Stuart Isaacson

Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial

BACKGROUND Parkinsons disease psychosis, which includes hallucinations and delusions, is frequent and debilitating in people with Parkinsons disease. We aimed to assess safety and efficacy of pimavanserin, a selective serotonin 5-HT2A inverse agonist, in this population. METHODS In our 6 week, randomised, double-blind, placebo-controlled study, we enrolled adults (aged ≥40 years) with Parkinsons disease psychosis. Antipsychotic treatments were not permitted during the study, but controlled antiparkinsonian medication or deep brain stimulation was allowed. Eligible participants entered a 2 week non-pharmacological lead-in phase to limit the placebo response, after which they were randomly allocated (1:1) to receive pimavanserin 40 mg per day or matched placebo. The primary outcome was antipsychotic benefit as assessed by central, independent raters with the Parkinsons disease-adapted scale for assessment of positive symptoms (SAPS-PD) in all patients who received at least one dose of study drug and had a SAPS assessment at baseline and at least one follow-up. We assessed safety and tolerability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01174004. FINDINGS Between Aug 11, 2010, and Aug 29, 2012, we randomly allocated 199 patients to treatment groups. For 90 recipients of placebo and 95 recipients of pimavanserin included in the primary analysis, pimavanserin was associated with a -5·79 decrease in SAPS-PD scores compared with -2·73 for placebo (difference -3·06, 95% CI -4·91 to -1·20; p=0·001; Cohens d 0·50). Ten patients in the pimavanserin group discontinued because of an adverse event (four due to psychotic disorder or hallucination within 10 days of start of the study drug) compared with two in the placebo group. Overall, pimavanserin was well tolerated with no significant safety concerns or worsening of motor function. INTERPRETATION Pimavanserin may benefit patients with Parkinsons disease psychosis for whom few other treatment options exist. The trial design used in this study to manage placebo response could have applicability to other studies in neuropsychiatric disease. FUNDING ACADIA Pharmaceuticals.

Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial.

IMPORTANCE Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD). OBJECTIVE To determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial. DESIGN, SETTING, AND PARTICIPANTS The Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled. INTERVENTIONS Participants were randomized to 1 of 3 treatment arms: placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month. MAIN OUTCOMES AND MEASURES The prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid. RESULTS Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P < .001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P = .006 and <.001, respectively). Secondary analyses demonstrated nonfutility of inosine treatment for slowing disability. CONCLUSIONS AND RELEVANCE Inosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00833690.

Haplotypes and gene expression implicate the MAPT region for Parkinson disease The GenePD Study

Background: Microtubule-associated protein tau (MAPT) has been associated with several neurodegenerative disorders including forms of parkinsonism and Parkinson disease (PD). We evaluated the association of the MAPT region with PD in a large cohort of familial PD cases recruited by the GenePD Study. In addition, postmortem brain samples from patients with PD and neurologically normal controls were used to evaluate whether the expression of the 3-repeat and 4-repeat isoforms of MAPT, and neighboring genes Saitohin (STH) and KIAA1267, are altered in PD cerebellum. Methods: Twenty-one single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 were genotyped in the GenePD Study. Single SNPs and haplotypes, including the H1 haplotype, were evaluated for association to PD. Relative quantification of gene expression was performed using real-time RT-PCR. Results: After adjusting for multiple comparisons, SNP rs1800547 was significantly associated with PD affection. While the H1 haplotype was associated with a significantly increased risk for PD, a novel H1 subhaplotype was identified that predicted a greater increased risk for PD. The expression of 4-repeat MAPT, STH, and KIAA1267 was significantly increased in PD brains relative to controls. No difference in expression was observed for 3-repeat MAPT. Conclusions: This study supports a role for MAPT in the pathogenesis of familial and idiopathic Parkinson disease (PD). Interestingly, the results of the gene expression studies suggest that other genes in the vicinity of MAPT, specifically STH and KIAA1267, may also have a role in PD and suggest complex effects for the genes in this region on PD risk.

The Gly2019Ser Mutation in LRRK2 is not Fully Penetrant in Familial Parkinson's Disease: The GenePD Study

BackgroundWe report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2)-related Parkinsons disease (PD) in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD.MethodsA sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample.ResultsThirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-LRRK2-related PD families.ConclusionLifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of nine PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men.

