Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| 15386-PRE21 | Other Identifier | IRCCS San Raffaele |
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This is a phase I/II protocol to evaluate the safety and efficacy of ADA gene transfer into hematopoietic stem/progenitor cells for the treatment of adenosine deaminase (ADA)-deficiency. This condition is an autosomal recessive form of Severe Combined Immunodeficiency (SCID) characterized by impaired immune responses, recurrent infections, failure to thrive and systemic toxicity due to accumulation of purine metabolites. Transplants from an human leukocyte-antigen (HLA)-identical sibling donor is the treatment of choice, but available for a minority of patients. The use of alternative bone marrow donors or enzyme replacement therapy is associated with important drawbacks. The drug product studied in this protocol consists of autologous cluster of differentiation (CD)34+ hematopoietic stem/progenitor cells engineered ex vivo with a retroviral vector encoding the therapeutic gene ADA. The engineered CD34+ cells are infused following a nonmyeloablative conditioning with busulfan to make space in the bone marrow. The study objectives are: a) to evaluate the safety and the clinical efficacy of gene therapy, in the absence of enzyme replacement therapy; b) to evaluate the biological activity (engraftment, ADA expression) of ADA transduced CD34+ cells and their hematopoietic progeny. c) to evaluate the immunological reconstitution and purine metabolism after gene therapy.
The safety of the study will be evaluated by description of all adverse events and adverse drug reactions.
The study is aimed at reaching the minimum sample size of ten patients.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Gene Therapy | Experimental | Infusion of autologous CD34+ cells transduced with retroviral vector encoding ADA after non-myeloablative conditioning with busulfan |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Gene Therapy | Genetic | Infusion of autologous CD34+ cells transduced with retroviral vector encoding ADA after non-myeloablative conditioning with busulfan |
|
| Measure | Description | Time Frame |
|---|---|---|
| Survival | From post-treatment to up to 3 years | baseline to 3 years post gene therapy |
| Measure | Description | Time Frame |
|---|---|---|
| Rate of Severe Infections | Severe infections were defined as those that required hospitalization or those that prolonged hospitalization. The rate of infection was estimated as number of severe infections over person-years of observation (free from severe infections) before and after treatment administration. The first 3 months after gene therapy were not considered in the post-gene therapy analysis, because all subjects were hospitalized during this period. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Fondazione Telethon | Fondazione Telethon | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Investigational Site | Jerusalem | Israel | ||||
| Ospedale San Raffaele |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38355973 | Derived | Migliavacca M, Barzaghi F, Fossati C, Rancoita PMV, Gabaldo M, Dionisio F, Giannelli S, Salerio FA, Ferrua F, Tucci F, Calbi V, Gallo V, Recupero S, Consiglieri G, Pajno R, Sambuco M, Priolo A, Ferri C, Garella V, Monti I, Silvani P, Darin S, Casiraghi M, Corti A, Zancan S, Levi M, Cesana D, Carlucci F, Pituch-Noworolska A, AbdElaziz D, Baumann U, Finocchi A, Cancrini C, Ladogana S, Meinhardt A, Meyts I, Montin D, Notarangelo LD, Porta F, Pasquet M, Speckmann C, Stepensky P, Tommasini A, Rabusin M, Karakas Z, Galicchio M, Leonardi L, Duse M, Guner SN, Di Serio C, Ciceri F, Bernardo ME, Aiuti A, Cicalese MP. Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency. Nat Med. 2024 Feb;30(2):488-497. doi: 10.1038/s41591-023-02789-4. Epub 2024 Feb 14. | |
| 28319446 |
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The Pivotal study enrolled 12 participants.
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Gene Therapy | Infusion of autologous cluster of differentiation (CD)34+ cells transduced with retroviral vector encoding ADA after non-myeloablative conditioning with busulfan |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Baseline |
| |||||||||||||
| Treatment |
|
The Intention to Treat (ITT) Population included all subjects who were treated with gene therapy and had at least 1 post-therapy evaluation during the 0-3year follow-up.
