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Safety, Efficacy, and Pharmacokinetics (PK) Study of Trans Sodium Crocetinate (TSC) in Patients With Intermittent Claudication

Primary Purpose

Intermittent Claudication

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Trans sodium crocetinate (TSC)
0.9% normal saline
Sponsored by
Diffusion Pharmaceuticals Inc
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Intermittent Claudication focused on measuring PAD, Peripheral arterial disease, Peripheral artery disease, Intermittent claudication, IC, atherosclerosis, leg pain, walking pain

Eligibility Criteria

40 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Aged 40 or older, male or female
  • 6-mo. history of walking limitation or symptoms of intermittent claudication (IC) in at least 1 lower limb, severity of which has not changed in the past 3 mo. and diagnosed by principal investigator as clinically stable Fontaine Stage II peripheral artery disease (PAD)
  • Diagnosis of PAD secondary to atherosclerosis
  • If ankle-brachial index (ABI) is > 1.3 or cannot be measured in either leg, vascular etiology documented by toe-brachial index (TBI) ≤ 0.7 in at least 1 leg
  • Claudication severity, meds. for the treatment of coronary artery disease (CAD), PAD and IC, and exercise habits should be clinically stable for 3 mo. prior to Screening (SCRN) and during study. Pt. is not likely to change smoking and/or exercise habits during study
  • On an exercise treadmill test (ETT), peak walking time (PWT) of at least 1 min., but no more than 12 min. at Baseline
  • Willing and able to discontinue Pletal or Trental for 21 days before SCRN and during study
  • Antihypertensive therapy, cholesterol-lowering therapy, chronic oral nitrates, and diabetic therapy have been stable for 30 days prior to SCRN
  • Willing and able to provide written, signed, informed consent after the nature of the study has been explained and prior to any research-related procedures
  • Willing and able to comply with all study-related procedures
  • Sexually active patients must use an acceptable method of contraception while participating in the study
  • Females of childbearing potential must have a negative pregnancy test at SCRN and have additional pregnancy tests during the study

Exclusion Criteria:

  • Pregnant or lactating
  • Current or history of critical limb ischemia (CLI)
  • Pts. in whom artery insufficiency in the lower extremity is the result of acute limb ischemia (ALI) or an immunological or inflammatory non-atherosclerotic disorder
  • Pts. in whom walking impairment due to pain is the result of other non-atherosclerotic co-morbid conditions
  • A surgical intervention to alleviate symptoms of IC or PAD-specific endovascular intervention or cardiovascular surgery within 3 mo. of SCRN
  • Walking limited by reasons other than claudication
  • Conditions other than IC of significant severity that could confound PWT on the ETT
  • Concurrent severe congestive heart failure (CHF)
  • Life-threatening ventricular arrhythmias, unstable angina, and/or myocardial infarction (MI) within 3 mo. before enrollment (ENRL)
  • Coronary artery bypass grafting or percutaneous coronary intervention within 4 mo. before ENRL
  • Renal and/or carotid revascularization procedure within 3 mo. of ENRL
  • Transient ischemic attack (TIA) within 3 mo. before ENRL
  • Deep vein thrombosis (DVT) within 3 mo. before ENRL
  • Severe chronic obstructive pulmonary disease (COPD)
  • Thrombocytopenia
  • Undergoing hemodialysis or peritoneal dialysis
  • Pts. w/immunocompromised conditions, organ transplant recipients and/or need for immunosuppressive therapy
  • Neurological dementia
  • Stroke
  • Clinically significant electrocardiogram (ECG) change during or after ETT at SCRN or Baseline visit(s)
  • Cerebrovascular infarct within 3 mo. of SCRN
  • Poorly controlled type 1 or type 2 diabetes at SCRN
  • History of migraine headaches within last 12 mo.
  • Patients with clinically significant abnormal hematology labs or blood chemistry labs
  • Body mass index > 35
  • Hypertension at SCRN defined as resting BP values of > 170 mmHg systolic and/or > 110 mmHg diastolic
  • Hypotension at SCRN defined as resting BP values < 100 mmHg systolic or < 55 mmHg diastolic or symptomatic hypotension
  • Previous treatment with any formulation of TSC
  • Known allergy or hypersensitivity to any excipient (gamma-cyclodextrin, mannitol, glycine) of TSC formulation
  • Previous treatment with gene therapy or other VEGF-related treatment within 12 mo. of SCRN
  • Patients with recent history of alcoholism or drug abuse, or severe emotional, behavioral, or psychiatric problems
  • Patients receiving experimental medications or participating in other study using an experimental drug or procedure within 45 days prior to ENRL

Sites / Locations

  • Cardiology, P.C.
  • Radiant Research, Inc.
  • Stanford University School of Medicine, Division of Cardiovascular Medicine
  • Andrews Research and Education
  • University of Oklahoma Health Sciences Center
  • Hospital of the University of Pennsylvania
  • Clinical Trials of Texas, Inc.

