Sepsis, Immunosuppression
Conditions
Keywords
Thymalfasin, Thymosin alpha-1, Monocyte HLA-DR, Immune resilience, Immunoparalysis, T-cell exhaustion
Brief summary
Sepsis is a life-threatening illness caused by an abnormal response to infection. Some people with sepsis have reduced immune function, which may make recovery more difficult. This study will examine whether adding thymalfasin, also called thymosin alpha-1, to usual sepsis care improves recovery of immune function. The study will enroll 60 adults with sepsis and evidence of reduced immune function at Zhongshan Hospital, Fudan University. Participants will be assigned by chance to one of two groups. Thirty participants will receive usual care plus a 1.6 mg thymalfasin injection under the skin twice daily for 7 days. Thirty participants will receive usual care alone, without study-drug or placebo injections. Participants and treating clinicians will know which treatment is given, but laboratory staff measuring immune outcomes will not know the assigned group. The main outcome is the change in monocyte HLA-DR expression, a blood marker of immune function, between baseline and Day 7. Other assessments include immune cells, organ function, organ support, infections, survival, and safety. Scheduled follow-up continues through Day 90. The study is designed primarily to assess an immune marker; it is not sized to establish a definitive survival benefit.
Detailed description
This investigator-initiated, single-center, prospective, randomized, controlled exploratory study will evaluate thymalfasin in adults with sepsis and an immunosuppressed phenotype. The study will be conducted in the Department of Critical Care Medicine at Zhongshan Hospital, Fudan University. Eligible participants will meet Sepsis-3 criteria, have an Acute Physiology and Chronic Health Evaluation II (APACHE II) score of 15 to 30 at ICU admission, and meet the protocol-defined monocyte HLA-DR eligibility criterion. Enrollment must occur within 48 hours of sepsis onset. Written informed consent will be obtained from the participant or a legally authorized representative. Sixty participants will be randomized in a 1:1 ratio. The experimental group will receive standard sepsis care plus thymalfasin 1.6 mg subcutaneously twice daily, approximately 12 hours apart, for 7 consecutive days. The control group will receive standard sepsis care alone. Standard care will be determined by the treating clinicians and may include infection source control, antimicrobial therapy, fluid resuscitation, vasopressors, and organ support as clinically indicated. The primary outcome is the change in monocyte HLA-DR expression from baseline before randomization to Day 7. Expression will be assessed by flow cytometry using Panel 1 of the six-panel immunophenotyping method and summarized as the median HLA-DR fluorescence intensity within the prespecified monocyte population. Full-panel immune assessments are scheduled at baseline and Day 7, with core assessments at Days 1, 3, and 14. The protocol specifies immune recovery slopes using measurements at baseline and Days 3, 7, and 14. Samples will be coded, and laboratory personnel will be blinded to treatment allocation. Secondary assessments will characterize immune recovery, T-cell phenotypes, natural killer cells, organ dysfunction, organ support, and survival. Mortality comparisons are exploratory because the sample size is based on the primary immunological outcome. Safety events will be assessed during the protocol-defined monitoring period. Scheduled survival follow-up continues through Day 90.
Interventions
Thymalfasin lyophilized powder for injection, 1.6 mg per vial, will be reconstituted with 1 mL of 0.9% sodium chloride and administered subcutaneously at a dose of 1.6 mg twice daily, approximately 12 hours apart, for 7 consecutive days. Injection sites will be rotated between the upper arm and abdomen.
Sponsors
Shanghai Zhongshan Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Participants, treating clinicians, and investigators will be aware of treatment allocation. Laboratory personnel performing flow cytometry and assessing immune outcomes will be blinded to treatment allocation. Samples and laboratory reports will be identified using coded study identifiers without treatment-group information.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age older than 18 years, of any sex. Sepsis according to Sepsis-3 criteria, defined as documented or suspected infection with an increase in Sequential Organ Failure Assessment (SOFA) score of at least 2 points from baseline. APACHE II score of 15 to 30, inclusive, at ICU admission. An immunosuppressed phenotype, defined by reduced monocyte HLA-DR expression meeting No more than 48 hours from sepsis onset to enrollment. Written informed consent provided by the participant or legally authorized representative.
