Safety, Tolerability and Pharmacokinetics Study of EGT0001474 in Subjects With Type 2 Diabetes

• Sponsor: Theracos (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00924053
• Collaborator: (none)
• Enrollment: 24
• Location: 1
• Arms: 2
• Duration (Days): 30
• Patients Per Site Per Month: 24.4

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus Type 2	Drug: EGT0001474; Drug: Placebo	Phase 1

Detailed Description

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase I, Randomized, Placebo-Controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of EGT0001474 in Subjects With Type 2 Diabetes
• Study Start Date: Jun 1, 2009
• Actual Primary Completion Date: Jul 1, 2009
• Actual Study Completion Date: Jul 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: EGT0001474	Drug: EGT0001474; 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.; Other Names: Human SGLT2 inhibitor
Placebo Comparator: Placebo	Drug: Placebo; Placebo capsules to match EGT0001474; Other Names: Human SGLT2 inhibitor

Outcome Measures

Primary Outcome Measures

1. Safety and Tolerability of EGT0001474 [25 days]

   Safety and tolerability were measured in terms of the number of mild, moderate and severe adverse events experienced by any participants.

2. AUC 0-t [3 days]

   Area under the plasma concentration-time curve from time 0 to time t

3. AUC0-24 [3 days]

   Area under the plasma concentration-time curve from time 0 to hour 24

4. AUC Inf [3 days]

   Area under the plasma concentration-time curve from time 0 to infinity

5. Cmax [3 days]

   Maximum plasma concentration

6. Tmax [3 days]

   Time of maximum plasma concentration

7. λz [3 days]

   Terminal phase rate constant

8. t1/2 [3 days]

   Apparent terminal half life

9. CL/F [3 days]

   The apparent rate of oral clearance of EGT0001474.Oral clearance was defined as rate of drug removal from the body after oral administration.

10. Vz/F [3 days]

    Apparent volume of distribution

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or females between the ages of 18 to 70 diagnosed with Type 2 diabetes.

• Body mass Index (BMI) between 18 kg/m2 and 37 kg/m2.

• HbA1c levels between 6.5 and 9.0 (inclusive) where the upper limit of normal for the HbA1c assay is 6.4% or 6.2-9.0% (inclusive) where the upper limit of normal for the HbA1c assay is 6.1% and fasting plasma glucose between 110 and 240 mg/dL (inclusive) while on diabetic medications.

• If taking drugs for diabetes, must be medically able and willing to discontinue diabetes medications for the duration of the study.

• Female subjects must be surgically sterilized or postmenopausal.

• Non-smoker for at least 3 months.

• Negative alcohol screen.

Exclusion Criteria:

• Type 1 diabetes.

• Use of insulin therapy or oral antidiabetic medication other than metformin, sitagliptin or a sulfonylurea.

• Sitting blood pressure above 150/95 mmHg on 2 evaluations at least 10 minutes apart at screening.

• Treatment with an investigational drug within 30 days or 7 half-lives, whichever is longer.

• Previous treatment with EGT0001474.

• Vaccination within 30 days prior to the first dose of study medication.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	dgd Research Inc., a Cetero Research Company	San Antonio	Texas	United States	78229

Sponsors and Collaborators

• Theracos

Investigators

• Study Chair: Mason W. Freeman, M.D., Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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. Review. Erratum in: Diabetes Care. 2008 Jun;31(6):1271.
• American Diabetes Association. Standards of medical care in diabetes--2008. Diabetes Care. 2008 Jan;31 Suppl 1:S12-54. doi: 10.2337/dc08-S012.
• 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.
• 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.
• Ehrenkranz JR, Lewis NG, Kahn CR, Roth J. Phlorizin: a review. Diabetes Metab Res Rev. 2005 Jan-Feb;21(1):31-8. Review.
• 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.
• 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. Review.
• 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. Erratum in: Clin Pharmacol Ther. 2009 May;85(5):558.
• Krook A, Kawano Y, Song XM, Efendić 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.
• 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.
• 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.
• 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.
• 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.
• 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.

• Responsible Party: Theracos
• ClinicalTrials.gov Identifier: NCT00924053
• Other Study ID Numbers: THR-1474-C-396
• First Posted: Jun 18, 2009
• Last Update Posted: Jun 17, 2019
• Last Verified: Jun 1, 2019

• Keywords provided by Theracos: Diabetes Mellitus Type 2
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Sodium-Glucose Transporter 2 Inhibitors

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	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).

