Critical Limb Ischemia
Conditions
Keywords
Stem cells, Autologous, Vascular disease, Peripheral arterial disease, Regenerative medicine, Amputation
Brief summary
The primary objective of this study is to determine the efficacy and safety of intramuscular injection of ACP-01, comprised of blood-derived autologous ACPs, in subjects with critical limb ischemia who are receiving standard of care therapy and have no endovascular or surgical revascularization options.
Detailed description
This prospective, randomized, double-blind, placebo controlled study will assess the efficacy and safety of autologous ACPs administered intramuscularly into the lower extremity of subjects with CLI who lack surgical or endovascular revascularization options. A total of approximately 95 subjects will be randomized to treatment with ACP-01 or placebo using a 2:1 randomization scheme, respectively, stratified by site. The study will continue until all subjects treated experience the study event (either de novo gangrene, doubling of wound size, major amputation, or death) or are event-free for at least 26 weeks. Subjects treated will be followed for no longer than 52 weeks. One futility analysis for potentially stopping study enrollment will be performed. Subjects treated at each investigative site will provide written informed consent prior to the conduct of any study-related procedures. Thereafter, they will be screened and those meeting the inclusion/exclusion criteria will be enrolled into the trial and undergo all the study procedures including intramuscular injection of the investigational medicinal product (IMP = ACP-01 or placebo). The IMP will be administered in addition to any conventional treatment the subject is receiving. The control group will receive placebo injections into the lower extremity to ensure blinding of the assessors and the subjects. The placebo will consist of the same medium used in the ACP product suspension. The study consists of four periods: Screening period, Treatment period, Acute safety follow-up and Long term follow-up periods. The total duration of study participation, including follow-up, is at least 26 weeks. Subjects will be followed for up to 52 weeks and at least until the last subject has completed his/her 26 week visit.
Interventions
BIOLOGICALACP-01
Injection into lower extremity
BIOLOGICALPlacebo
Injection into lower extremity
Sponsors
Hemostemix
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject is diagnosed with critical limb ischemia. * Subject has hemodynamic indicators of severe peripheral arterial occlusive disease. * Subject is not a candidate for standard revascularization treatment options for peripheral arterial disease. * Subject must be on standard of care medical therapy for peripheral vascular disease. * Male or female age 18 and above. * Non-pregnant, non-lactating female. * Subject is able to understand and provide voluntary signed informed consent.
Exclusion criteria
* Uncorrected aorto-iliac occlusive disease. * Subjects who, in the opinion of the investigator, have a vascular disease prognosis that indicates they would require a major amputation in a time frame shortly after administration of the IMP (investigational drug or placebo). * Advanced Critical Limb Ischemia (CLI) presenting as severe ischemic or dry gangrene. * Lower extremity non-treated active infection. * Hypercoagulable state. * Subject received a blood transfusion during the previous 4 weeks (to exclude the potential of non-autologous ACPs in the harvested blood). * Inability to communicate that may interfere with clinical evaluation. * Recent major non-vascular operation. * Myocardial infarction or uncontrolled myocardial ischemia or persistent severe heart failure. * Severe aortic stenosis. * Renal failure. * Hepatic failure. * Anemia. * Major stroke. * Diagnosis of malignancy. * Concurrent chronic or acute infectious disease and uncontrolled infectious symptoms. * Severe concurrent disease (other than Peripheral Vascular Disease (PAD)). * Bleeding diathesis. * Participation at the same time in another investigational product or device study. * Chronic cytotoxic drug treatment. * Life expectancy of less than 6 months. * Subject unlikely to be available for follow-up. * Acute worsening of CLI.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Wound Size, Amputation or Survival | Baseline vs. 1 year | Number of subject with doubling of wound size, major amputation or death |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pain Level | Baseline vs. 1 year | Change in pain score according to the Visual Analog Scale (VAS) for Pain. The visual VAS is a validated, subjective measure for acute and chronic pain. Scores are recorded by making a handwritten mark on a 10-cm line that represents a continuum between the two ends of the scale-no pain on the left end (0 cm) of the scale and the worst pain on the right end of the scale (10 cm). Measurements from the starting point (left end) of the scale to the subjects' marks are recorded in centimeters and are interpreted as their pain. The values ar used to track pain progression for a subject and to compare pain between subjects. |
