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| ID | Type | Description | Link |
|---|---|---|---|
| Pro00028970 | Other Identifier | Cedars-Sinai Medical Ctr. IRB |
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| Name | Class |
|---|---|
| Alexion Pharmaceuticals, Inc. | INDUSTRY |
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All individuals who receive a heart transplant are at risk for developing antibody-mediated rejection (AMR). An antibody is a protein produced by the body's immune system when it detects a foreign substance, called an antigen. The mechanism of an antibody is to attack an antigen. In antibody mediated rejection, antibodies will attack the transplanted heart, causing injury to the heart. The purpose of this investigation is to determine if a study drug, called eculizumab (Soliris), is safe to use in heart transplant recipients, and determine if it reduces risk of antibody-mediated rejection.
The growing proportion of sensitized cardiac recipients presents an additional challenge to the transplant practitioner attempting to minimize the occurrence of antibody mediated rejection (AMR). Patients pre-exposed or "sensitized" to antigen exposing events (i.e.: blood transfusions, multiple pregnancies, prior organ transplantations, ventricular support devices) are more likely to both possess preformed and develop de-novo antibodies. Sensitized patients with panel reactive antibodies > 25% are at risk for increased risk of rejection, development of cardiac allograft vasculopathy and increased mortality after heart transplantation.
A central component of antibody-mediated cell injury is complement activation. The inhibition of terminal complement activation may be the missing link to decreasing possibly both complement-mediated AMR and cellular rejection (CR) by inhibiting both the inflammatory effects of both circulating antibodies and cytokine induced cell death.
Eculizumab is a monoclonal antibody that specifically binds to complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. By this mechanism, eculizumab (Soliris®) inhibits terminal complement mediated intravascular hemolysis in paroxysmal nocturnal hemoglobinuria patients.
This study is a non-randomized, open-label, investigator-initiated safety and efficacy trial investigating the de-novo use of eculizumab alongside conventional therapy to prevent antibody mediated rejection. The duration of the study will include an open enrollment period and at least 12 months of follow-up (post-transplant). We will consent up to 45 eligible patients, highly "sensitized", with a panel reactive antibody score greater than 70%, who are not previously or currently enrolled in another ongoing trial. Of these 45 participants, up to 20 of these patients will be treated with eculizumab (Solaris), the study drug. The use of eculizumab will be un-blinded to all study and research practitioner participants.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Eculizumab | Experimental | Administration of Eculizumab to heart transplant recipients at Cedars Sinai Medical Center with a panel reactive antibody (PRA) ≥ 70%, for the prevention of antibody-mediated rejection. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Eculizumab | Drug | At the time of transplantation, 1200mg of Eculizumab will be administered via a 35 minute IV infusion, followed by thymoglobulin 1.5 mg/kg intravenous piggyback (IVPB). The administration of thymoglobulin will be repeated (if blood counts permit) for a total of five doses. On Day 1 post-transplant, 900 mg of Eculizumab will be given via an IV infusion. On Day 5 post-transplant, intravenous immunoglobulin (IVIG) 1 gram/kg will be administered daily for two consecutive days. On post-transplant days 7, 14, and 21 (+/- 2 days) 900mg of Eculizumab will be given via an IV infusion at each scheduled visit. On post-transplant days 28, 42, and 56 (+/- 2 days) 1200 mg of Eculizumab will be given via an IV infusion at each scheduled visit. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants of Pathologic Antibody-Mediated Rejection and Left Ventricular Dysfunction | The efficacy of Eculizumab will be assessed by a composite endpoint of:
| up to 26 weeks post heart transplant |
| Measure | Description | Time Frame |
|---|---|---|
| Patient Survival at 12 Months Post Heart Transplantation | The study will assess overall survival at 12 months following heart transplantation. | 1 year post heart transplant |
| Number of Participants With Hemodynamic Compromise at 6 Months Post Transplant |
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Inclusion Criteria:
Exclusion Criteria:
(Note: Patients at risk of TB reactivation preclude administration of conventional immunosuppression, as determined by the study investigator and based upon appropriate evaluation).
