PERL Continuous Glucose Monitoring (CGM) Study

Study Overview
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Brief Summary
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Seven-point capillary profiles have shown that mean glucose correlates with both diabetic retinopathy and nephropathy risk. However, there remains great controversy as to whether the degree of variability around mean glucose may also contribute to these microvascular complications. The PERL trial (NCT02017171), testing whether treatment with allopurinol can slow down kidney function loss in type 1 diabetes, provides a unique opportunity to assess the role of glycemic variability in the progression of diabetic kidney disease in individuals who already have mild to moderate kidney disease. By applying Continuous Glucose Monitoring (CGM) in the PERL Study population, the investigators will be able to better understand how metrics of glycemia (mean, time above and below range, and various measures of variability) are associated with renal outcomes in the PERL population as a whole, but also in important subgroups (e.g., albuminuric vs. normoalbuminuric subjects with ongoing GFR decline, allopurinol vs. placebo arms). The nvestigators also aim to obtain precise information on the range of blood glucose corresponding to any given HbA1c value in this population since previous studies generally excluded patients with renal disease.

Detailed Description
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Participants who consent to the study will have an Abbott Freestyle Libre Pro sensor placed on the back of their upper arm at their first PERL visit after this ancillary study has begun and at all subsequent PERL Visits. The sensor will be continuously worn by participants for 14 days. At the end of the 14 days, the sensor will be removed and mailed by the participant to the Coordinating center. Since subjects are at various stages of the PERL protocol, the number of remaining visits at which the CGM will be applied will vary among subjects. STUDY AIMS To assess the effect of glycemic variability, as measured by the coefficient of variation of CGM glucose (CV, the ratio of standard deviation and the mean of CGM glucose values), on the PERL renal functional endpoint (iohexol GFR at the end of study). To assess the effect of other glycemic parameters measured by CGM (mean glucose, % time 70-180 mg/dL, % time below 54 mg/dL, % time below 70 mg/dL, % time above 180 mg/dL, % time above 250 mg/dL, mean amplitude of glucose excursions [MAGE], low blood glucose index [LBGI], high blood glucose index [HBGI]) on the PERL renal functional endpoint. To assess the relationship between CGM-measured glycemic parameters and HbA1c at various levels of renal function. To compare the effects of CGM metrics on the PERL renal endpoint and the corresponding effect of HbA1c. To assess the effect of allopurinol treatment on all of the different glycemic metrics including HbA1c, CV, etc. and on their association with the PERL renal endpoint.

Official Title
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PERL (Preventing Early Renal Loss in Diabetes) Continuous Glucose Monitoring (CGM) Study

Conditions
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Diabetic Nephropathies

Intervention / Treatment
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* Other: Mean blood glucose
* Other: Blood glucose CV
* Other: % time 70-180 mg/dL
* Other: % time below 54 mg/dL
* Other: % time above 180 mg/dL
* Other: % time above 250 mg/dL
* Other: MAGE (Mean amplitude of glucose excursions)
* Other: LBGI (Low Blood Glucose Index)
* Other: HBGI (High Blood Glucose Index)
* Drug: Allopurinol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Being an active participant in the PERL clinical trial Exclusion Criteria: Having completed PERL Visit 16 Pregnancy History of skin reactions in relation to the application of Abbott Freestyle Libre Pro

