: RP-503 - TEMPLATE PROTOCOL



Protocol TitleTitle: ?Immunologic Response to Pneumococcal Polysaccharide Vaccine in Splenic Injury PatientsProtocol Version Date: 11-3-17ObjectivesThe objectives of this study are to determine the immunologic consequences of splenectomy and splenic artery embolization management following traumatic disruption of the spleen. Do patients who undergo splenectomy or splenic artery embolization, respond to pneumococcal vaccination to the same degree as a patient with intact splenic function or as an asplenic patient? Does the degree of response relate to the percentage of remaining vascularized spleen following splenic artery embolization?This is a multi-center study, based at the University of California, Davis, and investigator initiated. Funding has been obtained via an investigator-initiated grant program through Merck, Sharpe and Dome, Inc. Assays will be performed at Flow Dynamics, Inc. in McDonough, GA. BackgroundThe role of the spleen in reducing the risk of overwhelming infections has been recognized since the 1800s, but Morris and Bullock’s publication in 19191 demonstrated in a scientific manner that the spleen does indeed play a major role in the defenses against overwhelming sepsis. Though the true incidence of overwhelming postsplenectomy sepsis (OPSS) is unknown, it is probably less than 2%.2 Loss of the spleen imparts a small but significant infection risk to the trauma victim (< 0.5%)2. Though immunization against pneumococcal infection usually produces excellent antibody responses in most patients, vaccine failure has been documented and the risk of OPSS is life-long. Once contracted, the case mortality rate for OPSS in most studies approaches 50%3, hence, OPSS is a rare but very serious infection. Splenic salvage with adequate functional splenic tissue is optimal, and is the goal of splenic artery embolization in the setting of ongoing hemorrhage in the traumatically disrupted spleen. However, the incidence of OPSS after splenic artery embolization is entirely unknown.Though the surgical (splenectomy versus splenorrhaphy) and nonsurgical (angiography/embolization, observation) management of splenic trauma has been studied in randomized, prospective formats, the immunologic consequences are not as well studied. ACIP guidelines recommend pneumococcal vaccination two weeks prior to elective splenectomy, but provide no recommendation for those undergoing emergent splenectomy3. We have shown in previous studies that vaccination with pneumococcal polysaccharide vaccine 14 days after splenectomy for trauma elicits the best antibody response.4,5 However, no human studies have ever been published examining the immunologic status of patients following embolization or nonoperative management of their spleens following traumatic disruption.The unknown factor in splenic embolization is the degree of retained immunologic function and is probably primarily a function of the quantity of viable spleen remaining following embolization. Though embolization is a demonstrated valuable adjunct in splenic salvage6, if no, or inadequate, residual immune function remains, the value of embolization is not only questionable, but these patients must then be treated as any other asplenic patient, i.e., they must also be vaccinated and made aware of their life-long risk of OPSS. Van Wyck7,8 has demonstrated that splenic mass (in the animal model) does indeed dictate the ability of the spleen to impart a humoral response to pneumococcal antigen, demonstrating that at least one-third of the normal splenic mass provides a clear-cut protective edge over asplenia. The experimental animal model, however, used graded partial splenic amputation, preserving the native anatomy and blood supply, rendering this model of questionable value to answer the question posed in the current study.Inclusion and Exclusion CriteriaInclusion: Adult trauma patients aged 18 to 65 years old, sustaining a splenic injury and undergoing splenectomy or splenic artery embolization are eligible for enrollment in the study. Exclusion:PrisonersThe management decision for the splenic injury is entirely at the discretion of the attending trauma surgeon and radiologist (in the case of splenic artery embolization). All patients undergoing one of the treatment approaches under study will be brought to the attention of the Principal Investigator at the respective institutions. These patients will then be offered participation in the study.Study TimelinesDescribe:Patient’s participation in the study will conclude at the final blood draw, 4 weeks after immunization.The duration is entirely unknown and is completely dependent upon the number of trauma patients presenting with splenic injuries. Based on the average number of these patients seen annually at UCD and the participating institutions, the study is anticipated to last 3-5 years.The estimated date for the investigators to complete this study is 2021.Study EndpointsGeometric mean titer (GMT) increases of prevaccination versus postvaccination antibody is the primary endpoint of this study.GMT changes in patients undergoing splenic artery embolization will be compared in relation to the remaining vascularized spleen on follow-up CT scan. This is a secondary endpoint for that arm of the study.There are no primary or secondary safety endpoints as we are not studying the vaccines themselves.Procedures InvolvedAll patients undergoing one of the treatment approaches