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Three separate interventions will be undertaken with the primary outcome of improving pulse wave velocity. Initially, age and BMI-matched men and post-menopausal women, all with type 2 diabetes, will be treated with allopurinol (20 men, 20 women) for 6 months, in order to reduce serum uric acid (SUA) concentrations relative to placebo (10 men, 10 women). In a second intervention, dietary fructose will be restricted for a period of 6 months in type 2 diabetes (T2D) subjects who will maintain a stable weight (20 men, 20 women). In a third intervention, dietary fructose will be restricted for a period of 6 months in type 2 diabetes (T2D) subjects who will achieve a caloric deficit and weight reduction (20 men, 20 women). At the beginning and end of each of the studies, measures of arterial stiffness will be combined with assessments of endothelial function (flow-mediated dilation and insulin stimulated leg blood flow), measurements of systemic inflammation and oxidative stress.
Sedentary, overweight and obese subjects diagnosed with T2D, ages 40-75 years old, will be recruited from the local community, via the University of Missouri's Endocrinology Clinic and the primary care clinics. During screening, and after consent, anthropometrics (waist circumference and body composition) will be obtained and fasting blood will be drawn for serum chemistries, A1c, complete blood count, liver and kidney function. Screening will also include completion of an oral glucose tolerance test with measurements of arterial stiffness and assessment of endothelial function. Following screening, eligible subjects will be assigned to one of the four groups (allopurinol, placebo, fructose restriction/isocaloric, or fructose restriction/hypocaloric). Allopurinol will be titrated to achieve a target dose of 300 mg/day. Along with placebo, this arm of the study is double-blinded. A separate group of men and women will be assigned to the isocaloric fructose-restriction study in which dietary fructose is replaced by starch and body weight is held constant. Lastly, a separate group of men and women will be assigned to the hypocaloric fructose-restriction in which baseline caloric intake will be reduced by 500 Calories/day while baseline intakes of protein and fat will remain constant. The subjects in these groups will not be blinded to the dietary treatment but the staff making measurements will be. Subjects in the four groups will be matched for age and BMI.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Low-fructose diet, isocaloric | Experimental | Subjects assigned to this arm of the study will consume for 6 months a diet low in fructose while maintaining baseline body weight. |
|
| Allopurinol | Experimental | Subjects assigned to this arm of the study will be treated for 6 months with allopurinol (max dose 300 mg) |
|
| Placebo | Placebo Comparator | Subjects assigned to this arm will receive placebo |
|
| Low-fructose diet, hypocaloric | Experimental | Subjects assigned to this arm of the study will consume for 6 months a diet low in fructose with a 500 Calorie energy reduction. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Low-fructose diet, isocaloric | Other | 6 month of consumption a low fructose diet |
|
| Measure | Description | Time Frame |
|---|---|---|
| Carotid Femoral Pulse Wave Velocity (cfPWV) | It is the gold standard non-invasive index of arterial stiffness. Transit time between carotid and femoral pressure waves is calculated using the foot-to-foot method. cfPWV is calculated as distance traveled by the pulse wave (i.e., femoral location-sternal notch minus sternal notch-carotid location) divided by pulse transit time. All the measurements will be done by the same blinded technician | This will be assessed at baseline and 6 months (final). The goal is to assess changes from baseline when compared to final time point. |
| Measure | Description | Time Frame |
|---|---|---|
| Brachial Artery Flow Mediated Dilation (FMD) | Brachial artery FMD will be assessed at baseline and final. FMD is a measurement of conduit artery endothelial function. FMD is assessed immediately after each PWV measurement. Shear rate AUC until peak diameter is calculated as stimulus for FMD and used in covariate analysis as described. All measurements will be performed, under co-I supervision by the same blinded technician. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Camila Manrique Acevedo, MD | University of Missouri-Columbia | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Missouri | Columbia | Missouri | 65212 | United States |
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The current Clinical trials.gov information reflects the number of subjects that were recruited for the clinical trial portion of this study. No subjects were recruited the isocaloric portion of this study.
