Dataset Information

Sembragiline in Moderate Alzheimer's Disease: Results of a Randomized, Double-Blind, Placebo-Controlled Phase II Trial (MAyflOwer RoAD).

ABSTRACT: BACKGROUND:Sembragiline is a potent, selective, long-acting, and reversible MAO-B inhibitor developed as a potential treatment for Alzheimer's disease (AD). OBJECTIVE:To evaluate the safety, tolerability, and efficacy of sembragiline in patients with moderate AD. METHODS:In this Phase II study (NCT01677754), 542 patients with moderate dementia (MMSE 13-20) on background acetylcholinesterase inhibitors with/without memantine were randomized (1:1:1) to sembragiline 1?mg, 5?mg, or placebo once daily orally for 52 weeks. RESULTS:No differences between treated groups and placebo in adverse events or in study completion. The primary endpoint, change from baseline in ADAS-Cog11, was not met. At Week 52, the difference between sembragiline and placebo in ADAS-Cog11 change from baseline was - 0.15 (p?=?0.865) and 0.90 (p?=?0.312) for 1 and 5?mg groups, respectively. Relative to placebo at Week 52 (but not at prior assessment times), the 1?mg and 5?mg sembragiline groups showed differences in ADCS-ADL of 2.64 (p?=?0.051) and 1.89 (p?=?0.160), respectively. A treatment effect in neuropsychiatric symptoms (as assessed by the difference between sembragiline and placebo on BEHAVE-AD-FW) was also seen at Week 52 only: - 2.80 (p?=?0.014; 1?mg) and - 2.64 (p?=?0.019; 5?mg), respectively. A post hoc subgroup analysis revealed greater treatment effects on behavior and functioning in patients with more severe baseline behavioral symptoms (above the median). CONCLUSIONS:This study showed that sembragiline was well-tolerated in patients with moderate AD. The study missed its primary and secondary endpoints. Post hoc analyses suggested potential effect on neuropsychiatric symptoms and functioning in more behaviorally impaired study population at baseline.

SUBMITTER: Nave S

PROVIDER: S-EPMC5523913 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Sembragiline in Moderate Alzheimer's Disease: Results of a Randomized, Double-Blind, Placebo-Controlled Phase II Trial (MAyflOwer RoAD).

Nave Stephane S Doody Rachelle S RS Boada Mercè M Grimmer Timo T Savola Juha-Matti JM Delmar Paul P Pauly-Evers Meike M Nikolcheva Tania T Czech Christian C Borroni Edilio E Ricci Benedicte B Dukart Juergen J Mannino Marie M Carey Tracie T Moran Emma E Gilaberte Inma I Muelhardt Nicoletta Milani NM Gerlach Irene I Santarelli Luca L Ostrowitzki Susanne S Fontoura Paulo P

Journal of Alzheimer's disease : JAD 20170101 4

<h4>Background</h4>Sembragiline is a potent, selective, long-acting, and reversible MAO-B inhibitor developed as a potential treatment for Alzheimer's disease (AD).<h4>Objective</h4>To evaluate the safety, tolerability, and efficacy of sembragiline in patients with moderate AD.<h4>Methods</h4>In this Phase II study (NCT01677754), 542 patients with moderate dementia (MMSE 13-20) on background acetylcholinesterase inhibitors with/without memantine were randomized (1:1:1) to sembragiline 1 mg, 5 mg ...[more]

