scholarly journals A Phase II study to evaluate the safety and efficacy of prasinezumab in early Parkinson's disease (PASADENA): rationale, design and baseline data

2021 ◽  
Author(s):  
Gennaro Pagano ◽  
Frank G Boess ◽  
Kirsten I Taylor ◽  
Benedicte Ricci ◽  
Brit Mollenhauer ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rating Scale ◽  
Alpha Synuclein ◽  
Double Blind ◽  
Study Objective ◽  
Mao B ◽  
Progression Marker ◽  
Treatment Naïve ◽  
Baseline Characteristics

Background Currently available treatments for Parkinson's disease (PD) do not slow clinical progression nor target alpha-synuclein, the main pathology associated with the disease. Objective The study objective was to evaluate the efficacy and safety of prasinezumab, a humanized monoclonal antibody that binds aggregated alpha-synuclein, in individuals with early PD. The study rationale, design, and baseline characteristics of enrolled subjects are presented here. Methods The PASADENA study is a multicenter, randomized, double-blind, placebo-controlled treatment study. Individuals with early PD, recruited across the US and Europe, received monthly intravenous doses of prasinezumab (1500 mg or 4500 mg) or placebo for a 52-week period (Part 1), followed by a 52-week extension (Part 2) in which all participants received active treatment. Key inclusion criteria were: aged 40-80 years; Hoehn & Yahr (H&Y) Stage I or II; time from diagnosis ≤2 years; having bradykinesia plus one other cardinal sign of PD (e.g. resting tremor, rigidity); DaT-SPECT imaging consistent with PD; and either treatment naive or on a stable monoamine oxidase B (MAO-B) inhibitor dose. Study design assumptions for sample size and study duration were built using a patient cohort from the Parkinson1s Progression Marker Initiative (PPMI). In this report, baseline characteristics are compared between the treatment-naive and MAO-B inhibitor-treated PASADENA cohorts and between the PASADENA and PPMI populations. Results Of the 443 patients screened, 316 were enrolled into the PASADENA study between June 2017 and November 2018, with an average age of 59.9 years and 67.4% being male. The mean time from diagnosis at baseline was 10.11 months, with 75.3% in H&Y Stage II. Baseline motor and non-motor symptoms (assessed using Movement Disorder Society - Unified Parkinson's Disease Rating Scale [MDS-UPDRS]) were similar in severity between the MAO-B inhibitor-treated and treatment-naive PASADENA cohorts (MDS-UPDRS Total score [standard deviation (SD)]; 30.21 [11.96], 32.10 [13.20], respectively). The overall PASADENA population (63.6% treatment naive and 36.4% on MAO-B inhibitor) also showed a similar severity in MDS-UPDRS scores (e.g. MDS-UPDRS Total score [SD]; 31.41 [12.78], 32.63 [13.04], respectively) to the PPMI cohort (all treatment naive). Conclusions The PASADENA study population is suitable to investigate the potential of prasinezumab to slow disease progression in individuals with early PD.

scholarly journals Azathioprine immunosuppression and disease modification in Parkinson’s disease (AZA-PD): a randomised double-blind placebo-controlled phase II trial protocol

BMJ Open ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. e040527
Author(s):  
Julia C Greenland ◽  
Emma Cutting ◽  
Sonakshi Kadyan ◽  
Simon Bond ◽  
Anita Chhabra ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Immune System ◽  
Phase Ii ◽  
Rating Scale ◽  
Positron Emission Tomography Imaging ◽  
Clinical Markers ◽  
Double Blind ◽  
Positron Emission ◽  
Immunosuppressant Medication

