Study Effect of VIA-2291 on Atherosclerotic Vascular Inflammation in Patients Undergoing Elective Carotid Endarterectomy

• Sponsor: Tallikut Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00352417
• Collaborator: (none)
• Enrollment: 50
• Locations: 3
• Arms: 2
• Duration (Months): 24
• Patients Per Site: 16.7
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

This is a study to compare the effect of VIA-2291 vs. Placebo on various inflammatory biomarkers in patients with carotid stenosis scheduled for elective carotid endarterectomy

Condition or Disease	Intervention/Treatment	Phase
Atherosclerosis	Drug: VIA-2291; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Randomized, Double-blind, Placebo-controlled Study of the Effects of VIA-2291, a 5-Lipoxygenase Inhibitor, on Atherosclerotic Plaque and Biomarkers of Vascular Inflammation in Patients With Carotid Stenosis Undergoing Elective Carotid Endarterectomy
• Study Start Date: Jul 1, 2006
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Jul 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: VIA-2291	Drug: VIA-2291; 100 mg, oral dosing, 1 time daily for 12 weeks; Other Names: atreleuton
Placebo Comparator: Placebo Matching Placebo	Drug: Placebo; oral dosing, 1 time daily for 12 weeks

Outcome Measures

Primary Outcome Measures

1. Percent Cross-sectional Area of Macrophages in Plaque Tissue [12 weeks]

   Effect of VIA-2291 100-mg relative to placebo after 12 weeks of daily dosing on the percent cross-sectional area of macrophages in plaque tissue using an anti-CD68 antibody

Secondary Outcome Measures

1. Percent Cross-sectional Area of Anti-5-Lipoxygenase Staining in Plaque Tissue [12 weeks]

   Effect of VIA-2291 100-mg relative to placebo after 12 weeks of daily dosing on the percent cross-sectional area of anti-5-Lipoxygenase staining in plaque tissue

2. Change From Baseline in Whole Blood Leukotriene B4 Production [Baseline and 12 weeks]

3. Change From Baseline in Urine Leukotriene E4 Adjusted for Creatinine [Baseline and 12 Weeks]

4. Change From Baseline in High Sensitivity C-Reactive Protein (hsCRP) [Baseline and 12 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Female patients must be of non-childbearing potential

• Carotid stenosis between 60% and 90% and to be scheduled for CEA surgery

• One or more of the following clinical features: Prior history >4 weeks of cerebrovascular accident (CVA) or transient ischemic attack (TIA) consistent with North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria or prior history of amaurosis fugax occurring at any time

• Diabetes haemoglobin (Hb) A1c between 7.0 and 11% or a history of two or more fasting blood glucose levels >6.9 mmol/L

• Baseline hsCRP >2 mg/L

• Echolucent plaque

Exclusion Criteria:

• Acute CVA or TIA within 4 weeks of enrollment or the presence of ulcerated or unstable plaque requiring urgent carotid endarterectomy

• Renal insufficiency defined as creatinine >1.5 x upper limit of normal (ULN)

• Cirrhosis, recent hepatitis, alanine aminotransferase (ALT) >1 x ULN (i.e., above the normal range) or positive screening test for hepatitis B (hepatitis B surface antigen) or hepatitis C (by ELISA)

• Uncontrolled diabetes mellitus within 1 month prior to study screening, defined as HbA1c >11% at screening

• Congestive heart failure (CHF) defined by the New York Heart Association as functional Class III or IV

• Recent acute coronary syndrome event or coronary artery bypass graft (CABG) surgery (within 4 weeks of enrollment)

• Current atrial fibrillation

• Planned cardiac intervention

• Acetaminophen use in any form in the 7 days before enrollment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Azienda Ospedali Riuniti Ancona	Ancona		Italy
2	Presidio Ospedaliero SS Filippo e Nicola	Avezzano		Italy
3	Centro Studi Sull'Invecchiamento	Chieti Scalo		Italy

Sponsors and Collaborators

• Tallikut Pharmaceuticals, Inc.