| Ulcer Size | Baseline vs. 1 year | Change in ulcer size |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Ankle Pressure | 1 - 52 wks | — |
| Change From Baseline in the Dose and Quantity of Analgesic Drugs Used by the Subject | 1 - 52 wks | — |
| Change From Baseline in Toe Pressure | 1 - 52 wks | — |
| Reduction in Total Hospitalization Time of Subjects Treated With ACP-01 Compared to Subjects Treated With Placebo | 1 - 52 wks | — |
| Change From Baseline in Quality of Life | 1 - 52 wks | Change in quality of life according to the Vascular Quality of Life Questionnaire. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ACP-01 Injection into lower extremity
ACP-01: Injection into lower extremity | 46 |
| Placebo Injection into lower extremity
Placebo: Injection into lower extremity | 21 |
| Total | 67 |
Baseline characteristics
| Characteristic | ACP-01 | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 36 Participants | 17 Participants | 53 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 4 Participants | 14 Participants |
| Age, Continuous | 70 years STANDARD_DEVIATION 13.19 | 72 years STANDARD_DEVIATION 9.86 | 70.9 years STANDARD_DEVIATION 12.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 43 Participants | 18 Participants | 61 Participants |
| Region of Enrollment Canada | 8 participants | 5 participants | 13 participants |
| Region of Enrollment United States | 38 participants | 16 participants | 54 participants |
| Sex: Female, Male Female | 17 Participants | 8 Participants | 25 Participants |
| Sex: Female, Male Male | 29 Participants | 13 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 46 | 1 / 21 |
| other Total, other adverse events | 0 / 46 | 0 / 21 |
| serious Total, serious adverse events | 2 / 46 | 1 / 21 |
Outcome results
Primary
Wound Size, Amputation or Survival
Number of subject with doubling of wound size, major amputation or death
Time frame: Baseline vs. 1 year
Population: The primary endpoint was time from treatment to either de-novo gangrene in the treated limb, or doubling of wound size in the treated limb, or major amputation in the treated limb, or death.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ACP-01 | Wound Size, Amputation or Survival | 12 participants |
| Placebo | Wound Size, Amputation or Survival | 3 participants |
Comparison: The primary hypothesis of this study is that ACP-01 is superior to placebo in terms of the earlier time from treatment with Investigational Medicinal Product (IMP) to either de-novo gangrene, or doubling of wound size, or major amputation, or death.p-value: 0.25895% CI: [0.577, 7.255]ANCOVA
Secondary
Pain Level
Change in pain score according to the Visual Analog Scale (VAS) for Pain. The visual VAS is a validated, subjective measure for acute and chronic pain. Scores are recorded by making a handwritten mark on a 10-cm line that represents a continuum between the two ends of the scale-no pain on the left end (0 cm) of the scale and the worst pain on the right end of the scale (10 cm). Measurements from the starting point (left end) of the scale to the subjects' marks are recorded in centimeters and are interpreted as their pain. The values ar used to track pain progression for a subject and to compare pain between subjects.
Time frame: Baseline vs. 1 year
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ACP-01 | Pain Level | 38.75 units on a scale | Standard Error 9.479 |
| Placebo | Pain Level | 44.44 units on a scale | Standard Error 14.036 |
Secondary
Ulcer Size
Change in ulcer size
Time frame: Baseline vs. 1 year
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| ACP-01 | Ulcer Size | 1.6 cm^2 | Standard Error 1.07 |
| Placebo | Ulcer Size | 1.8 cm^2 | Standard Error 0.59 |
Other Pre-specified
Change From Baseline in Ankle Pressure
Time frame: 1 - 52 wks
Other Pre-specified
Change From Baseline in Quality of Life
Change in quality of life according to the Vascular Quality of Life Questionnaire.
Time frame: 1 - 52 wks
Other Pre-specified
Change From Baseline in the Dose and Quantity of Analgesic Drugs Used by the Subject
Time frame: 1 - 52 wks
Other Pre-specified
Change From Baseline in Toe Pressure
Time frame: 1 - 52 wks
Other Pre-specified
Reduction in Total Hospitalization Time of Subjects Treated With ACP-01 Compared to Subjects Treated With Placebo
Time frame: 1 - 52 wks