IntroductionThe immune system is implicated in the aetiology and progression of Parkinson’s disease (PD). Inflammation and immune activation occur both in the brain and in the periphery, and a proinflammatory cytokine profile is associated with more rapid clinical progression. Furthermore, the risk of developing PD is related to genetic variation in immune-related genes and reduced by the use of immunosuppressant medication. We are therefore conducting a ‘proof of concept’ trial of azathioprine, an immunosuppressant medication, to investigate whether suppressing the peripheral immune system has a disease-modifying effect in PD.Methods and analysisAZA-PD is a phase II randomised placebo-controlled double-blind trial in early PD. Sixty participants, with clinical markers indicating an elevated risk of disease progression and no inflammatory or immune comorbidity, will be treated (azathioprine:placebo, 1:1) for 12 months, with a further 6-month follow-up. The primary outcome is the change in the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale gait/axial score in the OFF state over the 12-month treatment period. Exploratory outcomes include additional measures of motor and cognitive function, non-motor symptoms and quality of life. In addition, peripheral and central immune markers will be investigated through analysis of blood, cerebrospinal fluid and PK-11195 positron emission tomography imaging.Ethics and disseminationThe study was approved by the London-Westminster research ethics committee (reference 19/LO/1705) and has been accepted by the Medicines and Healthcare products Regulatory Agency (MHRA) for a clinical trials authorisation (reference CTA 12854/0248/001–0001). In addition, approval has been granted from the Administration of Radioactive Substances Advisory Committee. The results of this trial will be disseminated through publication in scientific journals and presentation at national and international conferences, and a lay summary will be available on our website.Trial registration numbersISRCTN14616801 and EudraCT- 2018-003089-14.

scholarly journals TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson’s disease

2017 ◽  
Vol 114 (40) ◽  
pp. 10773-10778 ◽  
Author(s):  
Seong Su Kang ◽  
Zhentao Zhang ◽  
Xia Liu ◽  
Fredric P. Manfredsson ◽  
Matthew J. Benskey ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Death ◽  
Kinase Domain ◽  
Alpha Synuclein ◽  
Mao B ◽  
Protein Levels ◽  
Trkb Receptors ◽  
Alpha Synuclein Aggregation ◽  
Neurotrophic Signaling

BDNF/TrkB neurotrophic signaling is essential for dopaminergic neuronal survival, and the activities are reduced in the substantial nigra (SN) of Parkinson’s disease (PD). However, whether α-Syn (alpha-synuclein) aggregation, a hallmark in the remaining SN neurons in PD, accounts for the neurotrophic inhibition remains elusive. Here we show that α-Syn selectively interacts with TrkB receptors and inhibits BDNF/TrkB signaling, leading to dopaminergic neuronal death. α-Syn binds to the kinase domain on TrkB, which is negatively regulated by BDNF or Fyn tyrosine kinase. Interestingly, α-Syn represses TrkB lipid raft distribution, decreases its internalization, and reduces its axonal trafficking. Moreover, α-Syn also reduces TrkB protein levels via up-regulation of TrkB ubiquitination. Remarkably, dopamine’s metabolite 3,4-Dihydroxyphenylacetaldehyde (DOPAL) stimulates the interaction between α-Syn and TrkB. Accordingly, MAO-B inhibitor rasagiline disrupts α-Syn/TrkB complex and rescues TrkB neurotrophic signaling, preventing α-Syn–induced dopaminergic neuronal death and restoring motor functions. Hence, our findings demonstrate a noble pathological role of α-Syn in antagonizing neurotrophic signaling, providing a molecular mechanism that accounts for its neurotoxicity in PD.

scholarly journals A Randomized Controlled Trial of Chinese Medicine on Nonmotor Symptoms in Parkinson’s Disease

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Ka-Kit Chua ◽  
Adrian Wong ◽  
Kam-Wa Chan ◽  
Yin-Kei Lau ◽  
Zhao-Xiang Bian ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Chinese Medicine ◽  
Rating Scale ◽  
Controlled Trial ◽  
Nonmotor Symptoms ◽  
Double Blind ◽  
Term Administration ◽  
Post Hoc ◽  
Chinese Medicine Theory

