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| ID | Type | Description | Link |
|---|---|---|---|
| P01HL059412-06 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Heart, Lung, and Blood Institute (NHLBI) | NIH |
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Pompe disease is an inherited condition of acid alpha-glucosidase (GAA) deficiency resulting in lysosomal accumulation of glycogen in all tissues. Glycogen accumulation leads to muscle dysfunction and profound muscle weakness. A wide spectrum of disease is characteristic and the most severe patients have cardiorespiratory failure, often fatal in the first two years of life. Researchers have developed a way to introduce the normal GAA gene into muscle cells with the expectation that the GAA protein will be produced at levels sufficient to reduce glycogen accumulation. This study will evaluate the safety of the experimental gene transfer procedure in individuals with GAA deficiency. The study will also determine what dose may be required to achieve improvement in measures of respiratory function.
The goal of the current study is to evaluate an experimental gene transfer procedure in which normal copies of the GAA gene are inserted into cells. In this study, a modified virus, adeno-associated virus (AAV), has been engineered to carry a normal copy of the GAA gene, known as rAAV1-CMV-hGAA, which is used to place normal copies of the GAA gene into diaphragm muscle cells. The purpose of this study is to evaluate the safety of rAAV1-CMV-hGAA delivery into individuals with GAA deficiency (Pompe Disease).
Participants currently using enzyme replacement therapy will continue to receive their regular medical regimen during the 12 month duration of the study. Participants will first attend a screening study visit to confirm study eligibility. Participants will then attend a 3-5 day inpatient visit, during which they will receive a series of intradiaphragmatic injections consisting of the study agent (rAAV1-CMV-hGAA). Follow-up study visits will occur on Days 14, 90, 180, 270 and 365. Participants will have yearly follow-up evaluations by either telephone or mail for a total of 15 years, or as required by the FDA and other regulatory agencies.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| rAAV1-CMV-GAA administration-cohort 1 | Experimental | rAAV1-CMV-GAA (study agent) Administration: 1.0 x 10e12 vector genomes. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing. |
|
| rAAV1-CMV-GAA administration-cohort 2 | Experimental | rAAV1-CMV-GAA (study agent) Administration: 5.0 x 10e12 vector genomes Cohort 2 = 6 subjects. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| rAAV1-CMV-GAA (study agent) Administration | Drug | rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects. |
| Measure | Description | Time Frame |
|---|---|---|
| Safety Assessments of the rAAV1-CMV-GAA (Study Agent), Changes Post Study Agent Administration. | Change in Adeno-associated virus (AAV) antibody level; Change in Alglucosidase alpha (GAA) Antibody level | Change from baseline to 365 post study agent administration. |
| Measure | Description | Time Frame |
|---|---|---|
| Maximal Inspiratory Pressure | Median (range) Maximal Inspiratory Pressure (MIP), in cm H2O | Baseline and 365 post study agent administration |
| Evaluation of Ventilatory Performance Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training (RMST) Compared to RMST Alone. |
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Inclusion Criteria:
Exclusion Criteria:
The subject must not:
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| Name | Affiliation | Role |
|---|---|---|
| Barry J Byrne, MD, PhD | University of Florida | Principal Investigator |
| Shelley Collins, MD | University of Florida | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Shands at the University of Florida | Gainesville | Florida | 32610 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 11991748 | Background | Fraites TJ Jr, Schleissing MR, Shanely RA, Walter GA, Cloutier DA, Zolotukhin I, Pauly DF, Raben N, Plotz PH, Powers SK, Kessler PD, Byrne BJ. Correction of the enzymatic and functional deficits in a model of Pompe disease using adeno-associated virus vectors. Mol Ther. 2002 May;5(5 Pt 1):571-8. doi: 10.1006/mthe.2002.0580. | |
| 15920463 | Background | Mah C, Cresawn KO, Fraites TJ Jr, Pacak CA, Lewis MA, Zolotukhin I, Byrne BJ. Sustained correction of glycogen storage disease type II using adeno-associated virus serotype 1 vectors. Gene Ther. 2005 Sep;12(18):1405-9. doi: 10.1038/sj.gt.3302550. |
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All subjects underwent a screening process for eligibility determination as well as for safety evaluations.
