Bethesda, Maryland 20892


Purpose:

Background: - Canagliflozin (sold as InvokanaTM) is a new medicine for diabetes. But it might increase the bone fracture risk in people with diabetes. Objective: - To see if Invokana has negative side effects on bone health. Eligibility: - Healthy men ages 18 45. Design: - Participants will be screened with a medical history, physical exam, and blood tests. A nutritionist will discuss their dietary history and the study dietary requirements. Participants will get a food diary to record what they eat and drink on 3 separate days. - Participants will have a DEXA scan x-ray test of bone health. Participants will lie still on a table while a small camera passes over the body. - Participants will have 2 stays in the clinic. They will be 1 week apart and each last 6 overnights starting on a Sunday. - Before each stay, participants will: - Pick up food each day for 7 days. They will get breakfast, lunch, dinner, and snacks. They must eat only the food provided during these times. - Collect their urine twice. - During the stays, participants will: - Be evaluated by a doctor and have blood drawn. - On each Monday, participants will: - Skip breakfast - At about 8 a.m. take a placebo pill in one stay, the study drug in the other stay. - Drink 6 ounces of water every 2 hours for 4 hours. - An intravenous (IV) catheter will be inserted into an arm. Blood will be drawn every 2 hours from 8 a.m. until noon. - Get lunch. - Have blood testing again at 8pm and midnight. - Repeat the testing days 2 5. - Have urine collected.


Study summary:

