INTRODUCTION: Regenerative therapies in Parkinson's disease aim to slow neurodegeneration and re-establish damaged neuronal circuitry. Neurotrophins are potent endogenous regulators of neuronal survival, development and regeneration. They represent an attractive regenerative treatment option in Parkinson's disease. Porcine choroid plexus produces a number of neurotrophins, and can be safely delivered to the striatum in an encapsulated formulation (termed NTCELL®) to protect them from immune attack. NTCELL® has shown regenerative potential in animal models of stroke, Huntington's disease and Parkinson's disease. Following promising results from an initial open label safety study of intra-striatal delivery of NTCELL® in human subjects, we sought to specifically investigate the safety and efficacy of NTCELL® for the treatment of Parkinson's disease.
METHODS: 18 patients aged 56-65 years with idiopathic Parkinson's disease of at least 5 years duration were randomised to receive either sham surgery (general anaesthesia and partial thickness burr holes) or intra-striatal delivery of NTCELL® (the 3 groups in the treatment arm receiving incremental NTCELL® doses).
RESULTS: At 26 weeks, we found no significant difference in total UPDRS scores ('on' and 'off'), UPDRS motor scores ('on' and 'off'), PDQ-39, UDysRS, timed walk or modified Hoehn and Yahr stage between patients implanted with NTCELL® and patients undergoing sham procedure. There were no serious adverse events or xenogeneic viral transmission during the study.
CONCLUSION: The study did not meet its primary efficacy end-point of a change in UPDRS at 26 weeks post-intervention compared with baseline. Stereotactic NTCELL® implantation was safe and well tolerated.
OBJECTIVE: A 12-month double-blind sham-surgery-controlled trial assessing adeno-associated virus type 2 (AAV2)-neurturin injected into the putamen bilaterally failed to meet its primary endpoint, but showed positive results for the primary endpoint in the subgroup of subjects followed for 18 months and for several secondary endpoints. Analysis of postmortem tissue suggested impaired axonal transport of neurturin from putamen to substantia nigra. In the present study, we tested the safety and efficacy of AAV2-neurturin delivered to putamen and substantia nigra.
METHODS: We performed a 15- to 24-month, multicenter, double-blind trial in patients with advanced Parkinson disease (PD) who were randomly assigned to receive bilateral AAV2-neurturin injected bilaterally into the substantia nigra (2.0 × 10(11) vector genomes) and putamen (1.0 × 10(12) vector genomes) or sham surgery. The primary endpoint was change from baseline to final visit performed at the time the last enrolled subject completed the 15-month evaluation in the motor subscore of the Unified Parkinson's Disease Rating Scale in the practically defined off state.
RESULTS: Fifty-one patients were enrolled in the trial. There was no significant difference between groups in the primary endpoint (change from baseline: AAV2-neurturin, -7.0 ± 9.92; sham, -5.2 ± 10.01; p = 0.515) or in most secondary endpoints. Two subjects had cerebral hemorrhages with transient symptoms. No clinically meaningful adverse events were attributed to AAV2-neurturin.
INTERPRETATION: AAV2-neurturin delivery to the putamen and substantia nigra bilaterally in PD was not superior to sham surgery. The procedure was well tolerated, and there were no clinically significant adverse events related to AAV2-neurturin.
BACKGROUND: Arthroscopic partial meniscectomy is one of the most common orthopedic procedures, yet rigorous evidence of its efficacy is lacking.
METHODS: We conducted a multicenter, randomized, double-blind, sham-controlled trial in 146 patients 35 to 65 years of age who had knee symptoms consistent with a degenerative medial meniscus tear and no knee osteoarthritis. Patients were randomly assigned to arthroscopic partial meniscectomy or sham surgery. The primary outcomes were changes in the Lysholm and Western Ontario Meniscal Evaluation Tool (WOMET) scores (each ranging from 0 to 100, with lower scores indicating more severe symptoms) and in knee pain after exercise (rated on a scale from 0 to 10, with 0 denoting no pain) at 12 months after the procedure.