PMID: 28550255

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Project description:BACKGROUND:We investigated the effect of crenezumab, a humanized anti-amyloid-beta (A?) immunoglobulin (Ig)G4 monoclonal antibody, on biomarkers of amyloid pathology, neurodegeneration, and disease progression in patients with mild-to-moderate Alzheimer's disease (AD). METHODS:This double-blind, placebo-controlled, randomized phase II study enrolled patients with mild-to-moderate AD and a Mini-Mental State Examination (MMSE) score of 18-26. In part 1 of the study, patients were 2:1 randomized to receive low-dose subcutaneous (SC) 300 mg crenezumab every 2 weeks (q2w) or placebo for 68 weeks; in part 2, patients were 2:1 randomized to receive high-dose intravenous (IV) 15 mg/kg crenezumab every 4 weeks (q4w) or placebo for 68 weeks. The primary endpoint was change in amyloid burden from baseline to week 69 assessed by florbetapir positron emission tomography (PET) in the modified intent-to-treat population. Secondary endpoints were change from baseline to week 69 in cerebrospinal fluid (CSF) biomarkers and fluorodeoxyglucose PET, and change from baseline to week 73 in 12-point Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-Cog12) and Clinical Dementia Rating Sum of Boxes (CDR-SB). Safety was assessed in patients who received at least one dose of study treatment. RESULTS:From August 2011 to September 2012, 91 patients were enrolled and randomized (low-dose SC cohort: crenezumab (n?=?26) or placebo (n?=?13); high-dose IV cohort: crenezumab (n?=?36) or placebo (n?=?16)). The primary endpoint was not met using a prespecified cerebellar reference region to calculate standard uptake value ratios (SUVRs) from florbetapir PET. Exploratory analyses using subcortical white matter reference regions showed nonsignificant trends toward slower accumulation of plaque amyloid in the high-dose IV cohort. In both cohorts, a significant mean increase from baseline in CSF A?(1-42) levels versus placebo was observed. Nonsignificant trends toward ADAS-Cog12 and CDR-SB benefits were identified in a mild (MMSE 20-26) subset of the high-dose IV cohort. No amyloid-related imaging abnormalities due to edema/effusion were observed. CONCLUSION:The primary endpoint was not met. Exploratory findings suggest potential A? target engagement with crenezumab and possible slower accumulation of plaque amyloid. Studies investigating the effects of higher doses of crenezumab on amyloid load and disease progression are ongoing. TRIAL REGISTRATION:ClinicalTrials.gov, NCT01397578 . Registered on 18 July 2011.

Project description:Three small trials suggest that intravenous immunoglobulin can affect biomarkers and symptoms of mild-to-moderate Alzheimer's disease. We tested the safety, effective dose, and infusion interval of intravenous immunoglobulin in such patients.We did a multicentre, placebo-controlled phase 2 trial at seven sites in the USA and five in Germany. Participants with probable Alzheimer's disease aged 50-85 years were randomly assigned (by a computer-generated randomisation sequence, with block sizes of eight) to infusions every 4 weeks (0·2, 0·5, or 0·8 g intravenous immunoglobulin per kg bodyweight, or placebo) or infusions every 2 weeks (0·1, 0·25, or 0·4 g/kg, or placebo). Patients, caregivers, investigators assessing outcomes, and staff at imaging facilities and the clinical research organisation were masked to treatment allocation, but dispensing pharmacists, the statistician, and the person responsible for final PET analyses were not. Treatment was masked with opaque pouches and infusion lines. The primary endpoint was median area under the curve (AUC) of plasma amyloid ? (A?)(1-40) between the last infusion and the final visit (2 weeks or 4 weeks depending on infusion interval) in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT00812565) and controlled-trials.com (ISRCTN64846759).89 patients were assessed for eligibility, of whom 58 were enrolled and 55 included in the primary analysis. Median AUC of plasma A?(1-40) was not significantly different for intravenous immunoglobulin compared with placebo for five of the six intervention groups (-18·0 [range -1347·0 to 1068·5] for 0·2 g/kg, -364·3 [-5834·5 to 1953·5] for 0·5 g/kg, and -351·8 [-1084·0 to 936·5] for 0·8 g/kg every 4 weeks vs -116·3 [-1379·0 to 5266·0] for placebo; and -13·8 [-1729·0 to 307·0] for 0·1 g/kg, and -32·5 [-1102·5 to 451·5] for 0·25 g/kg every 2 weeks vs 159·5 [51·5 to 303·0] for placebo; p>0·05 for all). The difference in median AUC of plasma A?(1-40) between the 0·4 g/kg every 2 weeks group (47·0 [range -341·0 to 72·5]) and the placebo group was significant (p=0·0216). 25 of 42 (60%) patients in the intervention group versus nine of 14 (64%) receiving placebo had an adverse event. Four of 42 (10%) patients in the intravenous immunoglobulin group versus four of 14 (29%) receiving placebo had a serious adverse event, including one stroke in the intervention group.Intravenous immunoglobulin may have an acceptable safety profile. Our results did not accord with those from previous studies. Longer trials with greater power are needed to assess the cognitive and functional effects of intravenous immunoglobulin in patients with Alzheimer's disease.

