Tag: Clinical Trial

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Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial

Neurosurgery 2019 Dec 1;85(6):843-853

More than a million Americans harbor a cerebral cavernous angioma (CA), and those who suffer a prior symptomatic hemorrhage have an exceptionally high rebleeding risk. Preclinical studies show that atorvastatin blunts CA lesion development and hemorrhage through inhibiting RhoA kinase (ROCK), suggesting it may confer a therapeutic benefit.

OBJECTIVE: To evaluate whether atorvastatin produces a difference compared to placebo in lesional iron deposition as assessed by quantitative susceptibility mapping (QSM) on magnetic resonance imaging in CAs that have demonstrated a symptomatic hemorrhage in the prior year. Secondary aims shall assess effects on vascular permeability, ROCKactivity in peripheral leukocytes, signal effects on clinical outcomes, adverse events, and prespecified subgroups.

METHODS: The phase I/IIa placebo-controlled, double-blinded, single-site clinical trial aims to enroll 80 subjects randomized 1-1 to atorvastatin (starting dose 80 mg PO daily) or placebo. Dosing shall continue for 24-mo or until reaching a safety endpoint.

EXPECTED OUTCOMES: The trial is powered to detect an absolute difference of 20% in the mean percent change in lesional QSM per year (2-tailed, power 0.9, alpha 0.05). A decrease in QSM change would be a signal of potential benefit, and an increase would signal a safety concern with the drug.

DISCUSSION: With firm mechanistic rationale, rigorous preclinical discoveries, and biomarker validations, the trial shall explore a proof of concept effect of a widely used repurposed drug in stabilizing CAs after a symptomatic hemorrhage. This will be the first clinical trial of a drug aimed at altering rebleeding in CA.

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Autologous Mesenchymal Stem Cell Therapy for Spinal Cord Injury

A Phase III Clinical Trial Showing Limited Efficacy of Autologous Mesenchymal Stem Cell Therapy for Spinal Cord Injury

Neurosurgery 78:436–447, 2016

In our previous report, 3 of 10 patients with spinal cord injury who were injected with autologous mesenchymal stem cells (MSCs) showed motor improvement in the upper extremities and in activities of daily living.

OBJECTIVE: To report on the results of a phase III clinical trial of autologous MSCs therapy.

METHODS: Patients were selected based on the following criteria: chronic American Spinal Injury Association B status patients who had more than 12 months of cervical injury, and no neurological changes during the recent 3 months of vigorous rehabilitation. We injected 1.6 x10(7) autologous MSCs into the intramedullary area at the injured level and 3.2 x 10(7) autologous MSCs into the subdural space. Outcome data were collected over 6 months regarding neurological examination, magnetic resonance imaging with diffusion tensor imaging, and electrophysiological analyses.

RESULTS: Among the 16 patients, only 2 showed improvement in neurological status (unilateral right C8 segment from grade 1 to grade 3 in 1 patient and bilateral C6 from grade 3 to grade 4 and unilateral right C8 from grade 0 to grade 1 in 1 patient). Both patients with neurological improvement showed the appearance of continuity in the spinal cord tract by diffusion tensor imaging. There were no adverse effects associated with MSCs injection.

CONCLUSION: Single MSCs application to intramedullary and intradural space is safe, but has a very weak therapeutic effect compared with multiple MSCs injection. Further clinical trials to enhance the effect of MSCs injection are necessary.

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Results of the NeuroBlate System first-in-humans Phase I clinical trial for recurrent glioblastoma

 

NeuroBlate

J Neurosurg 118:1202–1219, 2013

Laser interstitial thermal therapy has been used as an ablative treatment for glioma; however, its development was limited due to technical issues. The NeuroBlate System incorporates several technological advances to overcome these drawbacks. The authors report a Phase I, thermal dose–escalation trial assessing the safety and efficacy of NeuroBlate in recurrent glioblastoma multiforme (rGBM).

Methods. Adults with suspected supratentorial rGBM of 15- to 40-mm dimension and a Karnofsky Performance Status score of ≥ 60 were eligible. After confirmatory biopsy, treatment was delivered using a rigid, gas-cooled, sidefiring laser probe. Treatment was monitored using real-time MRI thermometry, and proprietary software providing predictive thermal damage feedback was used by the surgeon, along with control of probe rotation and depth, to tailor tissue coagulation. An external data safety monitoring board determined if toxicity at lower levels justified dose escalation.