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Gene Therapy (Pivotal) | Infusion of autologous cluster of differentiation (CD)34+ cells transduced with retroviral vector encoding ADA after non-myeloablative conditioning with busulfan |
| 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 | Survival | From post-treatment to up to 3 years | Posted | Count of Participants | Participants | baseline to 3 years post gene therapy |
|
|
Adverse events were collected from pre-treatment through year 3, post gene therapy
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Gene Therapy (Pivotal) | Infusion of autologous cluster of differentiation (CD)34+ cells transduced with retroviral vector encoding ADA after non-myeloablative conditioning with busulfan |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Device related infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Autoimmune haemolytic anemia | Blood and lymphatic system disorders | MedDRA 16.1 | Non-systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Fondazione Telethon | Fondazione Telethon | cvezzali@telethon.it |
Not provided
| ID | Term |
|---|---|
| D007153 | Immunologic Deficiency Syndromes |
| ID | Term |
|---|---|
| D007154 | Immune System Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D015316 | Genetic Therapy |
| D002066 | Busulfan |
| ID | Term |
|---|---|
| D001691 | Biological Therapy |
| D013812 | Therapeutics |
| D005818 | Genetic Engineering |
| D005821 | Genetic Techniques |
Not provided
Not provided
Not provided
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Not provided
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Not provided
|
| Busulfan | Drug | Busulfan is used for non-myeloablative conditioning |
|
| Before Treatment and 3-months post-treatment up to 3 years |
| CD3+ Cell Counts | T-lymphocyte counts (CD3+): mean T-lymphocyte at Baseline and 3 years post gene therapy. Samples were taken from peripheral venous whole blood and tested by cytofluorometry; values are means (10^6/L). | baseline up to 3 years post gene therapy |
| Milan |
| Lombardy |
| 20132 |
| Italy |
| Derived |
| Carriglio N, Klapwijk J, Hernandez RJ, Vezzoli M, Chanut F, Lowe R, Draghici E, Nord M, Albertini P, Cristofori P, Richards J, Staton H, Appleby J, Aiuti A, Sauer AV. Good Laboratory Practice Preclinical Safety Studies for GSK2696273 (MLV Vector-Based Ex Vivo Gene Therapy for Adenosine Deaminase Deficiency Severe Combined Immunodeficiency) in NSG Mice. Hum Gene Ther Clin Dev. 2017 Mar;28(1):17-27. doi: 10.1089/humc.2016.191. |
| 27129325 | Derived | Cicalese MP, Ferrua F, Castagnaro L, Pajno R, Barzaghi F, Giannelli S, Dionisio F, Brigida I, Bonopane M, Casiraghi M, Tabucchi A, Carlucci F, Grunebaum E, Adeli M, Bredius RG, Puck JM, Stepensky P, Tezcan I, Rolfe K, De Boever E, Reinhardt RR, Appleby J, Ciceri F, Roncarolo MG, Aiuti A. Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency. Blood. 2016 Jul 7;128(1):45-54. doi: 10.1182/blood-2016-01-688226. Epub 2016 Apr 29. |
| 22184407 | Derived | Sauer AV, Brigida I, Carriglio N, Hernandez RJ, Scaramuzza S, Clavenna D, Sanvito F, Poliani PL, Gagliani N, Carlucci F, Tabucchi A, Roncarolo MG, Traggiai E, Villa A, Aiuti A. Alterations in the adenosine metabolism and CD39/CD73 adenosinergic machinery cause loss of Treg cell function and autoimmunity in ADA-deficient SCID. Blood. 2012 Feb 9;119(6):1428-39. doi: 10.1182/blood-2011-07-366781. Epub 2011 Dec 19. |
| 19652199 | Derived | Cassani B, Montini E, Maruggi G, Ambrosi A, Mirolo M, Selleri S, Biral E, Frugnoli I, Hernandez-Trujillo V, Di Serio C, Roncarolo MG, Naldini L, Mavilio F, Aiuti A. Integration of retroviral vectors induces minor changes in the transcriptional activity of T cells from ADA-SCID patients treated with gene therapy. Blood. 2009 Oct 22;114(17):3546-56. doi: 10.1182/blood-2009-02-202085. Epub 2009 Aug 3. |
| 19633200 | Derived | Sauer AV, Mrak E, Hernandez RJ, Zacchi E, Cavani F, Casiraghi M, Grunebaum E, Roifman CM, Cervi MC, Ambrosi A, Carlucci F, Roncarolo MG, Villa A, Rubinacci A, Aiuti A. ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency. Blood. 2009 Oct 8;114(15):3216-26. doi: 10.1182/blood-2009-03-209221. Epub 2009 Jul 24. |
| 19179314 | Derived | Aiuti A, Cattaneo F, Galimberti S, Benninghoff U, Cassani B, Callegaro L, Scaramuzza S, Andolfi G, Mirolo M, Brigida I, Tabucchi A, Carlucci F, Eibl M, Aker M, Slavin S, Al-Mousa H, Al Ghonaium A, Ferster A, Duppenthaler A, Notarangelo L, Wintergerst U, Buckley RH, Bregni M, Marktel S, Valsecchi MG, Rossi P, Ciceri F, Miniero R, Bordignon C, Roncarolo MG. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. 2009 Jan 29;360(5):447-58. doi: 10.1056/NEJMoa0805817. |
| 18218852 | Derived | Cassani B, Mirolo M, Cattaneo F, Benninghoff U, Hershfield M, Carlucci F, Tabucchi A, Bordignon C, Roncarolo MG, Aiuti A. Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients. Blood. 2008 Apr 15;111(8):4209-19. doi: 10.1182/blood-2007-05-092429. Epub 2008 Jan 24. |
|
| Participants |
|
| Age, Continuous | Mean | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
