Trial Outcomes & Findings for Bromocriptine-QR Therapy on Sympathetic Tone and Vascular Biology in Type 2 Diabetes Subjects (NCT NCT02682901)

NCT ID: NCT02682901

Last Updated: 2021-12-10

Results Overview

Cardiac Autonomic Reflex Tests (CARTs) based on heart rate variations are the deep breathing test (E/I ratio), the lying to standing test (30:15 ratio) and the Valsalva maneuver (Valsalva ratio). These tests require a continuous recording of heart rate by either a simple electrocardiograph (ECG), subsequently elaborated via a specialist software. It is essential to inspect the ECG trace (on paper or monitor) in order to exclude artifacts or any type of arrhythmias from the calculations. Expiration/Inspiration (E/I) ratio: Standardized CART that measures parasympathetic control of the HR. The subject in a supine or sitting position is asked to breathe deeply at six breaths per minute (5 seconds in and 5 seconds out) for one minute. The E/I ratio is obtained by calculating the ratio between the average of the 3 longest RR intervals during expiration and the average of the 3 shortest RR intervals during inspiration.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 84 participants
• Primary outcome timeframe: Baseline to 24 weeks
• Results posted on: 2021-12-10

Participant Flow

One hundred and thirteen subjects were screened between 05OCT2015 and 29MAR2018 at Eastern Virginia Medical School Endocrine and Metabolic Disorders Outpatient Clinic

Of the 113 patients screened, 29 screened failed and 84 were enrolled

Participant milestones

Measure	Cycloset (Bromocriptine-QR) Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus bromocriptine-QR. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (0.8 mg bromocriptine-QR) per day on a weekly basis until a maximal tolerated dose of at least two tablets (1.6 mg/day bromocriptine-QR) and no more than four tablets (3.2 mg/per day b-QR) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (1.6 to 3.2 mg bromocriptine-QR per day) for the duration of the study (24 weeks). Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Cycloset: Cycloset 1.6 -3.2 mg/day	Placebo Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus placebo. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (1 matching placebo tablet) per day on a weekly basis until a maximal tolerated dose of at least two tablets (2 placebo tablets) and no more than four tablets (4 placebo tablets) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (2 to 4 placebo tablets) for the duration of the study. Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Placebo: Non-active placebo for cycloset
Overall Study STARTED	43	41
Overall Study Completed 4 Weeks	38	39
Overall Study Completed 12 Weeks	36	37
Overall Study COMPLETED	33	37
Overall Study NOT COMPLETED	10	4

Reasons for withdrawal

Measure	Cycloset (Bromocriptine-QR) Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus bromocriptine-QR. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (0.8 mg bromocriptine-QR) per day on a weekly basis until a maximal tolerated dose of at least two tablets (1.6 mg/day bromocriptine-QR) and no more than four tablets (3.2 mg/per day b-QR) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (1.6 to 3.2 mg bromocriptine-QR per day) for the duration of the study (24 weeks). Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Cycloset: Cycloset 1.6 -3.2 mg/day	Placebo Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus placebo. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (1 matching placebo tablet) per day on a weekly basis until a maximal tolerated dose of at least two tablets (2 placebo tablets) and no more than four tablets (4 placebo tablets) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (2 to 4 placebo tablets) for the duration of the study. Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Placebo: Non-active placebo for cycloset
Overall Study Adverse Event	10	3
Overall Study Lack of Efficacy	0	1

Baseline Characteristics

Bromocriptine-QR Therapy on Sympathetic Tone and Vascular Biology in Type 2 Diabetes Subjects

