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| ID | Type | Description | Link |
|---|---|---|---|
| 1K23HL119602 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institutes of Health (NIH) | NIH |
| National Heart, Lung, and Blood Institute (NHLBI) | NIH |
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This study tests the following hypotheses:
Aim 1: Test the hypothesis that acute dipeptidyl peptidase 4 (DPP4) inhibition with the currently available anti-diabetic drug, sitagliptin, will increase stimulated growth hormone (GH) secretion in healthy lean adults by decreasing the degradation of growth hormone releasing hormone (GHRH).
Aim 2: Test the hypothesis that decreased degradation of GHRH during acute DPP4 inhibition will result in an increase in endothelium-dependent vasodilation mediated by GH and independent from GLP1 (glucagon like peptide-1) in healthy lean adults.
This study promises to provide novel data regarding how this increasingly used class of anti-diabetic drugs affects the pituitary GH axis and could affect blood vessel relaxation. Growth hormone levels are low in the setting of obesity and pre-diabetes. A further study may evaluate the effect of chronic DPP4 inhibitor therapy in a population of patients with obesity and pre-diabetes.
Growth hormone secretion is low in patients with obesity, insulin resistance, and hyperlipidemia. GH therapy in these populations and others has been limited by side effects which include hyperglycemia. Another strategy to increase GH secretion is to enhance pulsatile GH secretion by growth hormone releasing hormone. Growth hormone releasing hormone (GHRH) has a half life of 5 minutes due to its rapid inactivation by DPP4. An alternative strategy to increase endogenous GH secretion is by inhibiting degradation of GHRH by DPP4. DPP4 inhibitors are currently approved therapies for the treatment of hyperglycemia in patients with type 2 diabetes mellitus. They additionally cause blood vessel relaxation. We therefore propose to test the hypothesis that DPP4 inhibition simultaneously enhances GH secretion while improving blood glucoses and vascular function in patient populations with low GH and increased cardiovascular risk. These preliminary aims serve primarily as a novel "proof of concept" study to define the effect of acute pharmacologic DPPIV inhibition on stimulated GH secretion.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group A (14 healthy subjects) | Other | In Aim 1: Healthy Lean adults are randomized in a double-blinded cross over fashion to sitagliptin versus placebo. In Aim 2: Healthy Lean adults receive sitagliptin and are randomized in a double-blinded cross over fashion to pre-treatment with either LNMMA (L-N-Monomethyl-arginine) versus placebo. |
|
| Group B (14 healthy subjects) | Other | In Aim 1: Healthy Lean adults are randomized in a double-blinded cross over fashion to sitagliptin versus placebo. In Aim 2: Healthy Lean adults receive sitagliptin and are randomized in a double-blinded cross over fashion to pre-treatment with either pegvisomant versus placebo. |
|
| Group C (14 healthy subjects) | Other | In Aim 1: Healthy Lean adults are randomized in a double-blinded cross over fashion to sitagliptin versus placebo. In Aim 2: Healthy Lean adults receive sitagliptin and are randomized in a double-blinded cross over fashion to pre-treatment with either Exendin 9-39 versus placebo. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sitagliptin | Drug | During Aim 1, given on one of two study days (other study day subjects receive placebo.) During Aim 2, given during both of two study days. |
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| Measure | Description | Time Frame |
|---|---|---|
| Aim 1: Stimulated Peak Growth Hormone Level | Subjects underwent two study days separated by a washout period. On one study day they will receive sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine (30 grams i.v. over 30 minutes) on each study day. Growth hormone levels were assessed during a 3 hour period following arginine stimulation. | Growth Hormone Level at 30 minutes (i.e. at completion of arginine infusion), 45 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes |
| Aim 1: Percent Change From Baseline in Forearm Vascular Resistance | Forearm blood flow was determined by strain gauge plethysmography. Forearm vascular resistance was then calculated by dividing this into mean arterial pressure. The percent change from baseline was determined at each timepoint. | Percent change from baseline in forearm vascular resistance at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes |
| Aim 1: Percent Change From Baseline in Forearm Blood Flow | Forearm blood flow was determined by strain gauge plethysmography. The percent change from baseline was determined at each timepoint. | Percent change from baseline in forearm blood flow at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes. |
