Study to Explore the Effect of Lowering Blood Viscosity in Patients With Treatment-resistant Critical Limb Ischemia (CLI-PH)

Phase 2 Study to Explore the Effect of Lowering Blood Viscosity in Patients With Treatment-resistant Critical Limb Ischemia

PAD is caused by an increased flow resistance in atherosclerotic ischemic limbs. The investigators hypothesize that reducing blood viscosity (through controlled phlebotomy), thereby increasing the deformability of red blood cells, should reduce the flow resistance and improve tissue perfusion leading to improved clinical function and a reduction in symptoms.

Preliminary data demonstrates that phlebotomy causes a measurable change in blood viscosity as measured by the home-made rheologic method.

To evaluate the effectiveness of changes in blood viscosity, obtained through controlled phlebotomy, as a therapy to improve functional status associated with atherosclerotic ischemic limbs in pre-amputation patients.

Study Overview

• Status: Completed
• Conditions: Critical Limb Ischemia
• Intervention / Treatment: Procedure: phlebotomy

Detailed Description

The first study is a pilot study and will act as proof of principle. This first study will include 20 patients divided into 2 groups on the basis of a randomized controlled trial: 10 patients in the control group receiving conventional treatment and 10 patients receiving therapeutic phlebotomy to lower blood viscosity. The objective is to evaluate the effect of controlled phlebotomy in patients with Grade 3, Category 5 or 6 chronic critical limb ischemia having tissue loss on Rutherford classification (Fontaine stage IV), end-stage peripheral vascular disease resistant to maximal medical therapy and where revascularization therapy (both percutaneous and surgical) has either proved insufficient or is contra-indicated or declined by the patient, usually resulting in amputation.

The primary outcome parameters will be: the salvage rate of the limb as compared with the salvage rate of the limb with conventional therapy.

Objective classification of improvement in perfusion of the distal extremities using ankle-brachial index (ABI), visual analogue pain scale, and photos.

Subjective classification of improvement in pain scale on critical limbs.

The relationship between alteration in outcome parameters (i.e., the end point is a reduced amputation rate) and blood viscosity will be evaluated as measured by the home-made rheologic methods.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 134-060
    • Seoul Veterans Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Subjects should have diagnosed Rutherford classification Grade 3, Category 5 or 6 (Fontaine stage IV) treatment-resistant chronic critical limb ischemia having tissue loss, not relieved by maximal medical therapy and they should have exhausted or not be candidates for surgical (other than heart transplant) or percutaneous intervention
• Male
• Age: 18 to 80 years
• Current non-smokers
• BMI >19
• Estimated 6 month survival rate >90%
• Concomitant stable medications will be allowed.
• If the subjects have coronary artery disease established by history, angina pain, EKG, Lab including Troponin I, creatine kinase, lactate dehydrogenase, Echocardiography, Thallium scan or coronary angiography, the subjects should have established a classification of coronary artery involvement by coronary angiography or other procedure with similar precision.

Exclusion Criteria:

• Anemia
• Low blood pressure (systolic < 120 mmHg)
• Baseline hematocrit < 30
• Initial whole blood viscosity measurements below 15 miliPoiseille

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Non phlebotomy group (control group); • This control group is the patients who had Rutherford classification Grade 3, Category 5 or 6 (Fontaine stage IV) treatment-resistant chronic critical limb ischemia having tissue loss. They were treated with conventional standard treatment including revascularization operative procedure if feasible, maximum medical treatment with anticoagulation (heparin, low molecular weight heparin, etc), acetylsalicylic acid, cilostazol, and prostaglandin E1, dextran, and pain analgesia with opioid, and finally major amputation. We records all control arms' amputation, day to amputation, mortality, etc. We will compare amputation and mortality between control and treatment groups. Non phlebotomy arm has no phlebotomy treatment.
Experimental: PH (study group); The patients will be pre-amputation and have Rutherford classification Grade 3, Category 5 or 6 (Fontaine stage IV) treatment-resistant chronic critical limb ischemia having tissue loss. Procedures for therapeutic phlebotomy; Inject heparin 5000 units to prevent blood clot during phlebotomy; Inject volume expander equivalent to 5% of blood volume; Remove 5% of whole blood; Monitor the vital sign of the patient during the phlebotomy They were treated both phlebotomy and conventional standard management including surgery, medication, amputation, etc. We will compare amputation and mortality between control and study groups.	Procedure: phlebotomy; repeated phlebotomy for 4 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major amputation rate (limb salvage rate)	The rate of lower limb major amputation (limb salvage rate) was measured in both study arms, during 5 year follow-up period. They would be the evidences of phlebotomy treatment directly.	5 year follow-up period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time-to-major amputation	During 5 year follow-up period, we measured the time-to-major amputation between the two groups, phlebotomy study group and control group. They would be the evidences of phlebotomy treatment directly.	5 year follow-up period
Mortality rate	During 5 year follow-up period, we measured the mortality rate as a final result of a treatment and major amputation between the two groups, phlebotomy study group and control group. They would be the evidences of phlebotomy treatment directly.	5 year follow-up period
Blood viscosity measurements	The relationship between alteration in outcome parameters (i.e., the end point is a reduced amputation rate) and blood viscosity will be evaluated as measured by the home-made rheologic methods. Evaluate blood viscosity measurements with the home-made rheologic method as a monitor of and marker for the clinical effectiveness of therapeutic phlebotomy in patients with Rutherford classification Grade 3, Category 5 or 6 (Fontaine stage IV) treatment-resistant chronic critical limb ischemia having tissue loss.	Conducting study periods (4 weeks)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
VA pain scale	After 4 weeks phlebotomy, we measured and confirmed the VA pain scale improvement or not in study group. They would be the evidences of phlebotomy treatment indirectly.	Conducting study periods (4 weeks)
Ankle-Brachial Index	After 4 weeks phlebotomy, we measured and confirmed the ABI improvement or not in study group. They would be the evidences of phlebotomy treatment indirectly.	Conducting study periods (4 weeks)
Complete wound healing	After 4 weeks phlebotomy, we measured and confirmed the complete wound healing (no more discharge from wound and complete epithelialization) between two groups. They would be the evidences of phlebotomy treatment directly.	Conducting study periods (4 weeks)

Collaborators and Investigators

• Sponsor: Seoul Veterans Hospital
• Investigators: Principal Investigator: Doosang Kim, M.D.,Ph.D., Seoul Veterans Hospital

Study record dates

Study Major Dates

• Study Start: September 1, 2006
• Primary Completion (Actual): April 1, 2007
• Study Completion (Actual): April 1, 2012

Study Registration Dates

• First Submitted: May 14, 2012
• First Submitted That Met QC Criteria: December 27, 2012
• First Posted (Estimate): January 1, 2013

Study Record Updates

• Last Update Posted (Estimate): January 1, 2013
• Last Update Submitted That Met QC Criteria: December 27, 2012
• Last Verified: December 1, 2012

More Information

Terms related to this study

• Keywords: Amputation; Critical limb ischemia; Phlebotomy; Rutherford classification Grade 3, Category 5 or 6; Fontaine stage IV
• Additional Relevant MeSH Terms: Pathologic Processes; Ischemia
• Other Study ID Numbers: 2006-19