Exclusion criteria
* Known allergy to thymalfasin or any of its excipients. A history of primary or acquired immunodeficiency, such as HIV infection or post-transplant immunosuppression. Treatment with immunosuppressive agents or immunostimulants within 3 months before enrollment, including systemic corticosteroids at a prednisone-equivalent dose greater than 20 mg/day for at least 7 consecutive days, cyclosporine, tacrolimus, or azathioprine. Active malignancy or ongoing anticancer treatment. Chronic liver disease classified as Child-Pugh class C, or end-stage renal disease requiring maintenance dialysis. Pregnancy or breastfeeding. Expected survival of less than 48 hours at enrollment, such as irreversible brain death after cardiac arrest or terminal multiple organ failure. Concurrent participation in another interventional clinical trial. Any other condition that, in the investigator's judgment, makes participation unsuitable.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Monocyte HLA-DR Expression at Day 7 | Baseline (Day 0, before randomization) and Day 7 | Monocyte HLA-DR expression will be assessed by standardized multiparametric flow cytometry according to the six-panel immunophenotyping method and reported as median fluorescence intensity (MFI). Change will be calculated as the Day 7 MFI minus the baseline MFI measured before randomization. A positive change indicates increased monocyte HLA-DR expression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Recovery Slope of Monocyte HLA-DR Expression Through Day 14 | Baseline and Days 3, 7, and 14. | The recovery slope will be estimated using a linear mixed-effects model based on monocyte HLA-DR median fluorescence intensity (MFI) measured at baseline and Days 3, 7, and 14. Monocyte HLA-DR expression will be assessed by standardized multiparametric flow cytometry. The slope will be expressed as change in MFI per day. |
| Recovery Slope of Absolute Lymphocyte Count Through Day 14 | Baseline and Days 3, 7, and 14 | The recovery slope of absolute lymphocyte count will be estimated using a linear mixed-effects model based on absolute lymphocyte counts obtained from routine complete blood count measurements at baseline and Days 3, 7, and 14. The slope will be expressed as change in ×10⁹/L per day. |
| Change From Baseline in PD-1 Expression on CD8-Positive T Cells at Day 7 | Baseline (Day 0) and Day 7 | PD-1 expression on CD8-positive T cells will be assessed by standardized multiparametric flow cytometry and reported as median fluorescence intensity (MFI). Change will be calculated as the Day 7 MFI minus the baseline MFI. |
| Absolute Natural Killer Cell Count at Baseline and Day 7 | Baseline (Day 0) and Day 7 | Absolute natural killer (NK) cell counts will be assessed at baseline and Day 7 and reported as ×10⁹/L. |
| Reduction From Baseline in Sequential Organ Failure Assessment Score Through Day 14 | Baseline and Days 3, 7, and 14 | The Sequential Organ Failure Assessment (SOFA) score will be assessed at baseline and Days 3, 7, and 14. Reduction will be calculated as the baseline score minus the score at each follow-up assessment. Total scores range from 0 to 24; higher scores indicate more severe organ dysfunction. A positive reduction indicates improvement. |
| Mechanical Ventilation-Free Days Through Day 28 | From randomization through Day 28 | Number of days without mechanical ventilation from randomization through Day 28. |
| Vasopressor-Free Days Through Day 28 | From randomization through Day 28 | Number of days without vasopressor therapy from randomization through Day 28. |
| Renal Replacement Therapy-Free Days Through Day 28 | From randomization through Day 28 | Number of days without continuous renal replacement therapy (CRRT) from randomization through Day 28. |
| All-Cause Mortality During the Index ICU Stay | From enrollment until ICU discharge or death, up to Day 90 | Percentage of participants who die from any cause during the index ICU stay after enrollment. This outcome is exploratory. |
| All-Cause Mortality During the Index Hospitalization | From enrollment until hospital discharge or death, up to Day 90 | Percentage of participants who die from any cause during the index hospitalization after enrollment. This outcome is exploratory. |
| All-Cause Mortality Within 28 Days After Randomization | From randomization through Day 28 | Percentage of participants who die from any cause within 28 days after randomization. This is an exploratory outcome; the trial is sized for the primary immunological outcome rather than a definitive mortality comparison. |
| All-Cause Mortality Within 90 Days After Randomization | From randomization through Day 90 | Percentage of participants who die from any cause within 90 days after randomization. This is an exploratory outcome; the trial is sized for the primary immunological outcome rather than a definitive mortality comparison. |
| Participants With at Least One Adverse Event | From enrollment through Day 90 | Percentage of participants experiencing at least one adverse event during the treatment and follow-up periods. Adverse event severity will be graded using CTCAE version 5.0, and events will be coded using MedDRA. |
| Participants With at Least One Serious Adverse Event | From enrollment through Day 90 | Percentage of participants experiencing at least one serious adverse event during the study period, as defined in the study protocol. |
| Participants With a Thymalfasin-Related Adverse Event | From the first study-drug dose through Day 90 | Percentage of participants receiving thymalfasin who experience at least one adverse event judged by the investigator to be related to the study drug. |
| Participants With an Injection-Site Reaction | From the first dose through Day 7 | Percentage of participants receiving thymalfasin who experience at least one local injection-site reaction during the 7-day study-drug treatment period. |
| NKp46 Expression on Natural Killer Cells at Baseline and Day 7 | Baseline (Day 0) and Day 7 | NKp46 expression on natural killer (NK) cells will be assessed by standardized multiparametric flow cytometry and reported as median fluorescence intensity (MFI) at baseline and Day 7. |
Countries
China
Contacts
CONTACTHongyu He, PHD
PRINCIPAL_INVESTIGATORHongyu He
Fudan University
Outcome results
None listed