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| Name | Affiliation | Role |
|---|---|---|
| Jignesh Patel, M.D., Ph.D. | Cedars Sinai Medical Center and Heart Institute | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cedars Sinai Medical Center, Heart Institute | Los Angeles | California | 90048 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19632573 | Background | Kfoury AG, Hammond ME, Snow GL, Drakos SG, Stehlik J, Fisher PW, Reid BB, Everitt MD, Bader FM, Renlund DG. Cardiovascular mortality among heart transplant recipients with asymptomatic antibody-mediated or stable mixed cellular and antibody-mediated rejection. J Heart Lung Transplant. 2009 Aug;28(8):781-4. doi: 10.1016/j.healun.2009.04.035. | |
| 17614978 |
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Individual participant data that supports the results of the study after deidentification and in accordance with Cedars Sinai data sharing agreements.
Data will be available following publication and ending 3 years following article publication.
Data will be available to investigators whose proposed used of the data has been approved by Cedars Sinai IRB.
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The trial enrolled a total of 36 sensitized participants age ≥ 18 years with a panel reactive antibody ≥70% at any time prior to study screening. Participants were included in the eculizumab treatment group if at least one donor specific antibody at MFI≥5000 was crossed but with negative prospective complement-dependent cytotoxicity crossmatch. 16 enrolled patients did not receive eculizumab.
Participants were enrolled following written informed consent for a protocol approved by the Institutional Review Board of Cedars-Sinai Medical Center (NCT02013037).The duration of the study included an open enrollment period and at least 12 months of post-transplant follow-up. All patients worked up for a heart transplant at the Heart Institute at Cedars-Sinai Medical Center (CSMC) with a panel reactive antibody (PRA) ≥ 70% at any time prior to screening.
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| ID | Title | Description |
|---|---|---|
| FG000 | Eculizumab | Eculizumab: At the time of transplantation, 1200mg of Eculizumab will be administered via a 35 minute IV infusion, followed by thymoglobulin 1.5 mg/kg intravenous piggyback (IVPB). The administration of thymoglobulin will be repeated (if blood counts permit) for a total of five doses. On Day 1 post-transplant, 900 mg of Eculizumab will be given via an IV infusion. On Day 5 post-transplant, intravenous immunoglobulin (IVIG) 1 gram/kg will be administered daily for two consecutive days. On post-transplant days 7, 14, and 21 (+/- 2 days) 900mg of Eculizumab will be given via an IV infusion at each scheduled visit. On post-transplant days 28, 42, and 56 (+/- 2 days) 1200 mg of Eculizumab will be given via an IV infusion at each scheduled visit. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan: Study Protocol including Statistical Analysis Plan |
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The incidence of patient hemodynamic compromise will be assessed at 6 months post transplant, as defined by any one of the following:
|
| 6 months post heart transplant |
| Number of Participants With Hemodynamic Compromise at 1 Year Post Transplant | The incidence of patient hemodynamic compromise will be assessed at one year post transplant, as defined by any one of the following:
| 1 year post heart transplant |
| Number of Participants With Antibody Mediated Rejection (AMR) | The study assessed the number of patients who develop AMR as well as the total number of episodes of AMR. | up to 1 year post heart transplant |
| Number of Participants With of Acute Cellular Rejection (ACR) | The study assessed the number of participants with of Acute Cellular Rejection (ACR) | up to 1 year post heart transplant |
| Development of Cardiac Allograft Vasculopathy (CAV) by Intravascular Ultrasound (IVUS) | Development of cardiac allograft vasculopathy at 1 year determined by intravascular ultrasound defined as change in site-matched maximal intimal thickness ≥ 0.5mm from baseline to 1 year. | up to 1 year post heart transplant |