Project description:BACKGROUND:PQ912 is an inhibitor of the glutaminyl cyclase enzyme that plays a central role in the formation of synaptotoxic pyroglutamate-A-beta oligomers. We report on the first clinical study with PQ912 in subjects with biomarker-proven Alzheimer's disease (AD). The aim was to determine the maximal tolerated dose, target occupancy and treatment-related pharmacodynamic effects. The exploratory efficacy readouts selected were tailored to the patient population with early AD. The therapeutic approach focuses on synaptic dysfunction as captured by various measures such as electroencephalography (EEG), synaptic biomarkers and sensitive cognitive tests. METHODS:This was a randomized, double-blind, placebo-controlled trial evaluating the safety, tolerability and efficacy of PQ912 800 mg twice daily (bid) for 12 weeks in subjects with mild cognitive impairment or mild dementia due to AD. The 120 enrolled subjects were treatment-naïve at the start of the study, had confirmed AD biomarkers in their cerebrospinal fluid at screening and had a Mini Mental State Examination score between 21 and 30. After 1 week of treatment with 400 mg bid, patients were up-titrated to 800 mg bid for 11 weeks. Patients were randomized 1:1 to either PQ912 or placebo. The primary composite endpoints were to assess safety and tolerability based on the number of patients who discontinued due to (serious) adverse events (safety), and based on dose adjustment during the treatment period and/or nonadherence to randomized treatment (tolerability). All randomized subjects who took at least one dose of the study treatment or placebo were used for safety analyses. RESULTS:There was no significant difference between treatments in the number of subjects with (serious) adverse events, although there were slightly more patients with a serious adverse event in the PQ912 group compared to placebo. More subjects treated with PQ912 discontinued treatment due to adverse events, mostly related to gastrointestinal and skin/subcutaneous tissue disorders. PQ912 treatment resulted in a significant reduction in glutaminyl cyclase activity, which resulted in an average target occupancy of >?90%. A significant reduction of theta power in the EEG frequency analysis and a significant improvement in the One Back test of our Neuropsychological Test Battery was observed. The exploratory biomarker readouts, neurogranin for synaptic toxicity and YKL-40 as a marker of inflammation, appear to be sensitive enough to serve as efficacy markers in the next phase 2b study. CONCLUSIONS:The maximal tolerated dose of PQ912 has been identified and the results support future studies at still lower doses reaching >?50% target occupancy, a longer up-titration phase to potentially induce adaptation and longer treatment periods to confirm the early signals of efficacy as seen in this study. TRIAL REGISTRATION:Clinicaltrials.gov, NCT 02389413 . Registered on 17 March 2015.