Amantadine extended release for levodopa-induced dyskinesia in Parkinson's disease (EASED Study)

ADS‐5102 is a long‐acting, extended‐release capsule formulation of amantadine HCl administered once daily at bedtime. This study investigated the safety, efficacy, and tolerability of ADS‐5102 in Parkinsons disease (PD) patients with levodopa‐induced dyskinesia. This was a randomized, double‐blind, placebo‐controlled, parallel‐group study of 83 PD patients with troublesome dyskinesia assigned to placebo or one of three doses of ADS‐5102 (260 mg, 340 mg, 420 mg) administered daily at bedtime for 8 weeks. The primary efficacy analysis compared change from baseline to week 8 in Unified Dyskinesia Rating Scale (UDysRS) total score for 340 mg ADS‐5102 versus placebo. Secondary outcome measures included change in UDysRS for 260 mg, 420 mg, Fatigue Severity Scale (FSS), Movement Disorder Society Unified Parkinsons Disease Rating Scale (MDS‐UPDRS), patient diary, Clinicians Global Impression of Change, and Parkinsons Disease Questionnaire (PDQ‐39). ADS‐5102 340 mg significantly reduced dyskinesia versus placebo (27% reduction in UDysRS, P = 0.005). In addition, ADS‐5102 significantly increased ON time without troublesome dyskinesia, as assessed by PD patient diaries, at 260 mg (P = 0.004), 340 mg (P = 0.008) and 420 mg (P = 0.018). Adverse events (AEs) were reported for 82%, 80%, 95%, and 90% of patients in the placebo, 260‐mg, 340‐mg, and 420‐mg groups, respectively. Constipation, hallucinations, dizziness, and dry mouth were the most frequent AEs. Study withdrawal rates were 9%, 15%, 14%, and 40% for the placebo, 260‐mg, 340‐mg, and 420‐mg groups, respectively. All study withdrawals in the active treatment groups were attributable to AEs. ADS‐5102 was generally well tolerated and resulted in significant and dose‐dependent improvements in dyskinesia in PD patients.

Increased Melanoma Risk in Parkinson Disease: A Prospective Clinicopathological Study

OBJECTIVE To evaluate the possible association of Parkinson disease (PD) and melanoma in North America. DESIGN, SETTING, AND PATIENTS Thirty-one centers enrolled patients with idiopathic PD. At visit 1, a neurologist obtained a medical history. At visit 2, a dermatologist recorded melanoma risk factors, performed a whole-body examination, and performed a biopsy of lesions suggestive of melanoma for evaluation by a central dermatopathology laboratory. We compared overall prevalence of melanoma with prevalence calculated from the US Surveillance Epidemiology and End Results (SEER) cancer database and the American Academy of Dermatology skin cancer screening programs. RESULTS A total of 2106 patients (mean [SD] age, 68.6 [10.6] years; duration of PD, 7.1 [5.7] years) completed the study. Most (84.8%) had received levodopa. Dermatology examinations revealed 346 pigmented lesions; dermatopathological findings confirmed 20 in situ melanomas (0.9%) and 4 invasive melanomas (0.2%). In addition, histories revealed 68 prior melanomas (3.2%). Prevalence (5-year limited duration) of invasive malignant melanoma in the US cohort of patients with PD (n = 1692) was 2.24-fold higher (95% confidence interval, 1.21-4.17) than expected in age- and sex-matched populations in the US SEER database. Age- or sex-adjusted relative risk of any melanoma for US patients was more than 7 times that expected from confirmed cases in American Academy of Dermatology skin cancer screening programs. CONCLUSIONS Melanoma prevalence appears to be higher in patients with PD than in the general population. Despite difficulties in comparing other databases with this study population, the study supports increased melanoma screening in patients with PD.

Droxidopa for the Short‐Term Treatment of Symptomatic Neurogenic Orthostatic Hypotension in Parkinson's Disease (nOH306B)

Neurogenic orthostatic hypotension (nOH) results from failure of norepinephrine responses to postural change to maintain standing systolic blood pressure (s‐SBP). Droxidopa is an oral prodrug of norepinephrine. Study nOH306 enrolled patients with Parkinsons disease (PD) and symptomatic nOH. Subjects underwent up to 2 weeks of double‐blind titration of droxidopa or placebo, followed by 8 weeks of double‐blind maintenance treatment (100‐600 mg thrice‐daily). For the initial 51 subjects (study nOH306A, previously reported), the primary efficacy measure, Orthostatic Hypotension Questionnaire (OHQ) composite score, did not demonstrate significant change versus placebo at maintenance week 8. For the subsequent 171 subjects (study nOH306B, reported here), the primary efficacy measure was change versus placebo on item 1 (“dizziness, lightheadedness, feeling faint, or feeling like you might black out”) of the Orthostatic Hypotension Symptom Assessment (OHSA) subsection of the OHQ at maintenance week 1. At week 1, mean (standard deviation) improvement on OHSA item 1 was 2.3 (2.95) for droxidopa versus 1.3 (3.16) for placebo (P = 0.018). In addition, mean increase in s‐SBP at week 1 was 6.4 (18.85) for droxidopa versus 0.7 (20.18) mmHg for placebo (nominal P value: 0.032). Differences in change in OHSA item 1 scores from baseline to maintenance weeks 2, 4, and 8 were not statistically significant. Adverse‐event (AE) incidence was similar across groups, but 12.4% of droxidopa and 6.1% of placebo subjects withdrew because of AEs. The most common AEs on droxidopa (vs. placebo) were headache (13.5% vs. 7.3%) and dizziness (10.1% vs. 4.9%). Study nOH306B demonstrated subjective (OHSA item 1) and objective (s‐SBP) evidence of short‐term droxidopa efficacy (vs. placebo) for symptomatic nOH in PD.