Subjects were recruited from the Pediatric Neuromuscular Disorders Clinic at the University of Florida. Subjects were also self-referred from the ClinicalTrials.gov listing.
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| ID | Title | Description |
|---|---|---|
| FG000 | rAAV1-CMV-GAA Administration-cohort 1 | rAAV1-CMV-GAA (study agent) Administration: 1.0 x 10e12 vector genomes. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing. rAAV1-CMV-GAA (study agent) Administration: rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects. RMST: After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270. |
| FG001 | rAAV1-CMV-GAA Administration-cohort 2 | rAAV1-CMV-GAA (study agent) Administration: 5.0 x 10e12 vector genomes Cohort 2 = 6 subjects. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing. rAAV1-CMV-GAA (study agent) Administration: rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects. RMST: After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | rAAV1-CMV-GAA Administration-cohort 1 | rAAV1-CMV-GAA (study agent) Administration: 1.0 x 10e12 vector genomes. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing. rAAV1-CMV-GAA (study agent) Administration: rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects. RMST: After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | Safety Assessments of the rAAV1-CMV-GAA (Study Agent), Changes Post Study Agent Administration. | Change in Adeno-associated virus (AAV) antibody level; Change in Alglucosidase alpha (GAA) Antibody level | Posted | Mean | Standard Deviation | mU/mL | Change from baseline to 365 post study agent administration. |
|
Data on adverse events were collected on all subjects for 1 year after dosing.
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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 | rAAV1-CMV-GAA Administration-cohort 1 | rAAV1-CMV-GAA (study agent) Administration: 1.0 x 10e12 vector genomes. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing. rAAV1-CMV-GAA (study agent) Administration: rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects. RMST: After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Right-sided spontaneous pneumothorax | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Respiratory Tract Infection | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Barry Byrne, Professor and Associate Chair | University of Florida | 352-273-6563 | bbyrne@ufl.edu |
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| ID | Term |
|---|---|
| D006009 | Glycogen Storage Disease Type II |
| D006008 | Glycogen Storage Disease |
| ID | Term |
|---|---|
| D020140 | Lysosomal Storage Diseases, Nervous System |
| D020739 | Brain Diseases, Metabolic, Inborn |
| D001928 | Brain Diseases, Metabolic |
| D001927 | Brain Diseases |
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| ID | Term |
|---|---|
| D004364 | Pharmaceutical Preparations |
| D009934 | Organization and Administration |
| D005818 | Genetic Engineering |
| ID | Term |
|---|---|
| D006298 | Health Services Administration |
| D005821 | Genetic Techniques |
| D008919 | Investigative Techniques |
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Open label study
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|
| RMST | Other | After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270. |
|
|
Median (range) maximal inspiratory pressure, in cm H2O. Timeframe for RMST training was 90 days prior to rAAV1-CMV-GAA gene transfer. Timeframe for following subjects after rAAV1-CMV-GAA gene transfer was 365 days. |
| Screening, Baseline, and 365 post study agent administration. |
| Evaluation of Tidal Volume Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training, Compared to Respiratory Muscle Strength Training Alone. | Best effort tidal volume, referenced to body mass, without use of ventilator assistance. Timeframe for respiratory muscle strength training alone was 90 days prior to dosing, timeframe post adminstration of rAAV1-CMV-GAA was 365 days. | Screening, Baseline, and Day 365 post study agent administration |
| 17245350 | Background | Mah C, Pacak CA, Cresawn KO, Deruisseau LR, Germain S, Lewis MA, Cloutier DA, Fuller DD, Byrne BJ. Physiological correction of Pompe disease by systemic delivery of adeno-associated virus serotype 1 vectors. Mol Ther. 2007 Mar;15(3):501-7. doi: 10.1038/sj.mt.6300100. Epub 2007 Jan 23. |
| 11268285 | Background | Pauly DF, Fraites TJ, Toma C, Bayes HS, Huie ML, Hirschhorn R, Plotz PH, Raben N, Kessler PD, Byrne BJ. Intercellular transfer of the virally derived precursor form of acid alpha-glucosidase corrects the enzyme deficiency in inherited cardioskeletal myopathy Pompe disease. Hum Gene Ther. 2001 Mar 20;12(5):527-38. doi: 10.1089/104303401300042447. |
