Beta Cell Restoration Through Fat Mitigation
BetaFat is a 2-arm, unblinded study to compare gastric banding to treatment with metformin
over a 24-month period in moderately obese adults with pre- or mild type 2 diabetes. The
primary outcome will be change in β-cell compensation for insulin resistance, which the
investigators will compare between groups. Secondary analyses will include other potential
markers of β-cell health and potential mediators of treatment-specific effects. The main
focus will be on mediators related to obesity. Clinically, the project will serve as a test
of concept for use of gastric banding relatively early in the spectrum of obesity and β-cell
disease. Biologically, the results will provide crucial information on potential mediators
of β-cell failure and its arrest or reversal in the context of obesity. Those mediators will
guide the development of more effective treatment and monitoring for the β-cell disease that
causes type 2 diabetes.
A Randomized Phase 2, Double-blind, Placebo-controlled, Treat-to-Target, Parallel-group,
3-arm, Multicenter Study to Assess the Efficacy and Safety of Canagliflozin as Add-on
Therapy to Insulin in the Treatment of Subjects with Type 1 Diabetes Mellitus
Canagliflozin (CANA) is an oral antihyperglycemic agent (AHA) approved for the treatment of subjects with Type 2 Diabetes Mellitus (T2DM). In subjects with T2DM, CANA lowers blood glucose by an insulin-independent mechanism and has an intrinsic low risk of hypoglycemia. In subjects with T1DM the addition of CANA to intensive insulin therapy is expected to lead to less insulin requirement which is expected to lead to a reduced insulin dose requirement, weight gain, glucose variability and low the risk of hypoglycemia. The primary objective of this study is to assess the effect of CANA 100 mg and 300 mg compared with placebo on the change in HbA1c and body weight after 18 weeks of treatment. This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, interventional study of CANA in male and female subjects between the ages of 25 years to 65 years, inclusive, with a diagnosis of T1DM for at least 1 year, and inadequate glycemic control (ie, HbA1c of 7.0% to 9.0%) on basal plus bolus insulin at screening. Approximately 330 subjects will be randomly assigned in this study (20 at the USC site), with approximately 110 subjects randomized per treatment group. The primary hypothesis will be assessed using a composite primary endpoint: proportion of subjects with HbA1c reduction 0.4% and no increase in body weight. Assuming the proportion of subjects meeting the composite criteria is 20% for placebo and 40% for each CANA dose, and assuming a 2-sided family-wise Type I error rate of 0.05, it is estimated that a sample size of 100 randomized subjects per group will be required to achieve 84% power for the comparison of each CANA dose to placebo. A modestly larger sample size (110 subjects per arm) will be randomized to each treatment arm. The modified intent-to-treat (mITT) analysis set includes all randomized subjects who have received at least 1 dose of double-blind study medication. The per-protocol (PP) analysis set consists of all mITT subjects who complete the 18-week double-blind treatment phase, and have no major protocol deviations that may affect the interpretation of the primary efficacy endpoint. The completers analysis set consists of all mITT subjects who complete the 18-week double blind treatment period. The primary efficacy endpoint will be proportion of subjects with HbA1c reduction 0.4% and no increase in body weight after 18 weeks of treatment. The primary efficacy endpoint will be analyzed longitudinally using a generalized linear mixed model. The model will include the fixed, categorical effects of treatment, stratification factor (use of CSII vs MDI), visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline HbA1c, baseline body weight, and baseline-by-visit interactions. An unstructured covariance will be used to model the within-patient errors. The odds ratio and 2-sided 95% confidence interval (CI) for the treatment comparison at Week 18 (CANA vs placebo) will be estimated based on this model. As a sensitivity analysis, the last-observation-carried-forward method will be applied when the Week 18 values are missing. The odds ratio will be assessed by a logistic regression model with terms for baseline HbA1c, baseline body weight, treatment and stratification factor.
