Efficacy of Bacopa Monnieri (Brahmi) and Donepezil in Alzheimer’s Disease and Mild Cognitive Impairment: A Randomized Double-Blind Parallel Phase 2b Study

May combine two claims.

At the last follow-up, there was a significant difference in the change in total PGIMS score between brahmi and donepezil, with the donepezil arm showing lesser progression.

“In the last follow-up, there was a significant difference in the change in total PGIMS score between brahmi and donepezil, while there was no difference in individual scores of the PGI memory scale.”

• Also stated in: § DISCUSSION · plain

  “At the last follow-up, on the PGI memory scale (total score), donepezil arm had lesser progression compared to brahmi, while there was no difference in individual scores of PGI memory scale.”

Classified as probably not a substantial claim.

The current standard of care drug therapy for Alzheimer's disease is cholinesterase inhibitors, including donepezil.

“The current standard of care drug therapy for AD is cholinesterase inhibitors, including donepezil.[1]”

• cites [1] Birks JS Harvey RJ Donepezil for dementia due to Alzheimer's disease Cochrane Database Syst Rev 2018 6 CD001190 29923184 PMC6513124Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim. May combine two claims.

The institute ethics committee approved the protocol and consent forms, and informed consent was taken from all participants.

“Institute ethics committee (Postgraduate Institute of Medical Education and Research, Chandigarh, reference number PGI/IEC/2012/1171) approved the protocol of the trial and consent forms. Informed consent was taken from all the participants.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Multiple imputations were used to handle missing data because of loss to follow-up.

“Multiple imputations were used to handle missing data because of lost to follow up.”

Classified as probably not a substantial claim.

Baseline imbalances in prognostic variables were adjusted by analysis of covariance.

“These baseline imbalances in prognostic variables were adjusted by analysis of covariance.”

May combine two claims.

The study was terminated after 3 years and 9 months, after recruiting 34 patients, because of slow recruitment and a high dropout rate.

“The study was terminated after 3 years and 9 months, after recruiting 34 patients, because of slow recruitment and a high dropout rate.”

• Also stated in: § RESULTS · plain

  “The study was terminated after 3 years and 9 months, in view of slow recruitment and high dropout rate.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Brahmi reversed L-NNA-induced anterograde and retrograde amnesia.

“Further research from our group found that brahmi reversed the L-NNA (N (w)-nitro-L-arginine)-induced anterograde and retrograde amnesia.[59]”

• cites [59]Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim. May combine two claims.

Subjects, treating neurologists, outcome assessors, and data analysts were blinded to the allocation sequence.

“The subjects, treating neurologists, outcome assessors, and data analysts were blinded to the allocation sequence.”

May combine two claims.

There were significant differences in baseline characteristics, though they were adjusted in the final analysis.

“As expected in an RCT with small sample size, there were significant differences in the baseline characteristics though they were adjusted in the final analysis.”

May combine two claims.

Even though there was a statistical difference in the total PGI memory scale, there was no difference in the individual scale subsets and hence there was little clinical significance.

“Even though there was statistical difference in the total PGI memory scale, there was no difference in the individual scale subsets and, hence, there was little clinical significance.”

May combine two claims.

Although the primary outcome time point was at 12 months, many patients did not come for the last evaluation on time and there was a gap between end of study drug intake and final evaluation.

“Although the primary outcome time point was at 12 months, many patients did not come for the last evaluation on time and there was a gap between end of study drug intake and final evaluation.”

May combine two claims.

There were more patients with AD in the donepezil group and more patients with MCI in the brahmi group.

“There were more patients with AD in donepezil group and more patients with MCI in brahmi group.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The study demonstrates the practical problems of conducting an RCT on dementia in a country like India.

“The study demonstrates the practical problems of conducting an RCT on dementia in a country like India.”

Classified as probably not a substantial claim. May combine two claims.

Due to four different time points leading to eight primary outcomes, the time point of 12 months or last follow-up was kept as the time point for the primary outcome.

“Due to four different time points, effectively this led to eight primary outcomes. Hence, we had decided to keep the time point of 12 months or last follow-up as the time point for primary outcome.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The trial was conducted in accordance with the Declaration of Helsinki and the principles of good clinical practice.

“The trial was conducted in accordance with the declaration of Helsinki and the principles of good clinical practice.”

Probably not a substantial claim: may not pass S3 (load-bearing).

No blindness evaluation was planned in the study.

“No blindness evaluation was planned in the study.”

May combine two claims.

The dropout rate was high and recruitment rate was poor, and hence the trial had to be stopped prior to attaining the sample size.

“The dropout rate was high and recruitment rate was poor and, hence, trial had to be stopped prior to attaining the sample size.”

May combine two claims.

Our study is the first randomized controlled trial assessing the efficacy of brahmi in MCI-AD and AD, proven by CSF biomarkers (Abeta42 amyloid and T-Tau) and FDG-PET imaging.

“Our study is the first randomized controlled trial (RCT) assessing the efficacy of brahmi in MCI-AD and AD, proven by CSF biomarkers (Abeta42 amyloid and T-Tau) and FDG-PET imaging.”

Probably not a substantial claim: may not pass S3 (load-bearing).

An independent data and safety monitoring board monitored all adverse events.

“An independent data and safety monitoring board monitored all the adverse events.”

Classified as probably not a substantial claim. May combine two claims.

A meta-analysis of randomized controlled trials on the cognitive effects of brahmi concluded that Bacopa monnieri has potential to improve cognition, particularly speed of attention, but only a large well-designed head-to-head trial against an existing medication will provide definitive data on its efficacy.

