Effect of Early HA380 Hemoperfusion on Hemodynamic Recovery and Organ Dysfunction in Adult Patients with Septic Shock

To determine whether early HA380 hemoperfusion reduces vasopressor requirement and improves organ dysfunction compared with standard care alone in adult septic shock patients.

Randomized, parallel-group, open-label, controlled clinical trial on 76 patients (38 in each group). Randomization was by alternating block design with blocks of 4 and 6, 1:1 ratio. Allocation by sealed envelopes, no blinding.

After consent, patients are randomized. Intervention: standard sepsis care + HA380 hemoperfusion (standalone machine, within 12 hours, daily 4-hour sessions for 3 days, blood flow 150–200 mL/min, systemic heparin). CRRT if needed after 3 sessions. Control: standard sepsis care without hemoperfusion. CRRT as indicated. Primary outcome: Change in SOFA score from baseline at Days 1, 3, and 7. Secondary outcomes: Change in norepinephrine dose, capillary refill time, VIS, PaO₂/FiO₂ ratio, lactate clearance, 28-day mortality, vasopressor-free days, ventilator-free days. Blinding: Open-label. Statistician blinded (groups A/B). Setting: Adult ICU, Milad Hospital, Urmia Azad University, Iran.

Inclusion criteria: Age ≥ 18 years, septic shock (Sepsis-3), norepinephrine 0.1–0.2 mcg/kg/min, lactate ≥ 2 mmol/L, SOFA ≤ 7, enrollment within 12 hours of shock onset, informed consent. Exclusion criteria: Active major bleeding, platelets < 30,000/μL, severe liver failure (Child-Pugh C), end-stage malignancy, pregnancy, expected death within 24 hours, refusal.

Intervention group: Standard sepsis care + HA380 hemoperfusion Control group: Standard sepsis care without hemoperfusion. CRRT if needed.

Sequential Organ Failure Assessment (SOFA) Score

Randomization Method: Permuted block randomization with randomly varying block sizes of 4 or 6 will be used to ensure balanced allocation between the two groups. Allocation Ratio: 1:1 (intervention : control). Allocation Concealment: The randomization sequence will be generated by an independent statistician (not involved in screening, enrollment, or treatment) using statistical software. Allocation codes will be placed in sequentially numbered, opaque, sealed envelopes (SNOSE). Envelopes will be opened by the principal investigator only after informed consent is obtained. Sequence Generation: A random number sequence will be generated using statistical software (e.g., Stata, R, or SAS) with a random seed. Documentation: The randomization list will be kept by the independent statistician and will not be accessible to the clinical research team until data collection and database lock are completed.

Documents and Data Files to be Shared: Study Protocol: The final complete protocol (including background, objectives, design, methods, inclusion/exclusion criteria, interventions, outcomes, and statistical analysis plan) will be submitted for publication in an international peer-reviewed journal (such as BMJ Open or Trials) after ethics approval and trial registration. A PDF copy will also be available upon request via email from the corresponding author. Statistical Code: All statistical programming commands used for primary and secondary outcome analyses (including Stata or R code) will be published as supplementary files alongside the main manuscript. These files contain only statistical commands and no individual patient data. Data Dictionary: A comprehensive variable guide including variable names, definitions (Persian and English), data types (numeric/text/date), permissible values (minimum, maximum, coding), and data sources (ICU chart, laboratory, clinical examination) will be published alongside the statistical code. Individual Participant Data (IPD): The decision regarding sharing of de-identified IPD will be made after consultation with the ethics committee and research team, and based on the requirements of the target journal. If sharing is approved, only fully anonymized data related to the primary and key secondary outcomes (SOFA scores, vasopressor doses, CRT, VIS, lactate, PaO₂/FiO₂, mortality, and length of stay) will be made available to qualified researchers upon formal request to the corresponding author and signature of a Data Sharing Agreement. Detailed demographic data that could enable indirect identification (such as exact age combined with admission date) will not be shared.

Study Protocol: The final protocol will be submitted for publication in an international peer-reviewed journal within 6 months of ethics committee approval and IRCT registration. A PDF copy will be available upon request via email from the corresponding author from that time onward. Statistical Code and Data Dictionary: These will be published as supplementary files on the journal's website simultaneously with the main results paper. Estimated timeline: 6 to 12 months after completion of data collection and final analysis. Individual Participant Data (IPD): If the decision to share is made, access to de-identified IPD will begin 12 months after publication of the main results (estimated: Summer 2029) and will remain available for 5 years. Requests during this period will be reviewed by the corresponding author, and data will be provided to qualified applicants upon approval.

1.Study Protocol, Statistical Code, and Data Dictionary: These documents will be openly accessible without restriction via the publishing journal's website or upon request to the corresponding author, available to researchers, clinicians, and students worldwide. 2.Individual Participant Data (IPD): If the decision to share is made, access to de-identified IPD will be restricted to qualified researchers affiliated with accredited academic, scientific, and research institutions (universities, teaching hospitals, research centers). Applicants must: Submit a valid research proposal with clear scientific objectives. Have verifiable research experience in critical care, sepsis, or emergency medicine. Sign a Data Sharing Agreement stipulating that data will be used solely for the stated research purpose and will not be transferred or sold to third parties. Obtain approval from the Ethics Committee of Urmia University of Medical Sciences for use of the data. Industry Personnel: Requests from individuals or entities in industry (including pharmaceutical companies, medical device manufacturers, and health insurers) will be reviewed on a case-by-case basis by the research team and ethics committee, and are contingent upon submission of a scientific proposal with research (not commercial) objectives.

