Status:Not yet recruiting
Keywords:ischemia , critical limb ischemia , limb , leg , bone marrow
The main purpose of this research is to determine the efficacy and safety of ixmyelocel-T compared to placebo (an inactive solution) when given to patients with Critical Limb Ischemia (CLI) who have no options for surgery to fix their disease. At the time of enrollment, eligible research patients will have had all the surgeries on their affected legs that can be done (if any) and there are no further surgeries possible. Eligible research patients may be at risk of losing their leg(s) to amputation due to the worsening of their diseases. Researchers will study the effectiveness of ixmyelocel-T to delay amputation and improve survival, the ability of ixmyelocel-T to help close wounds, and patient reports of pain, quality of life, and use of medical resources.
This is a Phase 3 multicenter, randomized, double-blind, placebo-controlled, parallel-group study of the efficacy, safety and tolerability of autologous ixmyelocel-T treatment in CLI subjects with no option of revascularization. There are 4 distinct phases of this study outlined below:
Screening: An approximate 30-day assessment period. Those subjects who meet all eligibility requirements will be asked to return for the next phase of the study.
Randomization, aspiration, and manufacturing: Subjects meeting all entry criteria that can be assessed at this time will be randomized in a 1:1 ratio of active treatment (ixmyelocel-T) to vehicle control (placebo). Randomization will be stratified by study site. Following randomization, subjects will immediately undergo a bone marrow aspiration under local anesthetic or conscious sedation. The aspirate will be packaged and shipped to Aastrom’s central manufacturing facility to undergo 12 ± 1 days of cell expansion, after which the autologous ixmyelocel-T product or vehicle control (placebo) will be shipped back to the site for injection.
Injection: Subjects will return to the clinic for their scheduled injections, approximately 14 days after the bone marrow aspirate was obtained. An unblinded pharmacist or designee will prepare 20 syringes of the injection solution on the day of injection and deliver the syringes to the site where the subject will receive the injections. Evaluation of certain entry criteria will be done to ensure subject continues to meet eligibility criteria. With special attention paid to the expiration time of the investigational product subjects will be injected by trained and blinded site personnel 20 times intramuscularly in their index leg. The day on which subjects receive their injections is Study Day 1.
Subjects who are randomized but not injected will continue with the study and all associated assessments. These subjects will have Study Day 1 imputed as 14 days post-aspiration (if the subject was randomized and aspirated) or 30 days post-signing informed consent (if the subject was randomized and not aspirated).
Post-treatment/Follow-up (from Study Day 1 to Month 18): The first contact post-injection will be a follow-up phone call on Study Day 4. Subsequent clinic visits will occur at 1, 3, 6, 9, 12, 15, and 18 months. Unplanned visits may occur at any time due to safety, confirmation of wound closure, and/or prior to a scheduled amputation. After the last subject has the opportunity to complete the Month 12 assessments, the study database will be locked to support regulatory activities. Subjects will continue to be followed through Month 18.
Each of the following inclusion criteria must be met for entry into the study.
1. Males and nonpregnant, nonlactating females. Females of child-bearing potential must use an appropriate form of contraception during the study and be at least 12 months post pregnancy;
2. Ages 35 to 90 years of age inclusive at screening;
3. Diagnosis of CLI with tissue loss (corresponding to Rutherford Category 5; see Appendix B in Protocol) having an ulcer size of at least 0.5 cm2, a smaller sized ulcer penetrating into the subcutaneous tissue, and/or gangrene (dry). In addition, the subject must have ONE of the following documented at screening:
a. Ankle systolic pressure <70 mm Hg;
b. Toe systolic pressure <50 mm Hg;
c. TcPO2 <30 mm Hg (in a supine position);
NOTE: diabetic subjects and/or those with calcified or noncompressible vessels must qualify on toe pressure or TcPO2
4. Subjects must have no reasonable standard-of-care options for surgical or endovascular revascularization interventions. Subjects must have:
a. Anatomical and conduit limitations, defined as any of the following:
i. No reasonable outflow target;
ii. No appropriate conduit (e.g., no autologous vein suitable for bypass);
iii. Long segment occlusions or calcified lesions;
b. Clinical high risk (e.g., significant co-morbidities prohibiting the use of surgical revascularization procedures) and have a Transatlantic Society Consensus II (TASC) D lesion that, in the opinion of the site vascular specialist, is not amenable to an endovascular procedure.