| Aim 2: Percent Change From Baseline in Forearm Blood Flow | Subjects undergo two study days separated by a washout period. On one study day they received sitagliptin plus another study drug and on another sitagliptin plus placebo, in a randomized double-blind fashion. Forearm blood flow was assessed at each visit. | Percent change from baseline in forearm blood flow at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes. |
| Aim 2: Percent Change From Baseline in Forearm Vascular Resistance |
| Measure | Description | Time Frame |
|---|---|---|
| Aim 1: Venous Blood Sampling for Tissue Plasminogen Activator (TPA) Activity Levels | In Aim 1 subjects underwent two study days separated by a washout period. On one study day they received study drug and on another placebo, in a randomized double-blind fashion. Venous blood samples were obtained at each visit. | baseline and every 30 minutes for 180 minutes |
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Inclusion Criteria:
Status-post surgical sterilization, or If of child-bearing potential, utilization of a barrier method of birth control following negative serum pregnancy test at screening visit and on every study day
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jessica K Devin, MD, MSCI | Vanderbilt University Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Vanderbilt University Medical Center | Nashville | Tennessee | 37232 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29478970 | Derived | Wilson JR, Brown NJ, Nian H, Yu C, Bidlingmaier M, Devin JK. Dipeptidyl Peptidase-4 Inhibition Potentiates Stimulated Growth Hormone Secretion and Vasodilation in Women. J Am Heart Assoc. 2018 Feb 25;7(5):e008000. doi: 10.1161/JAHA.117.008000. |
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In Aim 1, Healthy adults were randomized in a double-blinded cross-over fashion to sitagliptin vs placebo. A minimum 8 week wash-out separated Aims 1 & 2. 23 of the same adults who completed Aim 1 participated in Aim 2. In Aim 2, these adults were divided into three subgroups and randomized to sitagliptin+placebo vs. sitagliptin+antagonist.
Healthy Lean Adults are randomized to two cross-over studies (Aim 1 and Aim 2).
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| ID | Title | Description |
|---|---|---|
| FG000 | Aim 1: Sitagliptin, Then Placebo | In Aim 1: Healthy Lean adults are randomized in a double-blinded cross over fashion to sitagliptin versus placebo. |
| FG001 | Aim 1: Placebo, Then Sitagliptin | In Aim 1: Healthy Lean adults are randomized in a double-blinded cross over fashion to sitagliptin versus placebo. |
| FG002 | Aim 2: Sitagliptin + Placebo,Then Sitagliptin + LNMMA | In Aim 2: Healthy Lean adults receive sitagliptin and are randomized in a double-blinded cross over fashion to pre-treatment with either L-NMMA (L-N-Monomethyl-arginine) versus placebo. |
| FG003 | Aim 2:Sitagliptin + LNMMA, Then Sitagliptin + Placebo | In Aim 2: Healthy Lean adults receive sitagliptin and are randomized in a double-blinded cross over fashion to pre-treatment with either L-NMMA (L-N-Monomethyl-arginine) versus placebo. |
| FG004 | Aim 2: Sitagliptin + Placebo, Then Sitagliptin + Pegvisomant | In Aim 2: Healthy Lean adults receive sitagliptin and are randomized in a double-blinded cross over fashion to pre-treatment with either pegvisomant versus placebo. |
| FG005 | Aim 2: Sitagliptin + Pegvisomant, Then Sitagliptin + Placebo | In Aim 2: Healthy Lean adults receive sitagliptin and are randomized in a double-blinded cross over fashion to pre-treatment with either pegvisomant versus placebo. |
| FG006 | Aim 2: Sitagliptin + Placebo, Then Sitagliptin + Exendin 9-39 | In Aim 2: Healthy Lean adults receive sitagliptin and are randomized in a double-blinded cross over fashion to pre-treatment with either Exendin 9-39 versus placebo. |
| FG007 | Aim 2: Sitagliptin + Exendin 9-39, Then Sitagliptin + Placebo | In Aim 2: Healthy Lean adults receive sitagliptin and are randomized in a double-blinded cross over fashion to pre-treatment with either Exendin 9-39 versus placebo. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
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| Aim 1: First Intervention (1 Day) |
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| Aim 1: Second Intervention (1 Day) |
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| Aim 2: First Intervention (1 Day) |
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| Aim 2: Second Intervention (1 Day) |
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| ID | Title | Description |
|---|---|---|
