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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02682901
Recruitment Status : Completed
First Posted : February 17, 2016
Results First Posted : December 10, 2021
Last Update Posted : December 10, 2021
Sponsor:
Information provided by (Responsible Party):
Elias S Siraj, Eastern Virginia Medical School

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Diabetic Autonomic Neuropathy
Interventions Drug: Cycloset
Drug: Placebo
Enrollment 84
Recruitment Details One hundred and thirteen subjects were screened between 05OCT2015 and 29MAR2018 at Eastern Virginia Medical School Endocrine and Metabolic Disorders Outpatient Clinic
Pre-assignment Details Of the 113 patients screened, 29 screened failed and 84 were enrolled
Arm/Group Title Cycloset (Bromocriptine-QR) Placebo
Hide Arm/Group Description

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

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

Period Title: Overall Study
Started 43 41
Completed 4 Weeks 38 39
Completed 12 Weeks 36 37
Completed 33 37
Not Completed 10 4
Reason Not Completed
Adverse Event             10             3
Lack of Efficacy             0             1
Arm/Group Title Cycloset (Bromocriptine-QR) Placebo Total
Hide Arm/Group Description

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

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 of all reporting groups
Overall Number of Baseline Participants 43 41 84
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 43 participants 41 participants 84 participants
59.01  (10.39) 61.92  (11.55) 60.43  (11.00)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 43 participants 41 participants 84 participants
Female
31
  72.1%
23
  56.1%
54
  64.3%
Male
12
  27.9%
18
  43.9%
30
  35.7%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 43 participants 41 participants 84 participants
Hispanic or Latino
2
   4.7%
1
   2.4%
3
   3.6%
Not Hispanic or Latino
41
  95.3%
40
  97.6%
81
  96.4%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 43 participants 41 participants 84 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
1
   2.3%
0
   0.0%
1
   1.2%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
25
  58.1%
22
  53.7%
47
  56.0%
White
17
  39.5%
19
  46.3%
36
  42.9%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 43 participants 41 participants 84 participants
43 41 84
Duration of Diabetes  
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 43 participants 41 participants 84 participants
8
(3 to 13)
10
(6 to 15.5)
8.5
(4.63 to 15)
Height  
Mean (Standard Deviation)
Unit of measure:  Inches
Number Analyzed 43 participants 41 participants 84 participants
66.69  (4.08) 67.19  (3.63) 66.93  (3.85)
Weight  
Mean (Standard Deviation)
Unit of measure:  Pounds
Number Analyzed 43 participants 41 participants 84 participants
214.81  (57.63) 225.12  (47.57) 219.84  (52.89)
Body Mass Index  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 43 participants 41 participants 84 participants
33.55  (6.96) 35.05  (7.87) 34.28  (7.41)
Percent Body Fat  
Mean (Standard Deviation)
Unit of measure:  Percentage of body fat
Number Analyzed 43 participants 41 participants 84 participants
39.09  (6.13) 39.86  (7.55) 39.45  (6.80)
Systolic Blood Pressure  
Mean (Standard Deviation)
Unit of measure:  mmHg
Number Analyzed 43 participants 41 participants 84 participants
131.62  (15.22) 133.93  (16.17) 132.76  (15.65)
Diastolic Blood Pressure  
Mean (Standard Deviation)
Unit of measure:  mmHg
Number Analyzed 43 participants 41 participants 84 participants
82.19  (10.65) 82.07  (9.11) 82.13  (9.86)
Heart Rate  
Mean (Standard Deviation)
Unit of measure:  Beats per minute
Number Analyzed 43 participants 41 participants 84 participants
80.91  (14.65) 75.29  (10.96) 78.17  (13.21)
1.Primary Outcome
Title Change in E/I Ratio From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo
Hide Description

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.

