Phase 2 trial of a neurokinin-1 receptor antagonist for the treatment of chronic itch in patients with epidermolysis bullosa: A randomized clinical trial.

BACKGROUND: Chronic pruritus causes major morbidity in epidermolysis bullosa (EB). The substance P-neurokinin 1 receptor (SP-NK1) pathway is a promising target for treating EB-related pruritus. OBJECTIVE: To evaluate the safety and efficacy of the oral NK1 receptor antagonist serlopitant in treating moderate-severe pruritus in EB. METHODS: The study randomized 14 patients to serlopitant or placebo for 8 weeks, followed by a 4-week washout and optional open-label extension. The primary end point was change in itch as measured by the Numeric Rating Scale. Secondary end points were change in itch during dressing changes and wound size. RESULTS: We observed greater itch reduction with serlopitant, equivalent to a 0.64-point comparative reduction on the 11-point Numeric Rating Scale by week 8, although this failed to meet statistical significance (P = .11). More serlopitant patients achieved ≥3-point reduction compared with placebo (43% vs 14%, P = .35). In post hoc analysis excluding 1 patient with a concurrent seborrheic dermatitis flare, serlopitant achieved significantly greater median itch reduction from baseline by week 4 (-2 points vs 0, P = .01). We observed no statistically significant differences in secondary end points. Serlopitant was well-tolerated. LIMITATIONS: Small sample size due to disease rarity. CONCLUSION: The potential itch reduction with serlopitant observed in this trial will be pursued by a larger powered trial (NCT03836001).

Defect evaluation by infant photographs in a multicenter pharmaceutical clinical trial.

OBJECT: The NT-04 clinical trial of investigational medication NT100 had a limited, though geographically diverse, study population. To enhance potential birth defect identification, photographic dysmorphology exam of infants was performed along with review of prenatal and postnatal medical records. METHODS: Standardized photographic views were developed: full body (prone and supine), face, both profiles, dorsal and ventral hands and feet, genitalia, and birthmarks/skin lesions. Professional photographers were identified and trained. Photos were taken in the first month of life at the subject's home and uploaded to a secure electronic online photo viewer. The evaluating geneticist accessed the photos electronically and submitted an evaluation. RESULTS: Forty subjects had 39 evaluable outcomes (55 babies). Twelve photographers were recruited, 10 of whom worked with multiple subjects. Photographic dysmorphology evaluation was done on 38 pregnancy outcomes. Only one baby had missing photos due to an apparent protocol error. Four babies were photographed with diaper on. CONCLUSIONS: The standardized photographs worked well. Advantages include: a single clinician evaluating all infants, the photographs could be reviewed repeatedly as needed, and minor malformations were more uniformly identified. Difficulties were: identifying local photographers and supplying training and training materials. There was no protocol for retaking or obtaining new photos and the study consent form did not include permission to publish the photographs. This was a successful pilot study of infant photographic assessment to detect congenital anomalies in a clinical trial.

Efficacy and safety of alfimeprase in patients with acute peripheral arterial occlusion (PAO).

PURPOSE: To investigate the safety and effectiveness of a novel thrombolytic, alfimeprase, in catheter-directed thrombolysis (CDT) of acute peripheral arterial occlusions (PAO). METHODS: Between April 2005 and March 2007, patients with acute PAO (Rutherford class I or IIa) of a lower extremity and onset of symptoms within 14 days prior to randomization were included. Studies HA004 and HA007 enrolled respectively 300 and 102 patients. Both studies HA004 and HA007 were placebo-controlled. HA004 had two placebo arms, intrathrombus and perithrombus, while HA007 had intrathrombus placebo arm. HA004 was partially double-blind (perithrombus group was not blinded) and HA007 was double-blind. Patients were randomized to intrathrombus alfimeprase (0.3 mg/kg), intrathrombus (IT) placebo, or perithrombus (PT) placebo (HA004 only) in two divided weight-based infusions 2 hours apart. Depending on arteriographic results after treatment, patients received no further intervention or underwent endovascular therapy or open vascular surgery. The primary endpoint of both studies was efficacy of alfimeprase compared with placebo as measured by avoidance of an open vascular surgery procedure at 30 days. RESULTS: The avoidance of open vascular surgery at 30 days was seen in 52 (34.9%), 42 (37.2%), and 7 patients (18.4%) with alfimeprase, IT placebo, and PT placebo in HA004 and 15 (29.4%) and 9 patients (17.6%) with alfimeprase and IT placebo in HA007; differences between alfimeprase and IT placebo were not statistically significant. Results were similar for secondary endpoints, including arterial flow restoration in 4 hours, 30-day ankle-brachial index, index limb pain severity, and hospital stay duration. The overall rate of adverse events was higher with alfimeprase than placebo. Hemorrhagic and peripheral embolic event rates with alfimeprase were 23% (34 patients) and 10.1% (15 patients) in HA004 and 9.4% (5 patients) and 9.8% (5 patients) in HA007; rates with IT placebo were 11% (12 patients, P = .107) and 5% (5 patients, P = .148) in HA004 and 10% (5 patients, P = .982) and 0% in HA007 (P = .07). No deaths were related to study drug administration. CONCLUSIONS: CDT for acute PAO with alfimeprase was as safe as placebo. However, alfimeprase was no more effective than placebo in increasing 30-day surgery-free survival. The surprising effectiveness of placebo alone demonstrates that the inclusion of a placebo arm is essential to the design of future lytic trials.