RESULTS: In the intention-to-treat analysis, there were no significant between-group differences in the change from baseline to 12 months in any primary outcome. The mean changes (improvements) in the primary outcome measures were as follows: Lysholm score, 21.7 points in the partial-meniscectomy group as compared with 23.3 points in the sham-surgery group (between-group difference, -1.6 points; 95% confidence interval [CI], -7.2 to 4.0); WOMET score, 24.6 and 27.1 points, respectively (between-group difference, -2.5 points; 95% CI, -9.2 to 4.1); and score for knee pain after exercise, 3.1 and 3.3 points, respectively (between-group difference, -0.1; 95% CI, -0.9 to 0.7). There were no significant differences between groups in the number of patients who required subsequent knee surgery (two in the partial-meniscectomy group and five in the sham-surgery group) or serious adverse events (one and zero, respectively).
CONCLUSIONS: In this trial involving patients without knee osteoarthritis but with symptoms of a degenerative medial meniscus tear, the outcomes after arthroscopic partial meniscectomy were no better than those after a sham surgical procedure. (Funded by the Sigrid Juselius Foundation and others; ClinicalTrials.gov number, NCT00549172.).
OBJECTIVE: In an effort to account for deficiencies in axonal transport that limit the effectiveness of neurotrophic factors, this study tested the safety and feasibility, in moderately advanced Parkinson disease (PD), of bilaterally administering the gene therapy vector AAV2-neurturin (CERE-120) to the putamen plus substantia nigra (SN, a relatively small structure deep within the midbrain, in proximity to critical neuronal and vascular structures).
METHODS: After planning and minimizing risks of stereotactically targeting the SN, an open-label, dose-escalation safety trial was initiated in 6 subjects with PD who received bilateral stereotactic injections of CERE-120 into the SN and putamen.
RESULTS: Two-year safety data for all subjects suggest the procedures were well-tolerated, with no serious adverse events. All adverse events and complications were expected for patients with PD undergoing stereotactic brain surgery.
CONCLUSIONS: Bilateral stereotactic administration of CERE-120 to the SN plus putamen in PD is feasible and this evaluation provides initial empirical support that it is safe and well-tolerated.
CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that bilateral neurturin gene delivery (CERE-120) to the SN plus putamen in patients with moderately advanced PD is feasible and safe.
BACKGROUND: Perineural inhibitors of tumor necrosis factor have recently generated intense interest as an alternative to epidural steroid injections for lumbosacral radiculopathy.
OBJECTIVE: To evaluate whether epidural steroids, etanercept, or saline better improves pain and function in adults with lumbosacral radiculopathy.
DESIGN: A multicenter, 3-group, randomized, placebo-controlled trial conducted from 2008 to 2011. Randomization was computer-generated and stratified by site. Pharmacists prepared the syringes. Patients, treating physicians, and nurses assessing outcomes were blinded to treatment assignment. (ClinicalTrials.gov registration number: NCT00733096)
SETTING: Military and civilian treatment centers.
PATIENTS: 84 adults with lumbosacral radiculopathy of less than 6 months' duration.
INTERVENTION: 2 epidural injections of steroids, etanercept, or saline, mixed with bupivacaine and separated by 2 weeks.
MEASUREMENTS: The primary outcome measure was leg pain 1 month after the second injection. All patients had 1-month follow-up visits; patients whose condition improved remained blinded for the 6-month study period.
RESULTS: The group that received epidural steroids had greater reductions in the primary outcome measure than those who received saline (mean difference, -1.26 [95% CI, -2.79 to 0.27]; P = 0.11) or etanercept (mean difference, -1.01 [CI, -2.60 to 0.58]; P = 0.21). For back pain, smaller differences favoring steroids compared with saline (mean difference, -0.52 [CI, -1.85 to 0.81]; P = 0.44) and etanercept (mean difference, -0.92 [CI,-2.28 to 0.44]; P = 0.18) were observed. The largest differences were noted for functional capacity, in which etanercept fared worse than the other treatments: steroids vs. etanercept (mean difference, -16.16 [CI, -26.05 to -6.27]; P = 0.002), steroids vs. saline (mean difference, -5.87 [CI, -15.59 to 3.85]; P = 0.23), and etanercept vs. saline (mean difference, 10.29 [CI, 0.55 to 20.04]; P = 0.04). More patients treated with epidural steroids (75%) reported 50% or greater leg pain relief and a positive global perceived effect at 1 month than those who received saline (50%) or etanercept (42%) (P = 0.09).