| Number of Participants With Evolution of DSA: Donor Specific Antibody Post Transplantation | Number of Participants who develop de novo donor specific antibody (DSA) in the first year following transplantation was determined. | Up to 1 year post transplant |
| Uber WE, Self SE, Van Bakel AB, Pereira NL. Acute antibody-mediated rejection following heart transplantation. Am J Transplant. 2007 Sep;7(9):2064-74. doi: 10.1111/j.1600-6143.2007.01900.x. Epub 2007 Jul 5. |
| 19416767 | Background | Wu GW, Kobashigawa JA, Fishbein MC, Patel JK, Kittleson MM, Reed EF, Kiyosaki KK, Ardehali A. Asymptomatic antibody-mediated rejection after heart transplantation predicts poor outcomes. J Heart Lung Transplant. 2009 May;28(5):417-22. doi: 10.1016/j.healun.2009.01.015. Epub 2009 Mar 14. |
| 12531414 | Background | Michaels PJ, Espejo ML, Kobashigawa J, Alejos JC, Burch C, Takemoto S, Reed EF, Fishbein MC. Humoral rejection in cardiac transplantation: risk factors, hemodynamic consequences and relationship to transplant coronary artery disease. J Heart Lung Transplant. 2003 Jan;22(1):58-69. doi: 10.1016/s1053-2498(02)00472-2. |
| 21942930 | Background | Stegall MD, Diwan T, Raghavaiah S, Cornell LD, Burns J, Dean PG, Cosio FG, Gandhi MJ, Kremers W, Gloor JM. Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant. 2011 Nov;11(11):2405-13. doi: 10.1111/j.1600-6143.2011.03757.x. Epub 2011 Sep 22. |
| 17954062 | Background | Nwakanma LU, Williams JA, Weiss ES, Russell SD, Baumgartner WA, Conte JV. Influence of pretransplant panel-reactive antibody on outcomes in 8,160 heart transplant recipients in recent era. Ann Thorac Surg. 2007 Nov;84(5):1556-62; discussion 1562-3. doi: 10.1016/j.athoracsur.2007.05.095. |
| 21300295 | Background | Kobashigawa J, Crespo-Leiro MG, Ensminger SM, Reichenspurner H, Angelini A, Berry G, Burke M, Czer L, Hiemann N, Kfoury AG, Mancini D, Mohacsi P, Patel J, Pereira N, Platt JL, Reed EF, Reinsmoen N, Rodriguez ER, Rose ML, Russell SD, Starling R, Suciu-Foca N, Tallaj J, Taylor DO, Van Bakel A, West L, Zeevi A, Zuckermann A; Consensus Conference Participants. Report from a consensus conference on antibody-mediated rejection in heart transplantation. J Heart Lung Transplant. 2011 Mar;30(3):252-69. doi: 10.1016/j.healun.2010.11.003. |
| 21555100 | Background | Berry GJ, Angelini A, Burke MM, Bruneval P, Fishbein MC, Hammond E, Miller D, Neil D, Revelo MP, Rodriguez ER, Stewart S, Tan CD, Winters GL, Kobashigawa J, Mehra MR. The ISHLT working formulation for pathologic diagnosis of antibody-mediated rejection in heart transplantation: evolution and current status (2005-2011). J Heart Lung Transplant. 2011 Jun;30(6):601-11. doi: 10.1016/j.healun.2011.02.015. No abstract available. |
| 18976298 | Background | Locke JE, Magro CM, Singer AL, Segev DL, Haas M, Hillel AT, King KE, Kraus E, Lees LM, Melancon JK, Stewart ZA, Warren DS, Zachary AA, Montgomery RA. The use of antibody to complement protein C5 for salvage treatment of severe antibody-mediated rejection. Am J Transplant. 2009 Jan;9(1):231-5. doi: 10.1111/j.1600-6143.2008.02451.x. Epub 2008 Oct 31. |
| 17878341 | Background | Wang H, Arp J, Liu W, Faas SJ, Jiang J, Gies DR, Ramcharran S, Garcia B, Zhong R, Rother RP. Inhibition of terminal complement components in presensitized transplant recipients prevents antibody-mediated rejection leading to long-term graft survival and accommodation. J Immunol. 2007 Oct 1;179(7):4451-63. doi: 10.4049/jimmunol.179.7.4451. |
| 9171898 | Background | Thomas TC, Rollins SA, Rother RP, Giannoni MA, Hartman SL, Elliott EA, Nye SH, Matis LA, Squinto SP, Evans MJ. Inhibition of complement activity by humanized anti-C5 antibody and single-chain Fv. Mol Immunol. 1996 Dec;33(17-18):1389-401. doi: 10.1016/s0161-5890(96)00078-8. |
| 7657827 | Background | Rinder CS, Rinder HM, Smith BR, Fitch JC, Smith MJ, Tracey JB, Matis LA, Squinto SP, Rollins SA. Blockade of C5a and C5b-9 generation inhibits leukocyte and platelet activation during extracorporeal circulation. J Clin Invest. 1995 Sep;96(3):1564-72. doi: 10.1172/JCI118195. |
| 37182818 | Derived | Coutance G, Kobashigawa JA, Kransdorf E, Loupy A, Desire E, Kittleson M, Patel JK. Intermediate-term outcomes of complement inhibition for prevention of antibody-mediated rejection in immunologically high-risk heart allograft recipients. J Heart Lung Transplant. 2023 Oct;42(10):1464-1468. doi: 10.1016/j.healun.2023.05.005. Epub 2023 May 12. |