| 24021025 | Background | Conlon TJ, Erger K, Porvasnik S, Cossette T, Roberts C, Combee L, Islam S, Kelley J, Cloutier D, Clement N, Abernathy CR, Byrne BJ. Preclinical toxicology and biodistribution studies of recombinant adeno-associated virus 1 human acid alpha-glucosidase. Hum Gene Ther Clin Dev. 2013 Sep;24(3):127-33. doi: 10.1089/humc.2013.147. |
| 23903569 | Background | Byrne BJ. Pathway for approval of a gene therapy orphan product: treading new ground. Mol Ther. 2013 Aug;21(8):1465-6. doi: 10.1038/mt.2013.157. No abstract available. |
| 25541616 | Background | Corti M, Elder M, Falk D, Lawson L, Smith B, Nayak S, Conlon T, Clement N, Erger K, Lavassani E, Green M, Doerfler P, Herzog R, Byrne B. B-Cell Depletion is Protective Against Anti-AAV Capsid Immune Response: A Human Subject Case Study. Mol Ther Methods Clin Dev. 2014;1:14033. doi: 10.1038/mtm.2014.33. |
| 23570273 | Result | Smith BK, Collins SW, Conlon TJ, Mah CS, Lawson LA, Martin AD, Fuller DD, Cleaver BD, Clement N, Phillips D, Islam S, Dobjia N, Byrne BJ. Phase I/II trial of adeno-associated virus-mediated alpha-glucosidase gene therapy to the diaphragm for chronic respiratory failure in Pompe disease: initial safety and ventilatory outcomes. Hum Gene Ther. 2013 Jun;24(6):630-40. doi: 10.1089/hum.2012.250. |
| 22794786 | Derived | Byrne BJ, Falk DJ, Clement N, Mah CS. Gene therapy approaches for lysosomal storage disease: next-generation treatment. Hum Gene Ther. 2012 Aug;23(8):808-15. doi: 10.1089/hum.2012.140. |
| BG001 | rAAV1-CMV-GAA Administration-cohort 2 | rAAV1-CMV-GAA (study agent) Administration: 5.0 x 10e12 vector genomes Cohort 2 = 6 subjects. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing. rAAV1-CMV-GAA (study agent) Administration: rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects. RMST: After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Full Range | months |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| OG001 | rAAV1-CMV-GAA Administration-cohort 2 | rAAV1-CMV-GAA (study agent) Administration: 5.0 x 10e12 vector genomes Cohort 2 = 6 subjects. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing. rAAV1-CMV-GAA (study agent) Administration: rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects. RMST: After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270. |
|
|
| Secondary | Maximal Inspiratory Pressure | Median (range) Maximal Inspiratory Pressure (MIP), in cm H2O | Posted | Median | Full Range | cm H2O | Baseline and 365 post study agent administration |
|
|
|
| Secondary | Evaluation of Ventilatory Performance Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training (RMST) Compared to RMST Alone. | Median (range) maximal inspiratory pressure, in cm H2O. Timeframe for RMST training was 90 days prior to rAAV1-CMV-GAA gene transfer. Timeframe for following subjects after rAAV1-CMV-GAA gene transfer was 365 days. | Posted | Median | Full Range | cm H2O | Screening, Baseline, and 365 post study agent administration. |
|
|
|
| Secondary | Evaluation of Tidal Volume Benefit of rAAV1-CMV-GAA Gene Transfer and Respiratory Muscle Strength Training, Compared to Respiratory Muscle Strength Training Alone. | Best effort tidal volume, referenced to body mass, without use of ventilator assistance. Timeframe for respiratory muscle strength training alone was 90 days prior to dosing, timeframe post adminstration of rAAV1-CMV-GAA was 365 days. | Posted | Median | Full Range | mL/kg | Screening, Baseline, and Day 365 post study agent administration |
|
|
|
| 1 |
| 3 |
| 1 |
| 3 |
| 3 |
| 3 |
| EG001 | rAAV1-CMV-GAA Administration-cohort 2 | rAAV1-CMV-GAA (study agent) Administration: 5.0 x 10e12 vector genomes Cohort 2 = 6 subjects. The following study assessments/interventions will be completed: Respiratory Muscle Strength Training (RMST), Safety labs, pulmonary function testing. rAAV1-CMV-GAA (study agent) Administration: rAAV1-CMV-GAA via intramuscular injection into the diaphragm. Dose selection for cohort 1: 1.0 x 10e12 vector genomes Cohort 1 will have a total of 3 participants enrolled. Dose selection for cohort 2 and 3: 5.0 x 10e12 vector genomes rAAV1-CMV-GAA. Cohort 2 = 6 subjects. RMST: After enrollment and screening visit, the subject will be given a RMST prescription and will complete RMST for a minimum of 4 weeks prior to study agent administration. RMST prescription will be adjusted as needed at Day 14, 90, 180, and 270. | 0 | 9 | 3 | 9 | 9 | 9 |
