Randomized, Double-Blind, Parallel-Group, 48-Week Study for Efficacy and Safety of a Higher-Dose Rivastigmine Patch (15 vs. 10 cm²) in Alzheimer’s Disease

Abstract

Aim: Determine whether patients with Alzheimer’s disease demonstrating functional and cognitive decline, following 24–48 weeks of open-label treatment with 9.5 mg/24 h (10 cm²) rivastigmine patch, benefit from a dose increase in a double-blind (DB) comparative trial of two patch doses. Methods: Patients meeting prespecified decline criteria were randomized to receive 9.5 or 13.3 mg/24 h (15 cm²) patch during a 48-week, DB phase. Coprimary outcomes were change from baseline to week 48 on the Instrumental Activities of Daily Living domain of the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-IADL) scale and the Alzheimer’s Disease Assessment Scale–cognitive subscale (ADAS-cog). Safety and tolerability were assessed. Results: Of 1,584 patients enrolled, 567 met decline criteria and were randomized. At all timepoints, ADCS-IADL and ADAS-cog scores favoured the 13.3 mg/24 h patch. The 13.3 mg/24 h patch was statistically superior to the 9.5 mg/24 h patch on the ADCS-IADL scale from week 16 (p = 0.025) onwards including week 48 (p = 0.002), and ADAS-cog at week 24 (p = 0.027), but not at week 48 (p = 0.227). No unexpected safety concerns were observed. Conclusions: The 13.3 mg/24 h rivastigmine patch significantly reduced deterioration in IADL, compared with the 9.5 mg/24 h patch, and was well tolerated.

A 24-Week, Open-Label Extension Study to Investigate the Long-term Safety, Tolerability, and Efficacy of 13.3 mg/24 h Rivastigmine Patch in Patients With Severe Alzheimer Disease

“…Safety results appeared to be broadly consistent with those previously reported with the 13.3 mg/24 h patch in patients with mild-to-moderate AD, 8 AEs, adverse events; N, number of patients in the population; n, number of patients reporting SAE, death or discontinuation; SAE, serious adverse event.…”

“…5,20 In the DB OPTIMA trial, GI AEs were more frequently reported in patients up-titrated from 9.5 mg/24 h to 13.3 mg/24 h patch than for patients continuing on 9.5 mg/24 h patch. 8 Likewise, in the DB ACTION study the incidence of GI AEs was higher in patients receiving 13.3 mg/24 h compared with 4.6 mg/24 h patch (nausea: 6.2% versus 2.8%; vomiting 7.0% versus 2.5%; diarrhea: 6.5% versus 5.3%, respectively). 9 It is also now recommended that patients receive 9.5 mg/24 h patch for a minimum of 4 weeks before up-titrating to the 13.3 mg/24 h patch dose.…”

“…4,5 The transdermal system was initially indicated for the treatment of mildto-moderate AD at rivastigmine dosages of 4.6 mg/24 h and 9.5 mg/24 h. 5 A 13.3 mg/24 h dosage strength was later approved based on data from the OPTIMA (OPtimising Transdermal Exelon In Mild-to-moderate Alzheimer's disease) study, described elsewhere. 8 In June 2013, the US Food and Drug Administration approved an expanded indication for the 13.3 mg/24 h rivastigmine transdermal system to include the symptomatic treatment of patients with severe AD. 5 Approval was based on the ACTION (ACTivities of Daily Living and CognitION in Patients with Severe Dementia of the Alzheimer's Type) study, a 24-week, randomized, double-blind (DB) study that compared the 5 efficacy, safety and tolerability of rivastigmine 13.3 mg/24 h patch with 4.6 mg/24 h patch in patients with severe AD.…”

“…These safety data support previous findings that GI AEs are associated with initial rivastigmine dose increase. 8,20 Once patients are established on the high dose, GI AE frequency decreases, suggesting that patient tolerability of 13.3 mg/24 h rivastigmine patch improves with time. Further supporting this, the reported incidence of overall AEs was lower for patients continuing on 13.3 mg/24 h in the 24-week OLE than those randomized to 13.3 mg/24 h in the first 24 weeks of rivastigmine patch treatment (DB phase) (57.9% versus 74.6%, respectively).…”

“…9 The 48-week DB OPTIMA trial of patients with mild-to-moderate AD declining on 9.5 mg/24 h rivastigmine patch, who were randomized either to continue on 9.5 mg/24 h patch or up-titrate to 13.3 mg/24 h patch, reported a similar decline in AEs with time (Week 0-24, 64.6% and 54.8%; Week 24-28, 42.3% and 40.2%, 13.3 mg/24 h and 9.5 mg/24 h, respectively). 8 In light of these findings, patients with poor tolerability of 13.3 mg/24 h patch who have down-titrated to a lower maintenance dose may later show improved tolerability to the high-dose patch after a more prolonged exposure to lower-dose rivastigmine patch treatment.…”