| BG000 | Participants From All Groups | Data was collected as one group |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Aim 1: Stimulated Peak Growth Hormone Level | Subjects underwent two study days separated by a washout period. On one study day they will receive sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine (30 grams i.v. over 30 minutes) on each study day. Growth hormone levels were assessed during a 3 hour period following arginine stimulation. | Data from all subjects who completed both study days in Aim 1 were analyzed. Subjects represented young, healthy adults without any chronic medical conditions and who did not take any medications. Oral birth control use was not permitted. | Posted | Mean | Standard Deviation | ng/ml | Growth Hormone Level at 30 minutes (i.e. at completion of arginine infusion), 45 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes |
|
The first subject started drug 2/11/13 and the last completed 2/10/2017. In Aim 1, each subject took oral study drug (placebo vs. sitagliptin). Adverse event data was collected over a one month period for each subject. In Aim 2, each subject took oral sitagliptin and also received a single dose of LNMMA, Exendin 9-39 or Pegvisomant based upon their subgroup assigment. Adverse event data was collected over a 6 week period for each subject.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Sitagliptin | Healthy lean adults completed a double blinded cross over study in which they took sitagliptin vs. placebo separated by a wash-out. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Bruising related to placement of intravenous catheter | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Jessica Devin | Vanderbilt University Medical Center | 6159361665 | jessica.devin@vanderbilt.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Sep 8, 2016 | Jan 18, 2018 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D009765 | Obesity |
| ID | Term |
|---|---|
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D000068900 | Sitagliptin Phosphate |
| C406545 | pegvisomant |
| D000073893 | Sugars |
| D019323 | omega-N-Methylarginine |
| C083773 | exendin (9-39) |
| ID | Term |
|---|---|
| D014230 | Triazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| Pegvisomant | Drug | During Aim 2, given 72 hours prior to one of two study days (Group B subjects only) |
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| Placebo | Drug | During Aim 1, given on one of two study days (other study day subjects receive sitagliptin.) During Aim 2, given on one of two study days (other study day subjects receive either L-NMMA, pegvisomant, or Exendin 9-39 pending their group assignment) |
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| L-NMMA | Drug | During Aim 2, given during one of two study days (Group A subjects only) |
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| Exendin 9-39 | Drug | During Aim 2, given during one of two study days (Group C subjects only) |
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Subjects undergo two study days separated by a washout period. On one study day they will receive sitagliptin plus another study drug and on another sitagliptin plus placebo, in a randomized double-blind fashion. Forearm blood flow was assessed at each visit every 30 minutes for 3 hours. This was divided into mean arterial pressure to determine forearm vascular resistance. |
| Percent change from baseline in forearm vascular resistance at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes |
| Aim 2: Venous Blood Sampling for Tissue Plasminogen Activator (TPA) Activity Levels | Subjects undergo two study days separated by a washout period. On one study day they received sitagliptin plus pegvisomant and on another sitagliptin plus placebo, in a randomized double-blind fashion. Tissue plasminogen activator activity (tPA) was assessed at each visit. | baseline and every 30 minutes until 180 minutes |
| Aim 2: Measurement of Growth Hormone (GH) Levels | Subjects undergo two study days separated by a washout period. On one study day they received sitagliptin plus pegvisomant and on another sitagliptin plus placebo, in a randomized double-blind fashion. Growth hormone secretion following arginine stimulation was assessed at each visit. Growth hormone levels were determined using an assay that is not subject to interference by pegvisomant. | baseline and every 30 minutes until 180 minutes |
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| COMPLETED |
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| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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Subjects underwent two study days separated by a washout period. On one study day they received sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine on each study day. Growth hormone levels were assessed during a 3 hour period following arginine stimulation.