Baseline characteristics by cohort

Measure	Cycloset (Bromocriptine-QR) n=43 Participants Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus bromocriptine-QR. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (0.8 mg bromocriptine-QR) per day on a weekly basis until a maximal tolerated dose of at least two tablets (1.6 mg/day bromocriptine-QR) and no more than four tablets (3.2 mg/per day b-QR) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (1.6 to 3.2 mg bromocriptine-QR per day) for the duration of the study (24 weeks). Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Cycloset: Cycloset 1.6 -3.2 mg/day	Placebo n=41 Participants Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus placebo. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (1 matching placebo tablet) per day on a weekly basis until a maximal tolerated dose of at least two tablets (2 placebo tablets) and no more than four tablets (4 placebo tablets) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (2 to 4 placebo tablets) for the duration of the study. Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Placebo: Non-active placebo for cycloset	Total n=84 Participants Total of all reporting groups
Age, Continuous	59.01 Years STANDARD_DEVIATION 10.39 • n=93 Participants	61.92 Years STANDARD_DEVIATION 11.55 • n=4 Participants	60.43 Years STANDARD_DEVIATION 11.00 • n=27 Participants
Sex: Female, Male Female	31 Participants n=93 Participants	23 Participants n=4 Participants	54 Participants n=27 Participants
Sex: Female, Male Male	12 Participants n=93 Participants	18 Participants n=4 Participants	30 Participants n=27 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=93 Participants	1 Participants n=4 Participants	3 Participants n=27 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	41 Participants n=93 Participants	40 Participants n=4 Participants	81 Participants n=27 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Asian	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Black or African American	25 Participants n=93 Participants	22 Participants n=4 Participants	47 Participants n=27 Participants
Race (NIH/OMB) White	17 Participants n=93 Participants	19 Participants n=4 Participants	36 Participants n=27 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Region of Enrollment United States	43 participants n=93 Participants	41 participants n=4 Participants	84 participants n=27 Participants
Duration of Diabetes	8 Years n=93 Participants	10 Years n=4 Participants	8.5 Years n=27 Participants
Height	66.69 Inches STANDARD_DEVIATION 4.08 • n=93 Participants	67.19 Inches STANDARD_DEVIATION 3.63 • n=4 Participants	66.93 Inches STANDARD_DEVIATION 3.85 • n=27 Participants
Weight	214.81 Pounds STANDARD_DEVIATION 57.63 • n=93 Participants	225.12 Pounds STANDARD_DEVIATION 47.57 • n=4 Participants	219.84 Pounds STANDARD_DEVIATION 52.89 • n=27 Participants
Body Mass Index	33.55 kg/m^2 STANDARD_DEVIATION 6.96 • n=93 Participants	35.05 kg/m^2 STANDARD_DEVIATION 7.87 • n=4 Participants	34.28 kg/m^2 STANDARD_DEVIATION 7.41 • n=27 Participants
Percent Body Fat	39.09 percentage of body fat STANDARD_DEVIATION 6.13 • n=93 Participants	39.86 percentage of body fat STANDARD_DEVIATION 7.55 • n=4 Participants	39.45 percentage of body fat STANDARD_DEVIATION 6.80 • n=27 Participants
Systolic Blood Pressure	131.62 mmHg STANDARD_DEVIATION 15.22 • n=93 Participants	133.93 mmHg STANDARD_DEVIATION 16.17 • n=4 Participants	132.76 mmHg STANDARD_DEVIATION 15.65 • n=27 Participants
Diastolic Blood Pressure	82.19 mmHg STANDARD_DEVIATION 10.65 • n=93 Participants	82.07 mmHg STANDARD_DEVIATION 9.11 • n=4 Participants	82.13 mmHg STANDARD_DEVIATION 9.86 • n=27 Participants
Heart Rate	80.91 Beats per minute STANDARD_DEVIATION 14.65 • n=93 Participants	75.29 Beats per minute STANDARD_DEVIATION 10.96 • n=4 Participants	78.17 Beats per minute STANDARD_DEVIATION 13.21 • n=27 Participants

PRIMARY outcome

Timeframe: Baseline to 24 weeks

Population: All participants who completed the study and received 24 weeks of intervention (33 subjects in the bromocriptine QR arm and 37 subjects in the placebo arm)

Cardiac Autonomic Reflex Tests (CARTs) based on heart rate variations are the deep breathing test (E/I ratio), the lying to standing test (30:15 ratio) and the Valsalva maneuver (Valsalva ratio). These tests require a continuous recording of heart rate by either a simple electrocardiograph (ECG), subsequently elaborated via a specialist software. It is essential to inspect the ECG trace (on paper or monitor) in order to exclude artifacts or any type of arrhythmias from the calculations.