| Bilateral pleural effusion | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
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| Bilateral pericardial effusion | Cardiac disorders | Non-systematic Assessment |
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| Supraventricular tachycardia | Cardiac disorders | Non-systematic Assessment |
|
| Right upper lobe collapse with respiratory distress and Clostridium difficile gastritis | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | The subject was hospitalized 10 months post-dosing during the first occurrence of this SAE. The same subject was hospitalized 11 months post-dosing for an acute episode of desaturation, right upper lobe collapse, recurrent gastritis. |
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| Bacteremia accompanied by fever | Blood and lymphatic system disorders | Non-systematic Assessment | Occurred 3 months post dosing. This unexpected event was determined to be unrelated to the test article and study procedures. |
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| Desaturation Episode | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
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| Hospitalization: dehydration, increased work of breathing | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | Hospitalization: dehydration, increased work of breathing |
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| Hospitalization | General disorders | Non-systematic Assessment |
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| hospitalization, worsening CHF, pulmonary edema | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | hospitalization, worsening CHF, pulmonary edema |
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| Pneumothorax/Capnothorax | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
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| respiratory symthomps | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | Cough, Increased secretions, cold symptoms, desaturation, oxygen requirement,Increased work of breathing, wheezing and Diminished breath sounds |
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| Pneumonia | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
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| fever, bacteremia, Dehydration | General disorders | Non-systematic Assessment | fever, bacteremia, Dehydration |
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| Pulmonary and chest problems | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | lung contusion, chest problems, |
|
| Reflux and Diarrhea, G-tube problems | Gastrointestinal disorders | Non-systematic Assessment | change to bowel and bladder regimen, Reflux and Diarrhea, stomach virus, G-tube problems, Abdominal abscess |
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| Pain | General disorders | Non-systematic Assessment | pain, cramps |
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| Skin issue | Skin and subcutaneous tissue disorders | Non-systematic Assessment | Swelling, rash, |
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| Trachestomy | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
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| ear infection and fluids | Ear and labyrinth disorders | Non-systematic Assessment |
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| eye infection | Eye disorders | Non-systematic Assessment | chalazion |
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| Contracturs and scoliosis | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
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| Hypokalemia and Hypoglycemia | General disorders | Non-systematic Assessment |
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| Tachycardia | Cardiac disorders | Non-systematic Assessment |
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| urinary issues | Renal and urinary disorders | Non-systematic Assessment | Increased difficulty urinating, positional; infections |
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| Nosebleed | Blood and lymphatic system disorders | Non-systematic Assessment |
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| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D008661 | Metabolism, Inborn Errors |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D002239 | Carbohydrate Metabolism, Inborn Errors |
| D016464 | Lysosomal Storage Diseases |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| Day 365 |
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| Day 365 |
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