A phase 1b/2 clinical study of marstacimab, targeting human tissue factor pathway inhibitor, in haemophilia.

A phase 1b/2, three-month study of marstacimab, a human monoclonal antibody targeting tissue factor pathway inhibitor (TFPI), was conducted in participants with haemophilia A or B, with or without inhibitors. Participants assigned to four cohorts received escalating weekly doses based on inhibitor status (without inhibitors: 300 mg, a single 300-mg loading dose with subsequent 150-mg doses, or 450 mg; with inhibitors: 300 mg). Safety outcomes were treatment-emergent adverse events (TEAEs), injection site reactions, clinical and laboratory parameter changes. Efficacy was assessed by annualised bleeding rates (ABRs). Pharmacokinetics and pharmacodynamics (PD) were also evaluated. Among 26 treated participants [haemophilia A without inhibitor, n = 16 (61.5%); haemophilia A with inhibitor, n = 7 (26.9%); haemophilia B, n = 3 (11.5%)], 24 completed the study. Overall, 80.8% experienced TEAEs. ABR during treatment was significantly reduced versus an external on-demand control group (p < 0.0001) and versus pretreatment ABR (p < 0.0001), with significant reductions observed across all dose cohorts. Marstacimab exposure generally increased in a dose-related manner, with steady-state concentration reached by day 57. Changes in pharmacodynamic biomarkers occurred across all dose cohorts. Marstacimab was safe and well tolerated. Clinically meaningful reductions in ABR and treatment-related changes for all PD biomarkers indicated effective targeting of TFPI. (Clinicaltrials.gov identifier, NCT02974855).

Phase 1b Study to Evaluate Safety, Tolerability, and Maximum Tolerated Dose of PF-05230907 for Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: This study aimed to determine the maximum tolerated dose and to evaluate the overall safety and tolerability of single doses of PF-05230907 in subjects with acute intracerebral hemorrhage. METHODS: Individuals presenting with intracerebral hemorrhage were enrolled in a phase 1, multicenter, open-label clinical trial. A Bayesian modified continual reassessment method design based on treatment-emergent thromboembolic or ischemic events was adopted. Sequential dosing, an external data monitoring committee, and prespecified stopping rules were incorporated as safeguards. RESULTS: Twenty-one subjects received PF-05230907. The mean (±SD) age in years and intracerebral hemorrhage volume in mL at baseline were 62 (±9) and 18 (±11), respectively. Two treatment-emergent thromboembolic or ischemic events occurred (deep vein thrombosis and cerebral ischemia), in the 30 µg/kg dose group. There were no other clear drug-related toxicities at dose levels ranging from 5 to 30 µg/kg. At the time of study termination, the maximum tolerated dose was estimated to be 24 µg/kg, with a mean fitted dose-toxicity estimate of 11.9% (95% CI, 1.2%-27.4%). CONCLUSIONS: Single doses of PF-05230907 appeared to be tolerated across a range of doses in the intracerebral hemorrhage population, with thrombotic events observed only at the highest dose level tested. Recruitment within the recommended therapeutic window of opportunity remains a challenge. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02687191.

The incidence of lower-extremity amputation and bone resection in diabetic foot ulcer patients treated with a human fibroblast-derived dermal substitute.

OBJECTIVE: Diabetic foot ulcers (DFUs) are frequently recalcitrant and at risk for infection, which may lead to lower-extremity amputation or bone resection. Reporting the incidence of amputations/bone resections may shed light on the relationship of ulcer healing to serious complications. This study aimed to evaluate the incidence of amputations/bone resections in a randomized controlled trial comparing human fibroblast-derived dermal substitute plus conventional care with conventional care alone for the treatment of DFUs. DESIGN: Ulcer-related amputation/bone resection data were extracted from data on all adverse events reported for the intent-to-treat population (N = 314), and amputations were categorized by type: below the knee, Syme, Chopart, transmetatarsal, ray, toe, or partial toe. Data were analyzed retrospectively for the incidence of amputation/bone resection by treatment. SETTING: Randomized controlled trial. PATIENTS: Patients with full-thickness DFUs greater than 6 weeks' duration. INTERVENTIONS: Standard wound care plus human fibroblast-derived dermal substitute versus standard wound care alone. MAIN RESULTS: The incidence of amputation/bone resection in the study was 8.9% (28/314) overall, 5.5% (9/163) for patients receiving human fibroblast-derived dermal substitute, and 12.6% (19/151) for patients receiving conventional care (P = .031). Of the 28 cases of amputation/bone resection, 27 were preceded by ulcer-related infection. CONCLUSION: There were significantly fewer amputations/bone resections in patients who received human fibroblast-derived dermal substitute versus conventional care, likely related to the lower incidence of infection adverse events observed in the human fibroblast-derived dermal substitute treatment group.

A prospective, multicentre, randomised controlled study of human fibroblast-derived dermal substitute (Dermagraft) in patients with venous leg ulcers.

