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Dipeptidyl Peptidase-4 Inhibitors and Alpha-cell Recovery (DARE)

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: NCT01272583
Recruitment Status : Completed
First Posted : January 10, 2011
Results First Posted : February 17, 2014
Last Update Posted : March 14, 2014
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
F Holleman, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Triple (Participant, Care Provider, Investigator)
Conditions Type 1 Diabetes
Hypoglycemia
Interventions Drug: Sitagliptin
Drug: Placebo
Enrollment 16
Recruitment Details Participants came to the Academic Medical Center in Amsterdam for a screening visit to determine eligibility for the study.
Pre-assignment Details Patients were excluded if they were found to have impaired awareness of hypoglycaemia, had a history of seizures, cardiac arrhythmia (or used beta-adrenoreceptor blockers) and/or acute infection in the 12 weeks before the study, or evidence of severe diabetes complications (autonomic neuropathy, nephropathy or proliferative retinopathy).
Arm/Group Title Sequence A (Sitagliptin→Placebo) Sequence B (Placebo→Sitagliptin)
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Cross-over, both arms reveived the same intervention in different order.

Sitagliptin : 100 mg once daily for six weeks

Placebo : placebo, once daily for six weeks

Cross-over, both arms reveived the same intervention in different order.

Sitagliptin : 100 mg once daily for six weeks

Placebo : placebo, once daily for six weeks

Period Title: Overall Study
Started 8 8
Completed 8 8
Not Completed 0 0
Arm/Group Title Sequence A (Sitagliptin→Placebo) Sequence B (Placebo→Sitagliptin) Total
Hide Arm/Group Description

Cross-over, both arms reveived the same intervention in different order.

Sitagliptin : 100 mg once daily for six weeks

Placebo : placebo, once daily for six weeks

Cross-over, both arms reveived the same intervention in different order.