A) Study Protocol, Statistical Code, and Data Dictionary (Open Access): Use for educational, research, and scientific purposes is freely permitted. Citation of the original publication is mandatory in any use. Commercial use or sale of these documents is prohibited. B) De-identified Individual Participant Data (IPD): 1. Permitted Types of Analysis: Statistical analyses related to sepsis outcomes and organ dysfunction Individual Patient Data Meta-analysis with ethics committee approval Validation studies of prognostic tools in sepsis Pre-specified secondary analyses with clear scientific objectives (not purely exploratory) All analyses must be pre-defined in the submitted proposal. 2. Prohibited Uses: Analysis for commercial purposes, marketing, or product development Re-identification of patients (including attempted re-identification) Transfer or sale of data to third parties Public dissemination of raw data Use in studies without ethics committee approval 3. Request Review and Approval Mechanism: Formal written request to the corresponding author via email Submission of a complete research proposal including: title, objectives, methods, planned analyses, research team, and their credentials Initial approval by the primary research team (assessment of scientific merit and overlap with ongoing analyses) Approval by the Ethics Committee of Urmia University of Medical Sciences Signature of a Data Sharing Agreement including the following clauses: Use solely for the approved research purpose No attempt to identify patients Deletion of data upon completion of the research Reporting of potential violations to the ethics committee Citation of the original study in resulting publications 4. Data Format and Delivery: Data will be provided as password-protected Excel or CSV files. Files will be sent only to the applicant's institutional email address (personal emails not accepted). Data will be stripped of all direct identifiers (name, national ID, medical record number, exact admission date) and indirect identifiers that could enable identification alone or in combination. 5. Response Timeline: Initial approval or rejection: within 4 weeks of receiving a complete request Data delivery after final approval: within 8 weeks

Guidance for Requesting Access to Documents and Data: Applicants may request study documents or data through the following channels, in order of priority: 1. Study Protocol, Statistical Code, and Data Dictionary (Open Access): These documents will be freely available as supplementary files on the publishing journal's website upon publication of the main article. If the journal website is inaccessible, applicants may contact the corresponding author via email. 2. Individual Participant Data (IPD) and Unpublished Documents: All formal requests must be sent to the Corresponding Author: Contact Information Name and Title: Dr. Amir Saeed – Principal Investigator and Corresponding Author Institutional Affiliation: Urmia University of Medical Sciences – Milad Hospital Postal Address: Adult Intensive Care Unit (ICU), Milad Hospital, Urmia, West Azerbaijan Province, Iran Postal Code: 5719151193 Email: Dr.saeedamir@umsu.ac.ir Alternative Email: (Insert alternative institutional email if available) Phone: +98-44-XXXXXXX (Direct line to ICU or Milad Hospital office) Fax: +98-44-XXXXXXX

a) Send a formal email from the applicant's institutional email address with the subject line: "Data Access Request – HA380 Septic Shock Trial" b) Attach the following documents: Complete research proposal (PDF) Summary CV of the lead applicant Names and institutional affiliations of all research team members Ethics committee approval from the applicant's institution (if available) c) Await initial response within 4 weeks. If approved, subsequent steps including signing the Data Sharing Agreement and obtaining approval from the Urmia University of Medical Sciences Ethics Committee will be coordinated via email. 4. Priority of Contact Methods: Priority Method Details 1 Institutional Email Preferably from an academic domain (edu. or ac.ir) 2 Personal Email Only if institutional email is unavailable 3 Formal Letter To the postal address above (in exceptional cases) 4 Telephone For follow-up only, not for initial requests Important Notes: Requests sent from personal emails (Gmail, Yahoo, etc.) will only be reviewed if the applicant has no institutional email. Incomplete requests (lacking a research proposal) will not be reviewed. All correspondence and documents are accepted in English or Persian.

Additional Information and Comments: Enriched Design: This study deliberately selects patients with early-stage septic shock (norepinephrine ≤ 0.2 and SOFA ≤ 7) to assess the efficacy of standalone HA380 hemoperfusion within the "therapeutic window" before the onset of irreversible organ failure. Patients with advanced organ failure who are likely to require CRRT are excluded. Separation from CRRT: Unlike many similar studies, HA380 is delivered via a standalone machine, not integrated into a CRRT circuit. This approach is designed to avoid confounding by concurrent CRRT and to more precisely evaluate the efficacy of HA380 as an independent therapy. CRRT, if clinically indicated, is initiated only after completion of the 3 hemoperfusion sessions. Funding: This study is funded by [Sponsor name: Jafron Biomedical / Urmia Azad University of Medical Sciences / Other]. HA380 cartridges are provided by Jafron Biomedical (China). The sponsor has no role in data collection, statistical analysis, interpretation of results, or the decision to publish. Conflict of Interest: The investigators declare no financial, personal, or professional conflicts of interest related to this study. Acknowledgments: The research team gratefully acknowledges the cooperation of the ICU staff at Milad Hospital, the Ethics Committee of Urmia University of Medical Sciences, and Jafron Biomedical for providing HA380 cartridges and technical support. Protocol Amendments: Any amendments to the study protocol (including changes to inclusion criteria, intervention, or outcomes) will be updated on IRCT following ethics committee approval.