This was an open-label, prospective, multicentre, randomised controlled study to evaluate the efficacy and safety of human fibroblast-derived dermal substitute (HFDS) plus four-layer compression therapy compared with compression therapy alone in the treatment of venous leg ulcers. The primary outcome variable was the proportion of patients with completely healed study ulcers by 12 weeks. The number healed was further summarised by ulcer duration and baseline ulcer size. Sixty-four (34%) of 186 patients in the HFDS group experienced healing by week 12 compared with 56 (31%) of 180 patients in the control group (P = 0·235). For ulcers ≤ 12 months duration, 49 (52%) of 94 patients in the HFDS group versus 36 (37%) of 97 patients in the control group healed at 12 weeks (P = 0·029). For ulcers ≤ 10 cm(2), complete healing at week 12 was observed in 55 (47%) of 117 patients in the HFDS group compared with 47 (39%) of 120 patients in the control group (P = 0·223). The most common adverse events (AEs) were wound infection, cellulitis and skin ulcer. The frequency of AEs did not markedly differ between the treatment and control groups.

Differentiating diabetic foot ulcers that are unlikely to heal by 12 weeks following achieving 50% percent area reduction at 4 weeks.

This retrospective analysis included intent-to-treat control patient data from two published, randomised, diabetic foot ulcer (DFU) trials in an effort to differentiate ulcers that are unlikely to heal by 12 weeks despite early healing progress [≥50% percent area reduction (PAR) at 4 weeks]. Predicted and actual wound area trajectories in DFUs that achieved early healing progress were analysed from weeks 5 to 12 and compared for ulcers that did and did not heal at 12 weeks. In 120 patients who achieved ≥50% PAR by week 4, 62 (52%) failed to heal by 12 weeks. Deviations from the predicted healing course were evident by 6 weeks for non healing ulcers. A 2-week delay in healing significantly lowered healing rates (P = 0·001). For DFUs with ≥50% PAR at 4 weeks, those achieving ≥90% versus <90% PAR at 8 weeks had a 2·7-fold higher healing rate at 12 weeks (P = 0·001). A PAR of <90% at 8 weeks provided a negative predictive value for DFU healing at 12 weeks of 82%. For ulcers that fail to progress or worsen from weeks 4 to 6, and those that fail to achieve 90% PAR at 8 weeks, reevaluation of the wound and its treatment is recommended.

Human fibroblast-derived dermal substitute: results from a treatment investigational device exemption (TIDE) study in diabetic foot ulcers.

OBJECTIVE: To gain experience in the use of Dermagraft (Advanced Biohealing Inc, La Jolla, California), a human fibroblast-derived dermal substitute (HFDS), for the treatment of nonhealing diabetic foot ulcers (DFUs). STUDY DESIGN: An open label, noncontrolled, multicenter clinical trial of HFDS in the treatment of DFU was conducted. Subjects with DFUs underwent sharp debridement of the study ulcer and were prescribed an off-loading device. All of the subjects enrolled received applications of HFDS, beginning at day 0 and applied weekly thereafter, along with saline gauze or polyurethane foam dressings from day 0 to week 20. A maximum of 8 HFDS applications was allowed. MAIN OUTCOME MEASURES: The primary and secondary end points of the study were complete wound closure by weeks 12 and 20, respectively. MAIN RESULTS: A total of 23 centers screened 91 subjects, and 18 centers enrolled an intent-to-treat (ITT) population of 62 subjects. For the ITT population, 27 (44%) subjects healed by week 12, and 32 (52%) healed by week 20. Fifty-one subjects (82%) completed the study to week 12, and 46 subjects (74%) completed the entire 20-week study; wound closure rates in these groups were 59% and 70%, respectively. Median time to healing was 13 weeks. The overall incidence of at least 1 adverse event (44%, 27/62) was typical for this subject population. No adverse events were attributable to HFDS. CONCLUSION: Data from this study support the safety and efficacy of HFDS in the treatment of nonhealing DFUs.

A post-hoc analysis of reduction in diabetic foot ulcer size at 4 weeks as a predictor of healing by 12 weeks.

Percent area reduction (PAR) after 4 weeks of diabetic foot ulcer (DFU) treatment has been suggested as a clinical monitoring parameter to distinguish DFUs that will heal within 12 weeks from those that will not despite standard wound care. The purpose of this post-hoc analysis of control DFU treatment outcomes from two published, randomized, controlled studies was to assess the relationship between PAR during early standard wound care and ulcer closure by week 12. The proportion of DFUs healed after 12 weeks was 57% (39 out of 69; 95% confidence interval [CI], 44% to 68%) in study A and 52% (38 out of 73; 95% CI, 40% to 64%) in study B for wounds with > or = 50% PAR by week 4 and 5% (three out of 64; 95% CI, 1% to 13%) and 2% (one out of 44; 95% CI, 0.1% to 12%), respectively, for DFUs with < 50% PAR at week 4. Regardless of baseline size category, DFUs with < 50% PAR at 4 weeks were less likely to heal by 12 weeks than DFUs with > or = 50% PAR (P < or = 0.001). Using pooled data, PAR at weeks 1 to 3 also varied between ulcers that did and did not heal after 12 weeks but sensitivity and specificity was highest on week 4. These findings confirm that percent reduction in wound size is an early predictor of treatment outcome and that protocols of care should be re-evaluated if > or = 50% PAR is not achieved. Studies to assess DFU healing before and after 4 weeks of standard wound care are needed to further refine these guidelines of care.