Clinical high risk is defined as any of the following:
– Known left ventricular ejection fraction (LVEF) <30%;
– Severe renal disease (serum creatinine >3 mg/dL);
– Severe chronic obstructive pulmonary disease (COPD) (defined as FEV1 <30% predicted).
In either case, a confirmation of “no option” must be supported by quality imaging results within 6 months of screening such as digital subtraction angiography (DSA), or within 3 months of screening for magnetic resonance angiography (MRA), or computed tomography angiography (CTA);
5. Subjects must have the following:
i. A narrative documenting the reasons why the site vascular specialist considers the subject “no option”. A vascular specialist will be the principal investigator (PI) or subinvestigator and is defined as: vascular surgeon, interventional cardiologist, certified vascular medicine specialist, or interventional radiologist;
ii. Secondary confirmation by an independent Eligibility Review Committee (ERC; see Section 8.1) after review of appropriate documents including, but not limited to: imaging results, medical records, surgical history, site vascular specialist narrative documenting reasons for “no option,” and/or lab reports.
6. Major amputation in the index leg or death is not anticipated within 3 months of screening in the opinion of the vascular specialist (who must be the PI or subinvestigator);
7. In the opinion of the investigator, the subject is controlled on medical therapy indicated for CLI (unless there is a documented contraindication or intolerance). This includes the following:
a. Antiplatelet therapy (e.g., ASA .81 mg/day or clopidogrel .75 mg/day);
b. Statin or other cholesterol lowering therapy.
8. Subject is current with all age-appropriate American Cancer Society (ACS) or similar
(e.g., United States Preventative Service Task Force) screening guidelines (see Appendix C);
9. Given medical history and concurrent medication, the subject is an acceptable candidate for bone marrow aspiration and intramuscular injection procedures in the opinion of the Investigator. Subject must be able to tolerate institutional guidelines regarding aspiration procedures, including anticoagulation and antiplatelet therapy.
10. Subject is willing and able to comply with the scheduled visits, aspiration/injection procedure, wound care instructions treatment plan, and other study procedures for the duration of the study;
11. Provide a personally-signed and dated informed consent document indicating that the subject (or a legally-acceptable representative, if permitted by the site’s Investigational Review Board [IRB]) has been informed of all pertinent aspects of the study.
Exclusion Criteria Patients presenting with any of the following will not be randomized:
1. Failed open surgical revascularization (on index leg) within 4 weeks of screening Visit 1.
2. Acute limb-threatening ischemia, trauma, known non-atherosclerotic vascular disease
(e.g., temporal/giant cell arteritis, Takayasu’s arteritis, Raynaud’s occlusive disease, Buerger’s disease), embolic disease, aortoiliac disease with >50% stenosis, or history of hypercoagulable states;
3. Advanced CLI (i.e., nonsalvageable) defined as Rutherford Category 6 (see Appendix B in Protocol);
4. Clinical evidence of invasive infection in index leg (e.g., cellulitis, osteomyelitis, wet gangrene); NOTE: on the day of injection (post-randomization), if the subject has clinical evidence of an invasive infection in the index leg, the leg must not be injected but the subject will remain in the study. See Section 6.3.3 in Protocol for further explanation.
5. At screening, nonheel wound size of >20 cm2 (excluding toe gangrene); or wounds on the heel >10 cm2 on the index leg as measured by the Wound Core Lab (WCL) from photographs (and/or acetates) provided by the site;
6. Previous amputation at or above the talus in the index leg;
7. On the day of injections if there is a safety reason that the subject should not be injected (e.g., unstable cardiac condition) or if the subject is absent or physically unable to receive the injections, no injections will be given. However, these randomized subjects will remain in the study and will follow the schedule of events despite not receiving injections;
8. Hemoglobin A1c (HbA1c) =10% at screening;
9. Diabetic subjects with uncontrolled or untreated proliferative retinopathy as determined by dilated eye exam (by qualified eye care professional as per American Diabetes Association guidelines);
10. Blood clotting disorder not caused by medication (e.g., thrombophilia);
11. Active non-basal cell cutaneous malignancy requiring surgery, chemotherapy, and/or radiation in the past 12 months.
NOTE: Subjects with localized prostate cancer under a watchful-waiting treatment plan without evidence of disease progression in the past year may participate in the study if approved by the investigator and sponsor or designee.
