A new expert consensus identifies patient-reported outcome measures to guide research—and finds that the most debilitating symptom still lacks an adequate tool.
By Alyx Arnett
For patients with central disorders of hypersomnolence, symptoms often persist even when on medications. What’s more, not all symptoms, or their impact on daily life, are captured in research used to develop and evaluate treatments.
A new paper from Global Genes and Sleep Consortium aims to address that gap by establishing a consensus set of patient-reported outcome measures for hypersomnolence research and clinical trials.1 Developed through a multi-stakeholder working group, the framework links specific questionnaires to the symptoms and daily-life impacts that patients and caregivers say matter most, with the goal of making results more consistent across studies and more relevant for therapy development.
“We want to make sure that what’s being measured in clinical trials are endpoints that really reflect the experience of individuals who are impacted by these diseases,” says Karmen Trzupek, senior director of scientific programs at Global Genes and the paper’s lead author.
Starting With What Patients Say Matters Most
To build that framework, working group members first defined what needed to be measured. They began with a list of 16 symptoms and eight impacts to daily life, drawn from a literature review, US Food and Drug Administration patient input reports, and insight from patient advocacy organizations. They then ranked the items to determine which were most important.
They narrowed the list to seven priority symptoms:
- excessive daytime sleepiness (EDS),
- cataplexy,
- brain fog,
- long periods of sleep,
- sleep inertia/sleep drunkenness,
- disrupted nighttime sleep/fragmented sleep/insomnia, and
- fatigue.
They also refined the scope to five key impacts on daily life:
- quality of life,
- work or school productivity,
- cognitive functioning,
- activities of daily living, and
- social functioning.
The distinction between symptoms and their impact on daily life became a central focus of the process. Claire Wylds-Wright, chief experience officer of Sleep Consortium and a co-author of the paper, says considering both is key. “The biggest gap is that EDS and cataplexy are measured in the office and in research, but the lived experience—impact of symptoms on activities of daily living—is not,” she says. “This includes brain fog, relationships, economic, and social impact.”
Trzupek agrees, saying, “If you think about excessive daytime sleepiness as a symptom, it’s easy to underappreciate the impact of that.”
She points to limits patients often place on daily activities—cutting back on driving, struggling to get through a full workday, or needing to spend evenings recovering instead of engaging socially. “When you lose social life, you are at high risk of depression,” she says. “There are lots of downstream impacts that we have to think about.”
Choosing the Right Measures
The next step was deciding how to measure these symptoms and daily-life impacts. The group reviewed 46 assessment tools for adults and 26 for pediatrics. They evaluated each measure based on how well it applied to the hypersomnolence population, whether it had been validated in sleep disorders, whether it could capture more than one domain, and how long it took to complete.
“We don’t want something that’s 40 questions long,” Trzupek says. “We want [patients] to do it when they’re not in any deep brain fog episode, and those moments of clarity are really important. That’s precious time. So we need to make sure that what we’re asking is critical to the research without being overly burdensome.”
For key symptoms for adults, the group selected:
- Epworth Sleepiness Scale and Idiopathic Hypersomnia Severity Scale for EDS,
- Narcolepsy Severity Scale for cataplexy,
- PROMIS Cognitive Function 8a for brain fog,
- Idiopathic Hypersomnia Severity Scale for sleep inertia/sleep drunkenness,
- Stanford Sleep Disorders Questionnaire Section V: Symptoms of Insomnia and Narcolepsy Severity Scale for disrupted nighttime sleep/fragmented sleep/insomnia,
- Flinders Fatigue Scale for fatigue, and
- no patient-reported outcome measures were identified for long periods of sleep.
To capture broader impacts, the group selected:
- SF-36 for quality of life,
- WHODAS 2.0 for work or school productivity and cognitive functioning (noting that it’s inadequate to fully capture brain fog),
- Functional Outcomes of Sleep Questionnaire for activities of daily living, and
- PROMIS Ability to Participate in Social Roles and Activities 8a for social functioning.
For pediatric populations, the group selected age-appropriate versions where available, including the Epworth Sleepiness Scale for Children and Adolescents, the Pediatric Narcolepsy Severity Scale, and PROMIS pediatric modules. However, “there are definitely more of these measures that have been developed for adults than kids,” Trzupek says, a gap the group identified as an area for future development.
The Brain Fog Problem
Of the symptoms considered, brain fog proved the hardest to measure—and potentially the most important. “What’s actually more disruptive [than EDS], and what the patient community tells us is much more debilitating, is the brain fog that results from never getting adequate, deep, restorative, non-REM sleep,” Trzupek says.
