Autologous Bone Marrow Stem Cell Transplantation for Critical, Limb-threatening Ischemia (BONMOT)

Peripheral arterial disease (PAD) represents very advanced arteriosclerosis. It is not unusual for this condition to result in limb-threatening ischemia that usually results in amputation of the limb. About 150.000 thigh or calf amputations due to PAD are done annually in the United states.

Treatment of critical limb threatening ischemia (corresponding to Rutherford grade II or III) consists of revascularization of the leg with critically reduced blood supply. Depending on the localization and morphology of the occlusion, surgical revascularization by means of bypass surgery or catheter-based percutaneous transluminal angioplasty (PTA) may be used (even as a complementary procedure). However, successful revascularization is possible in only max. 60% to 70% of the patients affected. Patients with limb threatening ischemia which cannot be revascularized have a one-year amputation rate exceeding 80% and a 20-30% mortality.

Several studies have shown that in less advanced PAD the implantation of a concentration of mononuclear cells harvested from the patient's own bone marrow has been effective in developing collateral vessel formation translating into an improvement in PAD symptoms. Additional clinical evidence that this simple, safe and inexpensive therapy can induce therapeutic angiogenesis in the ischemic limb sufficient to prevent amputation would be valuable to both patients and clinicians.

This study will evaluate the clinical potential for the implantation of a concentration of bone marrow mononuclear cells which contain stem cells for therapeutic angiogenesis through the augmented formation of collateral vessels in the ischemic limb. It is a placebo-controlled, 1:1 randomized study with a total of 90 patients included. The placebo procedure consists of a sham bone marrow puncture where no bone marrow aspiration is done; instead, only a stab puncture of the skin is made.

The bone marrow cell concentrate will be prepared "point of care", patient-side from an aspirate of 240 mL of bone marrow. A concentrate volume of 40-50 mL will be injected into 40-50 sites in the muscles of the ischemic limb. A blinded physician injects either the bone marrow cell concentrate or the visually identical placebo solution into the ischemic leg.

Improvement in perfusion of the limb will be measured using clinical assessment and ankle-brachial-index (ABI), transcutaneous oxygen (TcPO2) and contrast angiography. Quality of life and pain will be assessed.

Study participation ends for the subjects after a follow-up of three months with monthly visits. After this, clinical and perfusion status are recorded at least three-monthly up to two years after study inclusion.

HYPOTHESIS:

Implantation of Bone Marrow stem cell Aspirate Concentrate (BMAC) can be clinically effective in treating critical limb threatening ischemia so that the number of amputations can be reduced.

Inclusion criteria:

• Presence of Critical Limb ischemia according to the guidelines of the Transatlantic Consensus Group (TASC) Rutherford grade II or III. Perfusion is measured with absolute perfusion pressure and ankle-brachial index (ABI) and transcutaneous oxygen tension (TcpO2); for inclusion, ABI has to be less than or equal to 0.6 or absolute ankle pressure must be less than 60 mmHg. If ABI is technically not feasible, e.g. in patients with media calcification, inclusion criteria are a tcpO2 value (supine, forefoot, 44°C) of less than 20 mmHg if there is no tissue loss, or a tcpO2 of less than 40 mmHg if there is tissue loss.
• No sufficient response to best standard care delivered for six weeks.
• No surgical or radiological interventional option for revascularisation as confirmed by a vascular surgeon and an interventional radiologist
• Age older than 18 years
• Signed informed consent
• Absence of life-threatening complications from the ischemic limb

Exclusion criteria:

• Expected life span less than six months
• Bone marrow diseases which preclude transplantation (eg lymphoma, leukemia, myelodysplastic syndrome and others)
• Renal failure on hemodialysis
• Life threatening complications of limb ischemia with the need for immediate limb amputation to avoid death or clinical deterioration

End points:

• Primary end point: Major amputation (above the ankle) of the index limb after 3 months or persisting critical limb ischemia of the index limb after three months

• Secondary end points:

  • Wound healing (wound size, wound stage)
  • Pain and analgesics use
  • Rutherford grade and stage
  • Walking distance (treadmill) if possible
  • Quality of life (EQ-5D Questionnaire)
  • Transcutaneous oxygen pressure (TcpO2), ABI, absolute ankle perfusion pressure
  • Collateral artery number as judged by contrast angiography after 3 months
  • Rate and extent of minor (below the ankle) amputations in the index limb