NOTE: Subjects diagnosed with basal cell carcinoma of the skin within the past 12 months must receive adequate treatment for their basal cell skin carcinoma prior to randomization.
12. Current documented drug or alcohol abuse that would interfere with the subject’s compliance with study procedures;
13. Known allergies to any equine, porcine, or bovine products ;
14. Body mass index (BMI) =50 kg/m2 at screening;
15. Established chronic kidney disease (CKD) requiring dialysis (Stage 5); estimated creatinine clearance <15 mg/mL/min at screening;
16. Systolic blood pressure (SBP) >200 mm Hg or diastolic blood pressure (DBP) >120 mm Hg or papilledema noted via ophthalmoscope at screening physical exam;
17. Within 3 months prior to screening, a clinically significant history of cardiac disease including but not limited to:
a. Adverse cardiovascular event (stroke or myocardial infarction);
b. Life-threatening ventricular arrhythmias (unless automatic implantable cardioverter/defibrillator [AICD] implanted);
c. Unstable angina characterized by increasingly frequent episodes with modest exertion or at rest, or worsening severity, or prolonged duration;
d. Major cardiovascular surgical procedure: carotid endarterectomy, open arterial aneurysm or bypass surgery, or coronary artery bypass surgery or planned coronary artery bypass surgery during the course of the study;
e. Cardiac angioplasty or planned angioplasty prior to injection;
18. Abnormal laboratory values (performed at central lab) at screening:
a. Platelets <50,000 µL;
b. Aspartate aminotransferase/alanine aminotransferase (AST/ALT) >3 times the upper limit of normal (ULN);
c. Human immunodeficiency virus-1 (HIV-1), HIV-2, or syphilis positive (rapid plasma reagin [RPR]);
d. Active hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV);
NOTE: Additional lab tests may be performed per local requirements including but not limited to: hepatitis B core antibody, human T lymphotropic virus I/II.
Exclusionary Procedures, Devices, or Medication
19. Exposure to immunosuppressive therapy for oncologic or chronic non-oncologic reasons in the prior 12 months or expected requirement over the course of the study (e.g., chemotherapy, radiation therapy, methotrexate);
NOTE: If the subject was taking a course of high-dose steroids (i.e., taper dose required), Screening Visit 1 should be scheduled at least 2 weeks after the last dose of the steroid medication.
20. Concurrent participation in another clinical trial or receiving experimental medication within 30 days of screening or having previously been exposed to Aastrom’s ixmyelocel-T product [previously known as tissue repair cells (TRC), cardiac repair cells (CRC), vascular repair cells (VRC)];
21. On the index leg, use of concomitant wound treatments not currently approved for ischemic wound-healing within 30 days prior to screening or plans to initiate new, nonstandard-of-care treatments to the index leg during the study, including but not limited to:
a. Systemic or direct target limb injections of angiogenic growth factors at any time during the study in the index leg. This includes but is not limited to: vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), or autologous platelet gel;
b. Systemic or direct target limb injection of anti-angiogenic drugs (e.g., anti-VEGF);
c. Use of devices approved for improvement of circulation and not specifically approved for ischemic wound healing (e.g., ArtAssist pneumatic compression boot).
NOTE: Subjects should complete all courses of hyperbaric oxygen treatment and/or ultrasound therapy prior to screening Visit 1;
NOTE: Although these concomitant therapies are exclusionary within 30 days prior to screening and “discouraged” during the study, no therapeutic interventions that the investigator feels are clinically indicated will be withheld, independent of whether those
procedures were prohibited in the eligibility criteria noted above (Section 6.4.2 in Protocol).
22. In the opinion of the Investigator, the subject is unsuitable for cellular therapy or has a food/drug allergy, surgical or medical condition (active or chronic), clinically significant psychiatric disorders (bipolar disorder, major depressive disorder, psychosis, past hospitalization for psychiatric reasons), poor nutritional status, or lab abnormality requiring further medical evaluation that may interfere with the investigational product, interfere with the study results’ interpretation, interfere with the subject’s ability to complete the study or compromise subject’s safety.