Articles www.thelancet.com/neurology Vol 9 April 2010 363 Lancet Neurol 2010; 9: 363–72 Published Online March 1, 2010 DOI:10.1016/S1474- 4422(10)70043-0 See Reflection and Reaction page 333 Turku PET Centre and Clinical Research Services Turku, University of Turku and Turku University Hospital, Turku, Finland (J O Rinne MD); Division of Neuroscience and Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, UK (D J Brooks MD, A A Okello MRCP, S Rodriguez Martinez de LIano MD); Institute of Neurology, University College London, London, UK (M N Rossor FRCP, N C Fox FRCP); Kingshill Research Centre, Swindon, UK (R Bullock MRCPsych); University of Pittsburgh Medical Center, Pittsburgh, PA, USA (W E Klunk MD, C A Mathis PhD); University of Göteborg, Sahlgrenska University Hospital, Mölndal, Sweden (K Blennow MD); California Pacific Medical Center, San Francisco, CA, USA (J Barakos MD); Janssen Alzheimer Immunotherapy, South San Francisco, CA, USA (E Liu PhD, K M Gregg PhD, D Schenk PhD, M Grundman MD); Elan Pharmaceuticals, South San Francisco, CA, USA (M Koller MD, D Schenk, M Grundman); and Pfizer, Collegeville, PA, USA (R Black MD) Correspondence to: Juha O Rinne, Turku PET Centre, University of Turku, PO Box 52, 20521 Turku, Finland juha.rinne@tyks.fi 11C-PiB PET assessment of change in fibrillar amyloid-β load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study Juha O Rinne, David J Brooks, Martin N Rossor, Nick C Fox, Roger Bullock, William E Klunk, Chester A Mathis, Kaj Blennow, Jerome Barakos, Aren A Okello, Sofia Rodriguez Martinez de LIano, Enchi Liu, Martin Koller, Keith M Gregg, Dale Schenk, Ronald Black, Michael Grundman Summary Background Carbon-11-labelled Pittsburgh compound B (¹¹C-PiB) PET is a marker of cortical fibrillar amyloid-β load in vivo. We used ¹¹C-PiB PET to investigate whether bapineuzumab, a humanised anti-amyloid-β monoclonal antibody, would reduce cortical fibrillar amyloid-β load in patients with Alzheimer’s disease. Methods Patients with mild-to-moderate Alzheimer’s disease were randomly assigned to receive intravenous bapineuzumab or placebo in a ratio of seven to three in three ascending dose groups (0·5, 1·0, or 2·0 mg/kg). Each dose group was enrolled after safety review of the previous group. Randomisation was by interactive voice response system; masking was achieved with numbered kit allocation. Patients, investigators, study site personnel, sponsor staff, and carers were masked to treatment. Patients received up to six infusions, 13 weeks apart, and had ¹¹C-PiB PET scans at baseline and at weeks 20, 45, and 78. The primary outcome was the difference between the pooled bapineuzumab group and the pooled placebo group in mean change from screening to week 78 in ¹¹C-PiB cortical to cerebellar retention ratio averaged across six cortical regions of interest. Analysis was by modified intention to treat. This study is registered with EudraCT, number 2004-004120-12; ISRCTN17517446. Findings 28 patients were assigned to bapineuzumab (n=20) or placebo (n=8). 19 patients in the bapineuzumab group and seven in the placebo group were included in the modified intention-to-treat analysis. Estimated mean ¹¹C-PiB retention ratio change from baseline to week 78 was –0·09 (95% CI –0·16 to –0·02; p=0·014) in the bapineuzumab group and 0·15 (95% CI 0·02 to 0·28; p=0·022) in the placebo group. Estimated mean difference in ¹¹C-PiB retention ratio change from baseline to week 78 between the bapineuzumab group and the placebo group was –0·24 (95% CI –0·39 to –0·09; p=0·003). Differences between the bapineuzumab group and the placebo group in the individual regions of interest were similar to the overall mean difference. Adverse events were typically mild to moderate in severity and transient. Two patients in the 2·0 mg/kg bapineuzumab group had transient cerebral vasogenic oedema. Interpretation Treatment with bapineuzumab for 78 weeks reduced cortical ¹¹C-PiB retention compared with both baseline and placebo. ¹¹C-PiB PET seems to be useful in assessing the effects of potential Alzheimer’s disease treatments on cortical fibrillar amyloid-β load in vivo. Funding Elan Pharmaceuticals and Wyeth Research. Introduction Alzheimer’s disease is characterised neuropathologically by deposits of extracellular amyloid-β plaques, intraneuronal neurofibrillary tangles, and cerebral neuronal loss. 1 Antibodies directed against the N terminus of amyloid β reduce cerebral amyloid-β load in transgenic mice 2,3 and block the synaptotoxic effects of amyloid-β oligomers. 4 Bapineuzumab, an antibody targeted against the N terminus of amyloid β, is a passive immunotherapy that is being tested in Alzheimer’s disease. 5 Bapineuzumab might bind to amyloid β in the brain and facilitate its clearance. 2,3 Amyloid-β load can be measured in patients with Alzheimer’s disease by use of PET and the radiotracer carbon-11-labelled Pittsburgh compound B (¹¹C-PiB). 6,7 PiB is a thioflavin analogue that binds with low nanomolar affinity to aggregated fibrillar deposits of the amyloid-β peptide, enters the brain at concentrations detectable by PET, and clears rapidly from normal brain tissue. 6,8 At the low nanomolar concentrations used in PET studies, PiB selectively binds to fibrillar amyloid-β deposits in post-mortem human brain. 7,9 Compared with healthy controls, patients with Alzheimer’s disease have about two times greater retention of ¹¹C-PiB in areas of the association cortex that are targeted by amyloid-β deposits. 6,10 ¹¹C-PiB retention is similar in patients with Alzheimer’s disease and healthy controls in areas unaffected by amyloid-β deposition, such as the subcortical white matter, pons, and cerebellum. 6