under study will be brought to the attention of the Principal Investigator at the respective institutions. These patients will then be offered participation in the study.Those patients consenting to participation will receive the standard 23-valent pneumococcal polysaccharide vaccine vaccine 14 days following embolization or splenectomy (any other vaccines will be at the discretion of the primary surgeon and will not be investigated in this study). At the time of vaccination, 7cc of venous blood will be collected for baseline antibody analysis. Patients will return 4 weeks later for a follow-up phlebotomy of another 7cc of blood for analysis of functional antipneumococcal antibody. The vaccination procedure and serum analysis are described in detail in our previous publication (Shatz DV, Romero-Steiner S, Elie C, Holder T, Carlone GM. Antibody responses at 14- and 28-days postsplenectomy in trauma patients receiving the 23-valent pneumococcal vaccine. J Trauma 52(1);194, 2002). Blood samples will be centrifuged and stored in the CTSC Clinical Research Center Laboratory at UCD (and similar labs at the contributing centers) at -80C, and stored sera will be sent in batches on dry ice to Flow Dynamics, Inc. in McDonough, Georgia for antibody analysis. All samples will be assigned unique patient identifiers. The samples will be submitted to Flow Dynamics, Inc without personal identifiers, though data will remain linked through an electronic data file for future analysis. This patient linkage will remain in the sole possession of the PI (DVS). Responses to the 23-valent pneumococcal vaccine will be measured by ELISA to determine the geometric mean increase in IgG antibody titer to Pnc Ps serotypes. Functional antibody, measured by percent kill of a known pneumococcal concentration, will be determined by opsonophagocytosis assay. Patients treated via splenic artery embolization will undergo a standard post-embolization computed tomographic exam of the abdomen three to five days postinjury to evaluate the effectiveness of the embolization procedure (this CT examination is standard procedure for embolization and is not part of the current study). The percent of viable, perfused spleen will be calculated from this CT. Antibody response will be compared against the location of the intravascular coils (i.e., proximal versus distal embolization) and the percent of viable spleen as calculated on the follow-up CT scan. Antibody function will be compared to known values from normal control subjects held by Flow Dynamics, Inc., as well as the patients from the splenectomy group. Data and/or Specimen Management and ConfidentialitySignificant differences among groups will be calculated by the t-test for normally distributed data and by the Mann-Whitney rank sum test for data sets that are not normally distributed. The significance level will be set at p < 0.05. Correlations between opsonophagocytosis and ELISA antibody titers will be performed by the Pearson’s product moment correlation coefficient after a log2 transformation of the data. P values will be calculated in 2 x 2 tables using Chi Square or the two-tailed Fisher’s exact test when appropriate. Significance level will be set at p < 0.05. Statistical calculations will be performed using Sigma Stat version 1.0 (Jandel Corporation, San Rafael, CA) and Epi-Info version 6.02 (Centers for Disease Control and Prevention, Atlanta, GA).All samples will be assigned unique patient identifiers. The samples will be submitted to Flow Dynamics, Inc without personal identifiers, though data will remain linked through an electronic data file for future analysis. This patient linkage will remain in the sole possession of the PI (DVS).Data and/or Specimen BankingThere will be no specimen banking beyond the study as described. Once data analysis has been completed, any residual samples will be destroyed.Provisions to Monitor the Data to Ensure the Safety of SubjectsFor all groups, the antibody response to vaccination will in no way alter the course of clinical therapy, and will not be known until several weeks to months after their vaccination (samples are sent when batch sizes are large enough to send to Flow Dynamics, Inc). There are no safety issues and the data will therefore not be monitored.Withdrawal of SubjectsSubjects may withdraw from the study at any time at their own request, or they may be withdrawn at any time at the discretion of the investigator for safety or behavioral reasons, or the inability of the subject to comply with the protocol required follow up visits or procedures.If a subject does not return for a scheduled visit, every effort should be made to contact the subject. In any circumstance, every effort should be made to document subject outcome, if possible. The investigator will inquire about the reason for withdrawal, request the subject to return for a follow-up visit, if applicable, and follow-up with the subject regarding any unresolved AEs.If the subject withdraws from the study, and also withdraws consent for disclosure of future information, no further evaluations should be performed, and no additional data should be collected. The investigator may retain and continue to use any data collected before such withdrawal of consent.Risks to SubjectsThere are no anticipated psychological or social risks to this study. The risks of participating are only those of the blood draws. Fainting and local discomfort following venipuncture are