But says the current network of research & clinical trial funding is very hopeful Stephanie Stancil from Children's Mercy Kansas:

Notes no serious adverse events (the very severe LC & ME communities might have something to say about this - imo the problem of extreme medication intolerances has not been addressed & could risk trial efficacy or self-select out such patients)

Notes that fatigue has been chosen as the primary target from the NIH..... God, WHEN will we finally move to FUNCAP instead of vague, awful fatigue scales...........

Notes on intermittent vs constant blockade of opioid receptors: Large doses cause constant blockade, but blockade timing of lower doses unknown

"We haven't linked biological mechanisms of fatigue with naltrexone, but that shouldn't deter us moving forward - eg aspirin was originally used for pain but was later found to have profound blood thinning effects"

Kay Tomashek from NIAID has decided that her slide on how LDN is safe & tolerable, & published studies showing improvements in pain, malaise, cognitive performance, etc (from Bonilla & others) is "Confidential & pre-decisional" and can't be shared with the patient community

Same on her point that pediatricians don't like to prescribe LDN bc of lack of data in kids & availability only in compounding pharmacies

LDN working group has included a pharmacist, 2 parents of teen patients, 4 clinician-researchers - 2x/week meetings since June (20 meetings) with guest researchers & experts invited Working on finalizing a protocol synopsis

Studying LDN in 6-25yos, using PedsQL Multidimensional fatigue scale Chronic liver disease & severe kidney failure patients are a major exclusion 1.3 mg to 3.0 mg titration, 1300 participants, separating into early childhood, teen, & young adult cohorts

16 weeks Ongoing work to find their own manufacturer & deciding on a formulation to maximize quality, minimize variability, & sensitive drugs - hoping this can also develop a regulatory-grade LDN product that can be used in future trials & also clinically

Their PedsQL Multidimensional fatigue scale looks at a few different areas of fatigue with a likert scale & has been recommended by a delphi consensus Secondary endpoints: PedsQL QoL inventory Functional Disability Inventory score PROMIS pain

Measures of neurocognitive functioning (?) Wearables like step counts Blood draws for biomarkers 100 study sites, evaluation at 4 & 6 months Study group still looking at biomarkers, data collection, statistical analysis plan, schedule of events

Dr Hitan Naik from Vancouver Coastal Health on the British Columbia LDN study - still in progress, no results yet, but will review protocol & progress He is allowing us to view the citations of published data on LDN that the NIAID decided was confidential:

They're targeting LC-induced ME/CFS, which they characterize as "Post-COVID Fatigue Syndrome (PCFS)" - seems problematic

Overview of protocol & eligibility criteria:

Their definition of PCFS: Basically IOM criteria except that it occurs after a covid infection, & lasts 3 months min, not 6 (to be consistent with most LC criteria)

Titration schedule which patients will do themselves:

Secondary & exploratory outcomes - still no FUNCAP but a functional status scale(?)

Biomarkers they're looking at: some basic cytokines like IL-6, ACTH, cortisol, possibly others I didn't catch Clinical outcomes Plus an MRI sub-study to look at neurological effects

Patients will be evaluated repeatedly up to 16 weeks Trial timeline, & funding (incl funding from ME Association; bottom 4 are salary support):

Discussion: Megan Carmilani from Long Covid Families: "Symptoms are bigger in smaller bodies" -- the symptoms hit harder on the kids, plus affect the families (sleep, work, etc), plus affect their families Thus kids more likely to drop out of trials bc affect parents & siblings

Parents will be torn about taking their kids to trials - do they have parking, do they have strollers, how many kids are they bringing, will they be there during nap or meal time, do they have someone to watch their kids or take them to their activities, single parents

So the mental load is REALLY high, and then you have to fill out surveys on top of that! Anything logistical that trials can handle for parents (including providing strollers or wheelchairs, entertainment for kids, etc) removes impediments

Fatigue is experienced v differently between ages - esp with young kids, parents might experience them differently! She notes an issue with these scales (my point - that's why we REALLY need concrete benchmarks like the FUNCAP provides, not more vague likert scales!!)

Life outcomes matter more than labs - can they go to school? This isn't just about QoL but about development Priority is to keep the kids in school which they already struggle with - parents will prioritize school over trials - so please, night & weekend appointments

Safety concerns How do parents know it's helping - what are they looking for? Parents are observers - is this a side effect or is this LC or what? What happens if it gets worse? When will we know, when do we know when to stop? Families need to be walked through his all first

Trials WILL disrupt the entire family's life & routine - need to understand this LDN - there is a stigma from association with drug use - really need to talk about this Stigma from families AND other medical providers! (Notes she takes LDN herself & it's great for her)

Meet families where they're at - help with meals & childcare PLEASE keep communication honest, don't soften bad news Measure what matters for families - pain, sleep, mood, school attendance Offer medical notes, bc attendance is a LEGAL issue Flexible scheduling

Gas & lost wages are an impediment - families already financially stressed (families often spend upwards of $70k/year in research!) Access & equity - look beyond big hospitals

My note - these were all really fantastic points, altho I wish she'd named something like FUNCAP by name - although I think it could maybe be improved with specific questions for pediatric patients?

Sleep neuroscientist with 30yrs of ME/CFS in the audience - asks about sleep studies & microbiome impacts Tomashek: PedsQL-MFS has specific questions on sleep & rest

Stancil: Naltrexone more peripherally selective on gut than brain, but primary active metabolite may have gut effect? Question asker: Interesting thing to look at bc of association of ME with lack of bifidobacterium

Phil, online: Can you look at psychiatric symptoms here? Tomashek: We've discussed the need for it, not decided if will do that yet Missed final question, which Naik answered re: compounding pharmacies not really compounding for kids Session over, Baricitinib discussion in 10

Dr Laurie Ryan - Chief of Diagnostics & (?) branch at NIA (national institute on aging) - oversees Alzheimers clinical interventions & pharmacological programs (Is this the same part of the NIH that has botched Alzheimer's research for 20 years and then covered it up?)

