Follow-up clinical data from Tzimopoulou S et al. (2010) J Alzheimers Dis 22, 1241-1256

1 January 2012

We would like to make you aware of follow-up clinical data from an open-label extension (OLE) study (AVA104617) to the rosiglitazone positron emission tomography (PET) study 49653/461, which was recently published [1]. The complex and technical nature of the PET study and the need to present results in a comprehensive fashion precluded the inclusion of these open-label data in the original manuscript. Therefore we are making the following information available to your readers.

Subjects who completed the 12-month, placebo-controlled, parent study were eligible to enter into this OLE study. All subjects entering the OLE study received an investigational formulation of rosiglitazone (RSG-XR) 4 mg for the first 4 weeks and then 8 mg for the remaining 44 weeks of the study. Study outcomes evaluation visits were conducted at 4 or 8-week intervals. The primary objective of the study was to evaluate the long-term safety and tolerability of RSG-XR. The secondary objective was to measure changes in cognition using the Mini-Mental Status Examiniation (MMSE). This OLE was conducted at 7 of the sites (6 in the US, 1 in Canada) that participated in the PET study.

Thirty-three subjects entered into the OLE and comprise the safety population. The mean age of the subjects who entered the study was 71.9 (9.75 SD), 55% were male, 94% were Caucasian, and 21 (64%) completed the 48 weeks of treatment. Of the 12 subjects who withdrew prematurely, 2 were withdrawn due to serious adverse events (pelvic fracture, fall and convulsion) and 2 were withdrawn due to non-serious adverse events. The remainder of subjects who withdrew prematurely did so mostly for non-specific reasons (n= 4) or a lack of efficacy/disease progression (n=3).

The most common adverse events (reported in > 5% of subjects [n=33]) are listed below:
                                            n (%)
Any adverse event                25 (76)
Edema peripheral                 4 (12)
Depression                           3 (9)
Fall                                      3 (9)
Hematoma                           2 (6)
Abnormal loss of weight       2 (6)
Vomiting                              2 (6)
Agitation                              2 (6)
Bursitis                                 2 (6)

There were no fatalities during the study. Clinical laboratory data indicated a mild decline in mean (SD) hemoglobin (n=13, 11.1(4.2) g/L) and hematocrit (n=13, 3.9(1.8) %) consistent with the known effects of rosiglitazone. There were no clinically significant changes noted on ECGs during the conduct of this study.

There were no specific concerns noted regarding cardiovascular safety; rates of events for myocardial ischemia was low (1/33, 3%).

Subjects entered the study with a mean MMSE at baseline of 17.4. During the conduct of this study, there was a mean decline in MMSE scores of 4.5 (4.1 SD) points which is consistent with the natural rate of disease progression [2].

In conclusion, this OLE study enrolled 33 subjects who completed study 49653/461 [1]. The subjects who enrolled in this OLE study were demographically similar to those who enrolled in the parent study. The safety data obtained during this study are consistent with the known side-effect profile of rosiglitazone. The small sample size, non-randomized population and lack of control group preclude any conclusions about the efficacy of rosiglitazone in this population.

Michael Gold1, Barbara Jeter2, Paul M. Mathews3

1Formerly of GlaxoSmithKline, currently of Allon Therapeutics, Vancouver, British Columbia
2GlaxoSmithKline, Neurosciences Medicine Development Centre, Research Triangle Park, NC, USA
3GlaxoSmithKline, Clinical Imaging Centre, Hammersmith Hospital, London, UK and Department of Clinical Neuroscience, Imperial College, London, UK

[1] Tzimopoulou S, Cunningham VJ, Nichols TE, Searle G, Bird NP, Mistry P, Dixon IJ, Hallett WA, Whitcher B, Brown AP, Zvartau-Hind M, Lotay N, Lai RY, Castiglia M, Jeter B, Matthews JC, Chen K, Bandy D, Reiman EM, Gold M, Rabiner EA, Matthews PM (2010) A multi-center randomized proof-of-concept clinical trial applying [18F]FDG-PET for evaluation of metabolic therapy with rosiglitazone XR in mild to moderate Alzheimer's disease. J Alzheimers Dis 22, 1241-1256.
[2] Doody R, Massman P, Dunn J (2011) A method for estimating progression rates in Alzheimer disease. Arch Neurol 58, 449-454.