The trial was terminated because of the expectation of enrollment not being feasible, driven by the recent CMS national coverage determination. The phase 4 confirmatory ENVISION trial is still ongoing.
According to an update to the ICARE-AD clinical trial (NCT05097131) NIH study records, the phase 4 postmarketing study of aducanumab (Aduhelm; Biogen) has been terminated. Biogen noted in the details that the termination was “a result of the national policy for coverage,” as the expectation was that “there will be limited aducanumab-avwa prescription and usage in routine clinical practice making the study not feasible for enrollment.”1
Biogen and Eisai originally announced the design of the real-world observational during a late-breaking presentation at the 2021 Alzheimer’s Association International Conference (AAIC), July 26-30.2 The study was designed to evaluate long-term effectiveness and safety of aducanumab injection 100 mg/mL solution, which received approval to treat Alzheimer disease (AD) the month prior, in June 2021.3 The study intended to enroll patients with AD over 4 years from approximately 200 sites in the US, with ongoing monitoring for up to 5 years, though only 22 trial sites were included on the NIH study records.
At the time of the trial announcement, Ivana Rubino, PhD, US and Global Head of Medical, Alzheimer Disease, Biogen, said in a statement that the company "believe[s] this can help us better understand the safety and effectiveness of treatment in patients with Alzheimer’s disease across ethnicities, something that has challenged researchers in this field for decades. The ICARE AD-US study, designed in collaboration with Alzheimer’s disease experts, underscores both of these commitments.”
This follows the April finalization of a national coverage determination (NCD) from the Centers for Medicare & Medicaid Services (CMS) on aducanumab and future monoclonal antibodies directed against amyloid that might be approved by the FDA for the treatment of Alzheimer disease (AD).4 The NCD did not stray far from the proposed decision that the agency announced earlier in the year, in January 2022.5 The NCD decision is ultimately that Medicare will be able to cover agents in this class of medication if they receive traditional approval from the FDA under coverage with evidence development.
CMS noted that it will “provide enhanced access and coverage for people with Medicare participating in CMS-approved studies, such as a data collection through routine clinical practice or registries,” and that registry data may be used to observed reproduced results in real-world populations. Additionally, the agency noted that new therapies in this class that are approved may be available in additional care settings— outpatient departments or infusion centers, as examples—that people with Medicare utilize.
CMS also determined that for those agents have not shown a clinical benefit as determined by the FDA—or that receive an accelerated approval, such as aducanumab—Medicare will cover the cost of the treatment only in FDA or National Institutes of Health approved trials. CMS added that it will “support the FDA” by offering coverage of any related services required by trial protocol, as well, for those with Medicare in these trials.
Shortly after the NCD finalization, in late April, the European Medicines Agency has announced that Biogen Netherlands BV had withdrawn its application for marketing authorization of aducanumab for the treatment of AD in Europe. Despite these setbacks, Biogen still has another phase 4 post-marketing study, this one the confirmatory study of the therapy required by its approval, called ENVISION (NCT05310071). This trial is designed to be more diverse in its study population, anticipating Black/African American and Latinx patients with AD to comprise 18%. Biogen has noted that the effort is in tandem with efforts to overcome barriers to enrollment in AD trials for these populations, including access to medical centers, familiarity with the risks and benefits of treatment, and financial or logistical burdens.6
The primary end point of ENVISION will measure patients’ cognitive decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) 18 months after treatment initiation with aducanumab.1 Additionally, the target enrollment numbers for the ENVISION trial were increased in early January 2022 from 1300 to 1500, to include those with AD (defined as mild cognitive impairment due to AD and mild AD), with confirmation of amyloid-ß pathology. The trial is scheduled to commence patient screening in May 2022, with an anticipated completion date 4 years after the study begins.