Serial surgical debridement: a retrospective study on clinical outcomes in chronic lower extremity wounds.

This investigation was conducted to determine if a correlation exists between wound healing outcomes and serial debridement in chronic venous leg ulcers (VLUs) and diabetic foot ulcers (DFUs). We retrospectively analyzed the results from two controlled, prospective, randomized pivotal trials of topical wound treatments on 366 VLUs and 310 DFUs over 12 weeks. Weekly wound surface area changes following debridement and 12-week wound closure rates between centers and patients were evaluated. VLUs had a significantly higher median wound surface area reduction following clinical visits with surgical debridement as compared with clinical visits with no surgical debridement (34%, p=0.019). Centers where patients were debrided more frequently were associated with higher rates of wound closure in both clinical studies (p=0.007 VLU, p=0.015 DFU). Debridement frequency per patient was not statistically correlated to higher rates of wound closure; however, there was some minor evidence of a positive benefit of serial debridement in DFUs (odds ratio-2.35, p=0.069). Our results suggest that frequent debridement of DFUs and VLUs may increase wound healing rates and rates of closure, though there is not enough evidence to definitively conclude a significant effect. Future clinical research in wound care should focus on the relationship between serial surgical wound debridement and improved wound healing outcomes as demonstrated in this study.

Nonlinear modeling of venous leg ulcer healing rates.

BACKGROUND: The purpose of this manuscript was to determine whether the change in wound surface area over time could be described through nonlinear mathematics. METHODS: We studied 3,588 serial wound tracings of 338 venous leg ulcers (VLUs) that had been followed during a controlled, prospective, randomized trial of two topical wound treatments. RESULTS: A majority (72%) of VLUs exhibited surface area reduction via an exponential decay model, particularly during the early stages of healing. These results were consistent with the mechanics of wound contraction and epithelial cell proliferation, supported by the higher frequency at which exponential surface area reduction associated with full wound closure (35% of wounds that fit the exponential model healed vs. 21% of wounds that did not fit the exponential model completely healed during the study period, p = 0.018). Goodness-of-fit statistics suggested that much of the individual variation in healing could be described as nonlinear variation from the exponential model. CONCLUSION: We believe that parameter estimates from a mathematical model may provide a more accurate quantification of wound healing rates, and that similar models may someday reach routine use in comparing the efficacy of various treatments in routine practice and in product registration trials.

Wound shape geometry measurements correlate to eventual wound healing.

Wound geometry measurements have long been associated with wound-healing outcomes but there is little published evidence to support this. We studied serial wound tracings of 338 venous leg ulcers (VLUs) that had been followed during a controlled, prospective, randomized pivotal trial of two topical wound treatments, to determine whether the relationship between wound surface area and wound perimeter planimetry measurements, as well as the qualitative assessment of wound shape, could be correlated to wound-healing outcomes. VLUs that transitioned to a more convex wound shape, and maintained a linear relationship between their wound margin size and wound surface area size, had faster healing rates and were more likely to completely heal by 12 weeks (odds ratio=4.84, p=0.001). VLUs that initially presented with isolated areas of epithelium within the wound margins, large concavities, or were segmented into multiple ulcers typically had a poorer linear correlation between their margins and their surface area. Only 18 out of 134 (13%) VLUs with a linear r(2)<0.80 eventually reached full wound closure, vs. 43% (102 of 270) of the remaining wounds with an r(2)> or =0.80 (Fisher's exact p<0.001). We believe our results show that the proportional relationship between one-dimensional perimeter and area measurements accurately correlates to the healing progress of the wound. Wounds that do not correlate to this linear relationship (concave geometries or multiple islands of healing) may be physiologically different than wounds that have good linear correlation, which we concluded through the analysis of wound acetate tracings.

Early healing rates and wound area measurements are reliable predictors of later complete wound closure.

This study was undertaken to determine if healing rates are reliable early predictors of ultimate complete wound closure in venous leg ulcers and diabetic foot wounds. We conducted a retrospective analysis of 306 venous leg ulcers and 241 diabetic foot ulcers enrolled in two large controlled, prospective, randomized pivotal trials to compare topical wound treatments, to determine whether certain early markers of healing could be correlated with later total wound closure. Two-sided tests at 95% confidence demonstrated that wound margin advance, initial healing rate, percent wound surface area reduction, and wound healing trajectories (all p<0.001) were powerful predictors of complete wound healing at 12 weeks. Wounds with poor healing progress by these criteria at 4 weeks were highly likely to remain unhealed after 8 additional weeks of treatment. Analysis of the diabetic foot ulcers and venous leg ulcers subgroups separately demonstrated consistent statistical test results with high significance; similarly, the results remained valid independent of the topical treatment used. The early prediction of eventual wound healing or nonhealing using early healing rates may enable more efficient triage of patients to advanced healing technologies. We believe that these surrogate markers are robust predictors of healing regardless of wound etiology and that they merit wider use in clinical trials and routine patient care.