Trial Report A synbiotic preparation (SIM01) for post-acute COVID-19 syndrome in Hong Kong (RECOVERY): a randomised, double-blind, placebo-controlled tria Lau 2023

Summary
Background
Post-acute COVID-19 syndrome (PACS) affects over 65 million individuals worldwide but treatment options are scarce. We aimed to assess a synbiotic preparation (SIM01) for the alleviation of PACS symptoms.
Methods
In this randomised, double-blind, placebo-controlled trial at a tertiary referral centre in Hong Kong, patients with PACS according to the US Centers for Disease Control and Prevention criteria were randomly assigned (1:1) by random permuted blocks to receive SIM01 (10 billion colony-forming units in sachets twice daily) or placebo orally for 6 months. Inclusion criterion was the presence of at least one of 14 PACS symptoms for 4 weeks or more after confirmed SARS-CoV-2 infection, including fatigue, memory loss, difficulty in concentration, insomnia, mood disturbance, hair loss, shortness of breath, coughing, inability to exercise, chest pain, muscle pain, joint pain, gastrointestinal upset, or general unwellness. Individuals were excluded if they were immunocompromised, were pregnant or breastfeeding, were unable to receive oral fluids, or if they had received gastrointestinal surgery in the 30 days before randomisation. Participants, care providers, and investigators were masked to group assignment. The primary outcome was alleviation of PACS symptoms by 6 months, assessed by an interviewer-administered 14-item questionnaire in the intention-to-treat population. Forward stepwise multivariable logistical regression was performed to identify predictors of symptom alleviation. The trial is registered with ClinicalTrials.gov, NCT04950803.
Findings
Between June 25, 2021, and Aug 12, 2022, 463 patients were randomly assigned to receive SIM01 (n=232) or placebo (n=231). At 6 months, significantly higher proportions of the SIM01 group had alleviation of fatigue (OR 2·273, 95% CI 1·520–3·397, p=0·0001), memory loss (1·967, 1·271–3·044, p=0·0024), difficulty in concentration (2·644, 1·687–4·143, p<0·0001), gastrointestinal upset (1·995, 1·304–3·051, p=0·0014), and general unwellness (2·360, 1·428–3·900, p=0·0008) compared with the placebo group. Adverse event rates were similar between groups during treatment (SIM01 22 [10%] of 232 vs placebo 25 [11%] of 231; p=0·63). Treatment with SIM01, infection with omicron variants, vaccination before COVID-19, and mild acute COVID-19, were predictors of symptom alleviation (p<0·0036).
Interpretation
Treatment with SIM01 alleviates multiple symptoms of PACS. Our findings have implications on the management of PACS through gut microbiome modulation. Further studies are warranted to explore the beneficial effects of SIM01 in other chronic or post-infection conditions.

https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(23)00685-0/fulltext

 

https://twitter.com/user/status/1732931693605277971


This is the first successful randomized, placebo-controlled, double-blind trial with an adequate sample size (N=463 participants) for #LongCovid

 

SIM01 consisted of 20 billion colony-forming units of three bacterial strains (ie, B adolescentis, B bifidum, and B longum) with three prebiotic compounds (ie, galacto-oligosaccharides, xylo-oligosaccharides, and resistant dextrin), administered as 10 billion colony-forming units in sachets twice daily.

 

https://twitter.com/user/status/1732964610280439931


Unfortunately, those who got the treatment and those who did not are indistinguishable at six month mark so probiotics may be helping generally in the short term, but no specific LC impact. Maybe because the cohort isn’t very sick ? More mundane sequelae?

 

I think Zeynep's got the wrong end of the stick there. It's true that the treatment didn't seem to eliminate any symptoms, but it seems fairly convincing that it improved fatigue with 63% versus 43% reporting improvement (answering yes to 4 of 5 questions about improvement). Similar results for some other symptoms.

It would be interesting to see if this is a results specific to LC or you would see a similar result in a random population. That would be pretty interesting too!

 

Fairly detailed summary article:
https://www.cidrap.umn.edu/covid-19...ut-microbiome-shows-promise-long-covid-relief

 

Thanks for highlighting this. If I understand correctly the main results highlight the percentage of participants that had an alleviation for each of the 14 PASC symptoms while the supplementary table Zeynep highlights simply gives the number of participants that still reports each of the 14 measured symptoms.

I agree that the former is more informative than the latter but still unfortunate that we don't have any indication of the severity of symptoms and the size of the alleviation.

 

Yes, Zeynep and I had some back and forth on Twitter and she pointed out that they did say they asked the patients if they were mild, moderate or severe for each symptom. That they didn't report any results from that data suggests there weren't any, i.e. no significant change in severity. So this is looking worse than I thought.

I could see the possibility that this is also causing just a mild elevation in mood that results in patients saying various symptoms are better than they were six months ago. Might not have anything to do with LC specifically. Definitely needs a better study.

 

I think most people have gotten this study completely wrong. The primary endpoint on this study was changed according to the pre-registration page. Two of the authors are co-founders of GenieBiome, which makes SIM01.

More notes here:
https://forum.sickandabandoned.com/...long-covid-paper-on-the-sim01-synbiotic/370/2