EMR200147-500: A prospective, randomized, placebo-controlled, double-blind clinical trial to evaluate whether EGRIFTA (tesamorelin for injection), 2 mg once daily SC, increases the risk of development or progression of diabetic retinopathy when administered to HIV-infected subjects with abdominal lipohypertrophy and concomitant diabetes
Human immunodeficiency virus (HIV, the virus that causes AIDS)-associated lipodystrophy is a medical condition characterized by body changes, including accumulation of fat in the stomach cavity, breasts, and the upper back associated with multiple blood and hormone disturbances. EGRIFTA is a drug that mimics human hypothalamic GHRF (hGHRF, a hormone in the body made by a gland near the brain that increases other hormones such as Growth Hormone) which was shown to significantly reduce visceral adipose tissue (VAT, which is a name for fat in stomach cavity) after 26 weeks of treatment compared with injections of placebo (a substance with no activity) in two relatively large multi-center, yearlong studies. After 26 weeks, there was no change in blood sugar between the treated and the placebo groups. The mean change in hemoglobin A1c (HbA1c, a measure of what the blood sugar has been over the prior 3 months time) from baseline to 26 weeks was slightly higher in the treated group compared to the placebo group, but this is unlikely to represent a medically important difference. After 52 weeks the change in HbA1C from baseline was no longer considered different between groups.The subject populations examined in these studies may not be reflective of the diabetic HIV-infected subjects with increased abdominal fat who will be treated with EGRIFTA in the present study. EGRIFTA was approved by the US FDA on November 10, 2010 and is indicated for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy. As a condition of approval of EGRIFTA, a study will be conducted to assess the potential of EGRIFTA to cause or worsen diabetic retinopathy (DR, blood vessel problems in the eye that can lead to blindness in some cases) in HIV-infected subjects who also have abdominal lipohypertrophy and diabetes.Design: This is a placebo-controlled (meaning some participants will have injections of an inactive substance instead of EGRIFTA, double-blind (meaning neither the study team nor the participant) clinical trial to evaluate whether EGRIFTA (tesamorelin for injection), 2 mg once daily, increases the risk of development or progression of DR when given to HIV-infected subjects with abdominal lipohypertrophy and diabetes.The primary objective of the trial is to evaluate whether EGRIFTA, 2 mg once daily, is not worse than placebo for a minimum of 36 months of treatment as assessed by a worsening of DR.Following assignment to a treatment group, subjects will return to the study site for laboratory and safety assessments at 1.5, 3, 6, 12, 18, 24, 30, and 36 months. Additional visits will occur at Months 9, 15, 21, 27, and 33 for assessment of side effects and other medications and resupply of study drug. Assessment of DR will occur at screening and at the Months 6, 12, 24, and 36 visits. Main entry criteria: Adult HIV-infected subjects with abdominal lipohypertrophy and type 2 diabetes. Stable anti-retroviral therapy (ART, the medications used to treat HIV) at least 8 weeks; current HbA1c between 6.0% and 12.0%; Diabetes has been treated for at least 1 year by diet alone, insulin alone, pills, or other injections plus insulin according to current American Diabetes Association (ADA) guidelines, and doses have been stable for 3 months; cholesterol lowering drugs allowed if stable dose for at least 2 months; ; Women: not pregnant or breast feeding, are post-menopausal, surgically unable to have babies, or using acceptable birth control; Women over 40 years old: normal mammogram within 6 months prior; Men: normal prostate exam and PSA (prostate specific antigen, a blood test which is increased with prostate cancer and other conditions) within 6 months.Exclusion: Type 1 diabetes; Body mass index (BMI) < 20 kg/m2; Opportunistic infection or AIDS-defining illness within 3 months; Current or past malignancy (except certain skin and cervical cancers); Women: personal or family history (mother or sister) of breast cancer; severe DR; Current or past eye infection that would prevent assessment of DR; Previous DR treatment; certain hormonal problems; Head xrays or head trauma affecting hormones; Uncontrolled high blood pressure, severe heart disease, stroke; Abnormal liver or kidney function; severe anemia Men: change in, or high dose of, testosterone within 2 months; Anabolic steroids, certain hormonal treatments, drug or alcohol dependence within 6 months; drug treatment for overweight within 3 months.Primary endpoint: The difference in percentages of subjects with a significant increase in DR scale between subjects treated with EGRIFTA and those treated with placebo.Statistical methods: With a 2.5% 1-sided type I error rate (the chance that the study will come to the wrong conclusion), 80% power (how likely the study will show a positive result), and a 2:1 randomization ratio (2 participants on EGRIFTA for each on placebo), a total of 453 subjects (302 EGRIFTA and 151 placebo) will be required to show that the DR progression rate for the EGRIFTA-treated subjects is greater than that of the placebo subjects by no more than 10%. Assuming a 30% dropout rate, a total of 648 subjects (432 EGRIFTA and 216 placebo) will be needed for this trial.