But existing tools weren’t built for this population. Many were developed for other conditions, such as COVID-19. But Trzupek says the pattern of brain fog in hypersomnolence looks different. “In disorders of hypersomnolence, the brain fog that happens is episodic,” she says. “It doesn’t just come big and bad and go away in a few days or even a few months.”
A treatment that reduces brain fog episodes from multiple times a day to a few times a week would represent a meaningful improvement, Trzupek says, but current measures are not designed to capture that change. “They just want to know how severe is your brain fog when you have it,” Trzupek says.
The working group selected the PROMIS Cognitive Function 8a as the best available option for adults, but identified brain fog as a major gap in measurement.
Work to address that gap is already underway. Global Genes is conducting patient focus groups and collecting data on how often brain fog occurs and how long episodes last. A newer measure developed after the working group concluded is also being evaluated.
“Our intent is actually to create a new measure because, as part of this work, that came out as a really big need,” Trzupek says. She estimates the process—from patient input through validation—will take about two years before a tool is ready for use in clinical trials and research.
Building a Patient-Owned Research Database
The consensus measures are already being implemented on the DREAMS Portal, a community-led, patient-owned online research study operated by Sleep Consortium and Global Genes on the RARE-X research platform.
Participants—patients or caregivers—create an account, provide information about their diagnosis and symptom history, and complete the validated surveys selected by the working group. They can also upload clinical data such as polysomnogram and MSLT reports, which a curation team converts into discrete, research-ready data points.
The platform is designed as an open, patient-driven research model. Participants choose how their data can be used, and the dataset will be made available to researchers and therapy developers working in hypersomnolence.
For rare disease research, this model addresses a barrier, says Trzupek. Data from narcolepsy and idiopathic hypersomnia studies have historically been siloed at individual academic centers or within pharmaceutical company registries, she says.
“It’s very, very difficult to get new, emerging biopharma companies interested in your disease if they can’t get access to any data,” Trzupek says. “We’re creating that data set.”
As of April 2026, approximately 200 participants have enrolled in the DREAMS Portal. The team’s goal is to add another 100 this year. The platform is open to anyone affected by central disorders of hypersomnolence.
“If any clinicians are interested in giving their patients something more that they can do—a lot of patients and parents want something to do, something that might contribute to a better treatment in the future—it’s an all-comers platform,” Trzupek says.
What This Means for Clinical Trials
Drug developers have often relied on objective sleep metrics in trials because they haven’t had a way to measure other symptoms, Trzupek says.
“We’ve been told by multiple biopharma companies that they’ve known that brain fog was a really big issue for a while, but they didn’t have a good way of measuring it. And so they just tend to measure the absolute sleep numbers from sleep studies instead,” she says.
She hopes the consensus measures, and a forthcoming brain fog measure, will give researchers tools to evaluate symptoms patients say matter most and to use that data as endpoints in clinical trials.
“We need to provide them the tools to say, ‘We have this. The patient community says that this is very reflective of their experience.’ And this is what you need to show improvement on when you’re in front of the FDA to say, ‘Look, our drug really does make a difference,’” she says.
She adds, “That’s the number-one outcome that we want … because why approve drugs that aren’t helping the symptoms that are most impactful to the people who experience these?”
For investigator-led studies, she says these measures can be used immediately. “If I were a clinical researcher designing a study in my clinic … this is available for them today,” she says. “There’s no reason for them to not do it right away.”
What Comes Next
In addition to ongoing work on a hypersomnolence-specific brain fog measure, the group identified a shortage of validated pediatric measures as a key next step.
“Our hope is that maybe some of the groups that have already done the work of developing these measures in adults might extend their work to validate a version of that measure that is useful for a pediatric population,” Trzupek says.
More broadly, Trzupek says the recommendations are meant to shape how hypersomnolence research is conducted—not just in clinical trials, but in the studies that lead into them. “If we all agree that we should measure what matters to patients in clinical trials, then we also need to have it for the research that’s leading into clinical trials,” she says.
In parallel, Global Genes and Sleep Consortium are focused on building a larger, shared dataset through its patient-led RARE-X research platform. That data, Trzupek says, is intended to support a wide range of future research efforts.
“We’ve created this database, and we don’t have to have all of the hypotheses,” she says. “You can have a hypothesis, and you can come and can use the data, and it will help to fuel your research efforts.”
Reference
- Trzupek K, Wylds-Wright C, Kuan C, et al. Patient-reported outcome measures in central disorders of hypersomnolence: consensus of a sleep consortium/RARE-X expert working group. Sleep Adv. 2026 Feb 13;7(1):zpag021.
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