| 33251691 | Derived | Patel JK, Coutance G, Loupy A, Dilibero D, Hamilton M, Kittleson M, Kransdorf E, Azarbal B, Seguchi O, Zhang X, Chang D, Geft D, Czer L, Varnous S, Kobashigawa JA. Complement inhibition for prevention of antibody-mediated rejection in immunologically high-risk heart allograft recipients. Am J Transplant. 2021 Jul;21(7):2479-2488. doi: 10.1111/ajt.16420. Epub 2021 Feb 11. |
| COMPLETED |
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| NOT COMPLETED |
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The trial enrolled a total of 36 sensitized participants age ≥ 18 years with a panel reactive antibody (PRA) ≥70% at any time prior to study screening. Participants were included in the eculizumab treatment group if at least one DSA at MFI≥ 5000 was crossed but with negative prospective complement-dependent cytotoxicity (CDC) crossmatch. The eculizumab group consisted of 20 consecutive recipients transplanted between June 2, 2013 and July 31, 2018.
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| ID | Title | Description |
|---|---|---|
| BG000 | Eculizumab | Eculizumab: At the time of transplantation, 1200mg of Eculizumab will be administered via a 35 minute IV infusion, followed by thymoglobulin 1.5 mg/kg intravenous piggyback (IVPB). The administration of thymoglobulin will be repeated (if blood counts permit) for a total of five doses. On Day 1 post-transplant, 900 mg of Eculizumab will be given via an IV infusion. On Day 5 post-transplant, intravenous immunoglobulin (IVIG) 1 gram/kg will be administered daily for two consecutive days. On post-transplant days 7, 14, and 21 (+/- 2 days) 900mg of Eculizumab will be given via an IV infusion at each scheduled visit. On post-transplant days 28, 42, and 56 (+/- 2 days) 1200 mg of Eculizumab will be given via an IV infusion at each scheduled visit. |
| Units | Counts |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median | Full Range | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Non ischemic heart failure | Count of Participants | Participants |
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| Time on waiting list | Median | Full Range | Days |
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| Long term mechanical circulatory support (MCS) or extra-corporeal membrane oxygena at transplant | Count of Participants | Participants |
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| Combined transplantation | Count of Participants | Participants |
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| Retransplantation | Count of Participants | Participants |
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| Prior blood transfusion | Count of Participants | Participants |
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| Prior pregnancy (women) | The analysis population includes only the number of women (16) | Count of Participants | Participants |
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| Pre-transplant diabetes | Count of Participants | Participants |
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| Pre-transplant hypertension | Count of Participants | Participants |
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| Serum creatinine | Median | Full Range | mg/dL |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants of Pathologic Antibody-Mediated Rejection and Left Ventricular Dysfunction | The efficacy of Eculizumab will be assessed by a composite endpoint of:
| Posted | Count of Participants | Participants | up to 26 weeks post heart transplant |
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| Secondary | Patient Survival at 12 Months Post Heart Transplantation | The study will assess overall survival at 12 months following heart transplantation. | 20 participants were included in the Eculizumab study | Posted | Count of Participants | Participants | 1 year post heart transplant |
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| Secondary | Number of Participants With Hemodynamic Compromise at 6 Months Post Transplant | The incidence of patient hemodynamic compromise will be assessed at 6 months post transplant, as defined by any one of the following:
| 20 participants were included in the Eculizumab study | Posted | Count of Participants | Participants | 6 months post heart transplant |
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| Secondary | Number of Participants With Hemodynamic Compromise at 1 Year Post Transplant | The incidence of patient hemodynamic compromise will be assessed at one year post transplant, as defined by any one of the following:
| 20 participants participated in the eculizumab study | Posted | Count of Participants | Participants | 1 year post heart transplant |
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| Secondary | Number of Participants With Antibody Mediated Rejection (AMR) | The study assessed the number of patients who develop AMR as well as the total number of episodes of AMR. | 20 participants were treated in the eculizumab study | Posted | Count of Participants | Participants | up to 1 year post heart transplant |
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| Secondary | Number of Participants With of Acute Cellular Rejection (ACR) | The study assessed the number of participants with of Acute Cellular Rejection (ACR) | 20 participants were treated in the eculizumab study | Posted | Count of Participants | Participants | up to 1 year post heart transplant |
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| Secondary | Development of Cardiac Allograft Vasculopathy (CAV) by Intravascular Ultrasound (IVUS) | Development of cardiac allograft vasculopathy at 1 year determined by intravascular ultrasound defined as change in site-matched maximal intimal thickness ≥ 0.5mm from baseline to 1 year. | 20 enrolled patients were treated on the study | Posted | Count of Participants | Participants | up to 1 year post heart transplant |
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| Secondary | Number of Participants With Evolution of DSA: Donor Specific Antibody Post Transplantation | Number of Participants who develop de novo donor specific antibody (DSA) in the first year following transplantation was determined. | 20 enrolled patients were treated on the study | Posted | Count of Participants | Participants | Up to 1 year post transplant |
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1 year post transplant
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Eculizumab | Administration of Eculizumab to heart transplant recipients at Cedars Sinai Medical Center with a panel reactive antibody (PRA) ≥ 70%, for the prevention of antibody-mediated rejection. Eculizumab: At the time of transplantation, 1200mg of Eculizumab will be administered via a 35 minute IV infusion, followed by thymoglobulin 1.5 mg/kg intravenous piggyback (IVPB). The administration of thymoglobulin will be repeated (if blood counts permit) for a total of five doses. On Day 1 post-transplant, 900 mg of Eculizumab will be given via an IV infusion. On Day 5 post-transplant, intravenous immunoglobulin (IVIG) 1 gram/kg will be administered daily for two consecutive days. On post-transplant days 7, 14, and 21 (+/- 2 days) 900mg of Eculizumab will be given via an IV infusion at each scheduled visit. On post-transplant days 28, 42, and 56 (+/- 2 days) 1200 mg of Eculizumab will be given via an IV infusion at each scheduled visit. 2 deaths were reported in participants who received eculizumab. There were 6 deaths in participants who did not complete the study and did not receive eculizumab. | 8 | 36 | 13 | 36 | 0 | 36 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Viral infections | Infections and infestations | Systematic Assessment |
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| Bacterial Infections | Infections and infestations | Systematic Assessment |
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| Fungal infections | Infections and infestations | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Jignesh Patel | Cedars Sinai Smidt Heart Institute | 310-248-8300 | jignesh.patel@cshs.org |
| Jul 9, 2015 |
| Feb 12, 2021 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D018487 | Ventricular Dysfunction, Left |
| C565169 | Complement Component 3 Deficiency, Autosomal Recessive |
| ID | Term |
|---|---|
| D018754 | Ventricular Dysfunction |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| C481642 | eculizumab |
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