The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension

Neurogenic orthostatic hypotension (nOH) is common in patients with neurodegenerative disorders such as Parkinson’s disease, multiple system atrophy, pure autonomic failure, dementia with Lewy bodies, and peripheral neuropathies including amyloid or diabetic neuropathy. Due to the frequency of nOH in the aging population, clinicians need to be well informed about its diagnosis and management. To date, studies of nOH have used different outcome measures and various methods of diagnosis, thereby preventing the generation of evidence-based guidelines to direct clinicians towards ‘best practices’ when treating patients with nOH and associated supine hypertension. To address these issues, the American Autonomic Society and the National Parkinson Foundation initiated a project to develop a statement of recommendations beginning with a consensus panel meeting in Boston on November 7, 2015, with continued communications and contributions to the recommendations through October of 2016. This paper summarizes the panel members’ discussions held during the initial meeting along with continued deliberations among the panel members and provides essential recommendations based upon best available evidence as well as expert opinion for the (1) screening, (2) diagnosis, (3) treatment of nOH, and (4) diagnosis and treatment of associated supine hypertension.

Droxidopa in Patients with Neurogenic Orthostatic Hypotension Associated with Parkinson's Disease (NOH306A)

BACKGROUND Neurogenic orthostatic hypotension (nOH) is common in Parkinsons disease (PD), and represents a failure to generate norepinephrine responses appropriate for postural change. Droxidopa (L-threo-3,4-dihydroxyphenylserine) is an oral norepinephrine prodrug. OBJECTIVE Interim analyses of the initial patients enrolled in a multicenter, randomized, double-blind, placebo-controlled phase 3 trial of droxidopa for nOH in PD (ClinicalTrials.gov Identifier: NCT01176240). METHODS PD patients with documented nOH underwent ≤ 2 weeks of double-blind droxidopa or placebo dosage optimization followed by 8 weeks of maintenance treatment (100-600 mg t.i.d.). The primary efficacy measure was change in Orthostatic Hypotension Questionnaire (OHQ) composite score from baseline to Week 8. Key secondary variables included dizziness/lightheadedness score (OHQ item 1) and patient-reported falls. RESULTS Among 24 droxidopa and 27 placebo recipients, mean OHQ composite-score change at Week 8 was -2.2 versus -2.1 (p = 0.98); in response to this pre-planned futility analysis, the study was temporarily stopped and all data from these patients were considered exploratory. At Week 1, mean dizziness/lightheadedness score change favored droxidopa by 1.5 units (p = 0.24), with subsequent numerical differences favoring droxidopa throughout the observation period, and at Week 1, mean standing systolic blood-pressure change favored droxidopa by 12.5 mmHg (p = 0.04). Compared with placebo, the droxidopa group exhibited an approximately 50% lower rate of reported falls (p = 0.16) and fall-related injuries (post-hoc analysis). CONCLUSIONS This exploratory analysis of a small dataset failed to show benefit of droxidopa, as compared with placebo by the primary endpoint. Nonetheless, there were signals of potential benefit for nOH, including improvement in dizziness/lightheadedness and reduction in falls, meriting evaluation in further trials.

A Phase 2A Trial of the Novel mGluR5-Negative Allosteric Modulator Dipraglurant for Levodopa-Induced Dyskinesia in Parkinson's Disease.

The metabotropic glutamate receptor 5‐negative allosteric modulator dipraglurant reduces levodopa‐induced dyskinesia in the MPTP‐macaque model. The objective of this study was to assess the safety, tolerability (primary objective), and efficacy (secondary objective) of dipraglurant on levodopa‐induced dyskinesia in Parkinsons disease (PD).