Acute Effects of Canagliflozin, a Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitor on Bone Metabolism in Healthy Volunteers
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|ClinicalTrials.gov Identifier: NCT02404870|
Recruitment Status : Completed
First Posted : April 1, 2015
Last Update Posted : October 11, 2021
- Canagliflozin (sold as InvokanaTM) is a new medicine for diabetes. But it might increase the bone fracture risk in people with diabetes.
- To see if Invokana has negative side effects on bone health.
- Healthy men ages 18 45.
- 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.
|Condition or disease||Intervention/treatment||Phase|
|Healthy Volunteers||Drug: Placebo Drug: Canagliflozin||Phase 1|
Canagliflozin is a new oral drug for the treatment of type 2 diabetes mellitus (T2DM), and is one of four 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.
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).
A randomized, blinded, placebo-controlled cross-over pilot study of healthy volunteers age 18 years and older with a BMI of 20 - 30 kg/m2.
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 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 Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||67 participants|
|Intervention Model:||Crossover Assignment|
|Official Title:||Acute Effects of Canagliflozin, a Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitor on Bone Metabolism in Healthy Volunteers|
|Actual Study Start Date :||September 16, 2014|
|Actual Primary Completion Date :||May 1, 2019|
|Actual Study Completion Date :||September 3, 2019|
Experimental: Admission 1 or 2
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.
Placebo Comparator: Admission 2 or 1
- AUC of FGF23 [ Time Frame: First 24-72 hours ]In this study, our primary endpoint is the area under the curve (AUC) for FGF23 for the 24-72 hours from the first day of administration of canagliflozin. The null hypothesis is that there will be no change in the mean 24-72 hours AUC of FGF23 after the treatment compared with the mean baseline value. We acknowledge that the magnitude and time course of changes (if any) in FGF23 are totally unknown.
- FGF23 peack or AUC [ Time Frame: 12 hours ]We have chosen 24-72 hour AUC as our best predictionbased on limited previous data on this subject. Therefore, we will include other measurements of FGF23, namely the 12 hr peak and 12 hour AUC for FGF23 to analyze possible changes that occur prior to 24 hours.
- Transtubular reabsorption of phosphate [ Time Frame: 12 hours ]Renal phosphate transport is a complex interplay between freely filtered phosphate by the glomerulus, reabsorption of phosphate by brush border transporters in the proximal renal tubule, serum phosphate levels and hormonal regulation.
- PTH [ Time Frame: 12 hours ]We aim to explore if the postulated decreased 1,25 vitamin D leads to a secondary hyperparathyroidism leading to detrimental effects on bone. We hope to define this relationship further by investigating the timing and magnitude of changes in PTH over this short term study. The previous study by Rosenstock et al. 43 may have demonstrated initial increased in PTH that returned to a new baseline (data not available), but it should be noted that (1) the analysis presented is mean data and therefore some individuals likely have higher than average numbers, and (2) small changes in baseline PTH can have important changes in bone homeostasis over time.
- 1, 25 vitamin D [ Time Frame: 12 hours ]In vivo and in vitro studies have demonstrated FGF23 is a potent regulator of 1 - hydroxylase causing rapid reductions in 1,25 vitamin D 66,74,75. Shimada et al. 66 demonstrated in rats that a single injection of FGF23 caused a rapid decrease in 1,25 vitamin D levels by 3 hours, prior to any changes in phosphate (9 hours) or PTH (no change). Therefore, we intend to define the extend and time course of change in 1,25 vitamin D in humans by SGLT2 inhibition.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02404870
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Michael T Collins, M.D.||National Institute of Dental and Craniofacial Research (NIDCR)|