Investigators

• Study Director: Rebecca Taub, MD, VIA Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Tallikut Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT00352417
• Other Study ID Numbers: VIA-2291-02; 2006-001635-21
• First Posted: Jul 14, 2006
• Last Update Posted: Jul 27, 2012
• Last Verified: Jul 1, 2012

• Additional relevant MeSH terms: Atherosclerosis; Inflammation; Atreleuton

Study Results

Participant Flow

Recruitment Details	Patients recruited from three Italian Medical Centers

Arm/Group Title	VIA-2291	Matching Placebo
Arm/Group Description	100-mg dose	Placebo Dose
Period Title: Overall Study
STARTED	24	26
COMPLETED	19	21
NOT COMPLETED	5	5

Baseline Characteristics

Arm/Group Title	VIA-2291	Matching Placebo	Total
Arm/Group Description	100-mg dose	Placebo Dose	Total of all reporting groups
Overall Participants	24	26	50
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	11 45.8%	8 30.8%	19 38%
>=65 years	13 54.2%	18 69.2%	31 62%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66.8 (8.86)	69.5 (8.73)	68.2 (8.81)
Sex: Female, Male (Count of Participants)
Female	11 45.8%	14 53.8%	25 50%
Male	13 54.2%	12 46.2%	25 50%
Region of Enrollment (participants) [Number]
Italy	24 100%	26 100%	50 100%

Outcome Measures

1. Primary Outcome

Title	Percent Cross-sectional Area of Macrophages in Plaque Tissue
Description	Effect of VIA-2291 100-mg relative to placebo after 12 weeks of daily dosing on the percent cross-sectional area of macrophages in plaque tissue using an anti-CD68 antibody
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Evaluable Population with histological sections available

Arm/Group Title	VIA-2291	Matching Placebo
Arm/Group Description	100-mg dose	Placebo Dose
Measure Participants	12	13
Mean (95% Confidence Interval) [Percent Area]	8.08	8.19

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VIA-2291, Matching Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.97
	Comments
	Method	t-test, 2 sided
	Comments	Satterthwaite's method

2. Secondary Outcome

Title	Percent Cross-sectional Area of Anti-5-Lipoxygenase Staining in Plaque Tissue
Description	Effect of VIA-2291 100-mg relative to placebo after 12 weeks of daily dosing on the percent cross-sectional area of anti-5-Lipoxygenase staining in plaque tissue
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Evaluable Population with histological sections available

Arm/Group Title	VIA-2291	Matching Placebo
Arm/Group Description	100-mg dose	Placebo Dose
Measure Participants	12	13
Mean (95% Confidence Interval) [Percent Area]	1.80	0.87

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VIA-2291, Matching Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.37
	Comments
	Method	t-test, 2 sided
	Comments	Satterthwaite's method

3. Secondary Outcome

Title	Change From Baseline in Whole Blood Leukotriene B4 Production
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

Evaluable Population

Arm/Group Title	VIA-2291	Matching Placebo
Arm/Group Description	100-mg dose	Placebo Dose
Measure Participants	16	19
Least Squares Mean (95% Confidence Interval) [pg/ml]	-123,000	-42,900

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VIA-2291, Matching Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments

4. Secondary Outcome

Title	Change From Baseline in Urine Leukotriene E4 Adjusted for Creatinine
Time Frame	Baseline and 12 Weeks

Outcome Measure Data

Analysis Population Description

Evaluable Population

Arm/Group Title	VIA-2291	Matching Placebo
Arm/Group Description	100-mg dose	Placebo Dose
Measure Participants	14	14
Geometric Mean (95% Confidence Interval) [Percent Change]	-64.7	-15.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VIA-2291, Matching Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	ANCOVA
	Comments	ANCOVA was performed on the natural log transformed data

5. Secondary Outcome

Title	Change From Baseline in High Sensitivity C-Reactive Protein (hsCRP)
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

Evaluable population with both baseline and visit 8 results

Arm/Group Title	VIA-2291	Matching Placebo
Arm/Group Description	100-mg dose	Placebo Dose
Measure Participants	15	15
Least Squares Mean (95% Confidence Interval) [mg/L]	-2.0	0.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	VIA-2291, Matching Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	ANCOVA
	Comments