Expiration/Inspiration (E/I) ratio: Standardized CART that measures parasympathetic control of the HR. The subject in a supine or sitting position is asked to breathe deeply at six breaths per minute (5 seconds in and 5 seconds out) for one minute. The E/I ratio is obtained by calculating the ratio between the average of the 3 longest RR intervals during expiration and the average of the 3 shortest RR intervals during inspiration.

Outcome measures

Measure	Cycloset (Bromocriptine-QR) n=33 Participants Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus bromocriptine-QR. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (0.8 mg bromocriptine-QR) per day on a weekly basis until a maximal tolerated dose of at least two tablets (1.6 mg/day bromocriptine-QR) and no more than four tablets (3.2 mg/per day b-QR) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (1.6 to 3.2 mg bromocriptine-QR per day) for the duration of the study (24 weeks). Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Cycloset: Cycloset 1.6 -3.2 mg/day	Placebo n=37 Participants Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus placebo. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (1 matching placebo tablet) per day on a weekly basis until a maximal tolerated dose of at least two tablets (2 placebo tablets) and no more than four tablets (4 placebo tablets) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (2 to 4 placebo tablets) for the duration of the study. Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Placebo: Non-active placebo for cycloset
Change in E/I Ratio From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo	-0.02 E/I ratio change Interval -0.05 to 0.04	-0.05 E/I ratio change Interval -0.15 to 0.02

PRIMARY outcome

Timeframe: Baseline to 24 weeks

Population: All participants who completed the study and received 24 weeks of intervention (33 subjects in the bromocriptine QR arm and 37 subjects in the placebo arm)

Cardiac Autonomic Reflex Tests (CARTs) based on heart rate variations are the deep breathing test (E/I ratio), the lying to standing test (30:15 ratio) and the Valsalva maneuver (Valsalva ratio). These tests require a continuous recording of heart rate by simple electrocardiograph (ECG), subsequently elaborated via a specialist software. It is essential to inspect the ECG trace (on paper or monitor) in order to exclude artifacts or any type of arrhythmias from the calculations.

Valsalva maneuver is a forced expiration with an open glottis against resistance. This causes changes in both BP and heart rate. During strain, tachycardia is initially determined by vagal withdrawal and afterwards by sympathetic activation. The Valsalva ratio is calculated as the ratio between the longest RR interval after the expiratory straining and the shortest RR interval during the expiratory straining

Outcome measures

Measure	Cycloset (Bromocriptine-QR) n=33 Participants Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus bromocriptine-QR. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (0.8 mg bromocriptine-QR) per day on a weekly basis until a maximal tolerated dose of at least two tablets (1.6 mg/day bromocriptine-QR) and no more than four tablets (3.2 mg/per day b-QR) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (1.6 to 3.2 mg bromocriptine-QR per day) for the duration of the study (24 weeks). Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Cycloset: Cycloset 1.6 -3.2 mg/day	Placebo n=37 Participants Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus placebo. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (1 matching placebo tablet) per day on a weekly basis until a maximal tolerated dose of at least two tablets (2 placebo tablets) and no more than four tablets (4 placebo tablets) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (2 to 4 placebo tablets) for the duration of the study. Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Placebo: Non-active placebo for cycloset
Change in Valsalva Ratio From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo	-0.02 Valsalva ratio change Interval -0.14 to 0.09	0.02 Valsalva ratio change Interval -0.04 to 0.08

PRIMARY outcome

Timeframe: Baseline to 24 weeks

Population: All participants who completed the study and received 24 weeks of intervention (33 subjects in the bromocriptine QR arm and 37 subjects in the placebo arm)

Lying to Standing (30:15) ratio: HR increases after standing to maintain an appropriate stroke volume, and then decreases. The maximum increase in heart rate generally occurs between the 10th and the 20th beat after standing, whereas heart rate generally returns to lower values between the 25th and the 35th beat. After lying in the supine position for at least 5 minutes, the subject is invited to stand up quickly but remain relaxed for 3 to 5 minutes. The ratio is the longest RR interval measured between the 25th and the 35th beat divided by the shortest RR interval measured between the 10th and the 20th beat after standing up.