| OG001 | Aim 1: Placebo, Female Participants | Subjects underwent two study days separated by a washout period. On one study day they received sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine on each study day. Growth hormone levels were assessed during a 3 hour period following arginine stimulation. |
| OG002 | Aim 1: Sitagliptin, Male Participants | Subjects underwent two study days separated by a washout period. On one study day they received sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine on each study day. Growth hormone levels were assessed during a 3 hour period following arginine stimulation. |
| OG003 | Aim 1: Placebo, Male Participants | Subjects underwent two study days separated by a washout period. On one study day they received sitagliptin and on another placebo, in a randomized double-blind fashion. Growth hormone secretion was stimulated using arginine on each study day. Growth hormone levels were assessed during a 3 hour period following arginine stimulation. |
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|
| Primary | Aim 1: Percent Change From Baseline in Forearm Vascular Resistance | Forearm blood flow was determined by strain gauge plethysmography. Forearm vascular resistance was then calculated by dividing this into mean arterial pressure. The percent change from baseline was determined at each timepoint. | Posted | Mean | Standard Deviation | percentage change from baseline | Percent change from baseline in forearm vascular resistance at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes |
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| Primary | Aim 1: Percent Change From Baseline in Forearm Blood Flow | Forearm blood flow was determined by strain gauge plethysmography. The percent change from baseline was determined at each timepoint. | Data from all subjects who completed both study days in Aim 1 were analyzed. Subjects represented young, healthy adults without any chronic medical conditions and who did not take any medications. Oral birth control use was not permitted. | Posted | Mean | Standard Deviation | percent change from baseline | Percent change from baseline in forearm blood flow at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes. |
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| Primary | Aim 2: Percent Change From Baseline in Forearm Blood Flow | Subjects undergo two study days separated by a washout period. On one study day they received sitagliptin plus another study drug and on another sitagliptin plus placebo, in a randomized double-blind fashion. Forearm blood flow was assessed at each visit. | 19 of the original 29 females in Aim 1 returned to complete two more study days (Aim 2) in which they received sitagliptin + double-blinded study drug vs. sitagliptin plus placebo in a cross-over study. Three men from Aim 1 also returned to complete two more study days (Aim 2). | Posted | Mean | Standard Error | percent change from baseline | Percent change from baseline in forearm blood flow at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes. |
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| Primary | Aim 2: Percent Change From Baseline in Forearm Vascular Resistance | Subjects undergo two study days separated by a washout period. On one study day they will receive sitagliptin plus another study drug and on another sitagliptin plus placebo, in a randomized double-blind fashion. Forearm blood flow was assessed at each visit every 30 minutes for 3 hours. This was divided into mean arterial pressure to determine forearm vascular resistance. | 19 of the original 29 females who participated in Aim 1 returned to complete an additional two study days (Aim 2) in which they received sitagliptin + double-blinded study drug vs. sitagliptin plus placebo in a cross-over study. Three men from Aim 1 also returned to complete two more study days (Aim 2). | Posted | Mean | Standard Error | percent change from baseline | Percent change from baseline in forearm vascular resistance at 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes |
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| Secondary | Aim 1: Venous Blood Sampling for Tissue Plasminogen Activator (TPA) Activity Levels | In Aim 1 subjects underwent two study days separated by a washout period. On one study day they received study drug and on another placebo, in a randomized double-blind fashion. Venous blood samples were obtained at each visit. | Data from the first 14 subjects (7 men and 7 women) who completed both study days in Aim 1 were analyzed. We do not report tPA results from the remaining participants as the manufacturer changed the tPA assay standard and results were not comparable. | Posted | Mean | Standard Error | IU/ml | baseline and every 30 minutes for 180 minutes |
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| Secondary | Aim 2: Venous Blood Sampling for Tissue Plasminogen Activator (TPA) Activity Levels | Subjects undergo two study days separated by a washout period. On one study day they received sitagliptin plus pegvisomant and on another sitagliptin plus placebo, in a randomized double-blind fashion. Tissue plasminogen activator activity (tPA) was assessed at each visit. | Five of the original 29 women returned for two more study days separated by a wash-out. As pre-specified in the protocol, men did not complete this portion of the study. We do not report tPA results from participants who received LNMMA and Exendin 9-39 in this table as the manufacturer changed the tPA assay standard and results were not comparable. | Posted | Mean | Standard Error | IU/ml | baseline and every 30 minutes until 180 minutes |
