SAN DIEGO — An adjunctive, first-in-class investigational prescription digital therapeutic significantly reduced monthly migraine days (MMDs) in patients with episodic migraine (EM) compared with sham results of a large study showed.

CT-132 (Click Therapeutics) is a mobile smartphone app that “targets top-down pain processing and central sensitization” using behavioral approaches and includes an eDiary tracker and short daily lessons/exercises with a decision-support tool, the investigators reported.

In the phase 3 ReMMi-D trial, which included more than 500 adult patients with EM, those randomly assigned to receive CT-132 for 4 weeks showed significantly reduced MMDs compared with those who received a sham digital therapeutic — meeting its primary endpoint. They also had significantly reduced disability and improved quality-of-life outcomes, along with high adherence rates.

“I think this is very exciting as a clinician who takes cares of patients because we don’t have anything like this in our migraine armamentarium,” co-investigator Stewart J. Tepper, MD, professor of neurology at the Dartmouth Geisel School of Medicine, Hanover, New Hampshire, told Medscape Medical News.

“We know that behavioral techniques are helpful adjunctively, but large areas of the country just don’t have access to them,” added Tepper, who is also vice president of the New England Institute for Neurology and Headache, Stamford, Connecticut.

The findings were presented on April 6 in a poster presentation at the American Academy of Neurology (AAN) 2025 Annual Meeting.

Biologic, Behavioral Approaches

A company representative reported that CT-132 is currently under review by the US Food and Drug and Administration (FDA) as a medical device. It isn’t currently available to clinicians outside the research space.

“Despite advancements in pharmacotherapy, partial treatment response is common, driving an unmet need for additional reductions in MMDs,” the investigators noted in the abstract.

This need could be met by prescription digital therapeutics, which are not associated with adverse events (AEs) or other polypharmacy concerns, they added.

The CT-132 app “uses biologic and psychologic and behavioral approaches and then adapts to patient responses in order to take a person through a series of steps that, when they execute them, will help prevent migraine over the long term,” Tepper explained.

“It’s a way of enabling people to access various state-of-the-art behavioral techniques to use alongside their existing medication to offer additional relief,” he added.

Interestingly, Click Therapeutics Chief Medical Officer Shaheen Lakhan, MD, PhD, was one of Tepper’s neurology residents when he was at the Cleveland Clinic, Cleveland.

“He’s interested in doing this because he sees a need and knows from a neurologic standpoint the importance of all of this,” Tepper said.

Demonstrable Changes

Adults with 4-14 MMDs during a 4-week “run-in” baseline period, as recorded in an eDiary, were randomly assigned to receive either adjunctive CT-132 (n = 286; mean age, 38.4 years; 92% women; 94% White) or a sham digital therapeutic to act as the control (n = 284; mean age, 38.9 years; 94% women; 92% White) for a 12-week treatment period. All participated in a 1-week safety follow-up.

The sham group received a mock-up app that resembled CT-132. It included an “inert daily cognitive task” in order to match the daily engagement from the active study app and used the same eDiary for capturing endpoint data. It was also created to provide “negligible effect on the neurophysiological systems implicated in migraine,” the investigators reported.

“It used ‘make work’ tasks,” Tepper said. He added that a lot of work actually went into the creation of the noneffective sham app, including from in-house coders.

All participants received their allocated digital treatment as an add-on to acute and/or non–migraine-specific preventive medications. Exclusion criteria included use of calcitonin gene–related peptide (CGRP)–inhibiting medications.

Results at the end of 12 weeks of treatment showed a significant difference between the CT-132 group and the sham group for reduced MMDs (least-squares mean treatment difference, −0.9; P = .005). There was a mean drop of 3 MMDs for those receiving the active treatment.

The CT-132 group also had greater change in scores on the Migraine-Specific Quality-of-Life Questionnaire from baseline to week 12 than the sham group (12.3 vs 4.68; P < .001), as well as greater improvements on the Patient Global Impression of Change scale (82% vs 43% improvement P < .001) and the Migraine Disability Assessment (MIDAS, P = .002).

Tepper noted that a score > 20 on the MIDAS is considered severely disabled and a score > 40 is very severely disabled. “The study patients started in the 40s. And in the active group, they went down one subgrade — from very severely disabled to severely disabled. The sham group did not,” he said.

“In each of the patient-reported outcomes, there were demonstrable changes in the active group,” Tepper added.

New Addition to the Toolbox?

Engagement levels were high for both groups, with a median of 81 lessons out of 84 completed by those receiving the sham app and a median of 84 completed by those receiving the active app.

In addition, 7.9% of the CT-132 group vs 5.8% of the sham group experienced AEs, most of which were mild or moderate. No AEs were judged to be related to treatment and there were no AE-related discontinuations or deaths.

An additional matching randomized controlled trial, called the ReMMiD-C bridging study, has also been conducted and included a different patient population that included those taking CGRP inhibitors. It also compared the prescription digital therapeutic with a sham app.

Asked about a press release comment he made when topline results for both studies were released in September that CT-132 is the first migraine digital therapeutic “to be studied with this degree of rigor,” Tepper double-downed.

“Find me another digital therapeutic [study] with a sham control, and with orthodox outcome measures that the FDA recognizes for pivotal trials of medications or devices,” he said.

Based on these results, and depending on what the costs may eventually be after FDA approval, “why wouldn’t you add this to what you’re recommending to patients? This is a new prospective way to go forward with our current toolbox,” Tepper said.

Impressive, but More Data Needed

Commenting on the findings for Medscape Medical News, Teshamae Monteith, MD, chief of the Headache Division and professor of clinical neurology at the Miller School of Medicine, University of Miami, called the study “novel” and said its strength is “the impressive lack of adverse events.”

Monteith, who is also the Topic Chair for Headache at the AAN annual meeting, was not involved with this research.

She added that the study duration and outcome measures appeared appropriate and similar to what is commonly done in pharmaceutical clinical trials. However, she also had some questions and concerns.

Monteith noted that she would have appreciated more demographic information, and she couldn’t tell how many participants were in the intention-to-treat population.

Also, “I wish they had reported on analgesic use and on measures of comorbid anxiety and depression, which may be amendable to this type of intervention,” she said.

Overall, Monteith said that the concept of digital therapeutics “is tremendous,” because it offers a nondrug option and has the potential to improve access. However, in this particular case, she would have liked to have seen more details about the actual intervention and protocol.

“Some patients with migraine do not tolerate screentime, which may exacerbate symptoms such as photophobia, vertigo, and migraine in general. Also, we know there is a digital equity issue so that individuals with limited resources may have difficulties accessing the intervention,” Monteith said.

She added that in a future study she would also like to see the inclusion of individuals with chronic migraine.

This fully decentralized study was funded by Click Therapeutics. Tepper reported having numerous research funding and speakers bureau disclosures, as well as acting as a consultant and/or on advisory boards for several companies, including Click Therapeutics. Monteith reported that although she has a number of conflicts of interest related to migraine therapy, none is related to the study.