Experimental drugs in randomized controlled trials for long-COVID: what’s in the pipeline? A systematic and critical review

ABSTRACT

Introduction

Over three years have passed since the emergence of coronavirus disease 2019 (COVID-19), and yet the treatment for long-COVID, a post-COVID-19 syndrome, remains long overdue. Currently, there is no standardized treatment available for long-COVID, primarily due to the lack of funding for post-acute infection syndromes (PAIS). Nevertheless, the past few years have seen a renewed interest in long-COVID research, with billions of dollars allocated for this purpose. As a result, multiple randomized controlled trials (RCTs) have been funded in the quest to find an effective treatment for long-COVID.

Areas covered

This systematic review identified and evaluated the potential of current drug treatments for long-COVID, examining both completed and ongoing RCTs.

Expert opinion

We identified four completed and 22 ongoing RCTs, investigating 22 unique drugs. However, most drugs were deemed to not have high potential for treating long-COVID, according to three pre-specified domains, a testament to the ordeal of treating long-COVID. Given that long-COVID is highly multifaceted with several proposed subtypes, treatments likely need to be tailored accordingly. Currently, rintatolimod appears to have modest to high potential for treating the myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) subtype, LTY-100 and Treamid for pulmonary fibrosis subtype, and metformin for general long-COVID prevention.

KEYWORDS:

• Long-COVID
• drug
• randomized clinical trial
• treatment
• post-COVID-19 syndrome

Article highlights

• Presently, no standard treatment exists for long-COVID, a post-coronavirus disease 2019 (COVID-19) syndrome, characterized by symptoms such as fatigue and brain fog lasting for 3 months or more after acute COVID-19.

• Owing to increased funding, increasing numbers of randomized controlled trials (RCTs) on drug treatments for long-COVID are being conducted. We systematically and critically reviewed these RCTs to pinpoint drugs with high potential for treating long-COVID.

• Of the four completed RCTs identified, three examined long-COVID prevention, of which only metformin was deemed to exhibit high potential in preventing long-COVID when administered during acute COVID-19. Only one RCT investigated the potential efficacy of a drug (Treamid) in treating ongoing long-COVID, showing low to modest potential due to its inefficacy in improving the more meaningful outcomes of long-COVID.

• Of the 22 ongoing RCTs identified, only rintatolimod and LYT-100 (deupirfenidone) were judged as possessing modest to high potential for treating long-COVID.

• The fact that nearly all of the drug candidates did not seem to exhibit high potential in treating long-COVID is a testament to the ordeal of treating long-COVID.

• Given that long-COVID is a multifaceted condition with multiple proposed subtypes, its treatment may need to be tailored to specific subtypes.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

SJY conceptualized the research idea and wrote the manuscript. SJY, AH, and MH screened studies retrieved from databases to select eligible studies and rated the quality of studies included in the systematic review. LCM, KWG, and AAR critically revised and edited the manuscript. MA, BMA, MAAF, MA, TS, ZA, ASSA, FK, NAA, HA, AA, MG, JA, AHA, MA, KD, LMA, AHA, and ATA contributed to the literature review, study interpretations, and manuscript revisions. All authors approved the manuscript for publication.

Additional information

Funding

This study is supported via funding from Prince Sattam bin Abdulaziz University project number [PSAU/2023/R/1444].