Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Two Year Study to Evaluate the Effect of Subcutaneous RO4909832 on Cognition and Function in Prodromal Alzheimer's Disease with option for an additional two years of treatment

RO4909832 (Mab31) is a human antibody directed against the amyloid plaques
present in the brains of people with Alzheimer's disease. The deposition of
amyloid in the brains plays an important role in the pathogenesis of this
disease. Animal Models of passive immunization with anti-amyloid antibodies
showed a decrease in amyloidosis and show improvement of cognitive functions.
There is a great need to improve the treatment of Alzheimer's disease,
especially for drugs that affect the course of the disease. Passive
immunization with anti-amyloid antibodies, could improve the treatment of
Alzheimer's disease. This study is an early stage of Alzheimer's disease
(prodromal) investigating the effect of RO4909832. By decreasing amyloid amount
in an early stage of the disease, it is assumed that less damage is done. PET
scan data from the Phase 1 study (MAD study) raise the suggestion that an
amyloid-reducing effect of gantenerumab occurs during the period of 6 months at
doses of 60 and 200 mg IV.

Primary objective:

Evaluate the effect of two doses versus placebo gantenerumab subcutaneous
injections on the change in Clinical Dementia Rating Sum of Boxes scale (CDR
SOB), a global measure of cognition and functional capacity

Secondary objectives:

To evaluate the efficacy, safety and tolerability of gantenerumab placebo
subcutaneous injections

This is a Multicenter, Randomized, Double-Blind, Placebo-Controlled,
Parallel-Group Two Year Study with option for an additional two years of
treatment. The planned total number of subjects is approximately 360, 120 on
placebo and 120 on each of the two gantenerumab doses. Based on the ADNI data
the approximate genotype distribution is expected to be 33% 0 APoE4, 50% 1
APoE4 and 17% 2 APoE4 (with respective N*s of: 120, 180 and 60). Subjects with
ApoE genotypes 0APoE4 or 1APoE4 will be randomized to gantenerumab 105 mg, 225
mg, or placebo. Subjects with ApoE genotype 2 APoE4 will be assigned to
gantenerumab 105 mg or placebo. Within each of the three ApoE genotype groups
(0 APoE4, 1 APoE4 or 2 APoE4) subjects will be assigned to either gantenerumab
or placebo in 2:1 ratio.

The planned total number of subjects is approximately 360, 120 on placebo and
120 on each of the two gantenerumab doses. Based on the ADNI data the
approximate genotype distribution is expected to be 33% 0 APoE4, 50% 1 APoE4
and 17% 2 APoE4 (with respective N*s of: 120, 180 and 60). Subjects with ApoE
genotypes 0APoE4 or 1APoE4 will be randomized to gantenerumab 105 mg, 225 mg,
or placebo. Subjects with ApoE genotype 2 APoE4 will be assigned to
gantenerumab 105 mg or placebo. Within each of the three ApoE genotype groups
(0 APoE4, 1 APoE4 or 2 APoE4) subjects will be assigned to either gantenerumab
or placebo in 2:1 ratio.

The following examinations will be done: physical and neurological examination,
heart rate and blood pressure measurement, blood and urine tests, liquor
punction, pregnancy (for women of childbearing age), ECG, MRI scans, PET scans
and questionnaires. Very little is known about side effects and risks of
multiple doses of SC RO4908832 in subjects in the prodromal phase of
Alzheimer's disease there. There is a risk of unknown side effects.

See also E9.