Adverse Events

Time Frame	12 weeks
Arm/Group Title	VIA-2291		Matching Placebo
Arm/Group Description	100-mg dose		Placebo Dose
All Cause Mortality
	VIA-2291		Matching Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	VIA-2291		Matching Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/24 (16.7%)		1/26 (3.8%)
Cardiac disorders
ATRIOVENTRICULAR BLOCK SECOND DEGREE	1/24 (4.2%)	1	0/26 (0%)	0
Investigations
BLOOD CREATININE INCREASED	1/24 (4.2%)	1	0/26 (0%)	0
BLOOD UREA INCREASED	1/24 (4.2%)	1	0/26 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BENIGN RENAL NEOPLASM	0/24 (0%)	0	1/26 (3.8%)	1
Nervous system disorders
PRESYNCOPE	1/24 (4.2%)	1	0/26 (0%)	0
TRANSIENT ISCHAEMIC ATTACK	1/24 (4.2%)	1	0/26 (0%)	0
Other (Not Including Serious) Adverse Events
	VIA-2291		Matching Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/24 (75%)		9/26 (34.6%)
Blood and lymphatic system disorders
ANAEMIA	1/24 (4.2%)	1	0/26 (0%)	0
LEUKOCYTOSIS	1/24 (4.2%)	1	0/26 (0%)	0
Cardiac disorders
SINUS TACHYCARDIA	0/24 (0%)	0	1/26 (3.8%)	1
TACHYCARDIA	0/24 (0%)	0	1/26 (3.8%)	1
Eye disorders
CATARACT	0/24 (0%)	0	1/26 (3.8%)	1
Gastrointestinal disorders
ABDOMINAL PAIN	1/24 (4.2%)	1	0/26 (0%)	0
DIARRHOEA	2/24 (8.3%)	2	1/26 (3.8%)	1
DYSPEPSIA	0/24 (0%)	0	1/26 (3.8%)	1
GASTRITIS	1/24 (4.2%)	1	0/26 (0%)	0
MESENTERIC ARTERY STENOSIS	1/24 (4.2%)	1	0/26 (0%)	0
General disorders
INFLUENZA LIKE ILLNESS	1/24 (4.2%)	1	0/26 (0%)	0
PYREXIA	3/24 (12.5%)	3	0/26 (0%)	0
Infections and infestations
CYSTITIS	2/24 (8.3%)	2	1/26 (3.8%)	1
RHINITIS	1/24 (4.2%)	1	0/26 (0%)	0
Injury, poisoning and procedural complications
POSTOPERATIVE FEVER	0/24 (0%)	0	1/26 (3.8%)	1
Investigations
BLOOD AMYLASE INCREASED	1/24 (4.2%)	1	0/26 (0%)	0
BLOOD BILIRUBIN INCREASED	1/24 (4.2%)	1	0/26 (0%)	0
BLOOD BILIRUBIN UNCONJUGATED INCREASED	1/24 (4.2%)	1	0/26 (0%)	0
BLOOD CREATININE INCREASED	2/24 (8.3%)	2	0/26 (0%)	0
BLOOD GLUCOSE INCREASED	2/24 (8.3%)	2	0/26 (0%)	0
BLOOD UREA INCREASED	3/24 (12.5%)	3	0/26 (0%)	0
GAMMA-GLUTAMYLTRANSFERASE INCREASED	1/24 (4.2%)	1	0/26 (0%)	0
LIPASE INCREASED	1/24 (4.2%)	1	0/26 (0%)	0
Metabolism and nutrition disorders
DIABETES MELLITUS	0/24 (0%)	0	1/26 (3.8%)	1
GOUT	0/24 (0%)	0	1/26 (3.8%)	1
HYPOGLYCAEMIA	1/24 (4.2%)	1	0/26 (0%)	0
TYPE 2 DIABETES MELLITUS	1/24 (4.2%)	1	0/26 (0%)	0
Nervous system disorders
DIZZINESS	0/0 (NaN)	0	1/26 (3.8%)	1
HEADACHE	1/24 (4.2%)	1	1/26 (3.8%)	1
NEURALGIA	0/24 (0%)	0	1/26 (3.8%)	1
Renal and urinary disorders
GLYCOSURIA	1/24 (4.2%)	1	0/26 (0%)	0
Respiratory, thoracic and mediastinal disorders
PHARYNGOLARYNGEAL PAIN	0/24 (0%)	0	1/26 (3.8%)	1
Skin and subcutaneous tissue disorders
BLISTER	0/24 (0%)	0	1/26 (3.8%)	1
PRURITUS	0/24 (0%)	0	1/26 (3.8%)	1
Vascular disorders
HYPERTENSION	0/24 (0%)	0	1/26 (3.8%)	1

Limitations/Caveats

The small number, less than optimal quality, and diversity of types of plaque samples posed a significant limitation to the interpretation of the plaque data in this study.

More Information

Certain Agreements

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

The PIs agreed to allow the sponsor 30 days to review and require changes to presentations or publications but only to protect confidential information and intellectual property, and for the sponsor to file a patent application, as applicable.