CANNA-TICS: Efficacy and safety of oral treatment with nabiximols in adults with chronic tic disorders - Results of a prospective, multicenter, randomized, double-blind, placebo controlled, phase IIIb superiority study.

Preliminary data suggest that cannabis-based medicines might be a promising new treatment for patients with Tourette syndrome (TS)/chronic tic disorders (CTD) resulting in an improvement of tics, comorbidities, and quality of life. This randomized, multicenter, placebo-controlled, phase IIIb study aimed to examine efficacy and safety of the cannabis extract nabiximols in adults with TS/CTD (n = 97, randomized 2:1 to nabiximols:placebo). The primary efficacy endpoint was defined as a tic reduction of ≥ 25% according to the Total Tic Score of the Yale Global Tic Severity Scale after 13 weeks of treatment. Although a much larger number of patients in the nabiximols compared to the placebo group (14/64 (21·9%) vs. 3/33 (9·1%)) met the responder criterion, superiority of nabiximols could formally not be demonstrated. In secondary analyses, substantial trends for improvements of tics, depression, and quality of life were observed. Additionally exploratory subgroup analyses revealed an improvement of tics in particular in males, patients with more severe tics, and patients with comorbid attention deficit/hyperactivity disorder suggesting that these subgroups may benefit better from treatment with cannabis-based medication. There were no relevant safety issues. Our data further support the role of cannabinoids in the treatment of patients with chronic tic disorders.

The CANNA-TICS Study Protocol: A Randomized Multi-Center Double-Blind Placebo Controlled Trial to Demonstrate the Efficacy and Safety of Nabiximols in the Treatment of Adults With Chronic Tic Disorders.

Background: Gilles de la Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by motor and vocal tics. First-line treatments for tics are antipsychotics and tic-specific behavioral therapies. However, due to a lack of trained therapists and adverse events of antipsychotic medication many patients seek alternative treatment options including cannabis. Based on the favorable results obtained from case studies on different cannabis-based medicines as well as two small randomized controlled trials using delta-9-tetrahydrocannabinol (THC), we hypothesize that the cannabis extract nabiximols can be regarded as a promising new and safe treatment strategy in TS. Objective: To test in a double blind randomized clinical trial, whether treatment with the cannabis extract nabiximols is superior to placebo in patients with chronic tic disorders. Patients and Methods: This is a multicenter, randomized, double-blind, placebo controlled, parallel-group, phase IIIb trial, which aims to enroll 96 adult patients with chronic tic disorders (TS or chronic motor tic disorder) across 6 centers throughout Germany. Patients will be randomized with a 2:1 ratio into a nabiximols and a placebo arm. The primary efficacy endpoint is defined as tic reduction of at least 30% (compared to baseline) according to the Total Tic Score of the Yale Global Tic Severity Scale (YGTSS-TTS) after 13 weeks of treatment. In addition, several secondary endpoints will be assessed including changes in different psychiatric comorbidities, quality of life, driving ability, and safety assessments. Discussion: This will be the first large, controlled study investigating efficacy and safety of a cannabis-based medicine in patients with TS. Based on available data using different cannabis-based medicines, we expect not only a reduction of tics, but also an improvement of psychiatric comorbidities. If the cannabis extract nabiximols is proven to be safe and effective, it will be a valuable alternative treatment option. The results of this study will be of high health-economic relevance, because a substantial number of patients uses cannabis (illegally) as self-medication. Conclusion: The CANNA-TICS trial will clarify whether nabiximols is efficacious and safe in the treatment of patients with chronic tic disorders. Clinical Trial Registration: This trial is registered at clinicaltrialsregister.eu (Eudra-CT 2016-000564-42) and clinicaltrials.gov (NCT03087201).

Evaluation of CT vascularization patterns for survival prognosis in patients with hepatocellular carcinoma treated by conventional TACE.

