Efficacy of pramipexole and transdermal rotigotine in advanced Parkinson's disease: a double-blind, double-dummy, randomised controlled trial

BACKGROUND: Continuous dopaminergic drug delivery is an unmet medical need in advanced Parkinson's disease. The aim of this trial-Clinical Efficacy of Pramipexole And Transdermal Rotigotine in Advanced PD (CLEOPATRA-PD)-was to assess the efficacy of adjunct treatment with rotigotine in comparison with placebo and with pramipexole in levodopa-treated patients with advanced Parkinson's disease and wearing-off type motor fluctuations. METHODS: In this randomised controlled trial, eligible participants were randomly assigned to receive either rotigotine (up to 16 mg/24 h as a transdermal patch), pramipexole (up to 4.5 mg/day orally), or placebo for 6 months. Primary efficacy variables were absolute change in total hours "off" (assessed by home diaries) from baseline to end of study and responder rate (defined as the proportion of patients with >or=30% reduction in absolute off time per day). Analyses were done by intention to treat. This trial is registered with the US National Institutes of Health clinical trials database (ClinicalTrials.gov), number NCT00244387. FINDINGS: 204 patients were randomly assigned to receive rotigotine, 201 to receive pramipexole, and 101 to receive placebo; 427 (84%) completed the trial. The number of discontinuations in each group was similar; most were for adverse events. The mean dose of rotigotine was 12.95 mg/24 h (SD 3.54), the mean dose of pramipexole was 3.1 mg/day (1.24). Mean absolute change in off time from baseline was -2.5 h (SE 0.20) with rotigotine, -2.8 h (0.20) with pramipexole, and -0.9 h (0.29) with placebo. The absolute change in off time from baseline compared with placebo was -1.58 h (95% CI -2.27 to -0.90; p<0.0001) for rotigotine and -1.94 h (-2.63 to -1.25; p<0.0001) for pramipexole. Responder rates were 67% (134 of 200 patients) for pramipexole, 59.7% (120 of 201 patients) for rotigotine, and 35% (35 of 100 patients) for placebo. INTERPRETATION: In terms of change in absolute off time, rotigotine was non-inferior to pramipexole. Continuous delivery of rotigotine as transdermal patches could offer similar efficacy to oral pramipexole in patients with fluctuating Parkinson's disease over 6 months of treatment.     

Safety and effectiveness of levodopa-carbidopa intestinal gel for advanced Parkinson's disease: A large single-center study

BackgroundTreatment with levodopa-carbidopa intestinal gel (LCIG) can effectively relieve motor and non-motor symptoms in advanced Parkinson's disease (PD). However, adverse events (AEs) are frequent.ObjectiveTo describe AEs associated with LCIG treatment and the main reasons for treatment discontinuation. We also looked for factors that were potentially predictive of serious AEs and assessed the effectiveness of and satisfaction with LCIG.MethodWe retrospectively analyzed data on AEs in patients treated with LCIG at a French university medical center. For patients still receiving treatment at last follow-up, effectiveness was assessed according to the Clinical Global Impression (CGI) scale and the Movement Disorders Society – Unified Parkinson's Disease Rating Scale motor score.ResultsOf the 63 patients treated with LCIG for a mean (range) of 19 months (8–47), 57 (90%) experienced at least one AE (340 AEs in total). Most of the AEs (in 69.8% of the patients) were related to percutaneous endoscopic gastrostomy with a jejunal tube (PEG-J) or affected the gastrointestinal tract (granuloma, leakage, or a local infection). Device-related AEs (such as PEG-J removal and device occlusion) were frequent (in 63.5% of patients). Forty-three patients (68%) required at least one additional endoscopic procedure. Dopatherapy-related AEs occurred in 30 patients (48%). Most of the AEs occurred long after treatment initiations, and only a small proportion led to discontinuation. On the CGI scale, 53 patients (84.4%) considered that their condition had improved during LCIG treatment.ConclusionDespite the high frequency of AEs, patients with advanced PD gain clinical benefit from treatment with LCIG. This treatment requires a competent, multidisciplinary team on site.     

