CRITICAL LIMB ISCHEMIA
Recently we received clearance from Health Canada to proceed with a phase 2 trial of our ACP-01 product in patients with CLI. We are aggressively pursuing similar regulatory clearance to expanding this trial to clinical sites in other countries.
We have selected CLI as our lead indication since it can be considered a proof of principle for many other indications for which ischemia is the underlying pathophysiology.
Trial Steering Committee
We are working with our Scientific Advisory Board to establish a Clinical Trial Steering Committee comprised of eminent physicians with significant clinical expertise with critical limb ischemia and/or autologous cell therapies. This committee will be tasked with helping us refine our trial design, site selection, patient recruitment, and issues that arise during the trial’s conduct.
The clinical trial will be a prospective, randomized, double-blind, surgical-placebo-controlled study to assess the efficacy and safety of ACP-01.
Eligibility: Patients with Critical Limb Ischemia Rutherford Category 4 and 5 who meet other well defined inclusion/exclusion criterion
Control: Two-thirds of patients enrolled will receive the cell therapy; one-third will be in the surgical-placebo control group
Endpoints: Primary endpoints are (a) decrease in the rate of treatment failure as defined by major amputation/mortality rate, and (b) decrease from baseline to 3 and 6 months in chronic ulcer size and severity. Various secondary endpoints have also been established. They include clinical and numerical parameters that can support the value of the therapy in comparison to the existing standard of care.
DSMB: The company is in the process of constituting an independent Data Safety Monitoring Board (DSMB) comprised of non-conflicted and appropriately experienced clinicians and a biostatistician to blindly review safety data. The DSMS will conduct formal interim data evaluations in compliance with and as scheduled in the trial design. On the basis of its evaluation of the data, the DSMB will recommend the company to continue, modify, or possibly terminate the study. Termination of the study as per the Board’s decision can occur either due to increased risk of the experimental treatment, or due to significantly greater benefit of the therapy in comparison to the standard of care. According to its charter, the Board will be allowed to un-blind the data if the results reviewed blindly suggest that big differences between the two groups exist.
We are already in advanced discussions with several leading medical centers to collaborate on the clinical trial.
Past Clinical Trials
Health Canada’s clearance was based on data submitted from three clinical trials of the product completed to-date: two in Critical Limb Ischemia (CLI) and one in Angina Pectoris (AP)*.
Pilot clinical trial for CLI
A pilot non-randomized, open-label study was carried out in six patients with the permission of the Ethics Committee at the Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, the largest and most renowned academic hospital in Thailand. The goals of the study were to assess the safety and feasibility of the implantation of ACPs in patients with critical limb ischemia (CLI) who were not candidates for standard revascularization treatment options. The patients enrolled suffered from severe symptoms of CLI (Fontaine stage III and IV) such as ischemic rest pain, ischemic non-healing ulcers and digital gangrene. In addition, limb hemodynamic assessment indicated threatening ischemia of the limb.
The patients recruited in the study signed the informed consent and underwent intramuscular injections of autologous ACPs into the ischemic limb.
There was no evidence of local or systemic complications related to the procedure. Five of the six patients showed clinically significant improvement of the circulation in the distal limb. Four of them had complete healing of ischemic ulcers and stumps of toe amputation. However, the fifth patient who had initial adequate improvement, subsequently suffered from severe foot infection originating from the other toes and needed below-knee amputation. The sixth patient underwent major amputation since no improvement of circulation in the distal limb could be induced after ACP administration. The results of this trial showed that ACP therapy is potentially safe and could provide benefits in the improvement of circulation in patients with CLI.
Phase 1b clinical trial for CLI
The company provided ACPs to a Hungarian healthcare company that sponsored a controlled clinical study at two medical centres in Budapest, Hungary. The local sponsor obtained all the necessary approvals required by the authorities in order to perform the studies. A contract research organizations was retained to monitor and ensure the quality of the study and the data in accordance with the requirements of the local authorities.
The effect of intramuscular administration of ACPs was assessed in 20 patients with severe CLI (Fontaine phase III-IV) and high risk of amputation of the affected limb. Half of the patients were treated with ACPs while the other half, the control patients, received standard of care medical therapy. The patients were followed for 3 months post treatment.
The primary endpoints of the study were to assess the safety of ACP administration as well as its effect in the prevention of limb loss. The results showed that no side effects related to the therapy occurred. In the treatment group, one patient had toe amputation and another patient had trans-metatarsal amputation, following which the wounds healed well and the pain subsided. In contrast, in the control group, five patients had leg amputations and one of them died because of septicemia. Statistically significant improvement of the ankle-brachial index was also observed in the treatment group in comparison to controls (0.69 vs. 0.32, p=0.04).
It can be concluded that the safety of the ACPs as a treatment for CLI was successfully demonstrated in 16 patients. In addition, encouraging efficacy was seen in the treated patients.
* See Cardiac Disorders.