PURPOSE: Transarterial chemoembolization (TACE) is an established treatment for intermediate stage hepatocellular carcinoma (HCC). The aim of this retrospective study was to evaluate the power of lesion vascularization criteria based on computed tomography for prognosis of overall survival before initiation of treatment. METHODS: A total of 59 patients with intermediate stage HCC treated with TACE as first-line treatment were retrospectively evaluated. TACE procedures were performed using doxorubicin, cisplatin, and lipiodol. Response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) were used to determine the initial tumor response. Four vascularization patterns (VP) of the largest target lesion (homogeneous vascularization [VP1], homogeneous vascularization with additional arterial hypervascularization [VP2], heterogeneous vascularization with [VP3] and without zones of hypervascularization [VP4]) were assessed prior to the first TACE and correlated to survival. RESULTS: Kaplan-Meier analysis yielded a median overall survival of 608 days (standard error [SE], 120.5 days). Survival analysis showed significant differences depending on the vascularization patterns (P = 0.012; hazard ratio, 0.327): patients with homogeneously vascularized lesions (VP1, VP2) had a median overall survival of 1091 days (SE, 235.5 days). Patients with heterogeneous vascularization of the lesion (VP3 and VP4) showed a median overall survival of 508 days (SE, 113.9 days). CONCLUSION: The vascularization pattern of the largest HCC lesion is helpful for survival prognosis under TACE treatment and therefore has the potential to be used as an additional parameter for treatment stratification.

Perioperative Bromelain Therapy after Wisdom Teeth Extraction - A Randomized, Placebo-Controlled, Double-Blinded, Three-Armed, Cross-Over Dose-Finding Study.

Reduction in postoperative edema and inflammatory reactions is the key to the posttraumatic regeneration process. Use of bromelain is well established in this indication, but there is some controversy with regard to the optimal dosing of this drug. The aim of our study was therefore to investigate the efficacy of dosage-dependent therapy with bromelain in patients after wisdom teeth extraction by comparing the registered dosage 1000 FIP (Fédération Internationale Pharmaceutique) against higher dosages of 3000 FIP and 4500 FIP. A total of 75 patients were randomized to one of the three dosage arms, and 68 of these patients were finally analyzed in the modified intention-to-treat population. Patients involved underwent two surgery sessions: one study period being conducted under treatment with bromelain and the other with placebo. Postoperative swelling determined by a 3D face scanning system was defined as the primary endpoint; further efficacy parameters were maximum swelling, pain, difficulty in swallowing, and use of analgesics. A superiority of treatment with 3000 FIP and 4500 FIP versus 1000 FIP could not be demonstrated. The analysis of pooled bromelain treatments versus placebo did, however, show a clear trend in favor of bromelain for all assessments. Adverse events did not occur more frequently under bromelain therapy compared with placebo. This study thus clearly supports the clinical relevance of treatment of postoperative conditions with bromelain, and the recommended daily dose was sufficiently effective in this trial and indication. Copyright © 2016 John Wiley & Sons, Ltd.

A phase II trial comparing pazopanib with doxorubicin as first-line treatment in elderly patients with metastatic or advanced soft tissue sarcoma (EPAZ): study protocol for a randomized controlled trial.

BACKGROUND: Anthracycline-based treatment remains the backbone of chemotherapy for nonresectable soft tissue sarcomas (STS). More than 30 % of patients with STS are aged 60 years or older, limiting the choice of treatment to single-agent approaches for this elderly population. Hematological toxicity is frequent during doxorubicin monotherapy, grade 4 neutropenia is reported in 34 %, with a febrile neutropenia rate of 9 % in STS. We assume that comorbidities in the elderly population may limit tolerability of doxorubicin, and novel agents may improve tolerability and health-related quality of life while maintaining efficacy. We therefore investigated whether the tyrosine kinase inhibitor pazopanib exerts such a clinical benefit in elderly patients with STS (pazopanib for elderly [the EPAZ study]). METHODS/DESIGN: This study is a randomized, controlled, open-label, multicenter, phase II noninferiority trial in which pazopanib 800 mg once daily is being compared six cycles of intravenous doxorubicin 75 mg/m(2) as first-line treatment in elderly patients (≥60 years) with metastatic or advanced STS. A total of 120 patients will be randomized 1:2 to receive doxorubicin or pazopanib, stratified by Eastern Cooperative Oncology Group performance status (0-1 vs. 2) and liposarcoma histology (yes vs. no). The primary endpoint is progression-free survival based on local tumor assessment according to Response Evaluation Criteria in Solid Tumors criteria. Secondary endpoints include grade 4 neutropenia and febrile neutropenia in hierarchical order, as well as overall survival, objective response rate, health-related quality of life, and geriatric assessments. DISCUSSION: Pazopanib is associated with promising tolerability according to previous studies and may offer a significant clinical advantage in first-line treatment of STS compared with doxorubicin. The elderly population seems especially appealing for such an approach, since these patients are not suitable for aggressive combination therapy. The EPAZ study will confirm whether pazopanib may be an alternative to toxic chemotherapy for elderly patients with STS. TRIAL REGISTRATION: ClinicalTrials.gov NCT01861951 ; registered on 11 April 2013. EudraCT 2011-004168-30; registered on 4 June 2012.