LIMITATION: Short-term follow-up, small sample size, and a possibly subtherapeutic dose of etanercept.
CONCLUSION: Epidural steroid injections may provide modest short-term pain relief for some adults with lumbosacral radiculopathy, but larger studies with longer follow-up are needed to confirm their benefits.
PRIMARY FUNDING SOURCE: The John P. Murtha Neuroscience and Pain Institute, International Spinal Intervention Society, and Center for Rehabilitation Sciences Research.
BACKGROUND: Women without stress urinary incontinence undergoing vaginal surgery for pelvic-organ prolapse are at risk for postoperative urinary incontinence. A midurethral sling may be placed at the time of prolapse repair to reduce this risk.
METHODS: We performed a multicenter trial involving women without symptoms of stress incontinence and with anterior prolapse (of stage 2 or higher on a Pelvic Organ Prolapse Quantification system examination) who were planning to undergo vaginal prolapse surgery. Women were randomly assigned to receive either a midurethral sling or sham incisions during surgery. One primary end point was urinary incontinence or treatment for this condition at 3 months. The second primary end point was the presence of incontinence at 12 months, allowing for subsequent treatment for incontinence.
RESULTS: Of the 337 women who underwent randomization, 327 (97%) completed follow-up at 1 year. At 3 months, the rate of urinary incontinence (or treatment) was 23.6% in the sling group and 49.4% in the sham group (P<0.001). At 12 months, urinary incontinence (allowing for subsequent treatment of incontinence) was present in 27.3% and 43.0% of patients in the sling and sham groups, respectively (P=0.002). The number needed to treat with a sling to prevent one case of urinary incontinence at 12 months was 6.3. The rate of bladder perforation was higher in the sling group than in the sham group (6.7% vs. 0%), as were rates of urinary tract infection (31.0% vs. 18.3%), major bleeding complications (3.1% vs. 0%), and incomplete bladder emptying 6 weeks after surgery (3.7% vs. 0%) (P≤0.05 for all comparisons).
CONCLUSIONS: A prophylactic midurethral sling inserted during vaginal prolapse surgery resulted in a lower rate of urinary incontinence at 3 and 12 months but higher rates of adverse events. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health Office of Research on Women's Health; OPUS ClinicalTrials.gov number, NCT00460434.).
OBJECTIVE: To assess the efficacy of caudal epidural steroid or saline injection in chronic lumbar radiculopathy in the short (6 weeks), intermediate (12 weeks), and long term (52 weeks).
DESIGN: Multicentre, blinded, randomised controlled trial.
SETTING: Outpatient multidisciplinary back clinics of five Norwegian hospitals.
PARTICIPANTS: Between October 2005 and February 2009, 461 patients assessed for inclusion (presenting with lumbar radiculopathy >12 weeks). 328 patients excluded for cauda equina syndrome, severe paresis, severe pain, previous spinal injection or surgery, deformity, pregnancy, ongoing breast feeding, warfarin therapy, ongoing treatment with non-steroidal anti-inflammatory drugs, body mass index >30, poorly controlled psychiatric conditions with possible secondary gain, and severe comorbidity.
INTERVENTIONS: Subcutaneous sham injections of 2 mL 0.9% saline, caudal epidural injections of 30 mL 0.9% saline, and caudal epidural injections of 40 mg triamcinolone acetonide in 29 mL 0.9% saline. Participants received two injections with a two week interval.
MAIN OUTCOME MEASURES: Primary: Oswestry disability index scores. Secondary: European quality of life measure, visual analogue scale scores for low back pain and for leg pain.
