Randomized withdrawal design in action - Accord trial in Alzheimer's agitation

The biotech company, Axsome Therapeutics, announced the positive results from one of their pivotal phase 3 studies (Accord study). 

Axsome's approved depression drug clears Alzheimer's agitation trial months after Lundbeck-Otsuka duo

The unique side of the Accord study is the use of a randomized withdrawal design. The study was registered on clinicaltrials.gov as "A Double-blind, Placebo-controlled, Randomized Withdrawal Trial to Assess the Efficacy and Safety of AXS-05 for the Treatment of Agitation in Subjects With Dementia of the Alzheimer's Type"

With the randomized withdrawal design, all participants were given the active drug (AXS-05) in a run-in phase in an open-label manner. Then, those patients who responded to treatment during the run-in phase were randomly assigned, in a double-blind manner, to either continue treatment with AXS-05 or switch to a placebo.

According to the sponsor, the basic idea behind this randomized withdrawal study design is to see whether those who initially experience a benefit stop doing so when moved to a placebo, indicating that the therapy itself is effective — as opposed to results being due to a placebo effect. The randomized-withdrawal design of this phase 3 trial simultaneously improved signal detection and mitigated placebo response. 

With the randomized withdrawal design, the sample size was reduced. Total 178 patients with Alzheimer's disease agitation were enrolled into the study run-in phase. 108 patients who achieved a sustained clinical response were then included in the randomized withdrawal period. 

"The ACCORD study was a double-blind, placebo-controlled, multi-center, randomized withdrawal, U.S. trial which treated 178 patients with Alzheimer’s disease agitation. Patients achieving a sustained clinical response after open-label treatment with AXS-05 were randomized (n=108) in a 1:1 ratio to continue treatment with AXS-05 or to discontinue AXS-05 and switch to placebo."

According to an article on evaluate.com:

"When Axsome decided to stop the Accord study of AXS-05 in Alzheimer’s disease agitation early, hopes for that trial took a nosedive. So it was clearly a pleasant surprise today when the company announced that the study had hit. Axsome’s stock opened up 33%, and some investors might be hoping for an earlier-than-expected filing, despite the fact that results from the pivotal Advance-2 study are not due until 2025. Accord had initially been intended as a second pivotal, alongside the previously completed Advance-1, but when the number of agitation events turned out lower than expected, management decided to switch focus to Advance-2. Despite this, Accord met its primary endpoint, time to relapse of agitation, and a key secondary, relapse prevention. One potential fly in the ointment could be Accord’s randomised withdrawal design; it comprised an open-label lead-in phase in which all 178 patients were given AXS-05, and those that had a sustained clinical response to the agent were randomised to either continue treatment or switch to placebo. AXS-05, a combination of dextromethorphan and bupropion, is approved in depression as Auvelity and moving into Alzheimer’s agitation would be an important expansion."

Given that Alzheimer's agitation is a common disease (70% of Alzheimer's disease patients may have agitation), more than one adequate and well-controlled study (or pivotal, confirmatory studies) are needed to demonstrate substantial evidence for effectiveness. Besides the Accord study (with randomized withdrawal design), two additional studies were conducted by the sponsor: ADVANCE-1 trial was a Phase 2/3 study with an active control arm. ADVANCE-2 trial is a phase 3 confirmatory study with the largest sample size (350 patients in a 1:1 randomization ratio). ADVANCE-1 study results had already been announced. ADVANCE-2 study has just started the enrollment. Both ADVANCE-1 and ADVANCE-2 studies were designed as traditional RCT design - randomized, double-blind, placebo-controlled, parallel groups. 

In a clinical program containing multiple pivotal clinical trials, it is appropriate to select different clinical trial designs. In Axsome's Alzheimer's agitation clinical program, a randomized withdrawal design was used in one of the three pivotal trials, and a traditional RCT design was used in the other two pivotal trials. If all these three trials are successful, the evidence for effectiveness will be more substantial and stronger than three studies with the same study design.