Rationale and design of the Clinical and Histologic Analysis of Mesenchymal Stromal Cells in AmPutations (CHAMP) trial investigating the therapeutic mechanism of mesenchymal stromal cells in the treatment of critical limb ischemia

Abstract

Objective: Currently, there are no accepted nonsurgical therapies that improve the delivery of blood-derived nutrients to patients with critical limb ischemia. Here, we describe the ongoing phase 1/2 Clinical and Histologic Analysis of Mesenchymal Stromal Cells in AmPutations (CHAMP) trial, which will provide crucial evidence of the safety profile of mesenchymal stromal cells (MSCs) and explore their therapeutic mechanisms in the setting of critical limb ischemia requiring below-knee amputation (BKA).

Methods: In the CHAMP and the parallel marrowCHAMP trials (hereafter grouped together as CHAMP), a total of 32 extremities with rest pain or tissue loss requiring BKA will be enrolled to receive intramuscular injections of allogeneic MSCs (CHAMP; n = 16) or autogenous concentrated bone marrow aspirate (marrowCHAMP; n = 16) along the distribution of the BKA myocutaneous flap and proximal tibialis anterior. After treatment, subjects are randomized to BKA at four time points after injection (days 3, 7, 14, and 21). At the time of amputation, skeletal muscle is collected at 2-cm increments from the tibialis injection site and used to determine proangiogenic cytokine description, MSC retention, quantification of proangiogenic hematopoietic progenitor cells, and histologic description. Clinical limb perfusion before and after treatment will be quantified using transcutaneous oximetry, toe-brachial index, ankle-brachial index, and indocyanine angiography. Additional clinical end points include all-cause mortality, need for amputation revision, and gangrene incidence during the 6-month post-treatment follow-up.

Results: Enrollment is under way, with 10 patients treated per protocol thus far. We anticipate full conclusion of follow-up within the next 24 months.

Conclusions: CHAMP will be pivotal in characterizing the safety, efficacy, and, most important, therapeutic mechanism of allogeneic MSCs and autogenous concentrated bone marrow aspirate in ischemic skeletal muscle.

Trial registration: ClinicalTrials.gov NCT02685098.

Figure 1. Trial design of CHAMP

After screening, patients are enrolled into either the cBMA or MSC arm of CHAMP. Subjects are randomized to one of four time points within 21 days of cell therapy administration. At that time, BKA is performed and tissue is harvested. All patients are followed for six months post-amputation.

Figure 2. Simplified treatment plan of the CHAMP trial

A total of 280 million allogeneic MSCs (33 mL cBMA) are injected into the muscle beds of patients undergoing BKA (dots). 250 million MSCs (30 mL cBMA) are injected proximal to the myocutaneous flap along the gastrocnemius and distal thigh muscle beds. One additional site in the proximal tibialis anterior is injected with 30 million MSCs (3 mL cBMA). Tissue harvest sites of the tibialis anterior at time of BKA are denoted (rectangle) along the length of the muscle bed in 2 cm increments. Untouched soleus muscle will serve as an internal tissue control and harvested concurrently.