RESULTS: Power calculations required the inclusion of 41 patients per group. We did not allocate 17 of 133 eligible patients because their symptoms improved before randomisation. All groups improved after the interventions, but we found no statistical or clinical differences between the groups over time. For the sham group (n = 40), estimated change in the Oswestry disability index from the adjusted baseline value was -4.7 (95% confidence intervals -0.6 to -8.8) at 6 weeks, -11.4 (-6.3 to -14.5) at 12 weeks, and -14.3 (-10.0 to -18.7) at 52 weeks. For the epidural saline intervention group (n = 39) compared with the sham group, differences in primary outcome were -0.5 (-6.3 to 5.4) at 6 weeks, 1.4 (-4.5 to 7.2) at 12 weeks, and -1.9 (-8.0 to 4.3) at 52 weeks; for the epidural steroid group (n=37), corresponding differences were -2.9 (-8.7 to 3.0), 4.0 (-1.9 to 9.9), and 1.9 (-4.2 to 8.0). Analysis adjusted for duration of leg pain, back pain, and sick leave did not change this trend.
CONCLUSIONS: Caudal epidural steroid or saline injections are not recommended for chronic lumbar radiculopathy. Trial registration Current Controlled Trials ISRCTN No 12574253.
BACKGROUND: Human retinal pigment epithelial (RPE) cells produce levodopa and their transplantation into the striatum might improve continuity of administration compared with that achieved with oral levodopa. We aimed to assess the safety, tolerability, and efficacy of transplantation of microcarrier-bound human RPE cells versus a sham surgery control in patients with advanced Parkinson's disease.
METHODS: In this randomised, double-blind study eligible patients were aged 36-70 years, had been symptomatic for at least 5 years, were in Hoehn and Yahr stage 3-4 and had unified Parkinson's disease rating scale (UPDRS) motor scores of 38-70 when off medication (off state), and had symptoms that responded to oral levodopa but were insufficiently controlled by optimised pharmacotherapy. Randomisation was done in a 1:1 ratio. Only the neurosurgical team was aware of treatment assignments. During stereotactic transplantation around 325,000 cells per side were injected into the postcommissural putamen; sham surgery patients received partial burr holes. The primary efficacy endpoint was change in UPDRS off-state motor score at 12 months. This study is registered with ClinicalTrials.gov, number NCT00206687.
FINDINGS: Of 71 enrolled patients, 35 underwent cell transplantation and 36 sham surgery. Change in mean motor scores did not differ significantly between groups (-10.5 [SD 10.26] for transplantation vs -10.1 [SD 12.26] for sham surgery, p=0.9). The overall rate of adverse events was similar in the two study groups, although the number attributable to surgery or RPE cells (mostly neurological or psychiatric) was higher in transplant recipients. Two and seven patients died in the sham surgery and transplantation group, respectively; one death in the latter group was possibly related to surgery or RPE cells.
INTERPRETATION: Transplantation of human RPE cells provided no antiparkinsonian benefits compared with sham surgery.
FUNDING: Bayer HealthCare AG.
BACKGROUND: Gene transfer of glutamic acid decarboxylase (GAD) and other methods that modulate production of GABA in the subthalamic nucleus improve basal ganglia function in parkinsonism in animal models. We aimed to assess the effect of bilateral delivery of AAV2-GAD in the subthalamic nucleus compared with sham surgery in patients with advanced Parkinson's disease.
METHODS: Patients aged 30-75 years who had progressive levodopa-responsive Parkinson's disease and an overnight off-medication unified Parkinson's disease rating scale (UPDRS) motor score of 25 or more were enrolled into this double-blind, phase 2, randomised controlled trial, which took place at seven centres in the USA between Nov 17, 2008, and May 11, 2010. Infusion failure or catheter tip location beyond a predefined target zone led to exclusion of patients before unmasking for the efficacy analysis. The primary outcome measure was the 6-month change from baseline in double-blind assessment of off-medication UPDRS motor scores. This trial is registered with ClinicalTrials.gov, NCT00643890.