Arm/Group Title	Placebo	EGT0001474 25 mg	EGT0001474 75 mg	EGT0001474 150mg
Arm/Group Description	Received 1, 3, or 6 placebo capsules once daily.	Received one 25 mg capsule once daily.	Received three 25mg capsules once daily.	Received six 25 mg capsules once daily.
Period Title: Overall Study
STARTED	6	6	6	6
COMPLETED	6	6	6	6
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Placebo	EGT0001474 25 mg	EGT0001474 75 mg	EGT0001474 150mg	Total
Arm/Group Description	Received 1, 3, or 6 placebo capsules once daily.	Received one 25 mg capsule once daily.	Received three 25mg capsules once daily.	Received six 25 mg capsules once daily.	Total of all reporting groups
Overall Participants	6	6	6	6	24
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	6 100%	6 100%	6 100%	6 100%	24 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	2 33.3%	3 50%	4 66.7%	3 50%	12 50%
Male	4 66.7%	3 50%	2 33.3%	3 50%	12 50%

Outcome Measures

1. Primary Outcome

Title	Safety and Tolerability of EGT0001474
Description	Safety and tolerability were measured in terms of the number of mild, moderate and severe adverse events experienced by any participants.
Time Frame	25 days

Outcome Measure Data

Analysis Population Description

All patients who took study medication were included in the analysis.

Arm/Group Title	Placebo	EGT0001474 25 mg	EGT0001474 75 mg	EGT0001474 150mg
Arm/Group Description	Received 1, 3, or 6 placebo capsules once daily.	Received one 25 mg capsule once daily.	Received three 25mg capsules once daily.	Received six 25 mg capsules once daily.
Measure Participants	6	6	6	6
Mild adverse events	5	0	9	3
Moderate adverse events	0	0	0	1
Serious adverse events	0	0	0	0

2. Primary Outcome

Title	AUC 0-t
Description	Area under the plasma concentration-time curve from time 0 to time t
Time Frame	3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	EGT0001474 25 mg	EGT0001474 75 mg	EGT0001474 150mg
Arm/Group Description	Received 1, 3, or 6 placebo capsules once daily.	Received one 25 mg capsule once daily.	Received three 25mg capsules once daily.	Received six 25 mg capsules once daily.
Measure Participants	6	6	6	6
Mean (Standard Deviation) [ng*hr/mL]	NA (NA)	1103.89 (470.31)	3370.29 (499.36)	6177.8 (1691.04)

3. Primary Outcome

Title	AUC0-24
Description	Area under the plasma concentration-time curve from time 0 to hour 24
Time Frame	3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	EGT0001474 25 mg	EGT0001474 75 mg	EGT0001474 150mg
Arm/Group Description	Received 1, 3, or 6 placebo capsules once daily.	Received one 25 mg capsule once daily.	Received three 25mg capsules once daily.	Received six 25 mg capsules once daily.
Measure Participants	6	6	6	6
Mean (Standard Deviation) [ng*hr/mL]	NA (NA)	987.3 (368.21)	2990.63 (461.18)	5584.72 (1516.64)

4. Primary Outcome

Title	AUC Inf
Description	Area under the plasma concentration-time curve from time 0 to infinity
Time Frame	3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	EGT0001474 25 mg	EGT0001474 75 mg	EGT0001474 150mg
Arm/Group Description	Received 1, 3, or 6 placebo capsules once daily.	Received one 25 mg capsule once daily.	Received three 25mg capsules once daily.	Received six 25 mg capsules once daily.
Measure Participants	6	6	6	6
Mean (Standard Deviation) [ng*hr/mL]	NA (NA)	1165.59 (479.88)	3532.02 (524.74)	6399.55 (1736.38)

5. Primary Outcome

Title	Cmax
Description	Maximum plasma concentration
Time Frame	3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	EGT0001474 25 mg	EGT0001474 75 mg	EGT0001474 150mg
Arm/Group Description	Received 1, 3, or 6 placebo capsules once daily.	Received one 25 mg capsule once daily.	Received three 25mg capsules once daily.	Received six 25 mg capsules once daily.
Measure Participants	6	6	6	6
Mean (Standard Deviation) [ng/mL]	NA (NA)	157.23 (76.25)	518.67 (176.36)	1014 (372.63)

