Design of OASIS 1 and 2: phase 3 clinical trials assessing the efficacy and safety of elinzanetant for the treatment of vasomotor symptoms associated with menopause.

OBJECTIVE: Elinzanetant is a selective neurokinin-1,3 receptor antagonist in development for the treatment of vasomotor symptoms (VMS) associated with menopause. The pivotal, double-blind, randomized, placebo-controlled phase 3 studies Overall Assessment of efficacy and Safety of elinzanetant In patients with vasomotor Symptoms (OASIS) 1 and 2 will assess the efficacy and safety of elinzanetant in women with VMS. METHODS: The OASIS 1 and 2 pivotal studies are designed in accordance with regulatory guidance. Postmenopausal women with moderate/severe VMS are randomized to receive 120 mg elinzanetant or placebo once daily for 12 weeks, followed by a 14-week active treatment extension. Primary endpoints are the mean change in frequency and severity of moderate/severe VMS from baseline to weeks 4 and 12. Key secondary endpoints will assess the onset of action and effects on sleep disturbance and menopause-related quality of life. Primary and key secondary endpoints will be analyzed using a mixed model with repeated measures. Feedback from postmenopausal women with VMS was used during protocol development. RESULTS: Women confirmed the relevance of endpoints that assess the impact of VMS, sleep disturbance, and mood changes, and the need for new nonhormone treatments. Educational materials around study design, conduct and expected assessments and procedures were developed based on questions and concerns raised by women. CONCLUSIONS: The OASIS 1 and 2 pivotal phase 3 studies will enable assessment of the efficacy and safety of elinzanetant as a treatment for VMS, together with its effect on sleep disturbances, depressive symptoms, and menopause-related quality of life. Feedback from postmenopausal women with VMS was used to maximize patient centricity in the trials.

Hepatotoxicity of AKR1C3 Inhibitor BAY1128688: Findings from an Early Terminated Phase IIa Trial for the Treatment of Endometriosis.

INTRODUCTION: BAY1128688 is a selective inhibitor of aldo-keto reductase family 1 member C3 (AKR1C3), an enzyme implicated in the pathology of endometriosis and other disorders. In vivo animal studies suggested a potential therapeutic application of BAY1128688 in treating endometriosis. Early clinical studies in healthy volunteers supported the start of phase IIa. OBJECTIVE: This manuscript reports the results of a clinical trial (AKRENDO1) assessing the effects of BAY1128688 in adult premenopausal women with endometriosis-related pain symptoms over a 12-week treatment period. METHODS: Participants in this placebo-controlled, multicenter phase IIa clinical trial (NCT03373422) were randomized into one of five BAY1128688 treatment groups: 3 mg once daily (OD), 10 mg OD, 30 mg OD, 30 mg twice daily (BID), 60 mg BID; or a placebo group. The efficacy, safety, and tolerability of BAY1128688 were investigated. RESULTS: Dose-/exposure-dependent hepatotoxicity was observed following BAY1128688 treatment, characterized by elevations in serum alanine transferase (ALT) occurring at around 12 weeks of treatment and prompting premature trial termination. The reduced number of valid trial completers precludes conclusions regarding treatment efficacy. The pharmacokinetics and pharmacodynamics of BAY1128688 among participants with endometriosis were comparable with those previously found in healthy volunteers and were not predictive of the subsequent ALT elevations observed. CONCLUSIONS: The hepatotoxicity of BAY1128688 observed in AKRENDO1 was not predicted by animal studies nor by studies in healthy volunteers. However, in vitro interactions of BAY1128688 with bile salt transporters indicated a potential risk factor for hepatotoxicity at higher doses. This highlights the importance of in vitro mechanistic and transporter interaction studies in the assessment of hepatoxicity risk and suggests further mechanistic understanding is required. CLINICAL TRIAL REGISTRATION: NCT03373422 (date registered: November 23, 2017).

Comparing Accuracy of Cervical Pedicle Screw Placement between a Guidance System and Manual Manipulation: A Cadaver Study.

