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The purpose of this study is to determine the safety, tolerability and pharmacokinetics (how much of the drug gets into the blood and how long it takes the body to get rid of it) of single doses of EGT0001474 given to patients with Type 2 diabetes. The study will also evaluate how EGT0001474 affects the amount of glucose produced by the body in the urine.
EGT0001474 is a compound that may inhibit the effect of other compounds in the body known as sugar transporters. The use of EGT0001474 may enhance the elimination of glucose from the blood by increasing the amount of urine produced. This would help prevent an abnormal decrease in blood sugar (hypoglycemia) both during fasting and after meals without increasing insulin secretion (which may result in weight gain or an abnormal increase in blood sugar known as Type 2 diabetes).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| EGT0001474 | Experimental |
| |
| Placebo | Placebo Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| EGT0001474 | Drug | Cohort 1: single dose of 25 mg EGT0001474 given as an oral capsule; Cohort 2: single dose of 75 mg EGT0001474 given as 3 oral capsules; Cohort 3: single dose of 150 mg EGT0001474 given as 6 oral capsules. |
| Measure | Description | Time Frame |
|---|---|---|
| Safety and Tolerability of EGT0001474 | Safety and tolerability were measured in terms of the number of mild, moderate and severe adverse events experienced by any participants. | 25 days |
| AUC 0-t | Area under the plasma concentration-time curve from time 0 to time t | 3 days |
| AUC0-24 | Area under the plasma concentration-time curve from time 0 to hour 24 | 3 days |
| AUC Inf | Area under the plasma concentration-time curve from time 0 to infinity | 3 days |
| Cmax | Maximum plasma concentration | 3 days |
| Tmax | Time of maximum plasma concentration | 3 days |
| λz | Terminal phase rate constant | 3 days |
| t1/2 | Apparent terminal half life | 3 days |
| CL/F | The apparent rate of oral clearance of EGT0001474.Oral clearance was defined as rate of drug removal from the body after oral administration. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Mason W. Freeman, M.D. | Massachusetts General Hospital | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| dgd Research Inc., a Cetero Research Company | San Antonio | Texas | 78229 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 2198430 | Background | Blondel O, Bailbe D, Portha B. Insulin resistance in rats with non-insulin-dependent diabetes induced by neonatal (5 days) streptozotocin: evidence for reversal following phlorizin treatment. Metabolism. 1990 Aug;39(8):787-93. doi: 10.1016/0026-0495(90)90120-2. | |
| 16732006 | Background | Cowie CC, Rust KF, Byrd-Holt DD, Eberhardt MS, Flegal KM, Engelgau MM, Saydah SH, Williams DE, Geiss LS, Gregg EW. Prevalence of diabetes and impaired fasting glucose in adults in the U.S. population: National Health And Nutrition Examination Survey 1999-2002. Diabetes Care. 2006 Jun;29(6):1263-8. doi: 10.2337/dc06-0062. |
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For 3 weeks after enrollment and prior to assignment to treatment and receiving drug, subjects were screened (informed consent, medical history, vital signs, electrocardiogram, laboratory test results, and screening for drugs of abuse and alcohol use) and began a 14 day washout period (counseling, review of medications and adverse events).
The first subject was enrolled on 12 Jun 2009; the last subject was completed on 28 Jul 2009. Subjects participated at a CRO in San Antonio, TX.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo | Received 1, 3, or 6 placebo capsules once daily. |
| FG001 | EGT0001474 25 mg | Received one 25 mg capsule once daily. |
| FG002 | EGT0001474 75 mg | Received three 25mg capsules once daily. |
| FG003 | EGT0001474 150mg | Received six 25 mg capsules once daily. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | Received 1, 3, or 6 placebo capsules once daily. |
| BG001 | EGT0001474 25 mg | Received one 25 mg capsule once daily. |
| 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 | Safety and Tolerability of EGT0001474 | Safety and tolerability were measured in terms of the number of mild, moderate and severe adverse events experienced by any participants. | All patients who took study medication were included in the analysis. | Posted | Number | Events | 25 days |
|
25 days total (14 day washout, 4 days in study, 1 week follow up after dosing)
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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 | Placebo | Received 1, 3, or 6 placebo capsules once daily. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (11.1) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Yuan-Di Halvorsen | Theracos, Inc | 617 726-4236 | yhalvorsen@ccib.mgh.harvard.edu |
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| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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|
| Placebo | Drug | Placebo capsules to match EGT0001474 |
|
|
| 3 days |
| Vz/F | Apparent volume of distribution | 3 days |
| 18308683 | Background | American Diabetes Association. Economic costs of diabetes in the U.S. In 2007. Diabetes Care. 2008 Mar;31(3):596-615. doi: 10.2337/dc08-9017. |