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| ID | Title | Description |
|---|---|---|
| FG000 | Allopurinol | Subjects assigned to this arm of the study will be treated for 6 months with allopurinol (max dose 300 mg) Allopurinol: 6 months of allopurinol treatment with the goal of decreasing uric acid compared to control group |
| FG001 | Placebo | Subjects assigned to this arm will receive placebo Placebo: 6 months of placebo treatment |
| FG002 | Low-fructose Diet, Hypocaloric | Subjects assigned to this arm of the study will consume for 6 months a diet low in fructose with a 500 Calorie energy reduction. Low-fructose, hypocaloric: 6 month of consumption a low fructose diet with a 500 Calorie/day energy restriction |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Allopurinol | Subjects assigned to this arm of the study will be treated for 6 months with allopurinol (max dose 300 mg) Allopurinol: 6 months of allopurinol treatment with the goal of decreasing uric acid compared to control group |
| BG001 | Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | Carotid Femoral Pulse Wave Velocity (cfPWV) | It is the gold standard non-invasive index of arterial stiffness. Transit time between carotid and femoral pressure waves is calculated using the foot-to-foot method. cfPWV is calculated as distance traveled by the pulse wave (i.e., femoral location-sternal notch minus sternal notch-carotid location) divided by pulse transit time. All the measurements will be done by the same blinded technician | Measurement not available for all subjects | Posted | Mean | Standard Deviation | m/s | This will be assessed at baseline and 6 months (final). The goal is to assess changes from baseline when compared to final time point. |
|
6 months
Subjects enrolled in the allopurinol/placebo arm were administered a safety formulary at weeks 2, 4, 6, 8,12, 16, and 20 to assess for common side effects.
Subjects in the hypocaloric arm were contacted by the research team weekly from week 1 thru 6, and then at week 8, 12, 16, and 20 to assess for any changes in their health
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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 | Allopurinol | Subjects assigned to this arm of the study will be treated for 6 months with allopurinol (max dose 300 mg) Allopurinol: 6 months of allopurinol treatment with the goal of decreasing uric acid compared to control group |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Urinary tract infection/pneumonia | Infections and infestations | Non-systematic Assessment | hospital admission |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
The covid pandemic limited recruitment efforts. Protocol was modified to limit the risk of exposure of research staff and research participants.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Camila Manrique, MD | University of Missouri, School of Medicine | (573) 882-2554 | manriquec@umsystem.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 | Mar 25, 2021 | Apr 21, 2023 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form: General | Aug 11, 2021 | Apr 21, 2023 | ICF_001.pdf |
| ICF | No | No | Yes | Informed Consent Form: Allopurinol/Placebo Arm | Aug 11, 2021 | Apr 21, 2023 | ICF_002.pdf |
| ICF | No | No | Yes | Informed Consent Form: Hypocaloric Low Fructose Diet Arm | Aug 11, 2021 | Apr 21, 2023 | ICF_003.pdf |
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| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| D033461 | Hyperuricemia |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D000493 | Allopurinol |
| ID | Term |
|---|---|
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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| Allopurinol | Drug | 6 months of allopurinol treatment with the goal of decreasing uric acid compared to control group |
|
|
| Placebo | Drug | 6 months of placebo treatment |
|
| Low-fructose, hypocaloric | Other | 6 month of consumption a low fructose diet with a 500 Calorie/day energy restriction |
|
| Baseline and 6 months (final). The goal is to assess changes from baseline when compared to final time point. |