6. Primary Outcome

Title	Tmax
Description	Time of maximum plasma concentration
Time Frame	3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	EGT0001474 25 mg	EGT0001474 75 mg	EGT0001474 150mg
Arm/Group Description	Received 1, 3, or 6 placebo capsules once daily.	Received one 25 mg capsule once daily.	Received three 25mg capsules once daily.	Received six 25 mg capsules once daily.
Measure Participants	6	6	6	6
Median (Full Range) [hour]	NA	3	2	2

7. Primary Outcome

Title	λz
Description	Terminal phase rate constant
Time Frame	3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	EGT0001474 25 mg	EGT0001474 75 mg	EGT0001474 150mg
Arm/Group Description	Received 1, 3, or 6 placebo capsules once daily.	Received one 25 mg capsule once daily.	Received three 25mg capsules once daily.	Received six 25 mg capsules once daily.
Measure Participants	6	6	6	6
Mean (Standard Deviation) [1/hour]	NA (NA)	0.0741 (0.0215)	0.0613 (0.0168)	0.0622 (0.0195)

8. Primary Outcome

Title	t1/2
Description	Apparent terminal half life
Time Frame	3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	EGT0001474 25 mg	EGT0001474 75 mg	EGT0001474 150mg
Arm/Group Description	Received 1, 3, or 6 placebo capsules once daily.	Received one 25 mg capsule once daily.	Received three 25mg capsules once daily.	Received six 25 mg capsules once daily.
Measure Participants	6	6	6	6
Mean (Standard Deviation) [hour]	NA (NA)	10.1 (3.21)	12.18 (3.88)	12.15 (3.94)

9. Primary Outcome

Title	CL/F
Description	The apparent rate of oral clearance of EGT0001474.Oral clearance was defined as rate of drug removal from the body after oral administration.
Time Frame	3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	EGT0001474 25 mg	EGT0001474 75 mg	EGT0001474 150mg
Arm/Group Description	Received 1, 3, or 6 placebo capsules once daily.	Received one 25 mg capsule once daily.	Received three 25mg capsules once daily.	Received six 25 mg capsules once daily.
Measure Participants	6	6	6	6
Mean (Standard Deviation) [mL/hr]	NA (NA)	24479.26 (9146.52)	21616.42 (3112.38)	24996.33 (7009.45)

10. Primary Outcome

Title	Vz/F
Description	Apparent volume of distribution
Time Frame	3 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	EGT0001474 25 mg	EGT0001474 75 mg	EGT0001474 150mg
Arm/Group Description	Received 1, 3, or 6 placebo capsules once daily.	Received one 25 mg capsule once daily.	Received three 25mg capsules once daily.	Received six 25 mg capsules once daily.
Measure Participants	6	6	6	6
Mean (Standard Deviation) [mL]	NA (NA)	348376.12 (15666.55)	382783.75 (138953.19)	435944.78 (179821.44)

Adverse Events

Time Frame	25 days total (14 day washout, 4 days in study, 1 week follow up after dosing)
Arm/Group Title	Placebo		EGT0001474 25 mg		EGT0001474 75 mg		EGT0001474 150mg
Arm/Group Description	Received 1, 3, or 6 placebo capsules once daily.		Received one 25 mg capsule once daily.		Received three 25mg capsules once daily.		Received six 25 mg capsules once daily.
All Cause Mortality
	Placebo		EGT0001474 25 mg		EGT0001474 75 mg		EGT0001474 150mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		EGT0001474 25 mg		EGT0001474 75 mg		EGT0001474 150mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		EGT0001474 25 mg		EGT0001474 75 mg		EGT0001474 150mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/6 (33.3%)		0/6 (0%)		4/6 (66.7%)		2/6 (33.3%)
Gastrointestinal disorders
Nausea	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	2	1/6 (16.7%)	1
General disorders
Malaise	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/0 (NaN)	0
Vessel puncture site reaction	1/6 (16.7%)	1	0/6 (0%)	0	0/0 (NaN)	0	0/6 (0%)	0
Investigations
Blood triglyceride increased	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Vessel puncture site haematoma	1/6 (16.7%)	2	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0
Muscle spasms	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0
Nervous system disorders
Dizziness	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Headache	0/6 (0%)	0	0/6 (0%)	0	3/6 (50%)	4	2/6 (33.3%)	2
Musculoskeletal stiffness	0/0 (NaN)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.