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Placebo Comparator

Arm Label

1

2

3

4

5

6

7

8

9

Arm Description

.25 mg/kg TSC

.5 mg/kg TSC

.75 mg/kg TSC

1.0 mg/kg TSC

1.25 mg/kg TSC

1.5 mg/kg TSC

1.75 mg/kg TSC

2.0 mg/kg TSC

5.0 mL 0.9% normal saline

Outcomes

Primary Outcome Measures

Safety (laboratory tests, vital signs, ECG, physical exam, pulse oximetry) and pharmacokinetic assessments

Secondary Outcome Measures

Change in peak walking time (PWT) and claudication onset time (COT) in an exercise treadmill test

Full Information

First Posted
July 29, 2008
Last Updated
July 1, 2011
Sponsor
Diffusion Pharmaceuticals Inc
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1. Study Identification

Unique Protocol Identification Number
NCT00725881
Brief Title
Safety, Efficacy, and Pharmacokinetics (PK) Study of Trans Sodium Crocetinate (TSC) in Patients With Intermittent Claudication
Official Title
A Randomized, Double-Blinded, Placebo-Controlled Phase 1/2 Dose-Range-Finding Study to Evaluate the Safety, Efficacy and PK of Multiple Once Daily Intravenous Doses of TSC in Patients With Intermittent Claudication
Study Type
Interventional

2. Study Status

Record Verification Date
July 2011
Overall Recruitment Status
Completed
Study Start Date
August 2008 (undefined)
Primary Completion Date
March 2010 (Actual)
Study Completion Date
March 2010 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
Diffusion Pharmaceuticals Inc

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to evaluate the safety and pharmacokinetics of multiple, once-daily, intravenous doses of trans sodium crocetinate (TSC). The effectiveness of TSC in alleviating the symptoms of intermittent claudication (IC) will also be assessed.
Detailed Description
Peripheral Artery Disease (PAD) is a manifestation of systemic atherosclerosis, and patients with PAD commonly manifest symptoms of intermittent claudication (IC) such as cramping, aching, or fatigue in the calf muscles provoked by activity. In PAD, arterial occlusions lead to decreased leg blood flow during exercise or walking and the pain associated with this ischemia is IC. The diffusion of oxygen from blood to muscle could be a component of the overall decreased delivery or deficit of oxygen (hypoxia) to skeletal muscle resulting in symptoms in PAD patients. The overall goal of the development of TSC as a treatment for PAD is to allow for enhanced diffusion of oxygen through the plasma to alleviate the symptoms caused by the hypoxia in the tissues. This double-blinded, placebo-controlled clinical trial will randomize up to 48 patients at up to 8 clinical research sites in the US. In addition to safety and pharmacokinetic assessments conducted during the trial, the primary endpoint of the study will be demonstrated from standardized, graded exercise treadmill tests conducted throughout the study. The clearly measurable parameters will be peak walking time (PWT) and claudication onset time (COT) comparing baseline and after TSC or placebo and are well-established endpoints accepted by the medical community and regulatory authorities for IC clinical trials.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Intermittent Claudication
Keywords
PAD, Peripheral arterial disease, Peripheral artery disease, Intermittent claudication, IC, atherosclerosis, leg pain, walking pain

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
48 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Arm Description
.25 mg/kg TSC
Arm Title
2
Arm Type
Experimental
Arm Description
.5 mg/kg TSC
Arm Title
3
Arm Type
Experimental
Arm Description
.75 mg/kg TSC
Arm Title
4
Arm Type
Experimental
Arm Description
1.0 mg/kg TSC
Arm Title
5
Arm Type
Experimental
Arm Description
1.25 mg/kg TSC
Arm Title
6
Arm Type
Experimental
Arm Description
1.5 mg/kg TSC
Arm Title
7
Arm Type
Experimental
Arm Description
1.75 mg/kg TSC
Arm Title
8
Arm Type
Experimental
Arm Description
2.0 mg/kg TSC
Arm Title
9
Arm Type
Placebo Comparator
Arm Description
5.0 mL 0.9% normal saline
Intervention Type
Drug
Intervention Name(s)
Trans sodium crocetinate (TSC)
Intervention Description
Once-daily bolus intravenous injections in a superficial vein of the arm via syringe over a period of up to 2 minutes. Each patient will receive up to 5 doses given on 5 consecutive days
Intervention Type
Drug
Intervention Name(s)
0.9% normal saline
Intervention Description
A total volume of 5.0 mL normal saline will be dosed in a superficial vein of the arm via syringe over a period of up to 2 minutes.
Primary Outcome Measure Information:
Title
Safety (laboratory tests, vital signs, ECG, physical exam, pulse oximetry) and pharmacokinetic assessments
Time Frame
Screening, Baseline, Dose 1, Dose 2, Dose 3, Dose 4, Dose 5, 5-Day Follow-up, 14-Day Follow-up
Secondary Outcome Measure Information:
Title
Change in peak walking time (PWT) and claudication onset time (COT) in an exercise treadmill test
Time Frame
Baseline, Dose 1, Dose 5, 5-Day Follow-up