Nonmotor symptoms (NMS) of Parkinson’s disease (PD) have devastating impacts on both patients and their caregivers. Jiawei-Liujunzi Tang (JLT) has been used to treat some NMS of PD based on the Chinese medicine theory since Qing dynasty. Here we report a double-blind, randomized, placebo-controlled, add-on clinical trial aiming at evaluating the efficacy and safety of the JLT in treating NMS in PD patients. We randomly assigned 111 patients with idiopathic PD to receive either JLT or placebo for 32 weeks. Outcome measures were baseline to week 32 changes in Movement Disorder Society-Sponsored Revision of Unified PD Rating Scale (MDS-UPDRS) Parts I–IV and in NMS assessment scale for PD (NMSS). We observed improvements in the NMSS total score (p=0.019), mood/cognition (p=0.005), and reduction in hallucinations (p=0.024). In addition, post hoc analysis showed a significant reduction in constipation (p<0.001). However, there was no evidence of improvement in MDS-UPDRS Part I total score (p=0.216) at week 32. Adverse events (AEs) were mild and comparable between the two groups. In conclusion, long-term administration of JLT is well tolerated and shows significant benefits in improving NMS including mood, cognition, and constipation.

scholarly journals Efficacy and safety of rasagiline as an adjunct to levodopa treatment in Chinese patients with Parkinson's disease: a randomized, double-blind, parallel-controlled, multi-centre trial

2013 ◽  
Vol 16 (7) ◽  
pp. 1529-1537 ◽  
Author(s):  
Lina Zhang ◽  
Zhiqin Zhang ◽  
Yangmei Chen ◽  
Xinyue Qin ◽  
Huadong Zhou ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rating Scale ◽  
Chinese Patients ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Levodopa Treatment ◽  
Parallel Group ◽  
Disease Rating ◽  
Rasagiline Mesylate

Abstract Rasagiline mesylate is a highly potent, selective and irreversible monoamine oxidase type B (MAOB) inhibitor and is effective as monotherapy or adjunct to levodopa for patients with Parkinson's disease (PD). However, few studies have evaluated the efficacy and safety of rasagiline in the Chinese population. This study was designed to investigate the safety and efficacy of rasagiline as adjunctive therapy to levodopa treatment in Chinese PD patients. This was a randomized, double-blind, placebo-controlled, parallel-group, multi-centre trial conducted over a 12-wk period that enrolled 244 PD patients with motor fluctuations. Participants were randomly assigned to oral rasagiline mesylate (1 mg) or placebo, once daily. Altogether, 219 patients completed the trial. Rasagiline showed significantly greater efficacy compared with placebo. During the treatment period, the primary efficacy variable – mean adjusted total daily off time – decreased from baseline by 1.7 h in patients treated with 1.0 mg/d rasagiline compared to placebo (p < 0.05). Scores using the Unified Parkinson's Disease Rating Scale also improved during rasagiline treatment. Rasagiline was well tolerated. This study demonstrated that rasagiline mesylate is effective and well tolerated as an adjunct to levodopa treatment in Chinese PD patients with fluctuations.

scholarly journals Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson’s disease trial

2017 ◽  
Vol 3 (1) ◽  
Author(s):  
Howard E. Gendelman ◽  
Yuning Zhang ◽  
Pamela Santamaria ◽  
Katherine E. Olson ◽  
Charles R. Schutt ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rating Scale ◽  
Clinical Investigation ◽  
Phase 1 ◽  
Additional Patient ◽  
Double Blind ◽  
Modest Improvement ◽  
Cell Counts ◽  
Study Results

