibility of the proposed studies in youth and adults, our ability to 
perform the proposed studies, compelling reasons for further study and the productivity of the PI’s. (4) The Barbara Davis 
Center for Childhood Diabetes is a large, tertiary care center for type T1D, with approximately 3000 youth and 2500 adults 
with T1D. The PI’s are able to recruit from all patients seen at the BDC, in addition to clinics at the University, and 
Children’s Hospital making recruitment feasible. Likewise, we have previous experience recruiting from these 
demographics for similar studies. To limit drop-out, we maintain frequent contact with participants, use incentives for visits 
and adherence, and “surprise” incentives such as sports tickets and raffles to maintain contact with the study team. We 
find these strategies successful for maintaining compliance in our study participants. Due to our TODAY, RISE, and other 
metformin studies, our staff is experienced with long-term adolescent and adult diabetes studies, with excellent study 
retention for as long as ten years. 


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While the brachial artery ultrasound is considered by some to be the gold standard technique for endothelial function, its 
notorious user-dependence introduces more variability for repeated measures. The Endo-PAT device is also noninvasive, 
much simpler to use and is performed and analyzed in a standard way that allows comparability within subjects. Simulta-
neous assessment of the contralateral finger also allows an internal control not present with ultrasound, and therefore we 
will assess endothelial function with EndoPAT as in our most recent studies. In addition, while the hyperinsulinemic 
euglycemic clamp is the gold-standard measure of insulin sensitivity, our estimated measures correlate well with the gold 
standard and will help reduce invasiveness and cost and improve the feasibility and sample size of the study. 
Multiple confounders can affect IR and glycemic control. We will control or adjust for these as possible using standard 
methods. Subject activity and diet that affect IR will be addressed by prescribing a standardized study diet (with 
carbohydrate content labeled for counting) and limiting strenuous exercise for 3 days prior to the MMTT visits. Stage of 
menstrual cycle will also be controlled for as hormonal status in females influences vascular measures, IR and circadian 
rhythms. Finally, use of CGM will help limit hypo- and hyperglycemia during the trial. 
 
F. Data Analysis Plan:   
 
Planned enrollment: 133 T1D subjects (50% male) will be enrolled with the goal of completing 80 (see power analysis 
below).  
Power and Sample Size: Power analysis and sample size are based on expected changes from the literature and from 
preliminary data for the primary outcomes for each aim. The sample size for the entire study was based on the power 
analysis for the subgroup analyses by age, in order to ensure adequate power to detect clinically meaningful treatment 
effects within each subgroup. In addition, we plan to examine the results by other characteristics (e.g. by obesity level, 
positive c-peptide status, etc.) in exploratory analyses which are not fully powered, but which may provide insight into 
heterogeneity in response to the therapy, thus guiding a future clinical trial if results of this study are positive.  Desired α is 
set at 0.05. Since data used for this analysis are from within-subjects comparisons, repeated measures analysis will be 
used to compare outcome variables after each treatment (placebo, BCQR), adjusting for the randomization assignment of 
treatment order. 
Assessment of Efficacy 
The primary efficacy parameters will be change in insulin dose and CGM mean glucose on treatment versus placebo.  
Secondary efficacy measures will include change in post-MMT glucose and insulin AUC, and change in other CGM 
parameters (SD, %hyperglycemic, % hypoglycemic). Total daily basal and bolus insulin dose will be obtained at 
screening, and then at time zero for each medication phase.  Insulin diaries will be obtained during the last week of each 
phase.  Change in total, basal, and bolus insulin dose in units per day and total insulin in units per kg per day will be 
examined between medication phases to determine whether insulin requirements were lower at the end of the BCQR 
phase than the end of the placebo phase.  Similarly, change in mean CGM glucose from the last 2 weeks of each 
medication phase will be examined to determine if overall mean glucose is decreased while on treatment versus placebo. 
Analysis Plan:  All randomized subjects will be included in the analysis using an intention to treat analysis. The change in 
insulin dose, CGM-glucose and other metabolic parameters will be compared between the placebo and treatment visits in 
each subject using paired t-tests for univariate comparisons, and using repeated measures linear regression to adjust for 
covariates including age, diabetes duration, baseline HbA1c, and BMI.  An interaction term will be entered into the model 
to examine whether the effect of treatment on either outcome differs among adults linearly by age, and if there is a 
significant interaction (p<0.10), results will be stratified by age group. We will also use interaction terms to assess whether 
the effect of treatment differs by BMI.  We will also examine whether diabetes duration and initial HbA1c have an effect on 
outcomes by testing for an interaction between these continuous variables and the change in insulin dose and CGM-
glucose. Change in vascular parameters will also be examined using paired t-test and repeated measures regression to 
determine if the treatment with BCQR affects vascular stiffness or function.  
SA1: Effect on metabolic parameters (insulin dose, mean glucose and glycemic variability by CGM, postprandial glucose 
AUC by MMTT): While there are no published data on the effect of BCQR on insulin dose, prior data on the effect of 
Metformin88 indicate that the change in daily insulin dose is normally distributed with standard error of 2.2 units (SD 7.6) 
and data from prior studies in adults with T1D performed at our center indicate that the change in total daily insulin dose 


