A 36-week Multicenter, Randomised, Double-blind, Placebo-controlled, Parallel-group, Phase 3 Clinical Trial of Sodium Oligomannate for Mild-to-Moderate Alzheimer's Dementia

Abstract Background: New therapies are urgently needed for Alzheimer’s disease (AD). Sodium oligomannate (GV-971) is a marine-derived oligosaccharide which reconstitutes gut microbiota, reduces neuroinflammation, decreases amyloid deposition, and improves cognition in AD animal models. The first phase 3 clinical trial of GV-971 has been completed in China. Methods: We conducted a phase 3, double-blind, placebo-controlled trial in participants with mild-to-moderate AD to assess GV-971 efficacy and safety. Participants were randomized to placebo or GV-971 (900 mg) for 36 weeks. The primary outcome was the drug-placebo difference in change from baseline on the 12-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog12). Secondary endpoints were drug-placebo differences on the Clinician’s Interview-Based Impression of Change with caregiver input (CIBIC+), Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, and Neuropsychiatric Inventory (NPI). Safety and tolerability were monitored. Results: 818 participants were randomized: 408 to GV-971 and 410 to placebo. A significant drug-placebo difference on the ADAS-Cog12 favoring GV-971 was present at each measurement time-point, measurable at the week 4 visit and continuing throughout the trial. The difference between groups in change from baseline was −2.15 points (95% confidence interval, −3.07 to −1.23; P<0.0001; effect size 0.531) after 36 weeks treatment. Treatment-emergent adverse event incidence was comparable between active treatment and placebo (73.9%, 75.4%). Two deaths determined to be unrelated to drug effects occurred in the GV-971 group.Conclusions: GV-971 demonstrated significant efficacy in improving cognition with sustained improvement across all observation periods of a 36-week trial. GV-971 was safe and well tolerated. Trial registration: ClinicalTrials.gov, NCT02293915. Registered on November 19, 2014.

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A 36-week multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial of sodium oligomannate for mild-to-moderate Alzheimer’s dementia

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00795-7 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Shifu Xiao ◽

Piu Chan ◽

Tao Wang ◽

Zhen Hong ◽

Shuzhen Wang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trial ◽

Controlled Trial ◽

Drug Effects ◽

Disease Assessment ◽

Phase 3 ◽

Double Blind ◽

Double Blind Placebo ◽

The Difference

Abstract Background New therapies are urgently needed for Alzheimer’s disease (AD). Sodium oligomannate (GV-971) is a marine-derived oligosaccharide with a novel proposed mechanism of action. The first phase 3 clinical trial of GV-971 has been completed in China. Methods We conducted a phase 3, double-blind, placebo-controlled trial in participants with mild-to-moderate AD to assess GV-971 efficacy and safety. Participants were randomized to placebo or GV-971 (900 mg) for 36 weeks. The primary outcome was the drug-placebo difference in change from baseline on the 12-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog12). Secondary endpoints were drug-placebo differences on the Clinician’s Interview-Based Impression of Change with caregiver input (CIBIC+), Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, and Neuropsychiatric Inventory (NPI). Safety and tolerability were monitored. Results A total of 818 participants were randomized: 408 to GV-971 and 410 to placebo. A significant drug-placebo difference on the ADAS-Cog12 favoring GV-971 was present at each measurement time point, measurable at the week 4 visit and continuing throughout the trial. The difference between the groups in change from baseline was − 2.15 points (95% confidence interval, − 3.07 to − 1.23; p < 0.0001; effect size 0.531) after 36 weeks of treatment. Treatment-emergent adverse event incidence was comparable between active treatment and placebo (73.9%, 75.4%). Two deaths determined to be unrelated to drug effects occurred in the GV-971 group. Conclusions GV-971 demonstrated significant efficacy in improving cognition with sustained improvement across all observation periods of a 36-week trial. GV-971 was safe and well-tolerated. Trial registration ClinicalTrials.gov, NCT02293915. Registered on November 19, 2014

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P2-003: Clinical Trial Design of Cread: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 3 Study to Evaluate Crenezumab Treatment in Patients with Prodromal-To-Mild Alzheimer’s Disease

Alzheimer s & Dementia ◽

10.1016/j.jalz.2016.06.1207 ◽

2016 ◽

Vol 12 ◽

pp. P609-P609 ◽

Cited By ~ 7

Author(s):

Thomas Blaettler ◽

Janice Smith ◽

Jillian Smith ◽

Robert Paul ◽

Veronica Asnaghi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trial ◽

Trial Design ◽

Clinical Trial Design ◽

Phase 3 ◽

Double Blind ◽

Double Blind Placebo ◽

Parallel Group

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Safety and efficacy of pioglitazone for the delay of cognitive impairment in people at risk of Alzheimer's disease (TOMMORROW): a prognostic biomarker study and a phase 3, randomised, double-blind, placebo-controlled trial

