Dataset Information

Safety and Tolerability of R(+) Pramipexole in Mild-to-Moderate Alzheimer's Disease.

ABSTRACT: Alzheimer's disease (AD) is an aging-related, degenerative brain disease of adults. Most (?95%) of AD occurs sporadically and is associated with early-appearing deficits in brain regional glucose uptake, changes in cerebrospinal fluid (CSF) AD-related proteins, regional brain atrophy, and oxidative stress damage. We treated mild-moderate AD individuals with R(+)-pramipexole-dihydrochloride (R(+)PPX), a neuroprotective, lipophilic-cation, free-radical scavenger that accumulates into brain and mitochondria. 19 subjects took R(+)PPX twice a day in increasing daily doses up to 300?mg/day under a physician-sponsor IND (60,948, JPB), IRB-approved protocol and quarterly external safety committee monitoring. 15 persons finished and contributed baseline and post-treatment serum, lumbar spinal fluid, brain 18F-2DG PET scans, and ADAS-Cog scores. ADAS-Cog scores did not change (n?=?1), improved (n?=?2), declined 1-3 points (n?=?5), or declined 4-13 points (n?=?8) over 6 months of R(+)PPX treatment. Serum PPX levels were not related to changes in ADAS-Cog scores. Fasting AM serum PPX levels at 6 months varied considerably across subjects and correlated strongly with CSF [PPX] (r?=?0.97, p?< ?0.0001). CSF [PPX] was not related to CSF [A?(42)], [Tau], or [P-Tau]. Regional 18F-2DG measures of brain glucose uptake demonstrated a 3-6% decline during R(+)PPX treatment. 56 mild-moderate adverse events occurred, 26 probably/definitely related to R(+)PPX use, with 4 withdrawals. R(+)PPX was generally well-tolerated and entered brain extracellular space linearly. Further studies of R(+)PPX in AD should include a detailed pharmacokinetic study of peak and trough serum [PPX] variations among subjects prior to planning any larger studies that would be needed to determine efficacy in altering disease progression.

SUBMITTER: Bennett J

PROVIDER: S-EPMC5862139 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Safety and Tolerability of R(+) Pramipexole in Mild-to-Moderate Alzheimer's Disease.

Bennett James J Burns Jeffrey J Welch Paul P Bothwell Rebecca R

Journal of Alzheimer's disease : JAD 20160101 4

Alzheimer's disease (AD) is an aging-related, degenerative brain disease of adults. Most (∼95%) of AD occurs sporadically and is associated with early-appearing deficits in brain regional glucose uptake, changes in cerebrospinal fluid (CSF) AD-related proteins, regional brain atrophy, and oxidative stress damage. We treated mild-moderate AD individuals with R(+)-pramipexole-dihydrochloride (R(+)PPX), a neuroprotective, lipophilic-cation, free-radical scavenger that accumulates into brain and mit ...[more]

PMID: 26682692

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Project description:BackgroundAlzheimer's Disease (AD) is a multifactorial, progressive neurodegenerative disease that disrupts synaptic and neuronal activity and network oscillations. It is characterized by neuronal loss, brain atrophy and a decline in cognitive and functional abilities. Cognito's Evoked Gamma Therapy System provides an innovative approach for AD by inducing EEG-verified gamma oscillations through sensory stimulation. Prior research has shown promising disease-modifying effects in experimental AD models. The present study (NCT03556280: OVERTURE) evaluated the feasibly, safety and efficacy of evoked gamma oscillation treatment using Cognito's medical device (CogTx-001) in participants with mild to moderate AD.MethodsThe present study was a randomized, double blind, sham-controlled, 6-months clinical trial in participants with mild to moderate AD. The trial enrolled 76 participants, aged 50 or older, who met the clinical criteria for AD with baseline MMSE scores between 14 and 26. Participants were randomly assigned 2:1 to receive self-administered daily, one-hour, therapy, evoking EEG-verified gamma oscillations or sham treatment. The CogTx-001 device was use at home with the help of a care partner, over 6 months. The primary outcome measures were safety, evaluated by physical and neurological exams and monthly assessments of adverse events (AEs) and MRI, and tolerability, measured by device use. Although the trial was not statistically powered to evaluate potential efficacy outcomes, primary and secondary clinical outcome measures included several cognitive and functional endpoints.ResultsTotal AEs were similar between groups, there were no unexpected serious treatment related AEs, and no serious treatment-emergent AEs that led to study discontinuation. MRI did not show Amyloid-Related Imaging Abnormalities (ARIA) in any study participant. High adherence rates (85-90%) were observed in sham and treatment participants. There was no statistical separation between active and sham arm participants in primary outcome measure of MADCOMS or secondary outcome measure of CDR-SB or ADAS-Cog14. However, some secondary outcome measures including ADCS-ADL, MMSE, and MRI whole brain volume demonstrated reduced progression in active compared to sham treated participants, that achieved nominal significance.ConclusionOur results demonstrate that 1-h daily treatment with Cognito's Evoked Gamma Therapy System (CogTx-001) was safe and well-tolerated and demonstrated potential clinical benefits in mild to moderate AD.Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03556280.

