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Contribution of Hyperinsulinemia vs. Hyperglycemia to Insulin Resistance in Type 1 Diabetes and Maturity Onset Diabetes of the Young, Type 2 (MODY2)

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ClinicalTrials.gov Identifier: NCT02971202
Recruitment Status : Completed
First Posted : November 22, 2016
Results First Posted : August 1, 2019
Last Update Posted : August 1, 2019
Sponsor:
Information provided by (Responsible Party):
Justin Gregory, Vanderbilt University

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Basic Science
Conditions Type 1 Diabetes Mellitus
Maturity-Onset Diabetes of the Young, Type 2
MODY2
Insulin Resistance
Interventions Drug: Hyperinsulinemic, euglycemic clamp
Drug: 20% dextrose
Enrollment 33
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Hyperinsulinemic, Euglycemic Clamp: T1DM Hyperinsulinemic, Euglycemic Clamp:MODY2 Hyperinsulinemic Euglycemic Clamp:Control
Hide Arm/Group Description

Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:

  • insulin (12 milliunit (mU)/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
  • glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
  • somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.

A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.

Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:

  • insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
  • glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
  • somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.

A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.

Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:

  • insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
  • glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
  • somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.

A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.

Period Title: Overall Study
Started 12 10 11
Started Study 11 10 10
Completed 10 10 10
Not Completed 2 0 1
Reason Not Completed
Pregnancy             1             0             0
screen fail after consent             1             0             1
Arm/Group Title Hyperinsulinemic, Euglycemic Clamp: T1DM Hyperinsulinemic, Euglycemic Clamp:MODY2 Hyperinsulinemic Euglycemic Clamp:Control Total
Hide Arm/Group Description

Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:

  • insulin (12 milliunit (mU)/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
  • glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
  • somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.

A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.

Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:

  • insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
  • glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
  • somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.

A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.

Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:

  • insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
  • glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
  • somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.

A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.

Total of all reporting groups
Overall Number of Baseline Participants 12 10 11 33
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 10 participants 11 participants 33 participants
<=18 years
1
   8.3%
4
  40.0%
0
   0.0%
5
  15.2%
Between 18 and 65 years
11
  91.7%
6
  60.0%
11
 100.0%
28
  84.8%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 10 participants 11 participants 33 participants
Female
7
  58.3%
9
  90.0%
8
  72.7%
24
  72.7%
Male
5
  41.7%
1
  10.0%
3
  27.3%
9
  27.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 10 participants 11 participants 33 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Not Hispanic or Latino
12
 100.0%
10
 100.0%
11
 100.0%
33
 100.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 10 participants 11 participants 33 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
1
   9.1%
1
   3.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
White
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
More than one race
0
   0.0%
0
   0.0%
1
   9.1%
1
   3.0%
Unknown or Not Reported
12
 100.0%
10
 100.0%
9
  81.8%
31
  93.9%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 12 participants 10 participants 11 participants 33 participants
12 10 11 33
1.Primary Outcome
Title Whole-body Glucose Utilization (Rd)
Hide Description The primary outcome is the degree to which Rd (determined using isotopic glucose tracer techniques) during maximal insulin stimulation differs between cohorts.
Time Frame End of clamp study (the study will last 8 hours)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Hyperinsulinemic, Euglycemic Clamp: T1DM Hyperinsulinemic, Euglycemic Clamp:MODY2 Hyperinsulinemic Euglycemic Clamp:Control
Hide Arm/Group Description:

Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:

  • insulin (12 milliunit (mU)/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
  • glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
  • somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.

A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.

Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:

  • insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
  • glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
  • somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.

A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.

Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:

  • insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
  • glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
  • somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.

A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.

Overall Number of Participants Analyzed 10 10 10
Mean (95% Confidence Interval)
Unit of Measure: mg/kg FFM/min
8.5
(6.1 to 10.9)
11.0
(9.1 to 13.0)
12.1
(10.3 to 14.0)
2.Secondary Outcome
Title Hepatic Insulin Sensitivity
Hide Description Glucose production (Ra) will be determined using stable isotopic tracer techniques. The extent to which Ra is suppressed at the end of 4 1/2 hours (when glucose Ra by liver has been submaximally suppressed) compared to basal (ΔRa) is directly proportional to hepatic insulin sensitivity.
Time Frame 4 1/2 hours into clamp study
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Hyperinsulinemic, Euglycemic Clamp: T1DM Hyperinsulinemic, Euglycemic Clamp:MODY2 Hyperinsulinemic Euglycemic Clamp:Control
Hide Arm/Group Description:

Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:

  • insulin (12 milliunit (mU)/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
  • glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
  • somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.

A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.

Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:

  • insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
  • glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
  • somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.

A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.

Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:

  • insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
  • glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
  • somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.

A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.

Overall Number of Participants Analyzed 10 10 10
Mean (95% Confidence Interval)
Unit of Measure: mg/kg FFM/min
1.9
(1.5 to 2.2)
2.1
(1.7 to 2.4)
1.7
(1.4 to 2.0)
3.Secondary Outcome
Title Adipose Tissue Insulin Sensitivity
Hide Description Insulin sensitivity at fat is directly proportional to insulin's ability to suppress lipolysis. Thus, we will determine the extent to which submaximal insulin stimulation (4 1/2 hours into the study) suppresses glycerol and non-esterified free fatty acids (NEFAs) compared to baseline. The extent to which these two metabolites are suppressed is directly proportional to insulin sensitivity in adipose tissue. Here the suppression of NEFA is taken as the secondary outcome parameter.
Time Frame 4 1/2 hours into clamp study
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Hyperinsulinemic, Euglycemic Clamp: T1DM Hyperinsulinemic, Euglycemic Clamp:MODY2 Hyperinsulinemic Euglycemic Clamp:Control
Hide Arm/Group Description:

Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:

  • insulin (12 milliunit (mU)/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
  • glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
  • somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.

A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.

Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:

  • insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
  • glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
  • somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.

A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.

Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:

  • insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
  • glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
  • somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.

A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.

Overall Number of Participants Analyzed 10 10 10
Mean (95% Confidence Interval)
Unit of Measure: μmol/L
122.4
(-54.36 to 299.1)
382.3
(244.4 to 520.3)
392.7
(274.4 to 511.1)
Time Frame 1 week
Adverse Event Reporting Description per protocol, hyperglycemia and hypoglycemia are not considered adverse events unless serious
 
Arm/Group Title Hyperinsulinemic, Euglycemic Clamp: T1DM Hyperinsulinemic, Euglycemic Clamp:MODY2 Hyperinsulinemic Euglycemic Clamp:Control
Hide Arm/Group Description

Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:

  • insulin (12 milliunit (mU)/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
  • glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
  • somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.

A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.

Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:

  • insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
  • glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
  • somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.

A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.

Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:

  • insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
  • glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
  • somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.

A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.

All-Cause Mortality
Hyperinsulinemic, Euglycemic Clamp: T1DM Hyperinsulinemic, Euglycemic Clamp:MODY2 Hyperinsulinemic Euglycemic Clamp:Control
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/12 (0.00%)      0/10 (0.00%)      0/11 (0.00%)    
Hide Serious Adverse Events
Hyperinsulinemic, Euglycemic Clamp: T1DM Hyperinsulinemic, Euglycemic Clamp:MODY2 Hyperinsulinemic Euglycemic Clamp:Control
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/12 (0.00%)      0/10 (0.00%)      0/11 (0.00%)    
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Hyperinsulinemic, Euglycemic Clamp: T1DM Hyperinsulinemic, Euglycemic Clamp:MODY2 Hyperinsulinemic Euglycemic Clamp:Control
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   4/12 (33.33%)      3/10 (30.00%)      3/11 (27.27%)    
Cardiac disorders       
hypotension   2/12 (16.67%)  2 0/10 (0.00%)  0 0/11 (0.00%)  0
Gastrointestinal disorders       
nausea and vomiting   1/12 (8.33%)  1 1/10 (10.00%)  1 1/11 (9.09%)  1
General disorders       
IV site pain   0/12 (0.00%)  0 1/10 (10.00%)  1 2/11 (18.18%)  2
Nervous system disorders       
Vasovagal Response   1/12 (8.33%)  1 0/10 (0.00%)  0 0/11 (0.00%)  0
headache   2/12 (16.67%)  2 2/10 (20.00%)  2 1/11 (9.09%)  1
Surgical and medical procedures       
Swelling at biopsy site   0/12 (0.00%)  0 0/10 (0.00%)  0 2/11 (18.18%)  2
Redness at biopsy site   0/12 (0.00%)  0 0/10 (0.00%)  0 2/11 (18.18%)  2
Indicates events were collected by systematic assessment
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Justin M. Gregory MD MSCI
Organization: Vanderbilt University Medical Center
Phone: 615-875-9669
EMail: justin.m.gregory.1@vumc.org
Layout table for additonal information
Responsible Party: Justin Gregory, Vanderbilt University
ClinicalTrials.gov Identifier: NCT02971202    
Other Study ID Numbers: 161504
First Submitted: October 27, 2016
First Posted: November 22, 2016
Results First Submitted: May 30, 2019
Results First Posted: August 1, 2019
Last Update Posted: August 1, 2019