Abstract A potential therapeutic role for immune transformation in Parkinson’s disease evolves from more than a decade of animal investigations demonstrating regulatory T cell (Treg) nigrostriatal neuroprotection. To bridge these results to human disease, we conducted a randomized, placebo-controlled double-blind phase 1 trial with a well-studied immune modulator, sargramostim (granulocyte-macrophage colony-stimulating factor). We enrolled 17 age-matched non-Parkinsonian subjects as non-treated controls and 20 Parkinson’s disease patients. Both Parkinson’s disease patients and controls were monitored for 2 months for baseline profiling. Parkinson’s disease patients were then randomized into two equal groups to self-administer placebo (saline) or sargramostim subcutaneously at 6 μg/kg/day for 56 days. Adverse events for the sargramostim and placebo groups were 100% (10/10) and 80% (8/10), respectively. These included injection site reactions, increased total white cell counts, and upper extremity bone pain. One urticarial and one vasculitis reaction were found to be drug and benzyl alcohol related, respectively. An additional patient with a history of cerebrovascular disease suffered a stroke on study. Unified Parkinson’s disease rating scale, Part III scores in the sargramostim group showed modest improvement after 6 and 8 weeks of treatment when compared with placebo. This paralleled improved magnetoencephalography-recorded cortical motor activities and Treg numbers and function compared with pretreated Parkinson’s disease patients and non-Parkinsonian controls. Peripheral Treg transformation was linked to serum tryptophan metabolites, including L-kynurenine, quinolinic acid, and serotonin. These data offer a potential paradigm shift in modulating immune responses for potential therapeutic gain for Parkinson’s disease. Confirmation of these early study results requires larger numbers of enrolled patients and further clinical investigation.

scholarly journals Low dose niacin versus placebo in the treatment of Parkinson’s Disease:  A Randomized Controlled Trial

2021 ◽  
Author(s):  
Chandramohan Wakade ◽  
Raymond Chong ◽  
Marissa Seamon ◽  
Sharad Purohit ◽  
Banabihari Giri ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Low Dose ◽  
Rating Scale ◽  
Controlled Trial ◽  
Secondary Outcome ◽  
Open Label ◽  
Double Blind ◽  
One Year ◽  
Time Point

Abstract BackgroundParkinson’s Disease (PD) patients have lower niacin levels compared to their spouses. The main objective was to study low-dose daily niacin supplementation versus placebo on motor symptoms in Parkinson’s disease subjects.MethodsA randomized, placebo-controlled, double-blind, single-center clinical trial in Parkinson’s disease patients was performed in Augusta, GA, between September 2016 to September 2019. Randomized participants were 47 PD patients who received either low-dose niacin (N = 21 ) or placebo (N = 26) for the first six months (mean age 68.4 SD, 8.7; mean duration of disease 5.8 SD 4.9; H&Y scores between 0.5 to 4; 64% subjects were Veterans). The Veterans Affairs Pharmacy generated the randomized sequence. After the double-blind phase, all participants received open-label niacin for the next six months. All patients were evaluated at baseline, six months, and one year of treatment. The main outcome measure was the Unified Parkinson’s Disease Rating Scale III (UPDRS III) scores. Secondary outcome measures were depression, sleep quality, mental flexibility and cognition, and physical fatigue.Results39 subjects were analyzed with low-dose niacin (N = 18) and placebo (N = 21) for the completion of the first six months (randomized, double-blind), and 31 subjects were analyzed for the completion of the next six months (open-label) with low-dose niacin (N = 14) and placebo (N = 17). Niacin treatment was not tolerated by two subjects. The baseline mean UPDRS III score was 21.3 ± 15.8 for the niacin group and 22.4 ± 11.8 for placebo. The change with six months of placebo was 0.05 [95% CI, -2.4 to 2.32], and niacin was 1.06 [95% CI, -3.68 to 1.57]. From six to twelve months, the average UPDRS III score decreased for the placebo group by 4.58 [95% CI, -0.85 to 8.30] and the niacin group by 4.63 [95% CI, 1.42 to 7.83]. Eight subjects withdrew from the study before the 6-month time point and eight more before the one-year time point due to voluntary discontinuation, flushing, or inability to continue (SARS-CoV-2 shut-down).ConclusionLow-dose niacin supplementation may be helpful as an adjunct therapy in improving motor function in PD.Trial registrationClinicaltrials.gov, NCT03462680. Registered 12 March 2018- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03462680?term=gpr109A&draw=2&rank=1

scholarly journals 152 Pimavanserin for the Treatment of Parkinson’s Disease Psychosis: Number Needed to Treat, Number Needed to Harm, and Likelihood to Be Helped or Harmed