Post Approval Study of the TS (Threshold Suspend) Feature with a Sensor-Augmented Pump System
This Post Approval Study is a longitudinal, multi-center trial. Up to 1,200 subjects will be
enrolled in investigational centers across the United States. Subjects will attend 6 study
visits over a period of one year.
The study objective is to demonstrate that home use of Threshold Suspend (TS) is not
associated with glycemic deterioration, as measured by change in A1C.
A Randomized Trial Comparing Use of Continuous Glucose Monitoring With and Without Routine Blood Glucose Monitoring in Adults with Type 1 Diabetes (REPLACE)
Continuous glucose monitoring (CGM) offers the opportunity to improve glycemic control, including a reduction in hypoglycemia. However, current FDA CGM device labeling is labeled as an adjunct to self-monitoring of blood glucose rather than a replacement. Further, the Centers for Medicare and Medicaid Services (CMS) does not provide coverage for CGM as CGM devices do not meet the Medicare definition of durable medical equipment and do not fall under any other Medicare benefit category. A study comparing CGM used solely as an adjunctive device, as per the FDA labeling, versus CGM used largely in lieu of Blood Glucose Monitoring (BGM) measurements would provide valuable data. If indeed insulin dosing decisions are proven to be safe and effective using CGM alone (without BGM confirmation) compared to CGM with BGM confirmations, this study would also pave the way for a new standard diabetes management protocol and therapy that would not require eight BGM measurements (i.e. finger sticks) a day and ease the burden of managing type 1 diabetes. The primary objective of the study is to determine whether the routine use of CGM without BGM confirmation is as safe and effective as CGM used as an adjunct to BGM. The study design is a 6-month parallel group multi-center randomized noninferiority clinical trial. The study population includes adults >18 years old with T1D for at least 1 year who (1) are using an insulin pump, (2) have HbA1c level <9%, (3) have had no severe hypoglycemia in the last 12 months requiring assistance of another individual for treatment and no events resulting in seizure of loss of consciousness in the past 3 years, and (4) have no significant hypoglycemia unawareness. Successful run-in includes compliance with use of CGM >21 days during the prior 28 days and an average of >4 BGM measurements must have been made on at least 90% of days. Subjects with CGM values <60 mg/dl for more than 10.0% will not be eligible for randomization. Subjects will be randomly assigned with 2:1 probability to the CGM Only and CGM+BGM groups, respectively. The primary outcome will be the time in range of 70 to 180 mg/dl, measured with CGM over the full 6 months of the study. Analyses will follow the intent-to-treat principle with all participants analyzed in the group to which they were randomized. The primary analysis will include all participants. The relationship between the time in range and the treatment group will be examined through a least squares regression model adjusting for baseline time in range, CGM user at time of enrollment, and possibly clinical center. If the number of participants per clinical center is too small to include center as a fixed effect (<10 participants/center) then clinical center will be included as a random effect instead. Previous data suggest that the time in range is typically approximately normally distributed so a transformation should not be necessary. However, this will be explored and a transformation or nonparametric analyses will be used instead if the data are highly skewed. A one-sided 95% confidence interval for the difference in treatment groups (CGM+BGM group minus CGM Only group) will be computed.