Open-label Extension Phase of a Chronic Diabetic Foot Ulcer Multicenter, Controlled, Randomized Clinical Trial Using Cryopreserved Placental Membrane

Objective. The results of the single-arm, open-label extension phase of the Grafix (cryopreserved placental membrane; CPM; Osiris Therapeutics, Inc, Columbia, MD) multicenter, blinded, randomized, controlled clinical trial for chronic diabetic foot ulcers (DFUs) is reported. Materials and Methods. Twenty-six patients in the standard wound care (SWC) arm whose DFUs did not close in the blinded phase chose to receive weekly applications of the CPM in an open-label extension phase. Results. In the extension phase, 17 (65.4%) patients closed their wounds in a median of 34 days and 3 visits. There were fewer total adverse events (AEs) (24 CPM vs. 52 SWC) and index wound-related infections (5 CPM vs. 12 SWC) during the CPM application compared with the number of AEs for the same patients during the SWC treatment in the blinded phase of the trial. Conclusions. These results corroborate the benefits of this CPM combined with SWC over SWC alone for chronic DFUs previously reported for the blinded randomized phase of the trial, which directly relate to lower health care costs.

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The Use of Viable Placental Membranes in Complex Wounds

Previously, the investigators reported results of a multicenter, blinded, randomized controlled trial (RCT) evaluating the safety and efficacy of a cryopreserved placental membrane (CPM; Grafix; Osiris Therapeutics, Inc, Columbia, MD) to standard wound care (SWC) for chronic diabetic foot ulcer (DFU) management (Clinical Trial NCT01596920).¹ This commercially available product is a CPM derived from amnion. It is processed using proprietary technology that preserves the placental membrane extracellular matrix, growth factors, and viable tissue cells, including mesenchymal stem cells, in their native state. This composition makes the CPM unique among advanced wound care modalities.^2,3

The initial blinded phase of the trial was halted at 50% enrollment due to the overwhelming efficacy of the CPM over SWC.¹ To the best of the authors’ knowledge, this is the first DFU RCT in which the interim analysis was successful, with primary and secondary objectives achieved with less than half of the planned study population enrolled, and that included a single-arm extension phase. Twenty-six patients from the control arm whose wounds had not healed after 12 weeks of SWC continued in an open-label extension phase to receive the CPM.

The objective of this paper is to describe the results of this extension phase. Clinical outcomes and adverse events (AEs), including index wound infections, were compared between the CPM extension phase and the SWC blinded phase of the trial¹ for the same cohort of 26 patients.

The purpose of this study was to analyze outcomes of the open-label extension phase of the CPM multicenter, blinded RCT for chronic DFUs.¹ This study was conducted by an independent Academic Research Organization in accordance with Good Clinical Practice.

Major inclusion criteria included confirmed type I or type II diabetes; Wagner Grade I wounds present for at least 4 weeks, but not longer than 52 weeks; and wounds between 1 cm² and 15 cm². Major exclusion criteria included Wagner Grade II and III wounds, hemoglobin A_1c > 12%, evidence of active infection, inadequate circulation defined by either an ankle-brachial index < 0.70 or > 1.30 or toe-brachial index ≤ 0.50, or wound area reduction ≥ 30% during the 1-week screening period.

Using a third-party electronic data capture system, patients with chronic DFUs were randomized 1:1 after a 1-week screening period and received weekly SWC (n = 47) or SWC with CPM (n = 50) treatment in the blinded phase of the trial. The SWC consisted of surgical debridement to remove nonviable soft tissue, appropriate offloading, and dressing changes. ADAPTIC TOUCH Non-Adhering Silicone Dressing (Acelity, San Antonio, TX) was used as the primary dressing, and saline-moistened gauze or ALLEVYN (Smith & Nephew, Andover, MA) were used as secondary dressings. For wounds located on the plantar surface of the foot, patients were required to wear a walking boot. Postoperative shoes were used for wounds located on the dorsum of the foot or at the ankle. Total contact casting was not permitted for use during the trial. Wounds were evaluated weekly. Results of these 97 patients were reported.¹

Twenty-six of the 47 patients in the control arm (from 13 different sites) whose wounds failed to close during the 12-week blinded phase then opted to enroll in an extension phase to receive weekly applications of the CPM for up to 12 weeks in conjunction with SWC as previously described. Wound assessments were performed at each visit. The primary endpoint of the extension phase was the evaluation of complete closure of the index wound, defined as 100% reepithelialization with no drainage. This was determined by the site investigator and independently confirmed via a central wound core laboratory with 2 blinded wound care experts who reviewed all wounds via digitized acetate tracing and photography. Secondary objectives included the time to wound closure and number of applications (visits) needed for closure. Safety assessments included the number, type, and severity of AEs, as outlined in the National Cancer Institute’s Common Terminology Criteria for Adverse Events Version 3.0.

Descriptive summaries of the distribution of continuous variables included the mean, standard deviation, median, and patient counts; categorical variables were summarized in terms of frequencies and percentages. Statistical comparisons between treatment groups were performed using Fisher’s exact 1-sided test and Wilcoxon signed-rank test.

Patient demographics and wound baseline characteristics are described in Table 1. During the 12 weeks of SWC, the average wound size was reduced by only 39% (2.4 cm² ± 2.3 cm² to 0.94 cm² ± 1.1 cm²) for 25 of 26 wounds (measurements for 1 wound not provided). More than 75% of wounds were located on the bottom of the foot, which is difficult to offload.

Of the 26 patients who transitioned into the extension phase, 24 completed the study. Two patients (7.7%) withdrew: 1 due to change in providers and 1 from hospitalization. Although the patient who withdrew from hospitalization was counted as a failure, this patient’s DFU closed while in the hospital. After CPM treatment, 65.4% (17/26) of patients achieved wound closure (complete reepithelialization) (Table 2). These patients also experienced fewer AEs and wound-related infections during the CPM treatment in the open-label crossover phase compared with their SWC outcomes in the blinded-treatment phase of the trial (Table 2).