CNS Spectrums ◽  
2018 ◽  
Vol 23 (1) ◽  
pp. 94-95
Author(s):  
Leslie Citrome ◽  
James Norton ◽  
Kathy Chi-Burris ◽  
George Demos
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Adverse Event ◽  
Clinical Response ◽  
Fixed Dose ◽  
Number Needed To Treat ◽  
Double Blind ◽  
Term Care ◽  
Study Objective ◽  
Number Needed To Harm

AbstractStudy ObjectivePsychosis is common in Parkinson’s disease (PD) and increases in both frequency and severity with disease duration. It is associated with increased morbidity/mortality, complicates management of motor symptoms and often leads to long-term care placement. Pimavanserin (PIM) is a highly selective serotonin 5-HT2A receptor antagonist/inverse agonist indicated for the treatment of hallucinations and delusions associated with PD psychosis (PDP). The study aim is to review theevidence-base for PIM for the treatment of PDP using the metrics of evidence-based medicine, namely number needed to treat (NNT), number needed to harm (NNH), andlikelihood to be helped or harmed (LHH), in order to better place this intervention into clinical perspective.MethodsNNT and NNH are measures of effect size and indicate how many patients would need to be treated with one agent instead of the comparator in order to encounter one additional outcome of interest. A useful medication is one with a low NNT and a high NNH when comparing it with another intervention; a low NNT and a high NNH would mean one is more likely to encounter a benefit than a harm. Categorical efficacy and tolerability data was extracted from the clinical trial databases of the double-blind placebo-controlled studies of PIM in persons with PDP. The studies were 6 weeks in duration and fixed dose with the exception of study ACP-103-006 which was 4-weeks in duration. NNT and NNH values were calculated with their respective 95% confidence intervals. Efficacy endpoints were defined based on 2 definitions: a) Scale for the Assessment ofPositive Symptoms in Parkinson’s Disease (SAPS-PD) total score decrease ≥3 points from baseline and b) Clinical Global Impressions-Improvement scale (CGI-I) score of 1 (very much improved) or 2 (much improved). Tolerability outcomes of clinical interest, occurring at any time in available studies were assessed, including discontinuation due toan adverse event (AE). Likelihood to be helped or harmed (LHH) was then calculated contrasting therapeutic response vs. discontinuation because of an AE.ResultsNNT values for PIM 34 mg/d vs. placebo for several definitions of clinical response are <10, and as robust as 4, denoting that PIM is a potentially efficacious intervention. NNH values for tolerability outcomes for PIM 34 mg/d (as well as for doses that range from 8.5 mg/d to 51 mg/d) are >10, and/or are not statistically significant, and/or show an advantage for PIM over placebo (such as for postural hypotension), denoting that PIM is a potentially tolerable intervention. In terms of LHH, PIM 34 mg/d is about 5 times more likely to result in clinical response (as measured by ≥3 point decrease from baseline on the SAPS-PD) vs. discontinuation due to an adverse event.ConclusionsUsing the metrics of NNT, NNH, and LHH, PIM 34 mg/d for the treatment of PDP appears to have a compelling benefit-risk profile.Funding AcknowledgementsClinical study was funded by ACADIA Pharmaceuticals Inc.

scholarly journals Preliminary finding of a randomized, double-blind, placebo-controlled, crossover study to evaluate the safety and efficacy of 5-hydroxytryptophan on REM sleep behavior disorder in Parkinson’s disease

2021 ◽  
Author(s):  
Mario Meloni ◽  
Michela Figorilli ◽  
Manolo Carta ◽  
Ludovica Tamburrino ◽  
Antonino Cannas ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rem Sleep ◽  
Rating Scale ◽  
Sleep Onset ◽  
Rem Sleep Behavior Disorder ◽  
Behavior Disorder ◽  
Double Blind ◽  
Sleep Behavior ◽  
Double Blind Placebo