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Aged 40 or older, male or female 6-mo. history of walking limitation or symptoms of intermittent claudication (IC) in at least 1 lower limb, severity of which has not changed in the past 3 mo. and diagnosed by principal investigator as clinically stable Fontaine Stage II peripheral artery disease (PAD) Diagnosis of PAD secondary to atherosclerosis If ankle-brachial index (ABI) is > 1.3 or cannot be measured in either leg, vascular etiology documented by toe-brachial index (TBI) ≤ 0.7 in at least 1 leg Claudication severity, meds. for the treatment of coronary artery disease (CAD), PAD and IC, and exercise habits should be clinically stable for 3 mo. prior to Screening (SCRN) and during study. Pt. is not likely to change smoking and/or exercise habits during study On an exercise treadmill test (ETT), peak walking time (PWT) of at least 1 min., but no more than 12 min. at Baseline Willing and able to discontinue Pletal or Trental for 21 days before SCRN and during study Antihypertensive therapy, cholesterol-lowering therapy, chronic oral nitrates, and diabetic therapy have been stable for 30 days prior to SCRN Willing and able to provide written, signed, informed consent after the nature of the study has been explained and prior to any research-related procedures Willing and able to comply with all study-related procedures Sexually active patients must use an acceptable method of contraception while participating in the study Females of childbearing potential must have a negative pregnancy test at SCRN and have additional pregnancy tests during the study Exclusion Criteria: Pregnant or lactating Current or history of critical limb ischemia (CLI) Pts. in whom artery insufficiency in the lower extremity is the result of acute limb ischemia (ALI) or an immunological or inflammatory non-atherosclerotic disorder Pts. in whom walking impairment due to pain is the result of other non-atherosclerotic co-morbid conditions A surgical intervention to alleviate symptoms of IC or PAD-specific endovascular intervention or cardiovascular surgery within 3 mo. of SCRN Walking limited by reasons other than claudication Conditions other than IC of significant severity that could confound PWT on the ETT Concurrent severe congestive heart failure (CHF) Life-threatening ventricular arrhythmias, unstable angina, and/or myocardial infarction (MI) within 3 mo. before enrollment (ENRL) Coronary artery bypass grafting or percutaneous coronary intervention within 4 mo. before ENRL Renal and/or carotid revascularization procedure within 3 mo. of ENRL Transient ischemic attack (TIA) within 3 mo. before ENRL Deep vein thrombosis (DVT) within 3 mo. before ENRL Severe chronic obstructive pulmonary disease (COPD) Thrombocytopenia Undergoing hemodialysis or peritoneal dialysis Pts. w/immunocompromised conditions, organ transplant recipients and/or need for immunosuppressive therapy Neurological dementia Stroke Clinically significant electrocardiogram (ECG) change during or after ETT at SCRN or Baseline visit(s) Cerebrovascular infarct within 3 mo. of SCRN Poorly controlled type 1 or type 2 diabetes at SCRN History of migraine headaches within last 12 mo. Patients with clinically significant abnormal hematology labs or blood chemistry labs Body mass index > 35 Hypertension at SCRN defined as resting BP values of > 170 mmHg systolic and/or > 110 mmHg diastolic Hypotension at SCRN defined as resting BP values < 100 mmHg systolic or < 55 mmHg diastolic or symptomatic hypotension Previous treatment with any formulation of TSC Known allergy or hypersensitivity to any excipient (gamma-cyclodextrin, mannitol, glycine) of TSC formulation Previous treatment with gene therapy or other VEGF-related treatment within 12 mo. of SCRN Patients with recent history of alcoholism or drug abuse, or severe emotional, behavioral, or psychiatric problems Patients receiving experimental medications or participating in other study using an experimental drug or procedure within 45 days prior to ENRL
Facility Information:
Facility Name
Cardiology, P.C.
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35211
Country
United States
Facility Name
Radiant Research, Inc.
City
Santa Rosa
State/Province
California
ZIP/Postal Code
95405
Country
United States
Facility Name
Stanford University School of Medicine, Division of Cardiovascular Medicine
City
Stanford
State/Province
California
ZIP/Postal Code
94305-5406
Country
United States
Facility Name
Andrews Research and Education
City
Pensacola
State/Province
Florida
ZIP/Postal Code
32561
Country
United States
Facility Name
University of Oklahoma Health Sciences Center
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States
Facility Name
Hospital of the University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Clinical Trials of Texas, Inc.
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
22003000
Citation
Mohler ER 3rd, Gainer JL, Whitten K, Eraso LH, Thanaporn PK, Bauer T. Evaluation of trans sodium crocetinate on safety and exercise performance in patients with peripheral artery disease and intermittent claudication. Vasc Med. 2011 Oct;16(5):346-53. doi: 10.1177/1358863X11422742.
Results Reference
derived

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Safety, Efficacy, and Pharmacokinetics (PK) Study of Trans Sodium Crocetinate (TSC) in Patients With Intermittent Claudication

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