Study of INT-747 in Patients With Diabetes and Presumed NAFLD

• Sponsor: Intercept Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00501592
• Collaborator: (none)
• Enrollment: 64
• Locations: 4
• Arms: 3
• Duration (Months): 21
• Patients Per Site: 16
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

The primary objectives of this study are to assess, in patients with Type 2 diabetes mellitus (DM) and presumed nonalcoholic fatty liver disease (NAFLD), the following:

• The safety and tolerability of multiple doses of INT 747;

• The effects of 2 dose levels (25 mg and 50 mg) of INT 747 on insulin resistance and glucose homeostasis;

• Effects of INT-747 on hepatocellular function as measured by assessment of liver enzymes and biochemical markers of hepatic and metabolic function and inflammation, and;

• Trough concentrations of INT-747 and its metabolites, glyco 6-ethyl chenodeoxycholic acid (6-EDCA) and tauro 6-ECDCA.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type II; Fatty Liver	Drug: INT-747; Drug: Placebo	Phase 2

Detailed Description

This is a multi-center, double-blind, randomized, placebo-controlled, multiple-dose, parallel-group study. Three (3) cohorts of 12 patients each will receive either placebo, 25 mg INT-747, or 50 mg INT-747 by mouth daily for 6 weeks.

The primary objective of assessing changes in insulin resistance and glucose homeostasis will be attained by performing a euglycemic clamp procedure at baseline (Day 0) and at the end of 6 weeks of treatment (Day 43). Other endpoints will be evaluated by monitoring adverse experiences; vital signs; clinical laboratory values; plasma drug and metabolite concentrations; and general health and well-being.

Study Design

• Study Type: Interventional
• Actual Enrollment: 64 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: An Exploratory Study of INT-747 in Patients With Type 2 Diabetes Mellitus and Presumed Nonalcoholic Fatty Liver Disease
• Study Start Date: Jul 1, 2007
• Actual Primary Completion Date: Feb 1, 2009
• Actual Study Completion Date: Apr 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 25 mg INT-747	Drug: INT-747; 25 mg by mouth once daily, 50 mg by mouth once daily
Active Comparator: 50 mg INT-747	Drug: INT-747; 25 mg by mouth once daily, 50 mg by mouth once daily
Placebo Comparator: Placebo	Drug: Placebo; Placebo

Outcome Measures

Primary Outcome Measures

1. Insulin Resistance and Glucose Homeostasis [baseline and 6 weeks]

   The primary objective of assessing changes in insulin resistance and glucose homeostasis will be attained by performing a euglycemic clamp procedure at baseline (Day 0) and at the end of 6 weeks of treatment (Day 43).

Secondary Outcome Measures

1. Hepatocellular Function [baseline and 6 weeks]

   Hepatocellular function as measured by assessment of liver enzymes and biochemical markers of hepatic and metabolic function

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Type 2 diabetes, defined by the American Diabetes Association (ADA), as one of the following criteria:

• Symptoms of diabetes plus casual plasma glucose concentration >200 mg/dL (11.1 mmol/L) or

• Fasting plasma glucose >126 mg/dL (7.0 mmol/L) or

• 2-hour post-load glucose >200 mg/dL (11.1 mmol/L) during a 75 g oral glucose tolerance test (GTT).

• Presumed NAFLD, defined by one of the following criteria:

• Alanine aminotransferase (ALT) ≥47 U/L for females and ≥56 U/L for males

• Aspartate aminotransferase (AST) ≥47 U/L for females and ≥60 U/L for males

• Enlarged liver (demonstrated by ultrasound or other imaging technique)

• Diagnostic histological findings shown on prior biopsy (in the last 5 years).

Exclusion Criteria:

• Bilirubin >2 × ULN

• ALT >155 U/L for females and >185 U/L for males.

• AST >155 U/L for females and >200 U/L for males.

• Patients taking any antidiabetic medications, with the exception of metformin and sulfonylureas. If the HbA1c is <11%, patients may be enrolled who have been withdrawn from all other diabetic medications as specified in the protocol, at the discretion of the Principal Investigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Profil Institute for Clinical Research, Inc.	Chula Vista	California	United States	91911
2	UC San Diego VAMC	San Diego	California	United States	92161
3	Diabetes & Glandular Disease Research Associates, Inc.	San Antonio	Texas	United States	78229
4	Virginia Commonwelath University	Richmond	Virginia	United States	23298

Sponsors and Collaborators

• Intercept Pharmaceuticals

Investigators

• Study Director: David A Shapiro, M.D., Intercept Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Intercept Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00501592
• Other Study ID Numbers: 747-203
• First Posted: Jul 16, 2007
• Last Update Posted: Apr 20, 2012
• Last Verified: Apr 1, 2012

• Keywords provided by Intercept Pharmaceuticals: Farnesoid X receptor agonist; Metabolic Disorder; Diabetes; NAFLD
• Additional relevant MeSH terms: Fatty Liver; Diabetes Mellitus; Diabetes Mellitus, Type 2

Study Results

Participant Flow

Recruitment Details	Sixty four subjects were enrolled in the study at 4 sites. Of the randomized subjects, 20 were randomized to INT-747 25 mg, 21 subjects to INT-747 50 mg, and 23 subjects to placebo. Study enrollment by center ranged from 4 to 31 subjects.
Pre-assignment Detail	A protocol amendment allowed for the enrollment of 14 replacement subjects (to enroll up to 56 subjects meeting eligibility requirements). The amendment pre-specified that the original 14 subjects being replaced would not be included in the efficacy analysis since they did not meet the protocol requirements.