Abstract Purpose Altered serotonergic neurotransmission may contribute to the non-motor features commonly associated with Parkinson’s disease (PD) such as sleep disorders. The 5-hydroxytryptophan (5-HTP) is the intermediate metabolite of l-tryptophan in the production of serotonin and melatonin. The purpose of this study was to compare the effects of 5-HTP to placebo on REM sleep behavior disorder (RBD) status in patients with PD. Methods A single-center, randomized, double-blind placebo-controlled crossover trial was performed in a selected population of 18 patients with PD and RBD. The patients received a placebo and 50 mg of 5-HTP daily in a crossover design over a period of 4 weeks. Results 5-HTP produced an increase in the total percentage of stage REM sleep without a related increase of RBD episodes, as well as a marginal, non-significant reduction in both arousal index and wake after sleep onset. The self-reported RBD frequency and clinical global impression (CGI) were improved during 5-HTP and placebo treatment in comparison to baseline. 5-HTP significantly improved our patients’ motor experiences of daily living as rated by the Unified Parkinson’s Disease Rating Scale (UPDRS) part II. Conclusions This study provides evidence that 5-HTP is safe and effective in improving sleep stability in PD, contributing to ameliorate patients’ global sleep quality. Larger studies with higher doses and longer treatment duration are needed to corroborate these preliminary findings.

Two-Weeks of Twice-Daily Prism Adaptation Treatment does not Improve Posture or Gait in Parkinson’s Disease: A Double-Blind Randomized Controlled Trial

2021 ◽  
Author(s):  
Janet H Bultitude ◽  
Dawna M Pidgeon ◽  
Pauline R LeBlanc ◽  
Charlotte A Jeffreys ◽  
Faith P Alexandre ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Postural Control ◽  
Rating Scale ◽  
Center Of Gravity ◽  
Prism Adaptation ◽  
Double Blind ◽  
Sham Treatment ◽  
Limits Of Stability

Abstract BackgroundGait difficulties in Parkinson’s disease have been related to problems shifting center of gravity forward. We previously showed reduced forward stepping latencies for people with Parkinson’s disease after one session of adaptation to upward visual shifts, which produces downward motor after-effects and potentially shifts center of gravity forward. Here we tested if repeated prism adaptation improved gait and postural control in Parkinson’s disease through a parallel, double-blind, randomized, sham-controlled trial.MethodsWe recruited participants with idiopathic Parkinson’s disease aged 40 – 80 and meeting any one of three clinical criteria: 1) Hoehn and Yahr Stage II.5 – IV; 2) Scoring > 0 on the gait, freezing of gait, and/or postural stability items of the Movement Disorder Society Unified Parkinson’s Disease Rating Scale; or 3) Timed Up and Go > 12 seconds. Sealed envelope style randomization allocated participants to two weeks of twice-daily prism adaptation or sham treatment. Participants, care givers, and those assessing the outcomes were blinded to group assignment. Primary outcomes were changes in postural control measured using the Berg Balance Scale; and the Limits of Stability, Sensory Organisation, and Motor Control tests from the Smart EquiTest system. Secondary outcomes included other physiotherapy and questionnaire measures. Outcomes were assessed at the Dartmouth Hitchcock Medical Center immediately before and after the treatment period, with further long-term postal follow-up over two months. Outcomes were analysed using Analyses of Variance with follow-up t-tests. ResultsEighteen participants were allocated to undergo prism adaptation, of which sixteen were analysed. Thirteen participants were allocated to undergo sham treatment, and all were analysed. The prism adaptation group showed increased forward stepping velocity on the Limits of Stability test (Pre: M=2.33, SEM=0.24; post: M=2.88, SEM=0.26; t(15)=3.2, p=.005, d=.819). The sham group showed no such change (Pre: M=2.13, SEM=0.22; 1d post: M=2.24, SEM=0.22; t(13)=.636, p=.537, d=.176). However, there were no group differences for any other outcome measures, and no indications that prism adaptation produced functional improvements in posture, gait, or activities of daily living. ConclusionsPrism adaptation does not improve gait or postural control in Parkinson’s disease. Trial RegistrationRegistered prospectively at ClinicalTrials.gov, 5th March 2015, NCT02380859, https://clinicaltrials.gov/ct2/show/NCT02380859.

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