Background: Canagliflozin is a new oral drug for the treatment of type 2 diabetes mellitus (T2DM), and is one of two recently FDA approved sodium glucose co-transporter 2 (SGLT2) inhibitors, which target renal glucose reabsorption and offer promising improvement in HbA1c. In the approval process, the FDA Advisory Committee reviewed data suggesting that canagliflozin increased the incidence of fractures. In addition, the drug induced changes in phosphate, bone resorption markers, parathyroid hormone (PTH) and vitamin D metabolism which might mediate the adverse changes in bone homeostasis. For a variety of reasons, the data on bone fracture risk are relatively limited. First, the drug s development program was focused primarily on demonstrating efficacy, and bone fractures were only one of many safety end-points which were monitored. Second, only a minority of patients (approximately 1%) experienced bone fractures in the course of the development program. Finally, there appears to be a lag time prior to the time increased bone resorption translates into a significant increase in the rate of bone fractures. We hypothesize that this class of drugs causes a cascade of hormonal changes induced by increased phosphorus reabsorption that leads to significant changes in fibroblast growth factor 23 (FGF23), PTH, and vitamin D metabolism which ultimately increase fracture risk. Aim: The primary endpoint is to determine the effects of canagliflozin on bone health by evaluating changes in the area under the curve (AUC) of FGF23 during the first 24-72 hours. Secondary endpoints include the evaluation of canagliflozin on other biochemical parameters in the early phase (1 week) of drug administration during which we hypothesize a new steady state will be reached related to bone metabolism including PTH, 1,25 vitamin D, tubular reabsorption of phosphate (TRP), and carboxy-terminal telopeptide (CTX). Methods: A randomized, blinded, placebo-controlled cross-over pilot study of healthy volunteers ages 18 years and older with a BMI of 20 30 kg/m(2). Patients will be randomized to canagliflozin (300mg once daily) or placebo for 5 days and will be studied as inpatients (NIH Clinical Center metabolic unit). Serial blood and urine testing for 4 hours after daily drug administration and at 12, 16 and 24 hours thereafter will be used to assess changes in the pre-specified endpoints. Each subject will be provided a diet containing fixed contents of phosphate, sodium, and calcium throughout the study, beginning 7 days prior to the administration of drug (or placebo). Study Objectives: The primary objective of this study is to determine the AUC change in FGF23 within 24-72 hours caused by the SGLT2 inhibitor canagliflozin. We will also examine the effects of canagliflozin on various biochemical markers of bone metabolism (including phosphorus, PTH, various hydroxylated vitamin D derivatives, calcium, and markers of bone turnover) during the first 5 days of drug administration. Background and Rationale: Standards of Care in Diabetes Mellitus Type 2 (T2DM) The epidemic of T2DM encompasses a spectrum of pathophysiological derangements that require a focused and individualized therapeutic approach. When considering medication choices, the American Diabetes Association (ADA) guidelines suggest inclusion of the duration of disease, age, body weight, life expectancy, expense and variations in microvascular and macrovascular complications. Therapy is usually initiated with metformin which is well known to decrease hepatic gluconeogenesis and effectively lower hemoglobin A1c (HbA1c). This drug is usually chosen as first line as it is well tolerated, has comparable efficacy, an attractive generic price and low rate of toxicity. Over time, progressive deterioration of beta cell function and insulin resistance usually require add-on therapies. Options are sulfonlyureas, dipeptidyl peptidase-4 (DPP4) inhibitors and thiazoladinediones (TZDs). However, as Bennett et al recently evaluated in a meta-analysis, most therapies have similar effectiveness in reduction of HbA1c by 1 percent, but each class has different side effects. TZDs, for example, offer comparative improvements in hyperglycemia, but have more side effects than other agents. Additionally, evidence for serious adverse events emerged years after this class of drugs had been on the market, thus delaying appropriate recognition. Liver toxicity had been the first serious side effect to be discovered and lead to the withdrawal of troglitazone, and restrictions were temporarily placed on rosiglitazone because of concerns related to increased myocardial infarction risk. TZDs have also been shown to increase the incidence of chronic heart failure (CHF) in select patients 8, bone fractures especially in women, and bladder cancer especially in those receiving therapy for 5 years or longer. Risk assessments are important for all patients when considering initiation of a new drug. In particular, vulnerable populations are at the highest risk, including older T2DM patients with multiple co-morbidities who often suffer higher rates of adverse medication effect. Likewise, patients diagnosed with T2DM at a younger age are likely to receive these drugs for very long duration, which heightens concerns about long term drug toxicities. Therefore, it is critical that selection of antidiabetic medications account for both short term and long term consequences. Rationale for SGLT-2 inhibitors as Novel Drugs for the Treatment of T2DM Hyperglycemia is a complex disease state that has been described as an interplay among the ominous octet 18 in which the pancreas, liver, small intestine, skeletal muscle, adipose tissue, brain and kidney all contribute to glucose metabolism. Pharmacotherapy development has effectively sought to target each of these mechanisms via various pathways. The renal reabsorption of glucose has only recently become a focus for therapeutic intervention with the introduction of sodium glucose co-transporter 2 (SGLT2) inhibitors in 2013. SGLT2 is located in the S1 segment of proximal renal tubule and is a high-capacity, low-affinity transporter that mediates the majority of the glucose reabsorption. Glucose which escapes SGLT2 is reabsorbed by SGLT1, a low-capacity, high-affinity transporter located in the S3 segment of the proximal renal tubule. Under conditions where SGLT2 is inactivated by either a mutation or an inhibitor, urinary glucose excretion can range from 20-200 g/day or more. The evidence for SGLT2 as a major pathway for renal glucose reabsorption has come from genetic studies of individuals with familial renal glucosuria (FRG), an autosomal recessive disorder of SLGT2. It has been almost a century since the first case has been described which causes glucosuria in the setting of a normal blood glucose concentration and the absence of other signs of renal tubular dysfunction. Different phenotypes have been described based on the extent of glucosuria. Individual and kindred studies have helped identify least 44 different mutations in the SLC5A2 gene. Long term follow up of these individuals has demonstrated no major health problems. However, given inconsistency of follow up and a small number of reported cases, it is difficult to infer the true extent of complications. Another genetic defect of renal glucose transport is known to be due to mutations in the GLUT2 transporter, which is