Outcome measures

Measure	Cycloset (Bromocriptine-QR) n=33 Participants Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus bromocriptine-QR. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (0.8 mg bromocriptine-QR) per day on a weekly basis until a maximal tolerated dose of at least two tablets (1.6 mg/day bromocriptine-QR) and no more than four tablets (3.2 mg/per day b-QR) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (1.6 to 3.2 mg bromocriptine-QR per day) for the duration of the study (24 weeks). Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Cycloset: Cycloset 1.6 -3.2 mg/day	Placebo n=37 Participants Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus placebo. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (1 matching placebo tablet) per day on a weekly basis until a maximal tolerated dose of at least two tablets (2 placebo tablets) and no more than four tablets (4 placebo tablets) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (2 to 4 placebo tablets) for the duration of the study. Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Placebo: Non-active placebo for cycloset
Change in 30:15 Ratio From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo	-0.03 30:15 ratio change Interval -0.06 to 0.001	-0.02 30:15 ratio change Interval -0.04 to 0.006

PRIMARY outcome

Timeframe: Baseline to 24 weeks

Population: All participants who completed the study and received 24 weeks of intervention (33 subjects in the bromocriptine QR arm and 37 subjects in the placebo arm)

Time domain analysis of Heart Rate Variability includes SDNN and RMSSD measurements. It is acquired by continuous recording of heart rate by simple electrocardiograph (ECG) with the subject in supine or sitting position, resting and breathing at a controlled rate (15 breaths per minute) for 5 minutes. It is essential to inspect the ECG trace in order to exclude artifacts or any type of arrhythmias from the calculations.

SDNN is the standard deviation of the beat to beat (NN) variability which is a measure of both sympathetic and parasympathetic action on HR.

Outcome measures

Measure	Cycloset (Bromocriptine-QR) n=33 Participants Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus bromocriptine-QR. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (0.8 mg bromocriptine-QR) per day on a weekly basis until a maximal tolerated dose of at least two tablets (1.6 mg/day bromocriptine-QR) and no more than four tablets (3.2 mg/per day b-QR) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (1.6 to 3.2 mg bromocriptine-QR per day) for the duration of the study (24 weeks). Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Cycloset: Cycloset 1.6 -3.2 mg/day	Placebo n=37 Participants Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus placebo. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (1 matching placebo tablet) per day on a weekly basis until a maximal tolerated dose of at least two tablets (2 placebo tablets) and no more than four tablets (4 placebo tablets) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (2 to 4 placebo tablets) for the duration of the study. Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Placebo: Non-active placebo for cycloset
Change in SDNN From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo	-3.97 Milliseconds (ms) change Interval -9.2 to 1.26	-0.80 Milliseconds (ms) change Interval -9.14 to 7.54

PRIMARY outcome

Timeframe: Baseline to 24 weeks

Population: All participants who completed the study and received 24 weeks of intervention (33 subjects in the bromocriptine QR arm and 37 subjects in the placebo arm)

Time domain analysis of Heart Rate Variability includes SDNN and RMSSD measurements. It is acquired by continuous recording of heart rate by simple electrocardiograph (ECG) with the subject in supine or sitting position, resting and breathing at a controlled rate (15 breaths per minute) for 5 minutes. It is essential to inspect the ECG trace in order to exclude artifacts or any type of arrhythmias from the calculations.

RMSSD is the root mean square of successive R-R intervals and is a measure primarily of parasympathetic activity on HR.

Outcome measures

Measure	Cycloset (Bromocriptine-QR) n=33 Participants Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus bromocriptine-QR. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (0.8 mg bromocriptine-QR) per day on a weekly basis until a maximal tolerated dose of at least two tablets (1.6 mg/day bromocriptine-QR) and no more than four tablets (3.2 mg/per day b-QR) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (1.6 to 3.2 mg bromocriptine-QR per day) for the duration of the study (24 weeks). Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Cycloset: Cycloset 1.6 -3.2 mg/day	Placebo n=37 Participants Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus placebo. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (1 matching placebo tablet) per day on a weekly basis until a maximal tolerated dose of at least two tablets (2 placebo tablets) and no more than four tablets (4 placebo tablets) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (2 to 4 placebo tablets) for the duration of the study. Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Placebo: Non-active placebo for cycloset
Change in RMSSD From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo	-3.16 Milliseconds (ms) change Interval -9.08 to 2.76	-0.57 Milliseconds (ms) change Interval -9.43 to 8.29