The aim of the present study was to evaluate clinical outcomes of treatment with a CPM in the open-label extension phase of a multicenter, randomized, controlled clinical DFU trial.¹

This extension phase serves as an objective internal control in which the same patients who previously failed to achieve wound closure after 12 weeks of SWC were then treated with the CPM. This was the first wound care trial design based on the recommendations in the 2006 US Food and Drug Administration Guidance Document “Guidance for Industry, Chronic, Cutaneous Ulcer and Burn Wounds – Developing Products for Treatment.”⁴ This robust trial design included blinded wound closure assessments by an independent wound core lab and third-party randomization of patients; the National Institute of Health & Care Excellence rated the trial as being of a high quality with low bias.⁵ However, given the single-arm and open-label aspects of this extension, bias in the results is still possible.

Results from the extension phase confirmed the results of the RCT. In the extension phase, 65.4% of patients achieved wound closure after the CPM treatment. This closure rate is similar to the rate in the original blinded CPM group (62%).¹ The median time and number of visits required for wound closure with the CPM in the extension phase was 34 days and 3 visits (Table 2); in the blinded phase, it was 42 days and 6 visits,¹ which correlates with the smaller size of the wounds prior to applications of the CPM in the extension phase (mean, 0.94 cm² vs. 2.4 cm²). Likewise, fewer patients in the CPM group experienced AEs compared with those in the SWC group: 42.3% versus 69.2% in the open-label extension phase (Table 2) and 44% versus 66% in the randomized blinded phase for CPM versus SWC, respectively.¹ In addition, CPM-treated patients in the open-label extension phase had fewer AEs (24 CPM vs. 52 SWC) and index wound-related infections (5 CPM vs. 12 SWC) (Table 2). These results also are in line with those previously reported.¹

Wound-related infection is a risk factor leading to hospitalizations and amputations that are associated with significant increases in cost of care. In a prospective study of 1666 patients with diabetes, risk of hospitalization and amputation was 55.7 and 154.5 times greater, respectively, for those with an infected DFU compared with a noninfected DFU.⁶ Moreover, Hoffstad et al⁷ found that, on average, 50% of patients with DFU infection-related amputations die within 5 years. In a more recent review of nearly 1 million foot ulcer patients,⁸ infected DFUs accounted for 30.8% of all hospital admissions, and hospital costs per DFU admission were significantly higher for patients with an infection compared with noninfected admissions ($11 290 vs. $8145; P < .001). Another study⁹ found the average total cost of inpatient treatment for a DFU-related infection was $7177, with 73% of the total cost associated with hospitalization. Finally, an analysis from the 2013 report by the Agency for Healthcare Research and Quality¹⁰ estimated each general inpatient AE and serious AE (SAE) at $9567 and $17 210, respectively. Based on this report, cost modeling using the CPM DFU RCT data showed an estimated savings of ~$14 000 per patient for those treated with the CPM versus SWC during the blinded phase of the trial, based only on wound-associated AEs and SAEs.¹⁰ Thus, since the number of wound-related infections in the extension phase for the CPM was 2.4 times less than in the blinded phase for the same 26 patients treated with SWC (5 vs. 12), the authors extrapolate a 140% cost savings for treatment with the CPM compared with SWC alone.

Although the use of a third party for blinded assessment of wound closure reduced bias of the open-label phase of the trial, bias inherently cannot be eliminated from these types of studies. This bias is due to knowledge of the treatment assignment that may influence the behavior of patients. The small sample size is an additional limitation of this study. Selection bias is always an issue in RCTs. There are strict inclusion and exclusion criteria that do not necessarily reflect the general population of patients with DFUs.

In conclusion, results of the open-label extension phase of the multicenter RCT on DFUs support the benefits of this CPM over SWC for DFU treatment with fewer infections.

Affiliations: Howard Hughes Medical Institute - University of Texas Southwestern Medical Center at Dallas, Dallas, TX; River City Clinical Research, Jacksonville, FL; Clinical Trials of Texas, San Antonio, TX; Ocean County Foot and Ankle, Toms River, NJ; ILD Research Center, Carlsbad, CA; Omega Medical Research, Warwick, RI; University of North Carolina at Chapel Hill, Chapel Hill, NC; Cleveland Clinic, Cleveland, OH; Aiyan Diabetes Center, Evans, GA; and Osiris Therapeutics, Inc, Columbia, MD

Correspondence: Lawrence Lavery, DPM, Howard Hughes Medical Institute - University of Texas Southwestern Medical Center at Dallas, Radiology, Plastic Surgery, 5323 Harry Hines Boulevard, Dallas, TX 75390; Larry.Lavery@UTSouthwestern.edu

Disclosure: Dr. Lavery is a paid speaker for Osiris Therapeutics, Inc (Columbia, MD), Integra LifeSciences (Plainsboro, NJ), and Smith & Nephew (Andover, MA); a Consultant/Advisor for Aplion Medical LLC (Salt Lake City, UT), Harbor MedTech Inc (Irvine, CA), Boehringer Ingelheim (Ridgefield, CT), and Medline Industries, Inc (Northfield, IL); and has received a research grant from Cardinal Health (Dublin, OH). Dr. Regulski is a paid speaker and advisor for Osiris Therapeutics. Dr. Kashefsky is a previous consultant for Osiris Therapeutics and current consultant for Medi USA (Whitsett, NC). At the time of the study, Dr. Hesp is an employee of Osiris Therapeutics. All other authors disclose no financial or other conflicts of interest.