responsible for Fanconi-Bickel syndrome (FBS). This is a rare autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the GLUT2 (SLC2A2) gene. It is characterized by hepatorenal glycogen accumulation, proximal renal tubular dysfunction (Fanconi nephropathy), and hypophosphatemic vitamin D dependent rickets with severe growth retardation. The relation between glucose transport and phosphate metabolism is not well understood. Mannstadt et al evaluated two families with varying degrees of hypophosphatemic rickets and urinary phosphate wasting and found novel mutations in GLUT2 as a causative factor for calcium and phosphate imbalances, thought to be due to changes in the phosphate transporter Npt2c. To support this hypothesis, they studied tgGlut2-/- mice who also demonstrated a decrease in Npt2c expression in the proximal renal tubules. While the interplay between this genetic disease and hypophosphatemic rickets is still being elucidated, changes in glucose homeostasis have been shown to have profound effects on bone health and mineral metabolism. Pharmacological support for the development of SGLT2 inhibitors comes from studies using phlorizin, a natural product discovered in 1835 from root bark of apple trees. Von Mering discovered that ingestion of phlorizin produced glucosuria in humans. Rossetti and DeFronzo et al found that in partially pancreatectomized rats, phlorizin normalized blood glucose levels. While this theoretical concept supported the idea that glucosuria could normalize fasting and fed plasma glucose levels (and reverse insulin resistance in animals), it did not immediately translate into pharmacotherapy due to phlorizin s multiple limitations: (1) low selectivity for SGLT2 over SGLT1 causing frequent gastrointestinal side effects, (2) degradation by the gut enzyme disaccharidase reducing the oral bioavailability, and (3) the interaction of one of its metabolites, phloretin, which inhibits GLUT2 and GLUT1 glucose reabsorption in the gut. Canagliflozin was the first SGLT2 inhibitor to be approved by the FDA, and its approval took place in January, 2013. However, data on dapagliflozin had been presented to the FDA for review as early as July, 2011, but its approval was delayed until January 2014, mostly because of concerns about increased risks for bladder and breast cancer. The SGLT2 inhibitor which we will study in this protocol, decreases the renal threshold for glucose excretion (occurring on average > 70-90mg/dL in the presence of canagliflozin) and increases glucosuria to approximately 80-100 grams/day, thereby reducing plasma glucose. At the highest FDA approved dose of canagliflozin (300mg/day) given as monotherapy, HbA1c improves by 1.2%. In addition, canagliflozin therapy leads to several other pharmacological effects: evidence of 2-3% weight loss, decreases in systolic blood pressure by about 4.5mmHg from baseline, and an increase in insulin sensitivity all of which contribute to a beneficial clinical profile for patients with T2DM. SGLT2 Inhibitor Changes in Bone Health: A Summary of the Data The first indication that SGLT2 inhibitors could possibly influence bone health came from animal studies 38. Rats exposed to high doses of dapagliflozin (the first developed drug of this class) were observed to have disturbances in calcium homeostasis, tissue mineralization, increased trabecular bone and renal medullary tubular degeneration. The proposed mechanism was thought to be due to the high dose of dapagliflozin causing non-selective inhibition of SGLT1 in the gut, thereby altering the pH balance in the intestinal lumen and increasing calcium reabsorption. These findings are not thought to be relevant to human pharmacology when SGLT2 inhibitors are administered at approved doses. Nevertheless, given these findings, special attention was paid to bone mineralization and changes during clinical development. Specifically, data presented at the FDA advisory committee meeting on dapagliflozin in July 2011 demonstrated an increase in fracture rate after 104 weeks in a dedicated study of patients with moderate renal impairment (eGFR 30-59mL/min/1.73m(2)) with 9.4% fractures on the 10 mg dose and 6% fractures on the 5 mg dose, versus zero fractures on placebo. In patients with normal renal function, they also noted a 2-fold increase in fractures. However, the sponsor argued that the imbalance was non-significant because of the associated small laboratory changes, possible influence of weight loss on fracture rate, minimal effects on bone mineral density (BMD) and inconsistencies between various short term and long term studies. Ultimately, the drug was not approved for other safety related reasons, but further studies dedicated to bone health were recommended. Later, Ljuggren et al reported no significant changes in bone markers or changes in DEXA at 50 weeks, but mean increases in phosphate were observed and trends towards increased CTX and procollagen type 1 N-terminal propeptide (P1NP) were also evident. Canagliflozin, the second drug reviewed by the FDA in January 2013, also underwent a dedicated analysis on bone safety due to concerning findings in animal studies similar to those of dapagliflozin. Specific parameters that were evaluated included calcium, phosphorus, bone turnover markers and fracture rates. A phase II study found a 23-37% rise in the bone resorption marker CTX by week 3 which persisted until week 12. Likewise, an increase in PTH was observed by week 3, which returned toward baseline by week 6-12. At high doses, this study also demonstrated slight decreases in 25-hydroxyvitamin D as well as 1,25 hydroxyvitamin D. In a pooled analysis of placebo controlled studies (n=2,313) for 26 weeks, a 5.1% mean change in serum phosphate was observed among the highest dose of 300mg compared to placebo. In another 26-week analysis (n= 269) of renal impairment patients (eGFR greater than or equal to 30 and < 50 ml/min/1.73 m(2)), serum phosphate increased 7.8% above baseline and 1,25-hydroxyvitamin D decreased by 8.1% from baseline 44. Interestingly, the most acute changes in serum phosphate (0.5 mg/dL mean change from baseline) was reported within three weeks of study initiation. A dedicated bone study in older adults age 55-80 (n=715), the highest dose of 300mg of canagliflozin increased serum CTX over baseline by 24.9% at 26 weeks and by 22% at 52 weeks, with P1NP decreasing by 6.9% in the highest dose group at 26 weeks. Also in the highest dose group, DEXA scanning found a decrease of 0.7% mean percent change in the lumbar spine and total hip, and quantative-CT demonstrated a decrease of 1.9% and 1.6% in the lumbar spine and total hip, respectively. In terms of fractures, a prospectively adjudicated analysis across all phase III studies demonstrated a 0.6% difference in the fracture rate between canagliflozin and non-canagliflozin groups. Analysis by fracture location and trauma classification demonstrated an imbalance in upper limb fractures not favoring canagliflozin. This imbalance persisted in low trauma upper limb fractures and spine (Figure 1). In a pooled analysis of all treatment arms, females had a higher incidence of upper limb fractures (1.2% [31/2608]) compared to placebo (0.4% [5/1338]). The location of distal extremities, including the hand, distal forearm and wrist are similar to the wide variety of fracture sites found in other diseases such a primary hyperparathyroidism.