Project description:BackgroundDonepezil 23 mg/d, recently approved in the United States for treatment of moderate to severe Alzheimer's disease (AD), was developed to address the need for an additional treatment option for patients with advanced AD. This report, based on a pivotal phase 3 study, presents a detailed analysis of the safety and tolerability of increasing donepezil to 23 mg/d compared with continuing 10 mg/d.MethodSafety analyses comprised examination of the incidence, severity, and timing of treatment-emergent adverse events (AEs) and their relationship to treatment initiation; changes in weight, electrocardiogram, vital signs, and laboratory parameters; and the incidence of premature study discontinuation. The analysis population (n = 1434) included all randomized patients who took at least 1 dose of study drug and had a postbaseline safety assessment. To further examine the effect of transition from a lower to a higher donepezil dose, a pooled analysis of safety data from 2 phase 3 trials of donepezil 5 mg/d and 10 mg/d was also performed.ResultsThe safety population comprised 1434 patients: donepezil 23 mg/d (n = 963); donepezil 10 mg/d (n = 471); completion rates were 71.1% and 84.7%, respectively. The most common AEs were nausea, vomiting, and diarrhea (donepezil 23 mg/d: 11.8%, 9.2%, 8.3%; donepezil 10 mg/d: 3.4%, 2.5%, 5.3%, respectively). AEs that contributed most to early discontinuations were vomiting (2.9% of patients in the 23 mg/d group and 0.4% in the 10 mg/d group), nausea (1.9% and 0.4%), diarrhea (1.7% and 0.4%), and dizziness (1.1% and 0.0%). The percentages of patients with AEs in the 23 mg/d group, as well as the timing, type, and severity of these AEs, were similar to those seen in previous donepezil trials with titration from 5 to 10 mg/d. Serious AEs were uncommon (23 mg/d, 8.3%; 10 mg/d, 9.6%).DiscussionThe 23 mg/d dose of donepezil was associated with typical cholinergic AEs, particularly gastrointestinal-related AEs, similar to those observed in studies with a dose increase from 5 to 10 mg/d.ConclusionThe good safety and predictable tolerability profile for donepezil 23 mg/d supports its favorable risk/benefit ratio in patients with moderate to severe AD.

Project description:BackgroundDonepezil (23 mg/day) is approved by the US Food and Drug Administration for the treatment of patients with moderate to severe Alzheimer's disease (AD). Approval was based on results from a 24-week, randomized, double-blind study of patients who were stable on donepezil 10 mg/day and randomized 2:1 to either increase their donepezil dose to 23 mg/day or continue taking 10 mg/day. The objective of this study was to assess the long-term safety and tolerability of donepezil 23 mg/day in patients with moderate to severe AD.MethodsPatients who completed the double-blind study and were eligible could enroll into a 12-month extension study of open-label donepezil 23 mg/day. Clinic visits took place at open-label baseline and at months 3, 6, 9, and 12. Safety analyses comprised examination of the incidence, severity, and timing of treatment-emergent adverse events (AEs); changes in weight, electrocardiogram, vital signs, and laboratory parameters; and discontinuation due to AEs.Results915 double-blind study completers were enrolled in the open-label extension study and 902 comprised the safety population. Mean treatment duration in this study was 10.3 ± 3.5 months. In total, 674 patients (74.7%) reported at least one AE; in 320 of these patients (47.5%) at least one AE was considered to be possibly or probably study drug related. The majority of patients reporting AEs (81.9%) had AEs of mild or moderate severity. There were 268 patients (29.7%) who discontinued early, of which 123 (13.6%) were due to AEs.Patients increasing donepezil dose from 10 mg/day in the double-blind study to 23 mg/day in the extension study had slightly higher rates of AEs and SAEs than patients who were already receiving 23 mg (78.0% and 16.9% vs 72.8% and 14.0%, respectively). The incidence of new AEs declined rapidly after the first 2 weeks and remained low throughout the duration of the study.ConclusionThis study shows that long-term treatment with donepezil 23 mg/day is associated with no new safety signals. The elevated incidence of AEs in patients increasing the dose of donepezil from 10 mg/day to 23 mg/day was limited to the initial weeks of the study.

Project description:BACKGROUND:Alzheimer's disease is characterized by the deposition of amyloid-beta (Aβ) plaques in the brain. Aβ is produced from the sequential cleavage of amyloid precursor protein by β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) followed by γ-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the Aβ level in the cerebrospinal fluid of patients with Alzheimer's disease. METHODS:We conducted a randomized, double-blind, placebo-controlled, 78-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild-to-moderate Alzheimer's disease. The coprimary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL; scores range from 0 to 78, with lower scores indicating worse function). RESULTS:A total of 1958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 653 to receive matching placebo. The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (P=0.63 for the comparison between the 12-mg group and the placebo group and P=0.46 for the comparison between the 40-mg group and the placebo group). The estimated mean change from baseline to week 78 in the ADCS-ADL score was -8.4 in the 12-mg group, -8.2 in the 40-mg group, and -8.9 in the placebo group (P=0.49 for the comparison between the 12-mg group and the placebo group and P=0.32 for the comparison between the 40-mg group and the placebo group). Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change, were more common in the verubecestat groups than in the placebo group. CONCLUSIONS:Verubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer's disease and was associated with treatment-related adverse events. (Funded by Merck; ClinicalTrials.gov number, NCT01739348 .).

Dataset Information

Safety and Tolerability of R(+) Pramipexole in Mild-to-Moderate Alzheimer's Disease.

Publications

Safety and Tolerability of R(+) Pramipexole in Mild-to-Moderate Alzheimer's Disease.

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