title: Metal protein attenuating compounds for the treatment of Alzheimer's dementia.
abstract: BACKGROUND
  Alzheimer's dementia (AD) may be caused by the formation of extracellular senile plaques comprised of beta-amyloid (Aß). In vitro and mouse model studies have demonstrated that metal protein attenuating compounds (MPACs) promote the solubilisation and clearance of Aß.
  
  
  OBJECTIVE
  To evaluate the efficacy of metal protein attenuating compounds (MPACs) for the treatment of cognitive impairment due to Alzheimer's dementia.
  
  
  METHODS
  We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, on 29 July 2010 using the terms: Clioquinol OR PBT1 OR PBT2 OR "metal protein" OR MPACS OR MPAC.
  
  
  METHODS
  Randomised double-blind trials in which treatment with an MPAC was administered to participants with Alzheimer's dementia in a parallel group comparison with placebo were included.
  
  
  METHODS
  Three review authors (RM, LJ, ELS) independently assessed the quality of trials according to the Cochrane Handbook for Systematic Reviews of Interventions.The primary outcome measure of interest was cognitive function (as measured by psychometric tests). The secondary outcome measures of interest were in the following areas: quality of life, functional performance, effect on carer, biomarkers, safety and adverse effects, and death.
  
  
  RESULTS
  Two MPAC trials were identified. One trial compared clioquinol (PBT1) with placebo in 36 patients and 32 had sufficient data for per protocol analysis. There was no statistically significant difference in cognition (as measured on the Alzheimer's Disease Assessment Scale - Cognition (ADAS-Cog)) between the active treatment and placebo groups at 36 weeks. The difference in mean change from baseline ADAS-Cog score in the clioquinol arm compared with the placebo arm at weeks 24 and 36 was a difference of 7.37 (95% confidence interval (CI) 1.51 to 13.24) and 6.36 (95% CI -0.50 to 13.23), respectively.There was no significant impact on non-cognitive symptoms or clinical global impression. One participant in the active treatment group developed neurological symptoms (impaired visual acuity and colour vision) which resolved on cessation of treatment and were possibly attributable to the drug.In the second trial a successor compound, PBT2, was compared with placebo in 78 participants with mild Alzheimer's dementia; all were included in the intention-to-treat analysis. There was no significant difference in the Neuropsychological Test Battery (NTB) composite or memory between placebo and PBT2 in the least squares mean change from baseline at week 12. However, two executive function component tests of the NTB showed significant improvement over placebo in the PBT2 250 mg group from baseline to week 12: category fluency test (2.8 words, 95% CI 0.1 to 5.4; P = 0.041) and trail making part B (-48.0 s, 95% CI -83.0 to -13.0; P = 0.009). In the executive factor Z score, the difference in least squares mean change from baseline at week 12 for PBT2 250 mg compared with placebo was 0·27 (0·01 to 0·53; p=0·042).There was no significant effect on cognition on Mini-Mental State Examination (MMSE) or ADAS-Cog scales. PBT2 had a favourable safety profile.
  
  
  CONCLUSIONS
  There is an absence of evidence as to whether clioquinol (PBT1) has any positive clinical benefit for patients with AD, or whether the drug is safe. We have some concerns about the quality of the study methodology; there was an imbalance in treatment and control groups after randomisation (participants in the active treatment group had a higher mean pre-morbid IQ) and the secondary analyses of results stratified by baseline dementia severity. The planned phase III trial of PBT1 has been abandoned and this compound has been withdrawn from development. The second trial of PBT2 was more rigorously conducted and showed that after 12 weeks this compound appeared to be safe and well tolerated in people with mild Alzheimer's dementia. Larger trials are now required to demonstrate cognitive efficacy.
authors.affiliation: Marie Curie Palliative Care Research Unit, University College, 67-73 Riding House Street, London, UK, W1W 7EJ.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Sampson
authors.forename: Lydia
authors.initials: L
authors.lastname: Jenagaratnam
authors.forename: Rupert
authors.initials: R
authors.lastname: McShane
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D002614:Chelating Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007464:Clioquinol / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use*; D006801:Humans; D016032:Randomized Controlled Trials as Topic
chemical_list: D016229:Amyloid beta-Peptides; D002614:Chelating Agents; C531955:PBT2 compound; D007464:Clioquinol