Arm/Group Title	25 mg INT-747	50 mg INT-747	Placebo
Arm/Group Description	Once daily by mouth	Once daily by mouth	Once daily by mouth
Period Title: Overall Study
STARTED	20	21	23
COMPLETED	20	16	20
NOT COMPLETED	0	5	3

Baseline Characteristics

Arm/Group Title	25 mg INT-747	50 mg INT-747	Placebo	Total
Arm/Group Description	Once daily by mouth	Once daily by mouth	Once daily by mouth	Total of all reporting groups
Overall Participants	20	21	23	64
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	19 95%	20 95.2%	20 87%	59 92.2%
>=65 years	1 5%	1 4.8%	3 13%	5 7.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.7 (8.7)	50.5 (10.8)	53.1 (12.1)	52.1 (10.6)
Sex: Female, Male (Count of Participants)
Female	6 30%	12 57.1%	13 56.5%	31 48.4%
Male	14 70%	9 42.9%	10 43.5%	33 51.6%
Region of Enrollment (participants) [Number]
United States	20 100%	21 100%	23 100%	64 100%

Outcome Measures

1. Primary Outcome

Title	Insulin Resistance and Glucose Homeostasis
Description	The primary objective of assessing changes in insulin resistance and glucose homeostasis will be attained by performing a euglycemic clamp procedure at baseline (Day 0) and at the end of 6 weeks of treatment (Day 43).
Time Frame	baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	25 mg INT-747	50 mg INT-747	Placebo
Arm/Group Description	Once daily by mouth	Once daily by mouth	Once daily by mouth
Measure Participants	20	21	23
Low Dose Insulin	.69 (1.12)	.24 (1.62)	-0.51 (1.88)
High Dose Insulin	.73 (1.53)	.42 (1.42)	-0.61 (1.88)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	25 mg INT-747, Placebo
	Comments	The primary endpoints are calculated as the change (post minus pre treatment) during low dose and high dose insulin infusion periods. These are compared between placebo and INT-747 25 mg using t-tests for independent samples. These tests will be made without correction for multiple comparisons using 0.05 as the alpha criterion for significance. Results will be described with the corresponding means and standard deviations.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.040
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	50 mg INT-747, Placebo
	Comments	The primary endpoints are calculated as the change (post minus pre treatment) during low dose and high dose insulin infusion periods. These are compared between placebo and INT-747 50 mg using t-tests for independent samples. These tests will be made without correction for multiple comparisons using 0.05 as the alpha criterion for significance. Results will be described with the corresponding means and standard deviations.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.28
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	Hepatocellular Function
Description	Hepatocellular function as measured by assessment of liver enzymes and biochemical markers of hepatic and metabolic function
Time Frame	baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	25 mg INT-747	50 mg INT-747	Placebo
Arm/Group Description	Once daily by mouth	Once daily by mouth	Once daily by mouth
Measure Participants	20	21	23
ALT	-9 (14)	9 (47)	11 (48)
AST	-3 (7)	4 (24)	4 (46)
GGT	-39 (77)	-23 (56)	5 (27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	25 mg INT-747, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0031
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	50 mg INT-747, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	25 mg INT-747, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	50 mg INT-747, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	One year, 7 monhts
Arm/Group Title	25 mg INT-747		50 mg INT-747		Placebo
Arm/Group Description	Once daily by mouth		Once daily by mouth		Once daily by mouth
All Cause Mortality
	25 mg INT-747		50 mg INT-747		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	25 mg INT-747		50 mg INT-747		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/21 (0%)		0/23 (0%)
Other (Not Including Serious) Adverse Events
	25 mg INT-747		50 mg INT-747		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/20 (30%)		15/21 (71.4%)		13/23 (56.5%)
Cardiac disorders
Palpitations	2/20 (10%)	2	0/21 (0%)	0	0/23 (0%)	0
Gastrointestinal disorders
Constipation	0/20 (0%)	0	5/21 (23.8%)	5	0/23 (0%)	0
Diarrhoea	0/20 (0%)	0	0/21 (0%)	0	2/23 (8.7%)	2
General disorders
Vessel Puncture Site Pain	1/20 (5%)	1	4/21 (19%)	6	2/23 (8.7%)	3
Pyrexia	0/20 (0%)	0	0/21 (0%)	0	2/23 (8.7%)	2
Infections and infestations
Upper respiratory tract infection	0/20 (0%)	0	1/21 (4.8%)	1	2/23 (8.7%)	2
Nasopharyngitis	0/20 (0%)	0	0/21 (0%)	0	2/23 (8.7%)	2
Nervous system disorders
Headache	1/20 (5%)	2	3/21 (14.3%)	5	1/23 (4.3%)	2
Skin and subcutaneous tissue disorders
Pruritus	2/20 (10%)	2	1/21 (4.8%)	1	2/23 (8.7%)	2
Rash maculopapular	0/20 (0%)	0	1/21 (4.8%)	1	0/23 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

All proposed publications based on this study shall be approved by the Sponsor prior to submission for publication. Such approval will not be unreasonably witheld. Publications will reflect the contributions made by the Investigators, Sponsor personnel and other groups involved in the study.