The Lancet Neurology ◽

10.1016/s1474-4422(21)00043-0 ◽

2021 ◽

Vol 20 (7) ◽

pp. 537-547

Author(s):

Daniel K Burns ◽

Robert C Alexander ◽

Kathleen A Welsh-Bohmer ◽

Meredith Culp ◽

Carl Chiang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

At Risk ◽

Cognitive Impairment ◽

Prognostic Biomarker ◽

Controlled Trial ◽

Phase 3 ◽

Double Blind ◽

Safety And Efficacy ◽

Double Blind Placebo

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NILVAD protocol: a European multicentre double-blind placebo-controlled trial of nilvadipine in mild-to-moderate Alzheimer's disease

BMJ Open ◽

10.1136/bmjopen-2014-006364 ◽

2014 ◽

Vol 4 (10) ◽

pp. e006364 ◽

Cited By ~ 27

Author(s):

Brian Lawlor ◽

Sean Kennelly ◽

Sarah O'Dwyer ◽

Fiona Cregg ◽

Cathal Walsh ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rating Scale ◽

Controlled Trial ◽

Phase Iii ◽

Disease Assessment ◽

Secondary Outcome ◽

Outcome Analysis ◽

Double Blind ◽

Double Blind Placebo

IntroductionThis study is a European multicentre, randomised, double-blind, placebo-controlled trial investigating the efficacy and safety of nilvadipine as a disease course modifying treatment for mild-to-moderate Alzheimer's disease (AD) in a phase III study that will run for a period of 82 weeks with a treatment period of 78 weeks.Methods and analysisAdult patients, males and females over 50 years with mild-to-moderate AD as defined by the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease and Related Disorders Association (NINCDS-ADRDA) criteria, will be included in the study. It aims to recruit a total of 500 patients with AD; 250 in the nilvadipine group and 250 in the placebo group. Participants will be randomised to receive nilvadipine, an 8 mg overencapsulated, sustained release capsule, or a matching overencapsulated placebo (sugar pill) for a period of 78 weeks of treatment. The primary efficacy outcome measure in this study is the change in cognitive function as assessed by the Alzheimer's disease Assessment Scale (ADAS-Cog 12) from baseline to the end of treatment duration (78 weeks). There are two key secondary outcome measures, the Clinical Dementia Rating Scale Sum of Boxes (CDR-sb) and the Disability Assessment for Dementia (DAD). If a statistically significant effect is seen in the primary outcome, CDR-sb will be considered to be a coprimary end point and only the DAD will contribute to the secondary outcome analysis.Ethics and disseminationThe study and all subsequent amendments have received ethical approval within each participating country according to national regulations. Each participant will provide written consent to participate in the study. All participants will remain anonymised throughout and the results of the study will be published in an international peer-reviewed journal.Trial registration numberEUDRACT Reference Number: 2012-002764-27.

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A Randomized, Controlled Trial of Linopirdine in the Treatment of Alzheimer's Disease

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s031716710002148x ◽

1997 ◽

Vol 24 (2) ◽

pp. 140-145 ◽

Cited By ~ 31

Author(s):

Kenneth Rockwood ◽

B. Lynn Beattie ◽

M. Robin Eastwood ◽

Howard Feldman ◽

Erich Mohr ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Controlled Trial ◽

Small Degree ◽

Disease Assessment ◽

Double Blind ◽

Cognitive Subscale ◽

Parallel Group ◽

Treatment Dose ◽

Age Range

ABSTRACT:Objectives:We tested the efficacy and safety of linopirdine, a novel phenylindolinone, in the treatment of Alzheimer's disease.Methods:A multicentre, randomized, double-blind, parallel group, placebo-controlled trial of linopirdine (30 mg three times per day or placebo). Patients (n = 382, 55% male, 98% Caucasian, age range 51-95 years) with mild or moderate Alzheimer's disease, of whom 375 received at least one treatment dose were analysed. There were no important differences between the groups at baseline.Results:No difference was seen in Clinical Global Impression scores between patients receiving placebo and those receiving linopirdine (n = 189). Small differences in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores were seen throughout the study favouring linopirdine; at 6 months the ADAS-Cog scores were 20.2 (linopirdine) and 22.1 (placebo) p = 0.01.Conclusions:This trial did not detect clinically meaningful differences in patients receiving linopirdine for 6 months, despite evidence of a small degree of improved cognitive function. Further studies may benefit from more sensitive tests of treatment effects in Alzheimer's disease.

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