Pivotal trial of low-intensity pulsed ultrasound therapy for early Alzheimer's disease: Rationale and design.

Background: There are lines of evidence suggesting that cerebral microcirculatory dysfunction is involved in the pathogenesis of Alzheimer's disease (AD). We have developed a low-intensity pulsed ultrasound (LIPUS) therapy that upregulates endothelial NO synthase with therapeutic angiogenesis. We demonstrated that the LIPUS therapy ameliorates cognitive declines in mouse models of AD and tended to do so in patients with early AD (mild AD and mild cognitive impairment due to AD) in the pilot trial. Thus, the Japanese government has designated our LIPUS device as the first breakthrough medical device in Japan.

Objective: We are performing a pivotal clinical trial (LIPUS-AD) to finally address the efficacy and safety of our LIPUS therapy in patients with early AD in Japan.

Methods: LIPUS-AD is a randomized, double-blind, placebo-controlled trial, in which a total of 220 patients with early AD, who are positive for amyloid-β (Aβ) PET, will be randomized in a 1:1 fashion. The LIPUS therapy is performed for the whole brain for one hour 3 times a week as one session under the special conditions (32 cycles, 0.5 MHz, 0.25 W/cm²). It is performed for 6 sessions with 3-month intervals in the LIPUS group for 72 weeks, while the placebo group receives placebo therapy. Before and at 72 weeks of the trial, all subjects undergo brain Aβ PET and MRI and 9 cognitive functions tests. The primary efficacy endpoint is the changes in ADAS-J-cog-14 scores from baseline to 72 weeks.

Conclusions: LIPUS-AD addresses efficacy and safety of the LIPUS therapy in patients with early AD.Clinical Trial Gov. No.: NCT05983575.