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| Secondary | Aim 2: Measurement of Growth Hormone (GH) Levels | Subjects undergo two study days separated by a washout period. On one study day they received sitagliptin plus pegvisomant and on another sitagliptin plus placebo, in a randomized double-blind fashion. Growth hormone secretion following arginine stimulation was assessed at each visit. Growth hormone levels were determined using an assay that is not subject to interference by pegvisomant. | Five of the original 29 women returned for an additional two study days separated by a wash-out period. As pre-specified in the protocol, men did not complete this portion of the study. We did not measure GH levels in participants who received LNMMA or Exendin 9-39 as these drugs are not known to influence GH secretion. | Posted | Mean | Standard Error | ng/mL | baseline and every 30 minutes until 180 minutes |
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| 0 |
| 40 |
| 0 |
| 40 |
| 7 |
| 40 |
| EG001 | Placebo | Healthy lean adults completed a double blinded cross over study in which they took sitagliptin vs. placebo separated by a wash-out. | 0 | 43 | 0 | 43 | 1 | 43 |
| EG002 | Sitagliptin Plus Pegvisomant | Five women from Aim 1 returned for an additional two study days in which they were randomized to sitagliptin plus placebo vs. sitagliptin plus pre-treatment with pegvisomant. | 0 | 5 | 0 | 5 | 2 | 5 |
| EG003 | Sitagliptin Plus LNMMA | 9 participants from Aim 1 returned for an additional two study days in which they were randomized to sitagliptin plus placebo vs. sitagliptin plus L-N-mono-methylarginine (LNMMA). | 0 | 9 | 0 | 9 | 0 | 9 |
| EG004 | Sitagliptin Plus Exendin 9-39 | 8 participants from Aim 1 returned for an additional two study days in which they were randomized to sitagliptin plus placebo vs. sitagliptin plus Exendin 9-39. | 0 | 8 | 0 | 8 | 0 | 8 |
| Palpitations | Cardiac disorders | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Non-systematic Assessment |
|
| Nasal congestion | Ear and labyrinth disorders | Non-systematic Assessment |
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| Reflux | Gastrointestinal disorders | Non-systematic Assessment |
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| Dizziness and paresthesias during arginine infusion | Nervous system disorders | Non-systematic Assessment |
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| Abdominal cramping and diarrhea | Gastrointestinal disorders | Non-systematic Assessment |
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| D001835 |
| Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D011719 |
| Pyrazines |
| D002241 | Carbohydrates |
| D001120 | Arginine |
| D024361 | Amino Acids, Basic |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D000599 | Amino Acids, Diamino |
| D000601 | Amino Acids, Essential |
| 60 minutes |
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| 90 minutes |
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| 120 minutes |
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| 150 minutes |
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| 180 minutes |
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| 60 minutes |
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| 90 minutes |
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| 120 minutes |
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| 150 minutes |
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| 180 minutes |
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| 60 minutes |
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| 90 minutes |
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| 120 minutes |
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| 150 minutes |
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| 180 minutes |
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| 60 minutes |
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| 90 minutes |
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| 120 minutes |
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| 150 minutes |
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| 180 minutes |
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| 30 minutes |
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| 45 minutes |
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| 60 minutes |
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| 90 minutes |
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| 120 minutes |
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| 150 minutes |
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| 180 minutes |
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| 45 minutes |
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| 60 minutes |
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| 90 minutes |
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| 120 minutes |
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| 150 minutes |
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| 180 minutes |
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| 90 minutes |
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| 120 minutes |
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| 150 minutes |
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| 180 minutes |
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