uncommon, potential, minimal side effects of drawing blood. Rarely, infection or thrombosis of the vein may occur.?Pneumovax? is the standard vaccine available. Prevnar-13? is now available but as it covers only 13 serotypes of pneumococcal organisms, it is felt to be less desirable by the UCD Trauma Division faculty, which has decided in favor of the 23-valent Pneumovax? vaccine. Venipuncture therefore remains as the only potential risk. When available, indwelling catheters will be used for blood sampling.???Potential Benefits to SubjectsNo known benefits can be promised. Improved knowledge and understanding of immunologic responses of all patients sustaining injury of the spleen may provide a standard of care where one currently does not exist. If this includes vaccination of these patients, it could prevent a rare but fatal disease (Overwhelming Postsplenectomy Sepsis – OPSS).Immunization of all patients undergoing splenectomy or splenic embolization is standard protocol UCD.Multi-Site ResearchThe study will be a multicenter study.Sharing of Results with Subjects Results will not be shared with Subjects.Prior Approval Not applicable.Provisions to Protect the Privacy Interests of SubjectsPatients/family will be contacted by a member of the research team in a private setting such as a patient room or conference room. The research team will explain the study treatment, procedures, and the timing of each to the patient/family and they will be offered the opportunity to ask questions. Patients’ privacy interests will be respected at all times and requests for specific privacy requirements will be met if at all possible, taking into consideration the study protocol requirements and the patients’ rmation about study subjects will be kept confidential and managed according to the requirements of the Health Insurance Portability and Accountability Act (HIPAA). Only research personnel approved by the IRB to work on this project will have access to this study.Access to medical records that contain patient’s personal information for the purpose of this study will be limited to the approved research personnel. These personnel already have knowledge of and access to identifiable medical information of current trauma patients as part of their daily job functions. EMR access to PHI is password-protected and no PHI will be reused or disclosed to any other person or entity, except as required by pensation for Research-Related InjuryUCD Policy: If the subject is injured as a direct result of research procedures, the subject will receive reasonably necessary medical treatment. Depending on the circumstances, the costs of the treatment may be covered by the University or the study sponsor or may be billed to your insurance company just like other medical costs. The University and the study sponsor do not normally provide any other form of compensation for injury. Economic Burden to Subjects There are no costs for subjects participating in this study.Drugs or DevicesThis study only investigates the antibody response to vaccines given as standard of care. There are no investigational drugs involved. Registration This study is registered on - NCT02232191.FDAAA 801 establishes penalties for Responsible Parties who fail to comply registration or results submission requirements. Penalties include civil monetary penalties and, for federally funded studies, the withholding of grant funds.Section 1: NIH Funded StudiesIf yes to BOTH, the study must be registered on .Yes FORMCHECKBOX This study is funded by the NIH. (If this study is not funded by NIH, go to Section 2.) FORMCHECKBOX One or more human subjects will be prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.Section 2: Studies subject to FDA jurisdictionIf yes to ANY the study must be registered on .Yes FORMCHECKBOX This is a prospective clinical study of health outcomes in human subjects that compares an intervention with an FDA-regulated device against a control. This is not a small clinical trial to determine the feasibility of a device, or a clinical trial to test prototype devices where the primary outcome measure relates to feasibility and not to health outcomes. FORMCHECKBOX This is a pediatric postmarket surveillance of a device as required under section 522 of the Federal Food, Drug, and Cosmetic Act. FORMCHECKBOX This is a controlled clinical investigation, other than a phase I clinical investigation, of a drug subject to section 505 of the Federal Food, Drug, and Cosmetic Act or to section 351 of the Public Health Service Act.To view a flowchart describing applicable clinical trials subject to FDA jurisdiction click here.Section 3: Publishing the resultsIf yes to BOTH the study must be registered on .Yes FORMCHECKBOX This study prospectively assigns people or a group of people to an intervention, with or without concurrent comparison or control groups, to study the cause-and-effect relationship between a health-related intervention and a health outcome. FORMCHECKBOX The PI has access to and control over all the data from the clinical trial and has the right to publish the results of the trial and plans to publish the results in a journal that follows the ICMJE recommendations. This requirement includes studies of behavioral interventions.Section 4: Registration on is not requiredYes FORMCHECKBOX I have read sections 1-3 above and registration on is not required for this research. ................
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