She's not talking now I guess... On to Michael Peluso from UCSF at the podium on ADRD's (Alzheimer's Disease & related Dementias) - hope these are reversible at least in LC with the right treatments

Simplified summary on baricitinib, identified baricitinib as one of the most promising drugs for study in acute covid all the way back in 2020 (now approved for acute hospitalized covid)

A very commonly presented schematic by now:

A schematic I haven't seen before - how immunomodulators like JAK inhibitors might function to intervene in LC biology:

Current sites & PIs - 11 more planned:

Patient consultants; they also worked with PLRC to meet the "excellent" score on their Patient scorecard (which is a fantastic tool! Available on their website)

Their primary battery of tests takes 30-45 minutes to complete & don't seem to cause negative effects afterward They're trying to stem effects of PEM from CPETS (how?) Hoping to do a deep dive on exploratory objectives

Subset will do more intense procedures (lumbar punctures, MRIs) - uptake of these intensive procedures is very high! (Which Peluso has noted previously for other studies I think - LC patients are very eager to help research move forward)

Key eligibility criteria - they're screening in patients by cognitive impairment: Hoping to include non-LC/pre-LC IACC cohorts in future studies & urge others to do so (budgetary constraints here, previously mentioned by Wes Ely I believe)

Timeline of assessments:

Charles M. Vallee biospecimen repository housed at memory, in memory of a young man who died of LC Abbot Labs & NIH funding biospecimen analyses (Missed the downstream analyses slides, sorry)

More info at http://reverselongcovid.com Remaining sites launch by 2026 Enrollement completed by 2027 Topline results by 2028 Notes partnership between NIA & NIAID is "quite special" (not sure what this means)

Panel starting with Peluso, Laurie Ryan, Hannah Davis from PLRC, & Vince Marconi from Emory (works on HIV & other virus-host interactions I think?)

Hannah: best patient engagement experience with any trial yet; very gracefully took feedback & improved; Most trials involve patients in a tokenizing fashion but patient experience esp in LC has a lot to offer - hoping RECOVER adopts this model for its other three trials

Moderator Tracy Nolen, Research Triangle Institute International, asks about balancing high-touch nature of trial assessments with need for decentralized trial & accessibility (brought up by Michael Sieverts)

Marconi: sometimes have to make trade-offs, and hopefully high-touch studies can help identify endotypes & key groups to better inform low-touch studies (Not really sure how much this will really generalize well to patients too severe to do this kind of testing)

Patient: how are you assessing functional status esp for patients too severe to do CPETs? Peluso: Don't know questionnaire's off the top of my head, will share later Notes that generalizability to very severe patients is a potential limitation; defers to Davis

Hannah: This limitation will exist with all trials, so we need to include cohorts across the whole spectrum of severity (possibly in separate trials?) Notes this is one of her worries for the field generally (& affects moderate patients too)

Notes that we need trials looking at both cohorts, but severe is esp important for understanding PEM bc they haven't been studied as much

John CMO at Renegade Research - didn't catch question Peluso: We'll have very granular data on concommitant meds; this is an issue we've come up against a lot; randomization will help with this hopefully esp if meds are in common use; study includes weekly or more health tracker

partly to monitor AEs in real-time that patients might not readily offer, but can also help with concomitant medications (supplements, vaccines, meds, NPIs, etc) - this will generate a lot of data - but hope patients won't make huge changes during the study

Hector Bonilla: cardiovascular risk factors excluded? Marconi: Yes (bc of black label warnings on those from JAK/STAT inhibitors) Peluso: big cardiology team/involvement on this study - we've thought carefully through them

NIH scientist (didn't catch): This is a really exciting study, but if it's a big win, journals will be fighting over it - but how will we prioritize helping patients? Peluso: Eli Lilly is most important partnership - value of engaged pharma partner can't be overstated!

Key reason why this drug is being trialed - They've been engaged since day one This is not an experimental drug, just an experimental indication We need a longer-term plan (Meighan Stone is coming up with a 5-10yr roadmap plan)

Mady Hornig: Love the patient-scientific; engagement on this study. Q on eligibility criteria - she works in ADHD - lots of pediatric & adult onset reports - is framing of neurocognitive deficit as only ADRDs sufficient? We don't fully understand neurocog deficit pathophysiology

This may impede moving into pediatric populations on this topic as well Peluso: we've thought about this but don't have many answers; have 12 different domain scores on the neurocognitive testing we're excited to dive into altho primary endpoint will be based on global score

Mady Hornig: Consider collecting stool samples too Peluso: got pilot funding from Vallee family to support stool collection David Kaufman: Do you plan to evaluate for connective tissue disorders?

Peluso: At UCSF we can record this as a pre-existing condition, not sure if recorded systematically, can get back to you Marconi: Are including all medical diagnoses - we're not diagnosing within these trials but if their chart includes it or they mention it we record it

Melissa Stockwell - pediatric RECOVER PI - Can you include adolescents (altho authorizations are different in that age) - seems important mechanistically? & there's a fair amount of safety data? At least consider in the future?

Peluso - This trial was planned couple years ago, pre-pediatric data reporting (last few months published data on alopecia & acute covid) Marconi - The data exists now but we wanted to make sure it exists Patient - What if patients improve on secondary endpoints (I think?)?

Peluso: Patients can sometimes report neurocognitive deficits but doesn't show up on testing; we didn't exclude these types from the trial. We checked to make sure we can capture minimal clinically important difference. Other neurocognitive testing was too difficult to access