Dimebon improves cognitive function in people with mild to moderate Alzheimer’s disease
Does dimebon improve cognitive function in people with mild to moderate Alzheimer’s disease?
183 people over 50 years of age with Alzheimer’s disease (DSM-IV and National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders criteria); Mini-Mental State Examination (MMSE) score 10–24; modified Hachinski ischaemic score ⩽4; and CT/MRI scan consistent with Alzheimer’s within 12 months prior to enrolment. Main exclusion criteria: potential other cause of dementia (eg, thyroid disease); cholinesterase inhibitor or N-methyl-D-aspartate receptor antagonist use within 60 days prior to enrolment; schizophrenia; stroke; Parkinson’s disease; seizure disorder; unstable medical illness; or hepatic/renal disease.
11 sites in Russia; recruitment September 2005–February 2006.
Dimebon (10 mg three times a day for 7 days, increased to 20 mg three times a day for the remainder of the study) or placebo for 26 weeks. Blinded treatment could be continued for an additional 26 week extension period if the participant agreed.
Primary outcome: cognitive function (Alzheimer’s Disease Assessment Scale, cognitive subscale (ADAS-cog): an 11 item scale ranging from 0 to 70 (a lower score indicates better function) which assesses aspects of language use and comprehension). Secondary outcomes: cognitive function on the MMSE; behaviour (Neuropsychiatric Inventory); activities of daily living (Alzheimer’s Disease Cooperative Study, activities of daily living); and Clinician’s Interview based Impression of Change plus Caregiver Input (CIBIC-plus).
85% completed the initial 26 weeks of treatment (88% dimebon and 82% placebo); 73% re-enrolled for a further 26 weeks (76% dimebon and 70% placebo); 66% completed 52 weeks of treatment (68% dimebon and 63% placebo).
Cluster randomised controlled trial.
26 weeks of initial treatment period plus optional 26 week treatment continuation; no follow-up post treatment.
At week 26, there was an improvement in cognitive function on the ADAS-cog in the dimebon group and worsening in the placebo group (mean change from baseline −1.9 with dimebon vs +2.1 with placebo; difference −4.0, 95% CI −5.7 to −2.3; p<0.0001). This pattern was consistent across all secondary outcome measures. At 52 weeks, the difference between the dimebon and placebo groups in cognitive function on the ADAS-cog increased, primarily due to the decline in function in the placebo group (mean change from baseline −0.9 with dimebon vs +4.6 with placebo; −5.5, 95% CI −7.6 to −3.5; p<0.0001).
Dimebon improves cognitive performance, behaviour and general functioning compared with placebo in people with mild to moderate Alzheimer’s disease.
Intention to treat and last observation carried forward analyses were used and are reported above. Observed case analyses were also carried out and provided similar results.
Doody RS, Gavrilova SI, Sano M, et al. Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer’s disease: a randomized, double-blind, placebo-controlled study. Lancet 2008;372:207–15.
Source of funding: Medivation, San Francisco, California, USA.
Doody and colleagues have published the results of a clinical study that may have a lasting impact in the pharmacotherapy of Alzheimer’s disease (AD), if their positive findings are confirmed in other studies with dimebon given alone and in combination with a cholinesterase inhibitor, in different countries and with a larger sample size. Indeed, the efficacy that was demonstrated on all five outcomes selected was seen not only against the placebo group but against baseline, an effect not seen with the currently available symptomatic drugs. This is particularly true for an improvement in activities of daily living which have never improved so far in any clinical trial in AD.1 The three times a day schedule may be difficult to maintain outside of a structured clinical trial and hopefully a daily dosing using a slow release preparation will be possible. The safety of the drug appears good although worsening of depression, a neuropsychiatric symptom commonly present in mild to moderate AD, needs monitoring in future studies and later in clinical practice.
The mechanisms of action of the drug dimebon are not yet fully understood; there must be more than a weak inhibitory effect on cholinesterases and on the N-methyl-D-aspartate receptor signalling pathway to explain the clinical benefit which was sustained for at least 1 year. A potential disease modifying action is hinted at in the publication, based on preclinical data. This may be worth pursuing in the pre-dementia stage of AD2 where there is no background drug therapy and potentially better reversibility of the underlying pathology. Doody and colleagues should be congratulated for completing this study successfully which may be the first indication that we have a drug with a sustained clinical benefit, akin to levodopa in Parkinson’s disease.