Diphasic dyskinesias during levodopa-carbidopa intestinal gel (LCIG) infusion in Parkinson's disease

ObjectivesLevodopa-carbidopa intestinal gel infusion (LCIG) is indicated in patients with advanced levodopa-responsive Parkinson's disease (PD) for the treatment of motor fluctuations and dyskinesias. Here we describe 4 PD patients who developed disabling diphasic dyskinesias after LCIG initiation.MethodsThe clinical data of 33 PD patients consecutively treated with LCIG therapy were obtained through direct clinical observation and detailed review of medical records.ResultsWithin 10 days, after LCIG introduction, we identified 4 subjects (12.1%) with persistent and disabling diphasic dyskinesia (DD). We tried to manage these symptoms by increasing morning LCIG flow and adding “extended-release” formulations of dopamine-agonists and levodopa/carbidopa during bedtime. Within 1 month, all patients presented a gradual reduction in the duration and severity of DD.ConclusionsTo our knowledge, this is the first report describing the occurrence of DD in a small cohort of advanced PD patients after LCIG initiation. We wish to draw the attention of clinicians to the risk of developing disabling DD in PD patients switched to the LCIG monotherapy.     

Long-term intraduodenal infusion of a water based levodopa-carbidopa dispersion in very advanced Parkinson's disease

Objective – To evaluate the effects of continuous duodenal infusion of levodopa over time on the disabling fluctuations in motor performance in advanced parkinsonian patients. It has earlier been demonstrated that these fluctuations can be reduced by keeping the plasma concentration of levodopa constant. Material and methods – In view of the low water solubility of levodopa a stable dispersion of the drug was developed and used for continuous intraduodenal infusion in patients with advanced Parkinson's disease. Nine patients were evaluated with respect to an optimal oral treatment, during nasoduodenal infusion by a portable pump and then followed for 6 months to 2½ years when treated via transabdominal infusion. Upon each test occasion, over 2 non-consecutive days, objective movement analysis by means of an opto-electronic system was applied every 15-20 min and video recordings performed twice every h. On several test occasions plasma levodopa concentrations were analysed every 15 min. Results – The patients showed improvement and decreased variance of their motor function. In the 2 patients followed over a period of 2½ years levodopa plasma concentration showed reduced fluctuations on infusion and the levodopa consumption as well as mean levodopa plasma concentration decreased. Conclusion – Continuous duodenal infusion of levodopa is an alternative treatment strategy for patients with advanced Parkinson's disease when conventional therapy has failed.     

Multidisciplinary rehabilitation for people with Parkinson's disease: a randomised controlled study

OBJECTIVE: To determine whether a programme of multidisciplinary rehabilitation and group support achieves sustained benefit for people with Parkinson's disease or their carers. METHODS: The study was a randomised controlled crossover trial comparing patients and carers who had received rehabilitation four months before assessment with those who had not. Patients were recruited from a neurology clinic, attended a day hospital from home weekly for six weeks using private car or hospital transport, and received group educational activities and individual rehabilitation from a multidisciplinary team. Patients were assessed at entry and at six months using a 25 item self assessment Parkinson's disease disability questionnaire, Euroqol-5d, SF-36, PDQ-39, hospital anxiety and depression scale, and timed stand-walk-sit test. Carers were assessed using the carer strain index and Euroqol-5d. RESULTS: 144 people with Parkinson's disease without severe cognitive losses and able to travel to hospital were registered (seven were duplicate registrations); 94 had assessments at baseline and six months. Repeated measures analysis of variance comparing patients at the 24 week crossover point showed that those receiving rehabilitation had a trend towards better stand-walk-sit score (p = 0.093) and worse general and mental health (p = 0.002, p = 0.019). Carers of treated patients had a trend towards more strain (p = 0.086). Analysis comparing patients before and six months after treatment showed worsening in disability, quality of life, and carer strain. CONCLUSIONS: Patients with Parkinson's disease decline significantly over six months, but a short spell of multidisciplinary rehabilitation may improve mobility. Follow up treatments may be needed to maintain any benefit.     

Body mass index variations in patients with Parkinson's disease treated with levodopa-carbidopa intestinal gel infusion: A case control study versus standard of care and subthalamic nucleus deep brain stimulation