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Allopurinol-treated<br>Participants in the PERL Clinical Trial (NCT02017171) randomized to allopurinol | Other: Mean blood glucose<br>* Mean of blood glucose values measures by continuous glucose monitoring from week 80 to week 164 of the PERL trial.<br>Other: Blood glucose CV<br>* Coefficient of variation of blood glucose values measures by continuous glucose monitoring from week 80 to week 164 of the PERL trial.<br>Other: % time 70-180 mg/dL<br>* Percent of time with blood glucose in the 70-180 mg/dL range as measured by continuous glucose monitoring from week 80 to week 164 of the PERL trial.<br>Other: % time below 54 mg/dL<br>* Percent of time with blood glucose below 54 mg/dL as measured by continuous glucose monitoring from week 80 to week 164 of the PERL trial.<br>Other: % time above 180 mg/dL<br>* Percent of time with blood glucose above 180 mg/dL as measured by continuous glucose monitoring from week 80 to week 164 of the PERL trial.<br>Other: % time above 250 mg/dL<br>* Percent of time with blood glucose above 250 mg/dL as measured by continuous glucose monitoring from week 80 to week 164 of the PERL trial.<br>Other: MAGE (Mean amplitude of glucose excursions)<br>* Mean amplitude of glucose excursions as measured by continuous glucose monitoring as measured by continuous glucose monitoring from week 80 to week 164 of the PERL trial.<br>Other: LBGI (Low Blood Glucose Index)<br>* Low blood glucose index as measured by continuous glucose monitoring from week 80 to week 164 of the PERL trial.<br>Other: HBGI (High Blood Glucose Index)<br>* High blood glucose index as measured by continuous glucose monitoring from week 80 to week 164 of the PERL trial.<br>Drug: Allopurinol<br>* Oral allopurinol tablets administered in the PERL Clinical Trial<br>|
| Placebo-treated<br>Participants in the PERL Clinical Trial (NCT02017171) randomized to placebo | Other: Mean blood glucose<br>* Mean of blood glucose values measures by continuous glucose monitoring from week 80 to week 164 of the PERL trial.<br>Other: Blood glucose CV<br>* Coefficient of variation of blood glucose values measures by continuous glucose monitoring from week 80 to week 164 of the PERL trial.<br>Other: % time 70-180 mg/dL<br>* Percent of time with blood glucose in the 70-180 mg/dL range as measured by continuous glucose monitoring from week 80 to week 164 of the PERL trial.<br>Other: % time below 54 mg/dL<br>* Percent of time with blood glucose below 54 mg/dL as measured by continuous glucose monitoring from week 80 to week 164 of the PERL trial.<br>Other: % time above 180 mg/dL<br>* Percent of time with blood glucose above 180 mg/dL as measured by continuous glucose monitoring from week 80 to week 164 of the PERL trial.<br>Other: % time above 250 mg/dL<br>* Percent of time with blood glucose above 250 mg/dL as measured by continuous glucose monitoring from week 80 to week 164 of the PERL trial.<br>Other: MAGE (Mean amplitude of glucose excursions)<br>* Mean amplitude of glucose excursions as measured by continuous glucose monitoring as measured by continuous glucose monitoring from week 80 to week 164 of the PERL trial.<br>Other: LBGI (Low Blood Glucose Index)<br>* Low blood glucose index as measured by continuous glucose monitoring from week 80 to week 164 of the PERL trial.<br>Other: HBGI (High Blood Glucose Index)<br>* High blood glucose index as measured by continuous glucose monitoring from week 80 to week 164 of the PERL trial.<br>Drug: Placebo<br>* Oral placebo tablets administered in the PERL Clinical Trial<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| iGFR at the end of the PERL trial | Glomerular filtration rate (GFR) at the end of the PERL trial, measured by the plasma clearance of non-radioactive iohexol (iGFR) and adjusted for the iGFR at baseline. | Week 164 of the PERL trial | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c at week 80 of the PERL trial | Hba1c value at week 80 of the PERL trial | Week 80 of the PERL Trial | 
| HbA1c at week 96 of the PERL trial | Hba1c value at week 96 of the PERL trial | Week 96 of the PERL Trial | 
| HbA1c at week 112 of the PERL trial | Hba1c value at week 112 of the PERL trial | Week 112 of the PERL Trial | 
| HbA1c at week 128 of the PERL trial | Hba1c value at week 128 of the PERL trial | Week 128 of the PERL Trial | 
| HbA1c at week 142 of the PERL trial | Hba1c value at week 142 of the PERL trial | Week 142 of the PERL Trial | 
| HbA1c at week 156 of the PERL trial | Hba1c value at week 156 of the PERL trial | Week 156 of the PERL Trial | 
| HbA1c at week 164 of the PERL trial | Hba1c value at week 164 of the PERL trial | Week 164 of the PERL Trial | 
| Mean blood glucose | Mean of blood glucose values measured by continuous glucose monitoring | From week 80 to week 164 of the PERL trial | 
| CV (coefficient of variation) of blood glucose | Coefficient of variation of blood glucose values measured by continuous glucose monitoring | From week 80 to week 164 of the PERL trial | 
| % time 70-180 mg/dL | Percentage of time with blood glucose in the 70-180 mg/dL range (as measured by continuous glucose monitoring) | From week 80 to week 164 of the PERL trial | 
| % time below 54 mg/dL | Percentage of time with blood glucose below 54 mg/dL (as measured by continuous glucose monitoring) | From week 80 to week 164 of the PERL trial | 
| % time above 180 mg/dL | Percentage of time with blood glucose above 180 mg/dL (as measured by continuous glucose monitoring) | From week 80 to week 164 of the PERL trial | 
| % time above 250 mg/dL | Percentage of time with blood glucose above 250 mg/dL (as measured by continuous glucose monitoring) | From week 80 to week 164 of the PERL trial | 
| MAGE (Mean amplitude of glucose excursions) | Mean amplitude of glucose excursions as measured by continuous glucose monitoring | From week 80 to week 164 of the PERL trial | 
| LBGI (Low blood glucose index) | Low blood glucose index based on blood glucose values measured by continuous glucose monitoring | From week 80 to week 164 of the PERL trial | 
| HBGI (High blood glucose index) | High blood glucose index based on blood glucose values measured by continuous glucose monitoring | From week 80 to week 164 of the PERL trial |