“A meta-analysis of randomized control trials on the cognitive effects of brahmi concluded that “Bacopa monnieri has potential to improve cognition, particularly speed of attention but only a large well designed 'head-to-head' trial against an existing medication will provide definitive data on its efficacy on healthy or dementia patients using a standardized preparation.”[10]”

• cites [10] Kongkeaw C Dilokthornsakul P Thanarangsarit P Limpeanchob N Norman Scholfield C Meta-analysis of randomized controlled trials on cognitive effects of Bacopa monnieri extract J Ethnopharmacol 2014 151 528 35 24252493Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim. May combine two claims.

Donepezil is widely used in clinical practice for MCI-AD because it is challenging to differentiate mild AD from MCI-AD without detailed neuropsychological evaluation including assessment of activities of daily living.

“But donepezil is widely used in clinical practice for MCI-AD since in routine clinical practice, it is challenging to differentiate mild AD from MCI-AD without a detailed neuropsychological evaluation including assessment of activities of daily living.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The median duration of disease was more in the brahmi group.

“The median duration of disease was more in brahmi group and more severe scores of baseline neuropsychological scales in donepezil group.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The trial was registered retrospectively because of communication issues, but patients were recruited only after approval from the ethics committee.

“The trial was registered retrospectively because of communication issues, but the patients were recruited only after approval from the ethics committee.”

Classified as probably not a substantial claim.

Diagnosis of AD/MCI-AD was confirmed using MRI brain, FDG PET brain, and cerebrospinal fluid Ab amyloid and total tau.

“Diagnosis of AD/MCI-AD was confirmed using magnetic resonance imaging (MRI) brain, fluorodeoxyglucose-positron emission tomography (FDG PET) brain, and cerebrospinal fluid “(CSF) Ab amyloid and total tau.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The randomization sequence was generated by independent personnel from the department of pharmacology who were not involved in the study.

“The randomization sequence was generated by independent personnel from department of pharmacology who were not involved in the study.”

Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

Though we cannot claim noninferiority between brahmi and donepezil based on the results, it gives enough data for a larger phase-3 trial to detect superiority of brahmi over donepezil.

“Though we cannot claim noninferiority between brahmi and donepezil based on the results, it gives enough data for a larger phase-3 trial to detect superiority of brahmi over donepezil.”

Probably not a substantial claim: may not pass S3 (load-bearing).

MCI-AD or amnestic MCI is 15 times more likely to develop AD on follow-up.

“Moreover, MCI-AD or amnestic MCI is 15 times more likely to develop AD on follow-up.[3]”

• cites [3] Burns A Iliffe S Dementia BMJ 2009 338 b75 19196746Not checked yet

  Not checked in the free run.

May combine two claims.

Only 46.1% in the brahmi arm completed the course of treatment, while 76.1% completed the treatment in the donepezil arm.

“Only 46.1% in brahmi arm completed the course of treatment, while 76.1% completed the treatment in donepezil arm.”

Classified as probably not a substantial claim. May combine two claims.

Intention-to-treat analysis was conducted and all patients randomized were included in the final analysis.

“Intention to treat (ITT) analysis was conducted and all patients randomized were included in the final analysis.”

Classified as probably not a substantial claim.

Outcomes were adjusted for baseline age, sex, baseline neuropsychological test score, and duration of disease.

“The outcomes were adjusted for baseline age, sex, baseline neuropsychological test score, and duration of disease.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Postulated therapeutic effects of bacosides include enhancement of nerve impulse transmission, restoration of synaptic activity, and repair of damaged neurons by upregulating neuronal synthesis and kinase activity and maintaining neurotransmitter balance.

“The postulated therapeutic effects of bacosides include enhancement of nerve impulse transmission, restoration of synaptic activity, and repair of damaged neurons by upregulating neuronal synthesis and kinase activity and maintaining neurotransmitter balance.[46]”

• cites [46]Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Bacopa monnieri or brahmi is used in traditional Indian medicine for memory loss, and Ayurveda literature reports its medicinal properties for the treatment of anxiety, intellect, and memory disorders.

“Indian traditional medicine (Ayurveda) literature reports its medicinal properties for the treatment of anxiety, intellect, and memory disorders.[4]”

• cites [4] Singh HK Dhawan BN Neuropsychopharmacological effects of the Ayurvedic nootropic Bacopa monnieri Linn.(Brahmi) Indian J Pharmacol 1997 29 359Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Major active constituents in brahmi with possible action on memory and cognition are bacoside-A and bacoside-B.

“Major active constituents in brahmi with possible action on memory and cognition are bacoside-A and bacoside-B apart from other phytochemicals like alkaloids, saponins, flavonoids, etc.[5]”

• cites [5] Mathur D Goyal K Koul V Anand A The molecular links of re-emerging therapy: A review of evidence of Brahmi (Bacopa monniera) Front Pharmacol 2016 7 44 26973531 PMC4778428Not checked yet

  Not checked in the free run.

May combine two claims.

Both these studies may have included MCI and some normal healthy subjects also.

“Hence, both these studies may have included MCI and some normal healthy subjects also.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The sample size of 48 participants (24 each) was calculated for a phase-2 trial using Simon's randomized phase-2 design with a least expected baseline response rate of 12% and an assumed difference in response rate of 20%.

“The sample size of 48 participants (24 each) was calculated for phase-2 trial (using Simon's randomized phase-2 design) for intervention and active comparison groups with least expected baseline response rate of 12% and assumed difference in response rate between the best treatment and the other treatments as 20%.”