Results. Ten patients were treated at the Case Comprehensive Cancer Center (Cleveland Clinic and University Hospitals–Case Medical Center). Their average age was 55 years (range 34–69 years) and the median preoperative Karnofsky Performance Status score was 80 (range 70–90). The mean tumor volume was 6.8 ± 5 cm3 (range 2.6–19 cm3), the percentage of tumor treated was 78% ± 12% (range 57%–90%), and the conformality index was 1.21 ± 0.33 (range 1.00–2.04). Treatment-related necrosis was evident on MRI studies at 24 and 48 hours. The median survival was 316 days (range 62–767 days). Three patients improved neurologically, 6 remained stable, and 1 worsened. Steroid-responsive treatment-related edema occurred in all patients but one. Three had Grade 3 adverse events at the highest dose.

Conclusions. NeuroBlate represents new technology for delivering laser interstitial thermal therapy, allowing controlled thermal ablation of deep hemispheric rGBM. Clinical trial registration no.: NCT00747253 (ClinicalTrials. gov).

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Analysis of three IDE cervical arthroplasty trials

J Neurosurg Spine 16:216–228, 2012. DOI: 10.3171/2011.6.SPINE10623

There are now 3 randomized, multicenter, US FDA investigational device exemption, industry-sponsored studies comparing arthroplasty with anterior cervical discectomy and fusion (ACDF) for single-level cervical disease with 2 years of follow-up. These 3 studies evaluated the Prestige ST, Bryan, and ProDisc-C artificial discs. The authors analyzed the combined results of these trials.

Methods. A total of 1213 patients with symptomatic, single-level cervical disc disease were randomized into 2 treatment arms in the 3 randomized trials. Six hundred twenty-one patients received an artificial cervical disc, and 592 patients were treated with ACDF. In the three trials, 94% of the arthroplasty group and 87% of the ACDF group have completed 2 years of follow-up. The authors analyzed the 2-year data from these 3 trials including previously unpublished source data. Statistical analysis was performed with fixed and random effects models.

Results. The authors’ analysis revealed that segmental sagittal motion was preserved with arthroplasty (preoperatively 7.26° and postoperatively 8.14°) at the 2-year time point. The fusion rate for ACDF at 2 years was 95%. The Neck Disability Index, 36-Item Short Form Health Survey Mental, and Physical Component Summaries, neck pain, and arm pain scores were not statistically different between the groups at the 24-month follow-up. The arthroplasty group demonstrated superior results at 24 months in neurological success (RR 0.595, I2 = 0%, p = 0.006). The arthroplasty group had a lower rate of secondary surgeries at the 2-year time point (RR 0.44, I2 = 0%, p = 0.004). At the 2-year time point, the reoperation rate for adjacent-level disease was lower for the arthroplasty group when the authors analyzed the combined data set using a fixed effects model (RR 0.460, I2 = 2.9%, p = 0.030), but this finding was not significant using a random effects model. Adverse event reporting was too heterogeneous between the 3 trials to combine for analysis.

Conclusions. Both anterior cervical discectomy and fusion as well as arthroplasty demonstrate excellent 2-year surgical results for the treatment of 1-level cervical disc disease with radiculopathy. Arthroplasty is associated with a lower rate of secondary surgery and a higher rate of neurological success at 2 years. Arthroplasty may be associated with a lower rate of adjacent-level disease at 2 years, but further follow-up and analysis are needed to confirm this finding.

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Regression of Recurrent Malignant Gliomas With Convection-Enhanced Delivery of Topotecan

Neurosurgery 69:1272–1280, 2011 DOI: 10.1227/NEU.0b013e3182233e24

Convection-enhanced delivery of chemotherapeutics for the treatment of malignant glioma is a technique that delivers drugs directly into a tumor and the surrounding interstitium through continuous, low-grade positive-pressure infusion. This allows high local concentrations of drug while overcoming the limitations imposed by toxicity and the blood-brain barrier in systemic therapies that prevent the use of many potentially effective drugs.

OBJECTIVE: To examine the safety profile of a conventional chemotherapeutic agent, topotecan, via convection-enhanced delivery in the treatment of recurrent malignant gliomas and secondarily to assess radiographic response and survival.

METHODS: We performed a prospective, dose-escalation phase Ib study of the topoisomerase- I inhibitor topotecan given by convection-enhanced delivery in patients with recurrent malignant gliomas.

RESULTS: Significant antitumor activity as described by radiographic changes and prolonged overall survival with minimal drug-associated toxicity was demonstrated. A maximum tolerated dose was established for future phase II studies.