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over 4 weeks is normally distributed with a standard deviation of 15 –18.8 units/day.  Assuming a SD of 18.8 to be 
conservative, we will be able to detect a true change in the daily insulin dose of matched pairs of ± 5.9 units/day with 80% 
power in the overall group (n=80) and a change of 8.3 units/day within each age group (n=40). In a prior study of the 
efficacy of BCQR in adult patients with T2D, study participants treated with BCQR experienced a decrease in fasting 
plasma glucose level of 36.09 mg/dl and a decrease in post-prandial plasma glucose of 14.38 mg/dl after 12 weeks of 
treatment89.  In the overall study group, we will be able to detect a change in CGM-glucose of 3.1 mg/dl with 80% power in 
the entire study group and a change in CGM-glucose of ± 4.4 mg/dl in each age group, assuming an SD of 10.03 mg/dl.    
SA2: Effect in sub-groups:  For comparisons of change in insulin dose and CGM-glucose by group in two-sample 
independent comparisons assuming equal variance and using estimates of SD as in SA1, we will have 80% power to 
detect a difference in the effect of BCQR treatment on daily insulin dose of ± 11.9 units/day, and a difference in change in 
CGM-glucose of ± 6.4 mg/dl.  For evaluation of BMI and age as continuous variables, we will have 90% power to detect a 
correlation coefficient of 0.307 or greater in the overall group in univariate analysis, and a slope of 0.32 for daily insulin 
dose or 0.37 for BMI in linear regression analysis. 
SA3:  Effect on vascular measures:  Change in measures of vascular health (BrachD and RH-PAT RHI as primary 
outcomes, AI and HRV as secondary outcomes) will be compared following placebo and treatment with BCQR. In a prior 
study of BrachD in healthy adolescents and young adults, BrachD was normally distributed with a SD ranging from 1.04 to 
1.29.  We will have 80% power to detect a difference in BrachD of 0.343 mmHg-1 in the entire study group, and a 
difference of 0.60 mmHg-1 in each age group55. A prior study in children with T1D found an intrapatient standard deviation 
of 0.261 for RH-PAT RHI.  Assuming this intrapatient standard deviation, in the overall group we will have 80% power to 
detect a change in RH-PAT RHI of 0.10% between treatment and placebo visits, and 0.10% in each age subgroup 
(adolescents and adults). 
 
G.  Summarize Knowledge to be Gained:  BCQR has shown promise in type 2 diabetes as an oral 
antiglycemic agent that is generally well tolerated and safe and has a novel mechanism with the potential to have 
significant independent benefit for vascular complications. Studies so far have shown a dramatic decrease in 
cardiovascular events in type 2 diabetes. The mechanism and our current understanding of T1D suggest that BCQR 
may also benefit individuals with T1D in terms of glycemic control, insulin resistance, and vascular complication risk. 
This study will provide preliminary data supporting or refuting the hypothesis that BCQR is a novel oral agent that will 
benefit glycemic control, vascular function and stiffness, and hypoglycemia awareness in T1D. 
 
 
 H. References: 
 
1. 
Defronzo RA. Bromocriptine: a sympatholytic, d2-dopamine agonist for the treatment of type 2 diabetes. Diabetes 
Care. Apr 2011;34(4):789-794. 
2. 
Bell DS. Why does quick-release bromocriptine decrease cardiac events? Diabetes, obesity & metabolism. Oct 
2011;13(10):880-884. 
3. 
Wood JR, Miller KM, Maahs DM, Beck RW, DiMeglio LA, Libman IM, Quinn M, Tamborlane WV, Woerner SE. Most 
youth with type 1 diabetes in the T1D Exchange Clinic Registry do not meet American Diabetes Association or 
International Society for Pediatric and Adolescent Diabetes clinical guidelines. Diabetes Care.2013;36(7):2035-2037. 
4. 
DeFronzo RA, Hendler R, Simonson D. Insulin resistance is a prominent feature of insulin-dependent diabetes. 
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