Project description:TRIAL INFORMATION:ClinicalTrials.gov Identifier: NCT02048371 Sponsors: SARC, with support from Bayer HealthCare Pharmaceuticals (Berlin, Germany) Principal Investigator: Richard F. Riedel IRB Approved: Yes LESSONS LEARNED: The results from the liposarcoma cohort of SARC024 confirm previously published data and do not support the routine use of regorafenib in this patient population. Continued exploration of novel therapies, including combination approaches, is warranted for a patient population in whom limited treatment options exist. BACKGROUND:Regorafenib is a multitargeted kinase inhibitor with a kinase profile overlapping, but distinct from, pazopanib, an agent approved for recurrent and metastatic non-gastrointestinal stromal tumor (GIST), non-adipocytic soft tissue sarcoma. We conducted a randomized, phase II study of regorafenib versus placebo in refractory liposarcoma patients. METHODS:Patients with advanced or metastatic, treatment-refractory liposarcoma were randomized 1:1 to receive regorafenib 160 mg or placebo once daily (3?weeks on, 1 week off). Patients with well-differentiated liposarcoma only were excluded. Crossover for placebo was allowed upon progression. The primary endpoint was progression-free survival (PFS), according to RECIST version 1.1. RESULTS:Forty-eight subjects with liposarcoma (34 dedifferentiated, 12 myxoid/round cell, 2 pleomorphic) were enrolled. Median PFS was 1.87 (95% confidence interval [CI], 0.92-3.67) months for regorafenib versus 2.07 (95% CI, 1.64-3.44) months for placebo; stratified hazard ratio [HR], 0.85 (95% CI, 0.46, 1.58), p = .62. No responses were seen on regorafenib. One PR was observed on placebo. Median overall survival was 6.46 (95% CI, 4.16-23.48) months for regorafenib and 4.89 (95% CI, 3.02-9.77) months for placebo, stratified HR, 0.66 (95% CI, 0.31-1.40), p = .28). Treatment-related adverse events were similar to the known safety profile of regorafenib. CONCLUSION:Regorafenib did not appear to improve PFS in treatment-refractory liposarcoma. No new significant safety signals were observed.

Project description:BackgroundPatients with systemic lupus erythematosus (SLE) have substantial unmet medical need. Baricitinib is a Janus kinase (JAK)1 and 2 inhibitor that was shown to have therapeutic benefit in patients with SLE in a phase II clinical trial. The purpose of this study was to evaluate the median change from baseline in conventional serologic biomarkers in subgroups and the overall population of baricitinib-treated patients with SLE, and the SLE Responder Index-4 (SRI-4) response by normalization of anti-dsDNA.MethodsData were assessed from the phase II trial I4V-MC-JAHH (NCT02708095). The median change from baseline in anti-dsDNA, IgG, and other conventional serologic markers was evaluated over time in patients who had elevated levels of markers at baseline, and in all patients for IgG. Median change from baseline for baricitinib treatments were compared with placebo. Among patients who were anti-dsDNA positive at baseline, SRI-4 responder rate was compared for those who stayed positive or achieved normal levels by week 24.ResultsSignificant decreases of anti-dsDNA antibodies were observed in response to baricitinib 2 mg and 4 mg compared to placebo beginning at weeks 2 (baricitinib 2 mg = - 14.3 IU/mL, placebo = 0.1 IU/mL) and 4 (baricitinib 4 mg = - 17.9 IU/mL, placebo = 0.02 IU/mL), respectively, continuing through week 24 (baricitinib 2 mg = - 29.6 IU/mL, baricitinib 4 mg = - 15.1 IU/mL, placebo=3.0 IU/mL). Significant reductions from baseline of IgG levels were found for baricitinib 4 mg-treated patients compared to placebo at weeks 12 (baricitinib 4 mg = - 0.65 g/L, placebo = 0.09 g/L) and 24 (baricitinib 4 mg = - 0.60 g/L, placebo = - 0.04 g/L). For patients who were anti-dsDNA positive at baseline, no relationship between achieving SRI-4 responder and normalization of anti-dsDNA was observed by week 24.ConclusionsBaricitinib treatment resulted in a rapid and sustained significant decrease in anti-dsDNA antibodies compared to placebo among those with positive anti-dsDNA antibodies at baseline, as well as a significant decrease in IgG levels in the 4 mg group at weeks 12 and 24. These data suggest that baricitinib may influence B cell activity in SLE. Further studies are needed to evaluate if reductions in anti-dsDNA levels with baricitinib treatment reflect the impact of baricitinib on B cell activity.Trial registrationNCT02708095 .

Dataset Information

Sembragiline in Moderate Alzheimer's Disease: Results of a Randomized, Double-Blind, Placebo-Controlled Phase II Trial (MAyflOwer RoAD).

Publications

Sembragiline in Moderate Alzheimer's Disease: Results of a Randomized, Double-Blind, Placebo-Controlled Phase II Trial (MAyflOwer RoAD).

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