Criteria:

- INCLUSION CRITERIA: We are targeting healthy greater than or equal to 18 years old, inclusive of all races and ethnicity within a BMI of 20 30 kg/m(2). Specifically, we have defined healthy to mean: normal fasting glucose and hemoglobin A1c less than or equal to 6%, normal Hb, no glucosuria, normal renal function (based on normal serum creatinine + Cystatin C), urine albumin:creatinine ratio, protein:creatinine ratio, and GFR > 80 as calculated by the CKD-Epi equation and normal lab urinalysis. EXCLUSION CRITERIA: If you have any of the following health issues, you cannot participate in the study: - Presence of heart disease, untreated high blood pressure (>140/90 mm Hg), orthostatic hypotension or symptomatic hypotension, cancer, diabetes, recurrent symptomatic hypoglycemia and /or history of recurrent genital or urinary tract infection, thyroid disease, or any other condition that affects bone health - Past history of eating disorder or psychiatric disorders, including severe depression, anxiety, or psychosis or presently on treatment with medications for any of these conditions - Taking certain medications, especially those that affect bone metabolism (e.g., high dose vitamin D [>1000 units daily] or calcium supplements [>800mg daily], high dose vitamin A [>20,000 units daily], phosphate binding antacids, calcitonin, calcitriol, growth hormone, or any anti-seizure medications for any reason including valproic acid, lamotrigine), certain medications for high blood pressure (diuretics), steroids including inhalers, diet/weight loss medications, or any other medications at the discretion of the principal investigator and/or study team - Have started, increased or decreased calcium [>400mg daily] or vitamin D [>1000 units daily] supplements within 2 weeks of the study - Dependence or regular use of alcohol (>2 drinks per day), tobacco (smoking or chewing), amphetamines, cocaine, heroin or marijuana over the past 6 months - Volunteers will be excluded if they have abnormal blood concentrations of - inorganic phosphate level (less than or equal to 2.5 mg/dl or greater than or equal to 4.8 mg/dl), - parathyroid hormone (PTH) (less than or equal to 60 pg/ml), - creatinine (less than or equal to 1.5 mg/dl) or eGFR (< 80 ml/min/1.73sq.m), - fasting glucose (greater than or equal to 100 mg/dl), - hemoglobin (less than or equal to 11 g/dl), - liver function tests (more than twice normal), - testosterone (less than or equal to 260 ng/dl) - Participation in a vigorous exercise program (>3h/day of vigorous activity) - Consume more than 300 mg/day of caffeine (about two to three 8 fluid ounce servings) - Have strict dietary concerns (e.g., vegan or kosher diet, multiple food allergies) - Cannot commit to the research experience at the Clinical Research Center as required by the study timeline - Have previous hypersensitivity reaction to canagliflozin (including but not limited to rash, raised red patches on your skin (hives), swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing). - Positive urine pregnancy test and/or planning to become pregnant during the course of the study. - You are unwilling to use effective contraceptive methods for duration of study (hormonal or barrier. - Irregular menstrual cycles


NCT ID:

NCT02404870


Primary Contact:

Principal Investigator
Kristina I Rother, M.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Kristina I Rother, M.D.
Phone: (301) 435-4639
Email: kristinar@intra.niddk.nih.gov


Backup Contact:

N/A


Location Contact:

Bethesda, Maryland 20892
United States

For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)
Phone: 800-411-1222
Email: prpl@mail.cc.nih.gov

Site Status: Recruiting


Data Source: ClinicalTrials.gov

Date Processed: June 25, 2018

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