BACKGROUND: The aim of this study was to compare the accuracy of cervical pedicle screw placement between a three-dimensional guidance system and manual manipulation. MATERIAL AND METHODS: Eighteen adult cadavers were randomized into group A (n=9) and group B (n=9). Ninety pedicle screws were placed into the C3-C7 under the guidance of a three-dimensional locator in group A, and 90 screws were inserted by manual manipulation in group B. The cervical spines were scanned using computed tomography (CT). Parallel and angular offsets of the screws were compared between the two placement methods. RESULTS: In group A, 90% of the screws were within the pedicles and 10% breached the pedicle cortex. In group B, 55.6% were within the pedicle and 44.4% breached the pedicle cortex. Locator guidance showed significantly lower parallel and angular offsets in axial CT images (P<0.01), and significantly lower angular offset in sagittal CT images (P<0.01) than manual manipulation. CONCLUSIONS: Locator guidance is superior to manual manipulation in accuracy of cervical screw placement. Locator guidance might provide better safety than manual manipulation in placing cervical screws.

Secondary definitive surgery for multiple injuries from Wenchuan earthquake in China.

OBJECTIVE: To investigate the opportune time of secondary definitive surgery for patients with multiple injuries from earthquakes based on the acute physiology and chronic health evaluation II (APACHE II) score and the principles of damage control. METHODS: Twenty-one patients with critical earthquake injuries were treated with damage control strategies, followed by medical support and surgical intervention to restore their physical potential in the intensive care unit (ICU). Successive APACHE II scoring was adopted to evaluate the patients'physiological status, and then, internal fixation of fractures and other definitive operations were performed. RESULTS: All the patients were effectively treated with few complications, low deformity rate and no death. CONCLUSIONS: Appropriate evaluation of patients?physiological potential, right decision on surgical time and proper operative method can reduce the rates of complications, disability and death for patients with critical earthquake injuries.

Design of cervical pedicle locator and three-dimensional location of cervical pedicle.

STUDY DESIGN: To develop a high-accuracy, easy-manipulated, and low-cost cervical pedicle three-dimensional locator for guiding cervical pedicle screw placement. OBJECTIVES: To improve the safety of cervical pedicle screw insertion, simplify its manipulation, and offer safety guarantees in clinical application. SUMMARY OF BACKGROUND DATA: Because of the complicacy of the anatomic structure of cervical pedicle, clinical application of cervical pedicle screw remained hard to popularize. And recent advances on cervical pedicle location did not simplify the manipulation of procedure significantly. Without aid of locator, distance and angle errors were difficult to control. So far, the only instrument for the location of pedicle "computer-assisted image-guided surgical system" is too expensive for clinical use. Furthermore, it has not yet been documented on location instrument for insertion of cervical pedicle screws. METHODS: The high-accuracy three-dimensional locator, made of stainless steel was designed to aid cervical pedicle nail placement. The cadavers were inserted nails under guidance of the locator that has been input the corresponding parameters collected from CT images. Results were evaluated by CT scans. RESULTS: A total of 90 nails were inserted into cervical pedicles, 90% of which were found right in the pedicles; 10% had pedicle cortex breaches. Parallel offset error of the locator in cross-sectional and lateral CT image that was 0.56 +/- 0.70 and 1.04 +/- 0.99; angular offset error was 1.69 +/- 2.41 and 6.54 +/- 7.08. CONCLUSION: Three-dimensional locator of cervical pedicle and its localization technique achieved good results for individuated screws insertion into cervical pedicles, having such advantages as easy manipulation, high accuracy, and low cost. The system presented safety guarantee to the application and advanced the prevalence of pedicle techniques. Its principium and design were demonstrated feasible.

Indomethacin blocks the nucleus pulposus-induced effects on nerve root function. An experimental study in dogs with assessment of nerve conduction and blood flow following experimental disc herniation.

Inflammatory mechanisms have been suggested to be involved in the basic pathophysiologic events leading to nerve root injury after local application of nucleus pulposus. To assess if these nucleus pulposus-induced effects could be blocked by anti-inflammatory treatment, 41 dogs were exposed to either incision of the L6-7 disc to induce experimental disc herniation with (n=12) or without (n=14) indomethacin treatment per os (5 mg/kg per day), and no incision with (n=5) or without (n=10) indomethacin. Intraneural blood flow and nerve conduction velocity were assessed after 7 days to evaluate the degree of nerve injury. Disc incision induced a reduction in nerve root and dorsal ganglion blood flow as well as nerve function, similarly to previous studies. However, simultaneous treatment with indomethacin efficiently blocked the negative effects on both blood flow and nerve conduction but had no effects per se. The present study thus indicates that inflammatory mechanisms may be of relevance in the pathophysiology of nucleus pulposus-induced nerve root injury and thereby also for sciatica.