Effect of subcutaneous lidocaine–hydroxypropyl-β-cyclodextrin (HP-β-CD) on quality of life in patients with post-COVID condition…, 2025, Oostwouder+

[Chandelier]

Effect of subcutaneous lidocaine–hydroxypropyl-β-cyclodextrin (HP-β-CD) on quality of life in patients with post-COVID condition: a 36-week observational interrupted time series study

Spoiler: Authors

Oostwouder, Cees-Jan; Vos, Karin; Lutke Schipholt, Ivo J.; Merkus, Mathijs R.; Telders, Thomas; van Deursen, David F.A.; de Smit, Max B.; van Eijk, Marina D.; Bontkes, Hetty J.; Bouwman, Femke H.; Wüst, Rob C.I.; de Jong, Lara; van Hulst, Marinus; Twisk, Jos W.R.; van Kalken, Coenraad K.; Scholten-Peeters, Gwendolyne G.M.

Summary​

Background​

Post-COVID involves persistent, multisystem symptoms which are associated with inflammation, immune dysregulation, and autonomic dysfunction.
The effects of currently applied treatments for post-COVID are limited.
This study assessed the effectiveness of subcutaneous lidocaine–hydroxypropyl-β-cyclodextrin (HP-β-CD) for the treatment of post-COVID.

Methods​

This interrupted time series study was conducted at a Dutch outpatient clinic between August 2024 and April 2025.
Adults with physician-diagnosed post–COVID (n = 103) underwent a 4-week pre-treatment observation followed by 24–36 weeks of home-based subcutaneous lidocaine 5% with HP-β-CD, administered using a 3-phase protocol: 500 mg every other day (weeks 1–7), 500 mg daily (weeks 7–14), and up to 1000 mg/day (after week 14, in non-responders).
The primary outcome was health-related quality of life (Short Form-12 (SF-12), physical and mental component summary scores).
Secondary outcomes included symptom burden (daily app-based questionnaire) and adverse events.

Findings​

Among 103 participants (mean [SD] age 48·1 [13·0] years; 67% women; median [IQR] symptom duration 31·5 [24·3–43·3] months), 76% completed 24 weeks and 71% completed 36 weeks of treatment.
At week 24, the physical and mental component scores increased by 2·20 and 5·16 points, respectively; at week 36, by 4·13 and 7·00 points (all p < 0·0001).
Twenty-seven of 30 symptoms improved significantly at week 24 of treatment compared to pre-treatment.
Mild adverse events occurred in 89% of participants, mostly injection–site reactions; no serious adverse events were reported.

Interpretation​

Subcutaneous lidocaine–HP-β-CD was associated with significantly improved quality of life and symptom burden in patients with post–COVID.
This home-administered intervention offers a scalable and potentially disease-modifying approach for a disabling condition with no approved treatment to date.

Funding​

Excellent Care Clinics funded the treatment provided in this study.

Web | DOI | eClinicalMedicine

 

[forestglip]

Subjective outcomes and no placebo.

76% completed 24 weeks and 71% completed 36 weeks of treatment.

From methods:

All patients, including the dropouts, were used in the analysis (n = 103) at weeks 24 and 36.

Does that mean they incorporated scores for everyone up to the endpoint into the statistics? Not clear to me because this from the discussion says the dropouts may have biased the analysis:

Furthermore, demographic and clinical characteristics of those who withdrew were comparable to the overall cohort, suggesting no major attrition bias. The withdrawal rate aligns with expectations in a real-world post-COVID population. However, participant withdrawals may suggest that some data were missing not at random (MNAR). While the linear mixed model performs well under the assumption that data are missing at random (MAR), violations of this assumption may have biased the estimated values.

Speculation on why it would work:

Preclinical studies have demonstrated that lidocaine inhibits P2X7 receptor–mediated immune activity, leading to reduced NLRP3 inflammasome activation and subsequent cytokine release (e.g., IL-1β and IL-18).18,19 This pathway is hypothesised to play a role in post-COVID immune dysregulation.

subcutaneous administration may enhance lymphatic targeting and drug concentrations at immune effector sites, as suggested by preclinical studies showing selective lymph node accumulation after subcutaneous delivery.22

On why they think these don't resemble placebo effects:

However, several observations suggest that the improvements seen in this study reflect a true treatment effect rather than a placebo response or the natural course of the condition.

First, the delayed onset of symptom improvement-emerging around day five and increasing progressively over 24 and 36 weeks-differs markedly from typical placebo responses, which often occur rapidly within hours or days.31,32 Seventy-eight percent of participants demonstrated sustained improvements, exceeding the typical 25–35% placebo response rate.31,32

Additionally, the study design incorporated an extended pre-treatment observation period, allowing for the establishment of stable baseline symptom trajectories. This approach aligns with the absence of spontaneous improvement or recovery typically seen in post-COVID patients beyond 12 months, further reinforcing the internal validity of the findings.33 Natural recovery seems unlikely given the highly chronic and functionally impaired nature of our participants (median symptom duration 31·5 [24·3–43·3] months), and recent studies showing minimal natural recovery beyond 12 months in severely affected post-COVID patients.32

Primary outcomes:

Health-related quality of life (HRQoL) was assessed biweekly over 24 and 36 weeks using the Dutch version of the Short Form-12 (SF-12) survey via the mobile app, providing physical (PCS) and mental (MCS) component summary scores.25

Secondary outcomes were individual symptoms. The ones furthest to the left had the largest improvements: