REGENECYTE cord blood cell therapy in post-COVID syndrome: a phase IIa randomized, placebo-controlled trial

Summary

Background

Post-COVID syndrome affects a substantial proportion of individuals worldwide and imposes significant healthcare and economic burdens. Fatigue is one of the most common and debilitating symptoms in those with severe symptoms related to post-COVID fatigue syndrome, yet there remains a lack of targeted therapies, effective or approved treatments to address it. This study aimed to evaluate the safety, tolerability, and efficacy of repeated doses of REGENECYTE, an allogeneic hematopoietic progenitor cell (HPC) therapy derived from cord blood, in patients with post-COVID syndrome.

Methods

In this randomized, single-blind, placebo-controlled, phase IIa trial, we evaluated repeated intravenous infusions of REGENECYTE from different donors (without HLA matching) in patients with post-COVID syndrome in the USA. Eligible adults aged 18–65 years had persistent post-COVID symptoms between 6 and 18 months and tested negative for SARS-CoV-2 within 7 days before enrollment. Participants were randomized into a 2:1 ratio to receive either REGENECYTE or placebo. Three infusions were administered over 6 weeks, 3 weeks apart, followed by a 20-week follow-up. Each dose of REGENECYTE contains at least 1 × 10⁷ total nucleated cells (TNC)/kg, with a cumulative dose of at least 3 × 10⁷ TNC/kg per patient. The primary endpoint was safety, assessed using the Common Terminology Criteria for Adverse Events by National Cancer Institute (NCI CTCAE) v5.0. The key secondary endpoint focused on changes in fatigue using the Chalder Fatigue Questionnaire (CFQ-11), while exploratory endpoints evaluated frailty, quality of life, and cognition using validated instruments. This trial was registered with ClinicalTrials.gov, NCT05682560.

Findings

Between May 4 and Dec 26, 2023, 30 eligible patients were enrolled and completed the study. The mean age was 41.9 years; 70% were female. The average duration of post-COVID symptoms was 306 days. Only 2 patients (10%) in the REGENECYTE group experienced mild treatment-emergent adverse events (TEAEs), indicating good tolerability. Notably, REGENECYTE significantly and sustainably improved fatigue symptoms, as measured by CFQ-11 Bimodal and Likert scores, compared to placebo (p < 0.01). Improvements were observed as early as week 6 and persisted through the 20-week follow-up. The most pronounced benefit was seen in the physical fatigue domain. REGENECYTE also improved quality of life in domains such as usual activities and mental wellbeing. There were no significant changes in frailty or cognitive scores.

Interpretation

REGENECYTE was well tolerated and safe when administered as repeat infusions from unmatched cord blood donors. It produced a meaningful and durable reduction in fatigue symptoms, the most burdensome feature of post-COVID syndrome—highlighting its potential as a novel therapeutic strategy. These findings support further clinical development of cord blood-based therapies targeting fatigue in post-COVID and potentially other fatigue-related conditions.

Funding

StemCyte International, Ltd.

Research in context.

Evidence before this study

Post-COVID syndrome continues to impact a substantial number of individuals worldwide and imposes a considerable economic burden. Although COVID-19 vaccines and antiviral agents have mitigated the acute impact of the disease, there remains no effective, approved treatment for post-COVID syndrome. We searched PubMed on Aug 29, 2025, using the terms “Long COVID” OR “Post-COVID”, AND “clinical trial”, AND “cord blood” OR “cord blood cells”. This search yielded three early-phase clinical trials and one additional study evaluating umbilical cord-derived mesenchymal stem cells in acute COVID-19 and post-COVID syndrome settings, respectively, but no studies involving cord blood-derived therapies for post-COVID syndrome. A recent clinical trial of Paxlovid (nirmatrelvir–ritonavir) in post-COVID patients failed to demonstrate symptomatic benefit. Another phase II study of AXA1125, a mitochondrial modulator, showed short-term fatigue score improvements withing 4 weeks, but did not meet its primary endpoint and lacked sustained functional benefits. Given the absence of effective therapies, and the heterogeneity and complexity of post-COVID pathophysiology, novel approaches that are both safe and capable of addressing the most burdensome symptoms—particularly fatigue—are urgently needed. REGENECYTE, a cord blood-derived hematopoietic progenitor cell therapy, contains CD34⁺ and CD133⁺ cells and monocytes that may support immune modulation and tissue repair. This study evaluated the safety and efficacy of REGENECYTE in patients with post-COVID syndrome, with a primary focus on functional outcomes including fatigue, frailty, cognition, and quality of life.

Added value of this study

To our knowledge, this is the first placebo-controlled phase IIa clinical trial investigating repeated infusions of allogeneic cord blood-derived hematopoietic progenitor cells in post-COVID syndrome. Despite the small sample size, our study demonstrated that REGENECYTE was safe and well-tolerated when administered without HLA matching. Importantly, REGENECYTE treatment led to clinically meaningful and statistically significant improvements in fatigue symptoms—particularly physical fatigue—as measured by the CFQ-11, which persisted throughout the 20-week follow-up. Improvements were also observed in patient-reported outcomes related to usual activities, pain, and mental wellbeing. No significant differences between-group differences were seen in frailty or cognition, although baseline MoCA (Montreal cognitive assessment) scores were close to the normal range and cognitive impairment was not a primary study objective. These findings suggest a specific benefit of REGENECYTE on the symptom domain of fatigue—arguably the most debilitating and prevalent feature of post-COVID syndrome—and provide early-phase clinical support for its further evaluation.

Implications of all the available evidence

Cord blood has long been used in hematopoietic stem cell transplantation for hematologic diseases. The current study expands the scope of cord blood-based therapy by demonstrating its potential to address persistent fatigue in post-COVID syndrome, a condition for which no approved treatments currently exist. The observed improvements in fatigue and quality of life following REGENECYTE treatment—along with the favorable safety profile—highlight its promise as a regenerative approach targeting symptom relief rather than disease classification. These findings may have implications not only for post-COVID care, but also for other fatigue-dominant or age-related syndromes such as chronic fatigue syndrome, fibromyalgia, sarcopenia, and post-viral syndromes. While larger confirmatory trials are needed, this study provides an important proof-of-concept for the use of cord blood cell therapies beyond conventional transplant indications.

Introduction

The outbreak of Coronavirus Disease 2019 (COVID-19), caused by SARS-CoV-2, triggered a global health crisis, with more than 779 million confirmed cases and millions of deaths globally.¹ While most individuals recover within weeks, approximately 10–20% experience persistent symptoms lasting months or longer—a condition referred to as long COVID or post-COVID syndrome.2, 3, 4 The World Health Organization defines post-COVID as symptoms that develop within three months of infection, persist for at least two months, and cannot be explained by an alternative diagnosis.³ In the United States, approximately 14% of adults report post-COVID symptoms, with disproportionate impacts on women, socioeconomically disadvantaged populations, and individuals with underlying health conditions.⁵

Post-COVID syndrome not only affects individuals but also poses a growing public health concern due to its profound socioeconomic and long-term health consequences. Studies estimate that individuals with post-COVID symptoms are more likely to experience functional impairment, reduced work capacity, and increased healthcare utilization over prolonged periods.6, 7, 8 This has translated into substantial productivity loss, increased disability claims, and strain on national healthcare systems, especially in countries with aging populations and limited rehabilitation infrastructure. In both the U.S. and Europe, higher rates of sick leave, job turnover, and early retirement have been reported among post-COVID patients,^9,10 with fatigue being the leading contributor.¹¹ The impact extends beyond economic cost; the chronic nature of post-COVID also leads to cumulative mental health burdens, greater need for informal caregiving, and widening health disparities. Modeling studies suggest that even modest reductions in post-COVID prevalence could yield significant public health savings.12, 13, 14

Despite the widespread availability of vaccines and antiviral agents, no therapies have been approved specifically for the treatment of post-COVID, and standard care is limited to symptomatic relief.^15,16 Notably, the Selective Trial Of Paxlovid for post-acute sequelae of SARS-CoV-2 (STOP-PASC) trial evaluating Paxlovid (nirmatrelvir–ritonavir) showed no significant improvement in post-COVID patients.¹⁷ Although several large-scale studies such as the NIH-sponsored Researching COVID to Enhance Recovery (RECOVER) initiative are underway, the absence of effective treatments continues to leave a substantial unmet clinical need.¹⁸

Fatigue is the most common and debilitating symptom of post-COVID syndrome, affecting over half of patients.^11,19 It is frequently associated with impaired concentration, mood disorders, and reduced quality of life, contributing to increased healthcare utilization and economic loss.²⁰ Emerging studies have implicated mitochondrial dysfunction, oxidative stress, and chronic inflammation as possible mechanisms underlying fatigue in post-COVID.^11,19, 20, 21 Although nutraceuticals and metabolic modulators—such as AXA1125—have been explored, benefits have been modest and short-lived.^22,23

Given the immunologic, inflammatory and neurologic components of post-COVID, cellular therapies are increasingly being considered as a novel approach.24, 25, 26, 27, 28 Human umbilical cord blood (hUCB) is rich in hematopoietic progenitor cells, CD34⁺ stem cells, and immunomodulatory monocytes.²⁹ hUCB has been used for over three decades in hematologic diseases, offering advantages such as low immunogenicity and better tolerance of HLA mismatching.³⁰ Preclinical and early clinical data also support its potential to attenuate systemic inflammation and promote neuroregeneration.^31,32

To date, few studies have explored hUCB-based therapies in post-COVID treatment. A small trial using hUCB-derived mesenchymal stem cells demonstrated preliminary safety and possible improvement in sleep quality and mental health.³³ However, rigorous controlled clinical trials remain scarce. The investigational product evaluated in this study consists of cryopreserved cord blood-derived hematopoietic progenitor cells, monocytes, lymphocytes, and granulocytes administered intravenously. This formulation was developed by StemCyte and is currently referred to as REGENECYTE. Our prior studies have examined its regenerative potential in neurologic recovery in stroke models.³⁴

Given the urgent need for effective treatments targeting fatigue—the hallmark symptom of post-COVID syndrome—and the unique immunoregulatory and neurorestorative properties of hUCB, we conducted a randomized, placebo-controlled trial to evaluate the safety and efficacy of an investigational hUCB-derived cell therapy (REGENECYTE) in patients with post-COVID syndrome.

Methods

Study design and participants

This randomized, placebo-controlled, single-blind, phase II study enrolled 30 patients with post-COVID syndrome to evaluate the safety and efficacy of an investigational cell therapy REGENECYTE (HPC, Cord Blood) which is derived from human umbilical cord blood. REGENECYTE, manufactured by StemCyte, Inc., contains hematopoietic progenitor cells, monocytes, lymphocytes, and granulocytes derived from human cord blood. This study had been designed to adopt a 2:1 ratio driven by ethical and clinical considerations, aiming to maximize participant access to the investigational therapy while maintaining sufficient controlled data for comparative analysis. After providing informed consent, participants were randomized into a 2:1 ratio to receive three intravenous infusions of either REGENECYTE or normal saline (0.9% sodium chloride injection) as placebo. The randomization process for this trial was developed by the contracted CRO using a block randomization method to ensure balanced allocation across treatment groups. The investigator of this trial is responsible for patient enrollment without access to the random allocation sequence. All subjects wore a double-layered eye mask before and during infusion to ensure blinding.

Given that persistent fatigue and diminished quality of life are among the most debilitating symptoms reported by patients with post-COVID syndrome, this trial was specifically designed to evaluate the therapeutic potential of REGENECYTE in alleviating both physical and mental fatigue and in improving overall health-related quality of life.³⁵ These outcomes were assessed using validated, comprehensive patient-reported outcome measures administered throughout the study period.

Participants who were aged 18–65 years were screened to ensure eligibility criteria at a single site in the United States. As the first clinical trial to investigate the safety of unmatched cord blood cells for treating post-COVID syndrome, and with no clear age-related association established, individuals aged older than 65 years or below the legal adult age were excluded from enrollment to minimize potential confounding. Participants had experienced symptoms consistent with post-COVID syndrome lasting more than 6 months but not exceeding 18 months, with no alternative medical explanation and confirmed prior SARS-CoV-2 infection by rapid antigen or PCR test were included. The most recent date of SARS-CoV-2 infection and the onset date of post-COVID syndrome were confirmed by medical records or reported by participants (data not shown) and verified by investigators. To ensure no recurrent SARS-CoV-2 infection that might impact the efficacy evaluation, a negative SARS-CoV-2 test result was collected within 7 days prior to enrollment. Any reinfection of SARS-CoV-2 during the study was recorded. Key symptoms defining post-COVID syndrome included fatigue and cognitive impairment, were assessed using the Chalder Fatigue Questionnaire-11 (CFQ-11) and Montreal Cognitive Assessment (MoCA), respectively. Participants with CFQ-11 Bimodal score ≥4 and MoCA scores ≤28/30 at baseline were included. Additionally, participants had self-reported concerns regarding cognitive functioning or recent diagnosis of SARS-CoV-2 related cognitive impairment were included. At least three ABO/Rh-matched REGENECYTE must be available for each participant. Exclusion criteria included persistent fatigue prior to SARS-CoV-2 diagnosis, neurological disorders, known immune disorders, hospitalized in ICU within 1 year, pre-existing terminal illness, known hypersensitivity to dimethyl sulfoxide (DMSO) or Dextran-40, prior stem cell therapy, pregnancy or breastfeeding, recent vaccination (within 3 weeks), participation in other clinical trials (within 4 weeks), abnormal vital signs or lab values, and serious comorbidities such as advanced heart failure, kidney disease, ARDS, psychiatric disorders, or chronic pulmonary disease which were confirmed by study investigator and medical records.

All informed consent was obtained prior to enrollment and verified by the study investigators. The trial was approved by the Western Copernicus Group Institutional Review Board (WCG IRB, tracking number: 20230557) and registered with ClinicalTrials.gov, NCT05682560.

Procedures

Following screening of eligible post-COVID patients during weeks −4 to −1, participants received three intravenous infusions of REGENECYTE or normal saline (placebo group) at weeks 0, 3 and 6. Each REGENECYTE dose contained a minimum of 1.0 × 10⁷ TNC/kg. Blood type compatibility (ABO/Rh) was ensured between the patient and the assigned REGENECYTE product. To ensure the blinding procedure, all participants wore securely fitted eye masks during each infusion, and a study staff member was present on-site throughout the procedure. Participants were assessed for post-COVID symptoms during the screening period to establish baseline status. Validated questionnaires were used to evaluate treatment efficacy at prespecified study visits (see Outcomes section). Fatigue was primarily assessed using the CFQ-11, a validated instrument that measures both physical and mental fatigue using two scoring methods: a Bimodal scale (0–11), with ≥4 defining a fatigue case and a Likert scale (0–33), with higher scores indicating greater severity. The Patient Global Impression of Severity (PGI-S), a single-item instrument, allowed participants to self-rate the severity of their fatigue on a 7-point Likert-type scale ranging from “normal” to “extreme fatigue.” Frailty was measured using the FRAIL scale, which evaluates five components: fatigue, resistance, ambulation, illness, and weight loss. Total scores categorize participants as robust, pre-frail, or frail. Quality of life was assessed using the EuroQoL 5-Dimension 5-Level (EQ-5D-5L), covering five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, along with the EQ-VAS, a visual analogue scale from 0 to 100 indicating self-perceived health status. The U.S. version 1.1 was used in this study. Cognitive function was evaluated using the MoCA, a 30-point tool assessing seven cognitive domains. To minimize learning bias, alternate forms (Versions 8.1, 8.2, and 8.3) were administered at different time points.

Outcomes

The primary endpoint was the safety and tolerability of REGENECYTE, measured by the incidence and severity of treatment-emergent adverse events (TEAEs) from Day 1 through study completion, as graded by the Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0, and coded using MedDRA®. Secondary endpoints included efficacy of REGENECYTE in reducing fatigue, assessed by changes in CFQ-11 scores at weeks 6, 12, 18, and 26 relative to baseline. Exploratory endpoints included changes in fatigue severity using the PGI-S, frailty using the FRAIL scale, health-related quality of life using the EQ-5D-5L at weeks 0, 3, 6, 8, 12, 18, and 26, and cognitive performance using the MoCA at weeks 12 and 26 relative to baseline.

Statistical analysis

The sample size for this initial trial was determined in accordance with ICH E9 guidelines (Statistical Principles for Clinical Trials) and selected without formal calculations, aiming to enable a preliminary assessment of the safety and potential efficacy of REGENECYTE in patients with post-COVID syndrome. It is also intended to support the development of REGENECYTE of additional hypotheses for investigation in subsequent clinical research. All participants in this clinical trial successfully completed every scheduled visit and follow-up assessment, so that there was no loss to follow-up or missing data. The efficacy analysis was conducted using the intention-to-treat principle, comparing questionnaire outcomes between the REGENECYTE and placebo groups. Changes from baseline in fatigue (CFQ-11, PGI-S), frailty (FRAIL scale), quality of life (EQ-5D-5L), and cognitive performance (MoCA) were evaluated at prespecified follow-up intervals. Data were reported as means ± standard deviations for continuous variables. The parameters of demographics were calculated by independent sample t-test. The Wilcoxon rank-sum test was used for between-group comparisons of non-normally distributed data, and categorical variables were summarized as counts and percentages. Statistical significance was defined as p < 0.05.

Role of the funding source

The funder of the study had a role in study design, data analysis, and writing of the report, but no role in data collection, and data interpretation. All authors had full access to the data in the study.

Results

30 patients who met the eligibility criteria were enrolled and randomized in a 2:1 ratio to receive REGENECYTE (n = 20) or placebo (n = 10) once every 3 weeks, for a total of three infusions, followed by assessments at weeks 8, 12, 18, and 26 (Fig. 1). Prior to treatment, ABO/Rh blood type compatibility was required between each participant and their assigned human umbilical cord blood units (hUCBs). Each REGENECYTE dose contained at least 1 × 10⁷ TNC/kg in 25 mL and was cryopreserved until use. All participants completed the full treatment protocol. Baseline characteristics are summarized in Table 1. The cohort had a mean age of 41.9 ± 10.1 years, was predominantly female (n = 21, 70%) and White (n = 23, 76.7%), and presented an average duration of post-COVID syndrome of 306.0 ± 78.7 days. Fatigue was reported in all participants (100%), while depression or anxiety was reported in 80% of patients. There were no statistically significant differences in baseline characteristics between the REGENECYTE and placebo groups. Specifically, age (41.3 ± 9.9 vs. 43.3 ± 10.8 years, p = 0.62), body weight (81.7 ± 21.2 vs. 75.2 ± 10.5 kg, p = 0.37), BMI (29.6 ± 5.9 vs. 28.2 ± 3.7, p = 0.50), and duration of post-COVID syndrome (316.2 ± 81.4 vs. 285.6 ± 68.5 days, p = 0.32) which suggests that the two groups were well balanced across these parameters at baseline (Table 1).

Fig. 1.

Participant flow diagram and study design. Questionnaires have been utilized to evaluate the post-COVID syndrome at indicated visit. CFQ-11, Chalder fatigue questionnaire; EOS, end of study; EOT, end of treatment; EQ-5D-5L, EuroQoL 5-Dimension 5-Level; IP, investigational product; MoCA, Montreal cognitive assessment; PGI-S, Patient Global Impression of Severity; W, week; TEAEs, Incidence of treatment-emergent adverse events.

Table 1.

Baseline of characteristics of recruited patients.

Parameter	REGENECYTE (N = 20)	Placebo (N = 10)	Overall (N = 30)
Age (years)	41.3 ± 9.9	43.3 ± 10.8	41.9 ± 10.1
Sex, n (%)
Female	13 (65.0%)	8 (80.0%)	21 (70.0%)
Male	7 (35.0%)	2 (20.0%)	9 (30.0%)
Race, n (%)
Asian	0	0	0
American Indian or Alaska Native	0	0	0
Black or African American	6 (30.0%)	1 (10.0%)	7 (23.3%)
Native Hawaiian or Other Pacific Islander	0	0	0
White	14 (70.0%)	9 (90.0%)	23 (76.7%)
Other	0	0	0
Weight (kg)	81.7 ± 21.2	75.2 ± 10.5	79.6 ± 18.4
Body Mass Index (kg/m2)	29.6 ± 5.9	28.2 ± 3.7	29.1 ± 5.2
Psychiatric disorders	0	1 (10.0%)	1 (3.3%)
Vascular disorders	3 (15.0%)	1 (10.0%)	4 (13.3%)
Hypertension	3 (15.0%)	1 (10.0%)	4 (13.3%)
Post COVID Syndrome	20 (100%)	10 (100%)	30 (100%)
Duration of post-COVID syndrome	316.2 ± 81.4 days	285.6 ± 68.5 days	306.0 ± 78.7 days
Ageusia	6 (30.0%)	1 (10.0%)	7 (23.3%)
Anorexia	6 (30.0%)	1 (10.0%)	7 (23.3%)
Anosmia	5 (25.0%)	4 (40.0%)	9 (30.0%)
Brain Fog	5 (25.0%)	5 (50.0%)	10 (33.3%)
Cough	1 (5.0%)	1 (10.0%)	2 (6.7%)
Depression and Anxiety	15 (75.0%)	9 (90.0%)	24 (80.0%)
Dizziness	3 (15.0%)	0	3 (10.0%)
Fatigue	20 (100%)	10 (100%)	30 (100%)
Gastrointestinal symptoms	8 (40.0%)	0	8 (26.7%)
Headache	6 (30.0%)	5 (50.0%)	11 (36.7%)
Insomnia	11 (55.0%)	8 (80.0%)	19 (63.3%)
Nasal Congestion	5 (25.0%)	2 (20.0%)	7 (23.3%)
Shortness of Breath	0	1 (10.0%)	1 (3.3%)
Sore Throat	0	1 (10.0%)	1 (3.3%)

Data are presented as n (%) for patient count and percentage, and as mean ± SD for continuous variables.

REGENECYTE treatment was well tolerated, with no serious adverse events (SAEs) reported during treatment or follow-up periods (Table 2). Two participants in the REGENECYTE group experienced infusion site allergic reactions (e.g., erythema, pruritus, rash), and mild respiratory or psychiatric AEs (dyspnea, anxiety). There were no clinically significant abnormalities for hematology, biochemistry and urinalysis throughout the study period.

Table 2.

TEAE severity (grade) assessment of post-COVID patients in treatment and follow-up period.

Number of participants reporting at least 1	REGENECYTE (N = 20) n (%)	Placebo (N = 10) n (%)	Overall (N = 30) n (%)
TEAE	2 (10.0%)	2 (20.0%)	4 (13.3%)
Serious TEAE	0	0	0
Treatment Related TEAEa	2 (10.0%)	0	2 (6.7%)
TEAE with Common Terminology Criteria for Adverse Events (CTCAE) Toxicity ≥ Grade 3	0	0	0
System Organ Class Preferred Term
General disorders and administration site conditions	2 (10.0%)	0	2 (6.7%)
Infusion site erythema	2 (10.0%)	0	2 (6.7%)
Infusion site pruritus	2 (10.0%)	0	2 (6.7%)
Infusion site rash	2 (10.0%)	0	2 (6.7%)
Infections and infestations	0	1 (10.0%)	1 (3.3%)
Cystitis	0	1 (10.0%)	1 (3.3%)
Psychiatric disorders	2 (10.0%)	0	2 (6.7%)
Anxiety	2 (10.0%)	0	2 (6.7%)
Respiratory, thoracic and mediastinal disorders	2 (10.0%)	1 (10.0%)	3 (10.0%)
Dyspnoea	2 (10.0%)	0	2 (6.7%)
Rhinitis allergic	0	1 (10.0%)	1 (3.3%)
Vascular disorders	1 (5.0%)	0	1 (3.3%)
Hypertension	1 (5.0%)	0	1 (3.3%)

Bold text indicates the main category for each condition or disorder.

^aTEAE severity will be defined according to CTCAE Version 5.0 and reported by collecting, evaluating, and coding using Medical Dictionary for Regularity Activities (MedDRA®) at week 0, 3, 6, 8, 12, 18, 26.

To evaluate fatigue, we used the CFQ-11 questionnaire (Bimodal range 0–11; Likert range 0–33). At baseline, all patients had a CFQ-11 Bimodal score ≥4 (6.8 ± 2.1 in the REGENECYTE group and 7.7 ± 1.7 in the placebo group, p = 0.25), indicating clinically relevant fatigue (Fig. 2a). The REGENECYTE group showed a significant reduction in CFQ-11 Bimodal scores at week 6 (3.2 ± 2.1 vs. 6.8 ± 1.7, p < 0.001), with effects sustained through weeks 12 (1.0 ± 1.4 vs. 5.9 ± 2.4, p < 0.001), 18 (1.0 ± 2.0 vs. 5.4 ± 2.8, p < 0.001), and 26 (1.0 ± 2.2 vs. 5.2 ± 3.2, p = 0.004). Likert scores also improved significantly, decreasing from a baseline mean of 17.8 to 10.6 at week 26 in the REGENECYTE group, compared with a reduction from 18.9 to 15.9 in the placebo group (p = 0.001 at week 26; Fig. 2b). Notably, physical fatigue showed greater improvement than mental fatigue (Fig. 2c and d), aligning with previous studies reporting good reliability of CFQ-11 (split-half reliability = 0.85, Cronbach α = 0.86–0.92).36, 37, 38, 39, 40

Fig. 2.

Assessment of fatigue by CFQ-11 questionnaire. a. The scoring and the change between baseline and each visit of Bimodal scoring system of CFQ-11. Patients with a score 4 or more are defined as “fatigue” and those with a score of 0–3 are defined as “non-fatigue”. b. The scoring and the change between baseline and each visit of Likert scoring system of CFQ-11. The total CFQ-11 Likert score measures the severity of fatigue, ranging from 0 to 33. c. The scoring and change between baseline and each visit of physical fatigue index of CFQ-11. The score of 0–9 is “normal”, a score of 10–15 represents “mild fatigue”, and a score of 16 or more represents “moderate-to-severe fatigue”. d. The scoring and change between baseline and each visit of mental fatigue index of CFQ-11. The score of 0–3 is “normal”, a score of 4–7 represents “mild fatigue”, and a score of 8 or more is classed as “moderate-to-severe fatigue. ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001.

PGI-S fatigue scores also demonstrated improvement: by the end of the study, 90% of REGENECYTE recipients returned to normal or borderline levels, compared to 30% in the placebo group (Figure S1a). Between-group comparisons of PGI-S scores showed significant reductions in fatigue severity in the REGENECYTE group at weeks 12 (p = 0.001), 18 (p = 0.004), and 26 (p = 0.007).

Frailty was assessed via the FRAIL scale (0–5). The REGENECYTE group demonstrated a statistically significant and sustained reduction in total FRAIL scale scores from week 6 to week 26, compared to the placebo group. However, most participants in both arms had low frailty scores at baseline. While no statistically significant between-group differences of level change were observed at any visit, a trend toward reduced frailty scores was noted in the REGENECYTE group (Figure S2).

Quality of life, assessed by EQ-5D-5L, showed positive trends. The “usual activities” dimension significantly improved by week 12 and was maintained through week 26 in the REGENECYTE group (p = 0.005; Fig. 3c). The pain/discomfort dimension also showed significant improvement at weeks 12 (p = 0.020) and 26 (p = 0.009; Fig. 3d). Mental health recovery was supported by improved anxiety/depression dimension scores (Fig. 3e), with nearly half of REGENECYTE patients reaching the “no problem” level. Self-reported overall health using the EQ VAS showed significant improvement at weeks 12 (p = 0.004) and 26 (p = 0.008; Fig. 3f). However, the level changes observed at week 26 across the dimensions of EQ-5D-5L in the treatment group were not statistically significant compared to placebo.

Fig. 3.

Change in life quality as measured by EQ-5D-5L score from baseline (screening visit) to week 0, 3, 6, 8, 12, 18 and 26. a., b., c., d., e., f. represent the levels or level changes between baseline and each visit in the EQ-5D-5L dimensions, specifically mobility, self-care, usual activities, pain/discomfort, and anxiety/depression as well as overall health level, respectively. EuroQoL 5-Dimension 5-Level (EQ-5D-5L). ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001.

Furthermore, the EQ-5D-5L index value improved markedly in the REGENECYTE group, increasing from 0.76 at baseline to 0.94 at week 26, compared to an increase from 0.73 to 0.80 in the placebo group. These changes were statistically significant at weeks 12 (p < 0.001) and 26 (p = 0.002; Figure S3), demonstrating improvements in global quality of life in the REGENECYTE group.⁴¹

Cognitive performance, assessed by MoCA (normal ≥26), showed baseline scores near the cutoff in both groups. By week 26, the REGENECYTE group had improved to a mean MoCA score of 26.1, compared to 25.6 in the placebo group. However, the between-group differences were not statistically significant (Figure S4), which is consistent with previous findings in post-COVID cognitive recovery studies.^42,43

A summary of results from CFQ-11, PGI-S, FRAIL, EQ-5D-5L, and MoCA at baseline, week 12, and week 26 is presented in Table 3. Overall, REGENECYTE demonstrated statistically significant improvements in reducing post-COVID fatigue—particularly physical fatigue—as well as quality-of-life domains including usual activities, pain/discomfort, and subjective health rating. Improvements were also observed in mental health status, though these changes were not statistically significant. These findings support further evaluation of REGENECYTE as a potential therapeutic option for managing post-COVID symptoms that are often challenging to address with standard care.

Table 3.

Questionnaires results analysis.

Questionnaires	Category	REGENECYTE group N = 20			Placebo group N = 10			W12 p-value	W26 p-value
		Base	W12	W26	Base	W12	W26
CFQ-11
Bimodal	Fatigue	6.75 ± 2.07	1.00 ± 1.41	1.00 ± 2.22	7.70 ± 1.70	5.90 ± 2.42	5.20 ± 3.16	<0.001	<0.001
Likert		17.80 ± 2.14	11.30 ± 2.00	10.60 ± 3.14	18.90 ± 1.97	16.70 ± 2.98	15.90 ± 3.78	<0.001	0.001
Physical fatigue		12.65 ± 0.99	7.25 ± 1.77	6.60 ± 2.80	13.40 ± 1.35	11.80 ± 2.53	11.30 ± 3.27	<0.001	<0.001
Mental fatigue		5.20 ± 2.07	4.05 ± 0.51	4.00 ± 0.56	5.50 ± 1.35	4.90 ± 0.99	4.60 ± 0.84	0.002	0.035
PGI-S
	Fatigue	3.40 ± 0.50	1.80 ± 0.52	1.45 ± 0.69	3.50 ± 0.53	2.90 ± 0.74	2.50 ± 0.85	<0.001	0.003
FRAIL
	Frailty	0.90 ± 0.55	0.10 ± 0.31	0.05 ± 0.22	1.20 ± 0.42	0.90 ± 0.32	0.50 ± 0.53	<0.001	0.009
EQ-5D-5L
Life quality	Mobility	1.30 ± 0.47	1.00 ± 0.00	1.00 ± 0.00	1.20 ± 0.42	1.30 ± 0.48	1.00 ± 0.32	1.000	0.333
	Self-care	1.00 ± 0.00	1.00 ± 0.00	1.00 ± 0.00	1.20 ± 0.42	1.00 ± 0.00	1.20 ± 0.42	1.000	0.103
	Usual activities	2.00 ± 0.56	1.15 ± 0.37	1.15 ± 0.37	2.00 ± 0.63	2.00 ± 0.47	1.70 ± 0.48	<0.001	0.005
	Pain/Discomfort	2.00 ± 0.65	1.25 ± 0.55	1.10 ± 0.31	2.10 ± 0.57	2.00 ± 0.94	1.80 ± 0.92	0.020	0.009
	Anxiety/Depression	2.50 ± 0.51	1.85 ± 0.49	1.70 ± 0.73	2.50 ± 0.53	2.30 ± 0.67	2.40 ± 0.70	0.094	0.022
	EQ VAS	73.80 ± 10.36	91.10 ± 5.88	94.80 ± 7.74	67.00 ± 11.6	79.10 ± 13.23	83.80 ± 10.43	0.004	0.008
	Index Value	0.76 ± 0.09	0.93 ± 0.07	0.94 ± 0.07	0.73 ± 0.10	0.81 ± 0.10	0.80 ± 0.13	<0.001	0.002
MoCA
	Cognition	24.20 ± 2.44	26.05 ± 1.57	26.10 ± 1.59	24.40 ± 2.95	25.80 ± 1.32	25.60 ± 1.84	0.495	0.500

Data from all questionnaires in the REGENECYTE and placebo groups were analyzed at baseline, week 12, and week 26, with statistical analysis performed at week 12 and 26 (end of study) for comparison between REGENECYTE and placebo groups. Results are presented as mean ± SD, and statistical significance is indicated by p-values.

Discussion

This study represents the first clinical investigation to evaluate REGENECYTE, an allogeneic cord blood–derived cell therapy, for the treatment of post-COVID syndrome. Post-COVID symptoms such as fatigue and cognitive impairment are among the most debilitating sequelae of SARS-CoV-2 infection,⁴⁴ contributing to a substantial and growing global health and economic burden. While current post-COVID management remains primarily supportive, recent advances in clinical phenotyping, molecular profiling, and biomarker discovery offer potential for more targeted and individualized therapies.² This trial is also the first to utilize human cord blood units from diverse donors to treat post-COVID syndrome in this context, leveraging cord-blood derived hematopoietic progenitor cells and immune-active components to address post-COVID symptoms. Our clinical findings demonstrated that REGENECYTE treatment was associated with statistically significant reductions in fatigue symptoms and improvements across multiple validated patient-reported quality-of-life outcome measures.

Following complete follow-up with recruited post-COVID patients, clinical results indicated that REGENECYTE, an investigational cord blood-derived cell therapy at the time of study conduct, was associated with statistically significant improvements in fatigue symptoms, as measured by CFQ-11 assessments, at weeks 6, 12, 18, and 26 compared to the placebo group (Fig. 2a and b; Table 3). Fatigue was further characterized into population of patients that can be divided into physical and mental categories, with marked improvements observed in physical fatigue scores (p < 0.001) and more modest improvements in mental fatigue (Fig. 2c and d). Additionally, PGI-S results confirmed similar trends, with 90% of REGENECYTE recipients reporting a shift from moderate-to-extreme fatigue to normal or borderline levels by week 26, compared to 30% in the placebo group (Figure S1a).

Furthermore, usual activities, pain and discomfort, and anxiety/depression, as assessed by the EQ-5D-5L, showed improvement or normalization in the REGENECYTE group but not in the placebo group (Fig. 3c–e). Most notably, EQ VAS scores increased significantly from 73.8 to 94.8 (p = 0.008), and the EQ-5D-5L index value improved from 0.76 to 0.94 (p = 0.002) by week 26 in the REGENECYTE group (Table 3, Fig. 3f, and Figure S3), further supporting enhanced perceived health. These findings reinforce the potential of REGENECYTE to address fatigue and related quality-of-life impairments in patients with post-COVID syndrome.