CONCLUSION: Topotecan by convection-enhanced delivery has significant antitumor activity at concentrations that are nontoxic to normal brain. The potential for use of this therapy as a generally effective treatment option for malignant gliomas will be tested in subsequent phase II and III trials

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Traumatic brain injury in pediatric patients: evidence for the effectiveness of decompressive surgery

Neurosurg Focus 31 (5):E5, 2011. DOI: 10.3171/2011.8.FOCUS11177

Traumatic brain injury (TBI) is the current leading cause of death in children over 1 year of age. Adequate management and care of pediatric patients is critical to ensure the best functional outcome in this population.

In their controversial trial, Cooper et al. concluded that decompressive craniectomy following TBI did not improve clinical outcome of the analyzed adult population. While the study did not target pediatric populations, the results do raise important and timely clinical questions regarding the effectiveness of decompressive surgery in pediatric patients. There is still a paucity of evidence regarding the effectiveness of this therapy in a pediatric population, and there is an especially noticeable knowledge gap surrounding age-stratified interventions in pediatric trauma.

The purposes of this review are to first explore the anatomical variations between pediatric and adult populations in the setting of TBI. Second, the authors assess how these differences between adult and pediatric populations could translate into differences in the impact of decompressive surgery following TBI.

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Acidic fibroblast growth factor for repair of human spinal cord injury: a clinical trial

J Neurosurg Spine 15:216–227, 2011. DOI: 10.3171/2011.4.SPINE10404

The study aimed to verify the safety and feasibility of applying acidic fibroblast growth factor (aFGF) with fibrin glue in combination with surgical neurolysis for nonacute spinal cord injury.

Methods. This open-label, prospective, uncontrolled human clinical trial recruited 60 patients with spinal cord injuries (30 cervical and 30 thoracolumbar). The mean patient age was 36.5 ± 15.33 (mean ± SD) years, and the male/ female ratio was 3:1. The mean time from injury to treatment was 25.7 ± 26.58 months, and the cause of injury included motor vehicle accident (26 patients [43.3%]), fall from a height (17 patients [28.3%]), sports (4 patients [6.7%]), and other (13 patients [21.7%]). Application of aFGF with fibrin glue and duraplasty was performed via laminectomy, and an adjuvant booster of combined aFGF and fibrin glue (2 ml) was given at 3 and 6 months postsurgery via lumbar puncture. Outcome measurements included the American Spinal Injury Association (ASIA) motor scores, sensory scores, impairment scales, and neurological levels. Examination of functional independence measures, visual analog scale, MR imaging, electrophysiological and urodynamic studies, hematology and biochemistry tests, tumor markers, and serum inflammatory cytokines were all conducted. All adverse events were monitored and reported. Exclusions were based on refusal, unrelated adverse events, or failure to participate in the planned rehabilitation.

Results. Forty-nine patients (26 with cervical and 23 with thoracolumbar injuries) completed the 24-month trial. Compared with preoperative conditions, the 24-month postoperative ASIA motor scores improved significantly in the cervical group (from 27.6 ± 15.55 to 37.0 ± 19.93, p < 0.001) and thoracolumbar group (from 56.8 ± 9.21 to 60.7 ± 10.10, p < 0.001). The ASIA sensory scores also demonstrated significant improvement in light touch and pinprick in both groups: from 55.8 ± 24.89 to 59.8 ± 26.47 (p = 0.049) and 56.3 ± 23.36 to 62.3 ± 24.87 (p = 0.003), respectively, in the cervical group and from 75.7 ± 15.65 to 79.2 ± 15.81 (p < 0.001) and 78.2 ± 14.72 to 82.7 ± 16.60 (p < 0.001), respectively, in the thoracolumbar group. At 24-month follow-up, the ASIA impairment scale improved significantly in both groups (30% cervical [p = 0.011] and 30% thoracolumbar [p = 0.003]). There was also significant improvement in neurological level in the cervical (from 5.17 ± 1.60 to 6.27 ± 3.27, p = 0.022) and thoracolumbar (from 18.03 ± 4.19 to 18.67 ± 3.96, p = 0.001) groups. The average sum of motor items in functional independence measure also had significant improvement in both groups (p < 0.05). The walking/wheelchair locomotion subscale showed increased percentages of patients who were ambulatory (from 3.4% to 13.8% and from 17.9% to 35.7% in the cervical and thoracolumbar groups, respectively). There were no related adverse events.

Conclusions. The use of aFGF for spinal cord injury was safe and feasible in the present trial. There were significant improvements in ASIA motor and sensory scale scores, ASIA impairment scales, neurological levels, and functional independence measure at 24 months after treatment. Further large-scale, randomized, and controlled investigations are warranted to evaluate the efficacy and long-term results.

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