PRIMARY outcome

Timeframe: Baseline to 24 weeks

Population: All participants who completed the study and received 24 weeks of intervention (33 subjects in the bromocriptine QR arm and 37 subjects in the placebo arm)

The primary outcome is the change from baseline to endpoint (24 weeks) in measures of autonomic function using provocative tests (CARTs), measures of heart rate variability and resting heart rate

Outcome measures

Measure	Cycloset (Bromocriptine-QR) n=33 Participants Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus bromocriptine-QR. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (0.8 mg bromocriptine-QR) per day on a weekly basis until a maximal tolerated dose of at least two tablets (1.6 mg/day bromocriptine-QR) and no more than four tablets (3.2 mg/per day b-QR) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (1.6 to 3.2 mg bromocriptine-QR per day) for the duration of the study (24 weeks). Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Cycloset: Cycloset 1.6 -3.2 mg/day	Placebo n=37 Participants Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus placebo. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (1 matching placebo tablet) per day on a weekly basis until a maximal tolerated dose of at least two tablets (2 placebo tablets) and no more than four tablets (4 placebo tablets) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (2 to 4 placebo tablets) for the duration of the study. Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Placebo: Non-active placebo for cycloset
Change in Resting Heart Rate From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo	-0.73 beats per minute change Interval -3.66 to 2.14	-2.00 beats per minute change Interval -4.96 to 0.96

PRIMARY outcome

Timeframe: Baseline to 24 weeks

Population: All participants who completed the study and received 24 weeks of intervention (33 subjects in the bromocriptine QR arm and 37 subjects in the placebo arm)

The coprimary outcome is the change, from baseline to endpoint (24 weeks), of peripheral autonomic function using sudorimetry. Sudoscan measures the sweating capacity of palms and soles and is expressed as electrochemical skin conductance (ESC) of feet and hands. ESC, expressed in micro-Siemens (µS), is the ratio between the current generated and the constant direct voltage stimulus applied to palms and soles between the electrodes. ESC is dependent on the glands' capability to transfer chloride ions and reflects small-C fiber function.

Outcome measures

Measure	Cycloset (Bromocriptine-QR) n=33 Participants Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus bromocriptine-QR. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (0.8 mg bromocriptine-QR) per day on a weekly basis until a maximal tolerated dose of at least two tablets (1.6 mg/day bromocriptine-QR) and no more than four tablets (3.2 mg/per day b-QR) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (1.6 to 3.2 mg bromocriptine-QR per day) for the duration of the study (24 weeks). Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Cycloset: Cycloset 1.6 -3.2 mg/day	Placebo n=37 Participants Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus placebo. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (1 matching placebo tablet) per day on a weekly basis until a maximal tolerated dose of at least two tablets (2 placebo tablets) and no more than four tablets (4 placebo tablets) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (2 to 4 placebo tablets) for the duration of the study. Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Placebo: Non-active placebo for cycloset
Change in Feet ESC From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo	-2.40 microSiemmens (µS) change Interval -8.59 to 3.79	-4.57 microSiemmens (µS) change Interval -8.32 to -0.82

PRIMARY outcome

Timeframe: Baseline to 24 weeks

Population: All participants who completed the study and received 24 weeks of intervention (33 subjects in the bromocriptine QR arm and 37 subjects in the placebo arm)

The coprimary outcome is the change, from baseline to endpoint (24 weeks), of peripheral autonomic function using sudorimetry. Sudoscan measures the sweating capacity of palms and soles and is expressed as electrochemical skin conductance (ESC) of feet and hands. ESC, expressed in micro-Siemens (µS), is the ratio between the current generated and the constant direct voltage stimulus applied to palms and soles between the electrodes. ESC is dependent on the glands' capability to transfer chloride ions and reflects small-C fiber function.