| Insulin-stimulated Leg Blood Flow | We will perform a hyperinsulinemic euglycemic clamp to evaluate insulin-stimulated leg blood flow (to be assessed via Doppler ultrasound). Insulin will be infused at a constant rate to mimic postprandial insulin concentrations and glucose maintained at fasting values via a variable 20% dextrose infusion. Femoral artery blood flow will be assessed at the beginning and at end of the 60-minute insulin infusion, and data are presented as percent of change from pre-insulin infusion values. | The goal is to assess insulin stimulated responses in blood flow after 6 mo of intervention. |
Subjects assigned to this arm will receive placebo Placebo: 6 months of placebo treatment |
| BG002 | Low-fructose Diet, Hypocaloric | Subjects assigned to this arm of the study will consume for 6 months a diet low in fructose with a 500 Calorie energy reduction. Low-fructose, hypocaloric: 6 month of consumption a low fructose diet with a 500 Calorie/day energy restriction |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| Baseline PWV | Assessment of arterial stiffness, carotid femoral pulse wave velocity | Measurement not available in all participants | Mean | Standard Deviation | m/s |
|
| Brachial FMD | Measurement not available in all participants | Mean | Standard Deviation | Percentage (%) |
|
| OG001 | Placebo | Subjects assigned to this arm will receive placebo Placebo: 6 months of placebo treatment |
| OG002 | Low-fructose Diet, Hypocaloric | Subjects assigned to this arm of the study will consume for 6 months a diet low in fructose with a 500 Calorie energy reduction. Low-fructose, hypocaloric: 6 month of consumption a low fructose diet with a 500 Calorie/day energy restriction |
|
|
| Secondary | Brachial Artery Flow Mediated Dilation (FMD) | Brachial artery FMD will be assessed at baseline and final. FMD is a measurement of conduit artery endothelial function. FMD is assessed immediately after each PWV measurement. Shear rate AUC until peak diameter is calculated as stimulus for FMD and used in covariate analysis as described. All measurements will be performed, under co-I supervision by the same blinded technician. | Measurement not available for all subjects | Posted | Mean | Standard Deviation | Percentage (%) | Baseline and 6 months (final). The goal is to assess changes from baseline when compared to final time point. |
|
|
|
| Secondary | Insulin-stimulated Leg Blood Flow | We will perform a hyperinsulinemic euglycemic clamp to evaluate insulin-stimulated leg blood flow (to be assessed via Doppler ultrasound). Insulin will be infused at a constant rate to mimic postprandial insulin concentrations and glucose maintained at fasting values via a variable 20% dextrose infusion. Femoral artery blood flow will be assessed at the beginning and at end of the 60-minute insulin infusion, and data are presented as percent of change from pre-insulin infusion values. | The percentage change in blood flow in response to insulin was calculated as femoral blood flow insulin - femoral blood flow insulin no insulin x 100 | Posted | Mean | Standard Deviation | Percetage (%) change | The goal is to assess insulin stimulated responses in blood flow after 6 mo of intervention. |
|
|
|
| 0 |
| 7 |
| 0 |
| 7 |
| 5 |
| 7 |
| EG001 | Placebo | Subjects assigned to this arm will receive placebo Placebo: 6 months of placebo treatment | 0 | 5 | 0 | 5 | 4 | 5 |
| EG002 | Low-fructose Diet, Hypocaloric | Subjects assigned to this arm of the study will consume for 6 months a diet low in fructose with a 500 Calorie energy reduction. Low-fructose, hypocaloric: 6 month of consumption a low fructose diet with a 500 Calorie/day energy restriction | 0 | 16 | 1 | 16 | 8 | 16 |
|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Skin rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Non severe hypoglycemia | Endocrine disorders | Non-systematic Assessment |
|
| Glucosuria | Endocrine disorders | Non-systematic Assessment |
|
| Ankle Sprain | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Acid Reflux | Gastrointestinal disorders | Non-systematic Assessment |
|
| Severe hypoglycemia | Metabolism and nutrition disorders | Non-systematic Assessment |
|
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| D004700 | Endocrine System Diseases |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| Between 18 and 65 years |
|
| >=65 years |
|
| Male |
|
| Not Hispanic or Latino |
|
| Unknown or Not Reported |
|