Sitagliptin : 100 mg once daily for six weeks

Placebo : placebo, once daily for six weeks

Total of all reporting groups
Overall Number of Baseline Participants 8 8 16
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 8 participants 8 participants 16 participants
30.5
(26.3 to 39)
33.5
(27.8 to 40.8)
31.5
(27.0 to 40.0)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 8 participants 8 participants 16 participants
Female
0
   0.0%
0
   0.0%
0
   0.0%
Male
8
 100.0%
8
 100.0%
16
 100.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Netherlands Number Analyzed 8 participants 8 participants 16 participants
8 8 16
1.Primary Outcome
Title Glucagon Response to Acute Hypoglycaemia
Hide Description Change in glucagon concentration from the initialisation phase to 40 minutes after occurrence of the autonomic reaction to hypoglycaemia
Time Frame Change from initialisation phase to 40 minutes after onset of hypoglycaemia
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Baseline Sitagliptin Treatment Placebo
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 16 16 16
Median (Inter-Quartile Range)
Unit of Measure: pmol/L
1.33
(-0.67 to 2.67)
1.0
(-0.67 to 2.67)
1.33
(-1.00 to 2.33)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Baseline, Sitagliptin Treatment, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.0
Comments [Not Specified]
Method ANOVA
Comments The Friedman Test was used for ANOVA.
2.Primary Outcome
Title Glucagon Response to Acute Hypoglycaemia
Hide Description Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method.
Time Frame 0, 10, 20 and 40 minutes
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Baseline Sitagliptin Treatment Placebo
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 16 16 16
Median (Inter-Quartile Range)
Unit of Measure: pmol*minutes/L
120
(90 to 215)
125
(20 to 215)
120
(85 to 200)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Baseline, Sitagliptin Treatment, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.98
Comments [Not Specified]
Method ANOVA
Comments The Friedman Test was used for ANOVA.
3.Secondary Outcome
Title Intact and Total Glucagon Like Peptide-1 (GLP-1), Intact and Total Gastric Inhibitory Peptide (GIP) Response to Acute Hypoglycaemia
Hide Description Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method.
Time Frame 0, 10, 20, 40 minutes
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Hide Analysis Population Description
[Not Specified]
Arm/Group Title Baseline Sitagliptin Treatment Placebo
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 16 16 16
Median (Inter-Quartile Range)
Unit of Measure: pmol*minutes/L
GLP-1 intact
2.000
(0.0000 to 15.50)
43.50
(12.00 to 81.50)
4.500
(0.0000 to 21.00)
GLP-1 total
562.2
(435.0 to 623.8)
555.0
(450.0 to 611.3)
552.5
(433.8 to 596.3)
GIP intact
455.0
(361.3 to 513.8)
490.0
(461.3 to 630.0)
452.5
(435.0 to 532.5)
GIP total
302.5
(201.3 to 436.3)
285.0
(160.0 to 367.5)
342.5
(238.8 to 497.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Baseline, Sitagliptin Treatment, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments GLP-1 intact
Method ANOVA
Comments The Friedman Test was used for ANOVA
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Baseline, Sitagliptin Treatment, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.98
Comments GLP-1 Total
Method ANOVA
Comments The Friedman Test was used for ANOVA.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Baseline, Sitagliptin Treatment, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.049
Comments GIP intact
Method ANOVA
Comments The Friedman Test was used for ANOVA.
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Baseline, Sitagliptin Treatment, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.44
Comments GIP total
Method ANOVA
Comments The Friedman Test was used for ANOVA
4.Secondary Outcome
Title Epinephrine Response to Acute Hypoglycaemia
Hide Description Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method.
Time Frame 0, 10, 20, 40 minutes
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Baseline Sitagliptin Treatment Placebo
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 16 16 16
Median (Inter-Quartile Range)
Unit of Measure: nmol*minutes/L
36.1
(31.1 to 62.5)
32.6
(17.0 to 65.0)
58.7
(34.8 to 71.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Baseline, Sitagliptin Treatment, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.14
Comments [Not Specified]
Method ANOVA
Comments The Friedman Test was used for ANOVA.
5.Secondary Outcome
Title Norepinephrine Response to Acute Hypoglycaemia
Hide Description Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method.
Time Frame 0, 10, 20, 40 minutes
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Baseline Sitagliptin Treatment Placebo
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 16 16 16
Median (Inter-Quartile Range)
Unit of Measure: nmol*minutes/L
70.0
(52.5 to 88.1)
62.5
(44.9 to 73.0)
62.3
(49.1 to 72.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Baseline, Sitagliptin Treatment, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.22
Comments [Not Specified]
Method ANOVA
Comments The Friedman Test was used for ANOVA.
6.Secondary Outcome
Title Growth Hormone Response to Acute Hypoglycaemia
Hide Description Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method.
Time Frame 0, 10, 20, 40 minutes
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Baseline Sitagliptin Treatment Placebo
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 16 16 16
Median (Inter-Quartile Range)
Unit of Measure: mU*minutes/L
1299
(313.5 to 2560)
261.5
(47 to 1499)
1406
(781 to 2626)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Baseline, Sitagliptin Treatment, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.01
Comments [Not Specified]
Method ANOVA
Comments The Friedman Test was used for ANOVA.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Sitagliptin Treatment, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments [Not Specified]
Method Dunn's Multiple Comparison Test
Comments Post Hoc testing
7.Secondary Outcome
Title Cortisol Response to Acute Hypoglycaemia
Hide Description Area under the curve (AUC) from onset of the autonomic response to hypoglycaemia to 40 minutes after onset of the autonomic response. AUC values were calculated by the trapezoid method.
Time Frame 0, 10, 20, 40 minutes
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Baseline Sitagliptin Treatment Placebo
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 16 16 16
Median (Inter-Quartile Range)
Unit of Measure: mU*minutes/L
14480
(11300 to 17180)
13190
(10920 to 18680)
14800
(8985 to 19160)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Baseline, Sitagliptin Treatment, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.76
Comments [Not Specified]
Method ANOVA
Comments The Friedman Test was used for ANOVA.
8.Secondary Outcome
Title Symptomatic Hormone Responses to Acute Hypoglycaemia.
Hide Description The symptomatic responses to hypoglycaemia were assessed using a standard validated symptom questionnaire adapted for experimental hypoglycaemia (McCrimmon et al (2003) Diabet.Med. 20: 507-509). A 7-point Likert scale (1=symptom absent; 7=symptom experienced with great intensity) was used to score presence and intensity of autonomic and neuroglycopenic symptoms of hypoglycaemia. Symptom scores were obtained during the initialisation phase, at occurrence of autonomic reaction and again 30 minutes later. For analyses the scale was considered as a continuous variable.
Time Frame Change from baseline symptomatic response at hypoglycaemia and 30 minutes after hypoglycaemia
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Baseline Sitagliptin Treatment Placebo
Hide Arm/Group Description:
[Not Specified]
[Not Specified]
[Not Specified]
Overall Number of Participants Analyzed 16 16 16
Median (Inter-Quartile Range)
Unit of Measure: units on a scale
Autonomic symptoms score
1.7
(1.7 to 2.9)
1.3
(1.0 to 2.6)
1.5
(1.0 to 2.2)
Neurologic symptoms score
2.1
(1.7 to 3.4)
2.4
(1.7 to 3.8)
2.1
(1.5 to 3.3)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Baseline Sitagliptin Treatment Placebo
Hide Arm/Group Description [Not Specified] [Not Specified] [Not Specified]
All-Cause Mortality
Baseline Sitagliptin Treatment Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Baseline Sitagliptin Treatment Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/16 (0.00%)   0/16 (0.00%)   0/16 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Baseline Sitagliptin Treatment Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/16 (0.00%)   0/16 (0.00%)   0/16 (0.00%) 
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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
Name/Title: Dr. Josefine E. Schopman
Organization: Academic Medical Center
Phone: +31 20 5669111
Responsible Party: F Holleman, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier: NCT01272583     History of Changes
Other Study ID Numbers: DARE_2010
First Submitted: January 5, 2011
First Posted: January 10, 2011
Results First Submitted: October 15, 2013
Results First Posted: February 17, 2014
Last Update Posted: March 14, 2014