Table 3 Study objectives and endpoints

Primary objective

Primary endpoint

 To evaluate the efficacy of rapamycin treatment in patients with early-stage Alzheimer’s disease

Change-from-baseline for:

• [¹⁸F]FDG brain uptake, measured with PET

Secondary endpoints

Change-from-baseline for:

• MoCA total score

• CSF levels of amyloid beta, p-tau, and t-tau

• Cerebral blood flow, measured with MRI using a non-invasive pseudo-continuous arterial spin-labeling sequence

Exploratory endpoints

• Physical performance:

◦ Timed 10 m walking test

◦ Timed 10 m dual-task test

◦ 30 s chair stand test

◦ Hand strength

• Neuropsychological cognitive testing using:

◦ Rey Auditory Verbal Learning Test (learning and delayed recall)

◦ Rey–Osterrieth Complex Figure

◦ Hagman test

◦ Trail Making Test A + B

◦ Wechsler Adult Intelligence Scale, 4th edition coding subtest to assess processing speed/attention

Secondary objectives

 To evaluate pharmacokinetic properties of intermittent dosing of rapamycin

Whole blood measurements of rapamycin concentration:

◦ C_max

◦ C_trough

◦ Area under the curve

 To evaluate the safety and tolerability of rapamycin when intermittently dosed against AD

Safety and tolerability as measured by incidence of AEs/SAEs; clinical laboratory test data; vital signs

Exploratory objectives

 To evaluate a general “geroprotective” effect of rapamycin treatment, by measuring changes in age-related tissue pathologies, such as:

  • Periodontal associated inflammation

  • Retinal degeneration

  • Atherosclerosis in large arteries

  • Heart function

  • Myocardial inflammation

  • Bone mineral density

Change-from-baseline for:

• Periodontal oedema and bone remodeling, measured using MRI and CT

• Thickness and thickness ratios of retinal nerve fiber layers in the macula and optic disc, measured using OCT

• Pulse wave velocity in the aorta, measured using MRI

• [¹⁸F]FDG uptake in atherosclerotic plaques in large arteries

• Heart function (including, but not limited to: diastolic function, microvascular function, myocardial-volume and strain), measured with MRI

• Bone mineral density in lumbar vertebrae, measured using qCT