| 18165335 | Background | American Diabetes Association. Standards of medical care in diabetes--2008. Diabetes Care. 2008 Jan;31 Suppl 1:S12-54. doi: 10.2337/dc08-S012. No abstract available. |
| 15624123 | Background | Ehrenkranz JR, Lewis NG, Kahn CR, Roth J. Phlorizin: a review. Diabetes Metab Res Rev. 2005 Jan-Feb;21(1):31-8. doi: 10.1002/dmrr.532. |
| 18356408 | Background | Han S, Hagan DL, Taylor JR, Xin L, Meng W, Biller SA, Wetterau JR, Washburn WN, Whaley JM. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes. 2008 Jun;57(6):1723-9. doi: 10.2337/db07-1472. Epub 2008 Mar 20. |
| 18705823 | Background | Jabbour SA, Goldstein BJ. Sodium glucose co-transporter 2 inhibitors: blocking renal tubular reabsorption of glucose to improve glycaemic control in patients with diabetes. Int J Clin Pract. 2008 Aug;62(8):1279-84. doi: 10.1111/j.1742-1241.2008.01829.x. |
| 19129749 | Background | Komoroski B, Vachharajani N, Feng Y, Li L, Kornhauser D, Pfister M. Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus. Clin Pharmacol Ther. 2009 May;85(5):513-9. doi: 10.1038/clpt.2008.250. Epub 2009 Jan 7. |
| 9392506 | Background | Krook A, Kawano Y, Song XM, Efendic S, Roth RA, Wallberg-Henriksson H, Zierath JR. Improved glucose tolerance restores insulin-stimulated Akt kinase activity and glucose transport in skeletal muscle from diabetic Goto-Kakizaki rats. Diabetes. 1997 Dec;46(12):2110-4. doi: 10.2337/diab.46.12.2110. |
| 10480610 | Background | Oku A, Ueta K, Arakawa K, Ishihara T, Nawano M, Kuronuma Y, Matsumoto M, Saito A, Tsujihara K, Anai M, Asano T, Kanai Y, Endou H. T-1095, an inhibitor of renal Na+-glucose cotransporters, may provide a novel approach to treating diabetes. Diabetes. 1999 Sep;48(9):1794-800. doi: 10.2337/diabetes.48.9.1794. |
| 1740408 | Background | Pajor AM, Wright EM. Cloning and functional expression of a mammalian Na+/nucleoside cotransporter. A member of the SGLT family. J Biol Chem. 1992 Feb 25;267(6):3557-60. |
| 14569097 | Background | Santer R, Kinner M, Lassen CL, Schneppenheim R, Eggert P, Bald M, Brodehl J, Daschner M, Ehrich JH, Kemper M, Li Volti S, Neuhaus T, Skovby F, Swift PG, Schaub J, Klaerke D. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol. 2003 Nov;14(11):2873-82. doi: 10.1097/01.asn.0000092790.89332.d2. |
| 7201854 | Background | Toggenburger G, Kessler M, Semenza G. Phlorizin as a probe of the small-intestinal Na+,D-glucose cotransporter. A model. Biochim Biophys Acta. 1982 Jun 14;688(2):557-71. doi: 10.1016/0005-2736(82)90367-4. |
| 8814948 | Background | Tsujihara K, Hongu M, Saito K, Inamasu M, Arakawa K, Oku A, Matsumoto M. Na(+)-glucose cotransporter inhibitors as antidiabetics. I. Synthesis and pharmacological properties of 4'-dehydroxyphlorizin derivatives based on a new concept. Chem Pharm Bull (Tokyo). 1996 Jun;44(6):1174-80. doi: 10.1248/cpb.44.1174. |
| BG002 | EGT0001474 75 mg | Received three 25mg capsules once daily. |
| BG003 | EGT0001474 150mg | Received six 25 mg capsules once daily. |
| BG004 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
Received three 25mg capsules once daily. |
| OG003 | EGT0001474 150mg | Received six 25 mg capsules once daily. |
|
|
| Primary | AUC 0-t | Area under the plasma concentration-time curve from time 0 to time t | Posted | Mean | Standard Deviation | ng*hr/mL | 3 days |
|
|
|
| Primary | AUC0-24 | Area under the plasma concentration-time curve from time 0 to hour 24 | Posted | Mean | Standard Deviation | ng*hr/mL | 3 days |
|
|
|
| Primary | AUC Inf | Area under the plasma concentration-time curve from time 0 to infinity | Posted | Mean | Standard Deviation | ng*hr/mL | 3 days |
|
|
|
| Primary | Cmax | Maximum plasma concentration | Posted | Mean | Standard Deviation | ng/mL | 3 days |
|
|
|
| Primary | Tmax | Time of maximum plasma concentration | Posted | Median | Full Range | hour | 3 days |
|
|
|
| Primary | λz | Terminal phase rate constant | Posted | Mean | Standard Deviation | 1/hour | 3 days |
|
|
|
| Primary | t1/2 | Apparent terminal half life | Posted | 2011 | Mean | Standard Deviation | hour | 3 days |
|
|
|
| Primary | CL/F | The apparent rate of oral clearance of EGT0001474.Oral clearance was defined as rate of drug removal from the body after oral administration. | Posted | Mean | Standard Deviation | mL/hr | 3 days |
|
|
|
| Primary | Vz/F | Apparent volume of distribution | Posted | Mean | Standard Deviation | mL | 3 days |
|
|
|
| 0 |
| 6 |
| 2 |
| 6 |
| EG001 | EGT0001474 25 mg | Received one 25 mg capsule once daily. | 0 | 6 | 0 | 6 |
| EG002 | EGT0001474 75 mg | Received three 25mg capsules once daily. | 0 | 6 | 4 | 6 |
| EG003 | EGT0001474 150mg | Received six 25 mg capsules once daily. | 0 | 6 | 2 | 6 |
| Blood triglyceride increased | Investigations | MedDRA (11.1) | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA (11.1) | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (11.1) | Systematic Assessment |
|
| Malaise | General disorders | MedDRA (11.1) | Systematic Assessment |
|
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA (11.1) | Systematic Assessment |
|
| Musculoskeletal stiffness | Nervous system disorders | MedDRA (11.1) | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (11.1) | Systematic Assessment |
|
| Vessel puncture site haematoma | Investigations | MedDRA (11.1) | Non-systematic Assessment |
|
| Vessel puncture site reaction | General disorders | MedDRA (11.1) | Non-systematic Assessment |
|
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| D004700 | Endocrine System Diseases |