Outcome measures

Measure	Cycloset (Bromocriptine-QR) n=33 Participants Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus bromocriptine-QR. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (0.8 mg bromocriptine-QR) per day on a weekly basis until a maximal tolerated dose of at least two tablets (1.6 mg/day bromocriptine-QR) and no more than four tablets (3.2 mg/per day b-QR) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (1.6 to 3.2 mg bromocriptine-QR per day) for the duration of the study (24 weeks). Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Cycloset: Cycloset 1.6 -3.2 mg/day	Placebo n=37 Participants Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus placebo. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (1 matching placebo tablet) per day on a weekly basis until a maximal tolerated dose of at least two tablets (2 placebo tablets) and no more than four tablets (4 placebo tablets) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (2 to 4 placebo tablets) for the duration of the study. Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Placebo: Non-active placebo for cycloset
Change in Hands ESC From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo	-1.71 microSiemmens (µS) change Interval -5.37 to 1.95	-9.83 microSiemmens (µS) change Interval -14.03 to -5.64

Adverse Events

Cycloset (Bromocriptine-QR)

Serious events: 3 serious events

Other events: 7 other events

Deaths: 0 deaths

Placebo

Serious events: 2 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Measure	Cycloset (Bromocriptine-QR) n=43 participants at risk Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus bromocriptine-QR. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (0.8 mg bromocriptine-QR) per day on a weekly basis until a maximal tolerated dose of at least two tablets (1.6 mg/day bromocriptine-QR) and no more than four tablets (3.2 mg/per day b-QR) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (1.6 to 3.2 mg bromocriptine-QR per day) for the duration of the study (24 weeks). Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Cycloset: Cycloset 1.6 -3.2 mg/day	Placebo n=41 participants at risk Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus placebo. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (1 matching placebo tablet) per day on a weekly basis until a maximal tolerated dose of at least two tablets (2 placebo tablets) and no more than four tablets (4 placebo tablets) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (2 to 4 placebo tablets) for the duration of the study. Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Placebo: Non-active placebo for cycloset
Nervous system disorders Vasovagal Syncope	2.3% 1/43 • Number of events 1 • 6 months	0.00% 0/41 • 6 months
Metabolism and nutrition disorders Acute Metabolic Encephalopathy	2.3% 1/43 • Number of events 1 • 6 months	0.00% 0/41 • 6 months
Musculoskeletal and connective tissue disorders Motor vehicle accident	0.00% 0/43 • 6 months	2.4% 1/41 • Number of events 1 • 6 months
Respiratory, thoracic and mediastinal disorders Acute dyspnea	0.00% 0/43 • 6 months	2.4% 1/41 • Number of events 1 • 6 months
Respiratory, thoracic and mediastinal disorders Pleural and Pericardial Effusion	2.3% 1/43 • Number of events 1 • 6 months	0.00% 0/41 • 6 months

Other adverse events

Measure	Cycloset (Bromocriptine-QR) n=43 participants at risk Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus bromocriptine-QR. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (0.8 mg bromocriptine-QR) per day on a weekly basis until a maximal tolerated dose of at least two tablets (1.6 mg/day bromocriptine-QR) and no more than four tablets (3.2 mg/per day b-QR) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (1.6 to 3.2 mg bromocriptine-QR per day) for the duration of the study (24 weeks). Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Cycloset: Cycloset 1.6 -3.2 mg/day	Placebo n=41 participants at risk Subjects were randomized in a double blind 1:1 ratio to receive UDT (usual diabetes therapy) plus placebo. Following randomization subjects were titrated to the maximum tolerated dose of the study drug over a four-week period. During these first 4 weeks, the daily dose of the study drug was titrated up by one tablet (1 matching placebo tablet) per day on a weekly basis until a maximal tolerated dose of at least two tablets (2 placebo tablets) and no more than four tablets (4 placebo tablets) was achieved. Subjects were maintained at their maximum tolerated dose of between two to four tablets per day (2 to 4 placebo tablets) for the duration of the study. Subjects were evaluated at 4 weeks after randomization, at 12 weeks after randomization, and then at study end (week 24 or early termination). Placebo: Non-active placebo for cycloset
General disorders Fatigue	16.3% 7/43 • Number of events 7 • 6 months	4.9% 2/41 • Number of events 2 • 6 months

Additional Information

Henri Parson

Eastern Virginia Medical School

Phone: 7574467976

Email: parsonhk@evms.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place