Time Frame Baseline to 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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)
Arm/Group Title Cycloset (Bromocriptine-QR) Placebo
Hide Arm/Group Description:

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

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 Number of Participants Analyzed 33 37
Mean (95% Confidence Interval)
Unit of Measure: E/I ratio change
-0.02
(-0.05 to 0.04)
-0.05
(-0.15 to 0.02)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cycloset (Bromocriptine-QR), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.603
Comments Between treatment group (bromocriptine-QR vs. placebo) differences in change from baseline to week 24 was analyzed using Independent Samples T-tests. Means are statistically significantly different at the 5% level (P < 0.05) two-sided.
Method t-test, 2 sided
Comments [Not Specified]
2.Primary Outcome
Title Change in Valsalva Ratio From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo
Hide Description

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

Time Frame Baseline to 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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)
Arm/Group Title Cycloset (Bromocriptine-QR) Placebo
Hide Arm/Group Description:

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

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 Number of Participants Analyzed 33 37
Mean (95% Confidence Interval)
Unit of Measure: Valsalva ratio change
-0.02
(-0.14 to 0.09)
0.02
(-0.04 to 0.08)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cycloset (Bromocriptine-QR), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.068
Comments Between treatment group (bromocriptine-QR vs. placebo) differences in change from baseline to week 24 was analyzed using Independent Samples T-tests. Means are statistically significantly different at the 5% level (P < 0.05) two-sided.
Method t-test, 2 sided
Comments [Not Specified]
3.Primary Outcome
Title Change in 30:15 Ratio From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo
Hide Description 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.
Time Frame Baseline to 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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)
Arm/Group Title Cycloset (Bromocriptine-QR) Placebo
Hide Arm/Group Description:

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

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 Number of Participants Analyzed 33 37
Mean (95% Confidence Interval)
Unit of Measure: 30:15 ratio change
-0.03
(-0.06 to 0.001)
-0.02
(-0.04 to 0.006)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cycloset (Bromocriptine-QR), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.493
Comments Between treatment group (bromocriptine-QR vs. placebo) differences in change from baseline to week 24 was analyzed using Independent Samples T-tests. Means are statistically significantly different at the 5% level (P < 0.05) two-sided.
Method t-test, 2 sided
Comments [Not Specified]
4.Primary Outcome
Title Change in SDNN From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo
Hide Description

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.

Time Frame Baseline to 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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)
Arm/Group Title Cycloset (Bromocriptine-QR) Placebo
Hide Arm/Group Description:

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

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 Number of Participants Analyzed 33 37
Mean (95% Confidence Interval)
Unit of Measure: Milliseconds (ms) change
-3.97
(-9.20 to 1.26)
-0.80
(-9.14 to 7.54)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cycloset (Bromocriptine-QR), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.524
Comments Between treatment group (bromocriptine-QR vs. placebo) differences in change from baseline to week 24 was analyzed using Independent Samples T-tests. Means were statistically significantly different at the 5% level (P < 0.05) two-sided.
Method t-test, 2 sided
Comments [Not Specified]
5.Primary Outcome
Title Change in RMSSD From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo
Hide Description

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.

Time Frame Baseline to 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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)
Arm/Group Title Cycloset (Bromocriptine-QR) Placebo
Hide Arm/Group Description:

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

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 Number of Participants Analyzed 33 37
Mean (95% Confidence Interval)
Unit of Measure: Milliseconds (ms) change
-3.16
(-9.08 to 2.76)
-0.57
(-9.43 to 8.29)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cycloset (Bromocriptine-QR), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.630
Comments Between treatment group (bromocriptine-QR vs. placebo) differences in change from baseline to week 24 was analyzed using Independent Samples T-tests. Means were statistically significantly different at the 5% level (P < 0.05) two-sided.
Method t-test, 2 sided
Comments [Not Specified]
6.Primary Outcome
Title Change in Resting Heart Rate From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo
Hide Description 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
Time Frame Baseline to 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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)
Arm/Group Title Cycloset (Bromocriptine-QR) Placebo
Hide Arm/Group Description:

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

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 Number of Participants Analyzed 33 37
Mean (95% Confidence Interval)
Unit of Measure: beats per minute change
-0.73
(-3.66 to 2.14)
-2.00
(-4.96 to 0.96)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cycloset (Bromocriptine-QR), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.537
Comments Between treatment group (bromocriptine-QR vs. placebo) differences in change from baseline to week 24 was analyzed using Independent Samples T-tests. Means were statistically significantly different at the 5% level (P < 0.05) two-sided.
Method t-test, 2 sided
Comments [Not Specified]
7.Primary Outcome
Title Change in Feet ESC From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo
Hide Description 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.
Time Frame Baseline to 24 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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)
Arm/Group Title Cycloset (Bromocriptine-QR) Placebo
Hide Arm/Group Description:

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

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 Number of Participants Analyzed 33 37
Mean (95% Confidence Interval)
Unit of Measure: microSiemmens (µS) change
-2.40
(-8.59 to 3.79)
-4.57
(-8.32 to -0.82)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cycloset (Bromocriptine-QR), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.530
Comments Between treatment group (bromocriptine-QR vs. placebo) differences in change from baseline to week 24 was analyzed using Independent Samples T-tests. Means were statistically significantly different at the 5% level (P < 0.05) two-sided.
Method t-test, 2 sided
Comments [Not Specified]
8.Primary Outcome
Title Change in Hands ESC From Baseline to Endpoint After 24 Weeks of Intervention With Bromocriptine QR vs Placebo
Hide Description 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.
Time Frame Baseline to 24 weeks
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Hide Analysis Population Description
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)
Arm/Group Title Cycloset (Bromocriptine-QR) Placebo
Hide Arm/Group Description:

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

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 Number of Participants Analyzed 33 37
Mean (95% Confidence Interval)
Unit of Measure: microSiemmens (µS) change
-1.71
(-5.37 to 1.95)
-9.83
(-14.03 to -5.64)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Cycloset (Bromocriptine-QR), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.005
Comments Between treatment group (bromocriptine-QR vs. placebo) differences in change from baseline to week 24 was analyzed using Independent Samples T-tests. Means were statistically significantly different at the 5% level (P < 0.05) two-sided.
Method t-test, 2 sided
Comments [Not Specified]
Time Frame 6 months
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Cycloset (Bromocriptine-QR) Placebo
Hide Arm/Group Description

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

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

All-Cause Mortality
Cycloset (Bromocriptine-QR) Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/43 (0.00%)      0/41 (0.00%)    
Hide Serious Adverse Events
Cycloset (Bromocriptine-QR) Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/43 (6.98%)      2/41 (4.88%)    
Metabolism and nutrition disorders     
Acute Metabolic Encephalopathy * [1]  1/43 (2.33%)  1 0/41 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Motor vehicle accident *  0/43 (0.00%)  0 1/41 (2.44%)  1
Nervous system disorders     
Vasovagal Syncope * [2]  1/43 (2.33%)  1 0/41 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Acute dyspnea *  0/43 (0.00%)  0 1/41 (2.44%)  1
Pleural and Pericardial Effusion *  1/43 (2.33%)  1 0/41 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
[1]
Acute Metabolic Encephalopathy secondary to dehydration with consequent acute kidney failure and rhabdomyolisis
[2]
Vasovagal Syncope secondary to Valsalva maneuver
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Cycloset (Bromocriptine-QR) Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   7/43 (16.28%)      2/41 (4.88%)    
General disorders     
Fatigue *  7/43 (16.28%)  7 2/41 (4.88%)  2
*
Indicates events were collected by non-systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Henri Parson
Organization: Eastern Virginia Medical School
Phone: 7574467976
EMail: parsonhk@evms.edu
Layout table for additonal information
Responsible Party: Elias S Siraj, Eastern Virginia Medical School
ClinicalTrials.gov Identifier: NCT02682901    
Other Study ID Numbers: 15-06-FB-0119
First Submitted: February 4, 2016
First Posted: February 17, 2016
Results First Submitted: February 2, 2021
Results First Posted: December 10, 2021
Last Update Posted: December 10, 2021