BackgroundLevodopa-carbidopa intestinal gel (LCIG) is an advanced therapy for patients with Parkinson Disease (PD). Weight loss has been pointed out as an adverse event of LCIG infusion.Aims of the studyTo compare weight changes between three groups of PD patients: patients treated with LCIG, patients within the first year of subthalamic deep brain stimulation (STN-DBS) and patients treated exclusively with oral treatment during 1 year of follow up.MethodsPatients treated with LCIG were retrospectively matched by age, gender, disease duration and Hoehn and Yahr to patients undergoing STN-DBS and to patients both receiving the standard of care treatment and unwilling advanced therapies (SOC). Clinical features and weight were collected at baseline, and 12 months after introducing the treatment (LCIG and STN-DBS groups) or for one year of treatment (SOC).ResultsEighteen patients were included in each group. They had no differences in clinical and demographic features, except for cognitive impairment. There was a mean weight (−5.8 kg ±6.8) and BMI (−2.1 kg/m² ± 2.6) reduction in the LCIG group after 12 months, while there was a slight weight loss in the SOC (−1.4 kg ±3.1) and a weight increase in the STN-DBS group (5.4 kg ±4.7). Differences of weight were statistically different between, LCIG and STN-DBS (P < 0.001), LCIG and SOC (P = 0.002) and STN-DBS and SOC (P < 0.001).ConclusionsThe study shows a significant weight reduction after starting LCIG infusion compared to the other groups. Weight loss should be closely monitored in patients treated with LCIG.     

TCH346 as a neuroprotective drug in Parkinson's disease: a double-blind, randomised, controlled trial

BACKGROUND: There is an important unmet medical need in Parkinson's disease for a neuroprotective treatment that slows or stops disease progression. TCH346 is a potent anti-apoptotic drug that protects against loss of dopaminergic neurons in laboratory models. Our aim was to assess TCH346 as a neuroprotective drug in patients with Parkinson's disease. METHODS: Patients presenting at 45 international movement disorder clinics with early untreated Parkinson's disease were assessed as part of this parallel-group, double-blind, randomised controlled trial. 301 eligible patients were randomly assigned 12-18 months' treatment with TCH346 at a daily dose of 0.5 mg (n=78), 2.5 mg (n=79), or 10 mg (n=73), or placebo (n=71), followed by a 4 week washout period. The primary outcome measure was time to development of a disability requiring dopaminergic treatment. Secondary outcome measures were the annual rate of change in the unified Parkinson's disease rating scale (UPDRS) and the PDQ-39, a measure of quality of life. Analyses were by intention-to-treat. This study is pending registration with . FINDINGS: 255 patients completed the study. TCH346 did not differ from placebo for any of the study outcomes. Treatment was needed in 26 (34%) patients in the TCH346 0.5 mg group, 30 (38%) in the TCH346 2.5 mg group, 24 (33%) in the TCH346 10 mg group, and 23 (32%) in the placebo group. There were no significant differences between groups. There were no differences between groups in the annual change in the UPDRS or PDQ-39 either. Few patients withdrew because of adverse events and none was judged to be related to the study intervention. INTERPRETATION: TCH346 did not show evidence of a neuroprotective effect. The discrepancy between the preclinical promise of TCH346 and the clinical outcome could have arisen because of the use of laboratory models that do not accurately reflect the pathogenesis of Parkinson's disease, the doses of study drug used, insensitive clinical endpoints, and the patient population selected for study.     

Donepezil for cognitive impairment in Parkinson's disease: a randomised controlled study

OBJECTIVE: To study the safety and efficacy of the cholinesterase inhibitor donepezil in patients with Parkinson's disease (PD) and cognitive impairment. METHODS: This was a double blind, randomised and placebo controlled, crossover study in which 14 patients with PD and cognitive impairment received donepezil (5 or 10 mg per day) or matching placebo during two sequential periods lasting 10 weeks each. The primary outcome measures were the mini mental state examination (MMSE) score, the clinician's interview based impression of change plus caregiver input (CIBIC+) score, and the motor subscale of the unified Parkinson's disease rating scale (UPDRS). RESULTS: Two patients on donepezil (14%) dropped out after one and four weeks of the first treatment period because of peripheral cholinergic side effects, otherwise the adverse effects were few and not severe. Carryover or residual effects were not observed. Parkinsonism did not increase during donepezil treatment. After 10 weeks of treatment, the mean MMSE score was increased by 2.1(SD 2.7) points on donepezil and 0.3 (SD 3.2) points on placebo, and the CIBIC+ score was 3.3 (SD 0.9) on donepezil and 4.1 (SD 0.8) on placebo. Statistical analysis of the repeated measurements and crossover study design showed significant effects of donepezil compared with placebo for MMSE (p=0.013) and CIBIC+ (p=0.034). Five (42%) patients on donepezil and two (17%) on placebo were rated as improved on the basis of the CIBIC+ score. CONCLUSIONS: Donepezil improves cognition, and seems to be well tolerated and not to worsen parkinsonism in patients with cognitive impairment.