SARS-CoV-2 infection triggers a systemic immune response throughout the body, leading to widespread inflammation, and in some cases, tissue damage. One proposed mechanism involves increased permeability of the blood–brain barrier, which may allow viral particles, inflammatory cytokines, or immune cells to infiltrate the brain, contributing to persistent neurological symptoms.⁴⁵ The pathophysiology of post-COVID syndrome is likely heterogeneous and may include dysregulated immune responses, post-inflammatory tissue damage, autoimmune activation, vascular endothelial dysfunction, thromboinflammation, microglial activation, and gut microbiota dysbiosis.⁴⁶ One study reported increased spontaneous interferon (IFN)-γ secretion by peripheral CD8⁺ T cells in post-COVID patients, which resolved after 6 months post-infection.⁴⁷ These findings suggest that immune activation persists even during the virus clearance stage (or the acute phase of infection), highlighting potential therapeutic opportunities for involving immune system modulation or reconstruction.

hUCBs are rich in stem and progenitor cells, as well as growth factors, and have been clinically validated as a source of hematopoietic stem cells for the treatment of hematological malignancies and inherited disorders for over three decades.³⁰ Additionally, several clinical studies have explored their application in neurological conditions, including acute stroke,^34,48 cerebral palsy,⁴⁹ and spinal cord injury.⁵⁰ Beyond hematopoietic stem cells, hUCBs also contain mesenchymal stromal cells, endothelial progenitor cells, and immunosuppressive cells, such as regulatory T cells and monocyte-derived suppressor cells, which may help repair tissue injury resulting from hypoxic and inflammatory events during the perinatal period.⁵¹ The significant improvement in physical fatigue observed in our trial (Table 3) may reflect the immunomodulatory and regenerative properties of hUCBs, suggesting a plausible biological mechanism of action for REGENECYTE.

Based on the observed improvements in fatigue among patients with post-COVID syndrome, along with the favorable attributes of REGENECYTE—such as ready availability, low immunogenicity, and a strong safety profile—this therapy may also hold potential for addressing other fatigue-related conditions. Patients with post-COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) reported persistently high symptom severity up to 20 months post-infection, in contrast to individuals with post-COVID syndrome alone, who demonstrated overall health improvement over the same period.^52,53 Given its mechanism and delivery approach, this treatment protocol could potentially be extended to ME/CFS, a severe and often persistent illness that impairs daily functioning and affects an estimated 3.3 million people in the U.S.⁵⁴

Systemic inflammation may lead to blood–brain barrier dysfunction, initiating chronic neuroinflammation and potentially accelerating aging processes or promoting relapse–recovery cycles. Previous studies on rejuvenation using mouse models have demonstrated that introducing youthful blood circulation or small extracellular vesicles derived from plasma can extend the lifespan of older mice. These approaches have shown potential in promoting rejuvenation, reversing age-related mitochondrial dysfunction, and improving brain and respiratory functions.^55,56 These findings suggest that the mechanisms and symptoms of ME/CFS may share pathophysiological features with post-COVID syndrome or other aging-associated conditions, including neurodegenerative diseases, frailty, and sarcopenia.^57,58 Our findings support the hypothesis that hUCB-based therapies such as REGENECYTE may warrant further exploration not only for post-COVID recovery, but also for broader regenerative and anti-aging applications.

This study has several limitations. First, the sample size was relatively small (n = 30) and recruited from single site, which may limit the generalizability of the findings. Second, mental fatigue did not show significant improvement, suggesting that the intervention may have limited differential effects across symptom domains. Third, mechanistic biomarkers were not comprehensively evaluated in this phase, which restricts insight into the biological pathways underlying the observed clinical benefits. These limitations highlight the importance of conducting larger, multi-center randomized controlled trials with integrated biomarker analyses to validate and expand upon the present findings.

In summary, this first-in-human clinical trial provides strong though preliminary evidence that REGENECYTE, an allogeneic hUCB-based therapy, is safe and well tolerated. More importantly, the study achieved its secondary endpoint by demonstrating statistically significant improvements in fatigue and quality of life among patients with post-COVID syndrome. These contributed to the U.S. Food and Drug Administration (FDA) granting REGENECYTE Regenerative Medicine Advanced Therapy (RMAT) designation for the treatment of post-COVID as of September 2024. The observed clinical responses and associated biomarkers will be further investigated in an expanded patient cohort in future clinical trials. This protocol may expand the therapeutic application of cord blood beyond traditional hematopoietic stem cell transplantation, offering new avenues for immune modulation, tissue regeneration, and quality-of-life restoration.

Contributors

Y-WH and T-YL wrote the manuscript and provided critical revisions from all authors. JR, JW and T-YL approved the final version of the manuscript. Y-CC, EYLL and Y-CS have accessed and verified the data. Y-WH, Y-CC and EYLL provided support for data analysis and preparation of the clinical report. Y-CC, Y-CS, L-KT, JR and T-YL were responsible for the clinical trial design. JR, as the director, pediatric bone marrow transplantation at City of Hope and medical director of StemCyte, Inc., is responsible for reviewing all the clinical trial results. All authors confirm the accuracy and completeness of the data presented in the study, ensuring that the clinical trial was conducted strictly following the approval protocol including its subsequent amendments. Furthermore, this clinical study is performed in compliance with Good Clinical Practice guidelines, maintaining the highest standards of ethical and scientific integrity.

Data sharing statement

Regarding the request for available data or clinical protocol from this clinical trial, please contact the corresponding author. All data and information sharing based on the requests which will be estimated by the members of this clinical trial for their intended use and methodology. Once reviewed, the data sharing will be provided appropriate format by requests after data-transfer agreement proceeded with signing by involved parties.

Declaration of interests

Y-WH, Y-CC, EYLL, Y-CS, T-YL are employees of StemCyte Taiwan, Co., Ltd. and L-KT, JR, JW and T-YL are employees of StemCyte, Inc.