FINDINGS: Of 66 patients assessed for eligibility, 23 were randomly assigned to sham surgery and 22 to AAV2-GAD infusions; of those, 21 and 16, respectively, were analysed. At the 6-month endpoint, UPDRS score for the AAV2-GAD group decreased by 8·1 points (SD 1·7, 23·1%; p<0·0001) and by 4·7 points in the sham group (1·5, 12·7%; p=0·003). The AAV2-GAD group showed a significantly greater improvement from baseline in UPDRS scores compared with the sham group over the 6-month course of the study (RMANOVA, p=0·04). One serious adverse event occurred within 6 months of surgery; this case of bowel obstruction occurred in the AAV2-GAD group, was not attributed to treatment or the surgical procedure, and fully resolved. Other adverse events were mild or moderate, likely related to surgery and resolved; the most common were headache (seven patients in the AAV2-GAD group vs two in the sham group) and nausea (six vs two).
INTERPRETATION: The efficacy and safety of bilateral infusion of AAV2-GAD in the subthalamic nucleus supports its further development for Parkinson's disease and shows the promise for gene therapy for neurological disorders.
FUNDING: Neurologix.
Objectives: The primary objective was to compare a single, 6 ml, intra-articular injection of hylan G-F 20 with placebo in patients with symptomatic knee osteoarthritis. The safety of a repeat injection of hylan G-F 20 was also assessed. Methods: Patients with primary osteoarthritis knee pain were randomly assigned to arthrocentesis plus a 6 ml intra-articular injection of either hylan G-F 20 or placebo in a prospective, double-blind (one injector/one blinded observer) study. Results were evaluated at 4, 8, 12, 18 and 26 weeks post-injection. The primary outcome criterion was change from baseline over 26 weeks in Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index A pain. Secondary outcome measures included WOMAC A1 and C, patient global assessment (PGA) and clinical observer global assessment (COGA) and Outcome Measures in Rheumatology, Osteoarthritis Research Society International responder rates. A 4-week, open, repeat treatment phase evaluated safety only. Results: A total of 253 patients (Kellgren-Lawrence grade II or III) was randomly assigned. Patients receiving hylan G-F 20 experienced statistically significantly greater improvements in WOMAC A pain scores (20.15, SE 0.076, p = 0.047), and several of the secondary outcome measures (WOMAC A1, PGA and COGA), than patients receiving placebo. There was no difference between the safety results of the two groups. No increased risk of local adverse events was observed in the open, repeat treatment phase. Conclusions: This placebo-controlled study demonstrated that, in patients with knee osteoarthritis, a single 6 ml intra-articular injection of hylan G-F 20 is safe and effective in providing statistically significant, clinically relevant pain relief over 26 weeks, with a modest difference versus placebo. Trial registration number: NCT00131352.
Regenerative therapies in Parkinson's disease aim to slow neurodegeneration and re-establish damaged neuronal circuitry. Neurotrophins are potent endogenous regulators of neuronal survival, development and regeneration. They represent an attractive regenerative treatment option in Parkinson's disease. Porcine choroid plexus produces a number of neurotrophins, and can be safely delivered to the striatum in an encapsulated formulation (termed NTCELL®) to protect them from immune attack. NTCELL® has shown regenerative potential in animal models of stroke, Huntington's disease and Parkinson's disease. Following promising results from an initial open label safety study of intra-striatal delivery of NTCELL® in human subjects, we sought to specifically investigate the safety and efficacy of NTCELL® for the treatment of Parkinson's disease.
METHODS:
18 patients aged 56-65 years with idiopathic Parkinson's disease of at least 5 years duration were randomised to receive either sham surgery (general anaesthesia and partial thickness burr holes) or intra-striatal delivery of NTCELL® (the 3 groups in the treatment arm receiving incremental NTCELL® doses).
RESULTS:
At 26 weeks, we found no significant difference in total UPDRS scores ('on' and 'off'), UPDRS motor scores ('on' and 'off'), PDQ-39, UDysRS, timed walk or modified Hoehn and Yahr stage between patients implanted with NTCELL® and patients undergoing sham procedure. There were no serious adverse events or xenogeneic viral transmission during the study.
CONCLUSION:
The study did not meet its primary efficacy end-point of a change in UPDRS at 26 weeks post-intervention compared with baseline. Stereotactic NTCELL® implantation was safe and well tolerated.