| Secondary | Rate of Severe Infections | Severe infections were defined as those that required hospitalization or those that prolonged hospitalization. The rate of infection was estimated as number of severe infections over person-years of observation (free from severe infections) before and after treatment administration. The first 3 months after gene therapy were not considered in the post-gene therapy analysis, because all subjects were hospitalized during this period. | Posted | Number | Severe Infections per person year | Before Treatment and 3-months post-treatment up to 3 years |
|
|
|
|
| Secondary | CD3+ Cell Counts | T-lymphocyte counts (CD3+): mean T-lymphocyte at Baseline and 3 years post gene therapy. Samples were taken from peripheral venous whole blood and tested by cytofluorometry; values are means (10^6/L). | Only subjects with available data at each visit were included in the analysis | Posted | Geometric Mean | 95% Confidence Interval | 10^6 cells/L | baseline up to 3 years post gene therapy |
|
|
|
|
| 0 |
| 12 |
| 10 |
| 12 |
| 12 |
| 12 |
| Gastroenteritis | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Esptein-Barr virus infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Respiratory Tract Infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Upper Respiratory tract infection (bacterial) | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Urinary Tract Infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Varicella | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Aplastic anemia | Blood and lymphatic system disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Autoimmune thrombocytopenia | Blood and lymphatic system disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Pyrexia | General disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Autoimmune hepatitis | Hepatobiliary disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Lipofibroma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 16.1 | Non-systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Guillian-Barre Syndrome | Nervous system disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Eosinophilia | Blood and lymphatic system disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Febrile neutropenia | Blood and lymphatic system disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Rhinitis | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Device related infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Gastroenteritis | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Oral candidiasis | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Bronchitis | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Escherichia urinary tract infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Upper respiratory tract infection bacterial | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Urinary traction infection pseudomonal | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Varicella | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Hemophilus infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Otitis media | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Respiratory tract infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Gastroenteritis norovirus | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Gingivitis | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Influenza | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Otitis media acute | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Pharyngitis | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Pneumococcal infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Respiratory syncytial virus infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Skin infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Staphylococcal infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Streptococcal infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Tinea capitis | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Urinary tract infection enterococcal | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Viral diarrhea | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Computerized tomogram thorax abnormal | Investigations | MedDRA 16.1 | Non-systematic Assessment |
|
| Hepatic enzyme increased | Investigations | MedDRA 16.1 | Non-systematic Assessment |
|
| Blood immunoglobulin E increased | Investigations | MedDRA 16.1 | Non-systematic Assessment |
|
| Electrophoresis protein abnormal | Investigations | MedDRA 16.1 | Non-systematic Assessment |
|
| Blood alkaline phosphatase increased | Investigations | MedDRA 16.1 | Non-systematic Assessment |
|
| Pseudomonas test positive | Investigations | MedDRA 16.1 | Non-systematic Assessment |
|
| Tympanometry abnormal | Investigations | MedDRA 16.1 | Non-systematic Assessment |
|
| Weight decreased | Investigations | MedDRA 16.1 | Non-systematic Assessment |
|
| Adenovirus test positive | Investigations | MedDRA 16.1 | Non-systematic Assessment |
|
| Bacterial test positive | Investigations | MedDRA 16.1 | Non-systematic Assessment |
|
| Clostridium test positive | Investigations | MedDRA 16.1 | Non-systematic Assessment |
|
| Pulmonary function test abnormal | Investigations | MedDRA 16.1 | Non-systematic Assessment |
|
| Serum ferritin decreased | Investigations | MedDRA 16.1 | Non-systematic Assessment |
|
| Spirometry abnormal | Investigations | MedDRA 16.1 | Non-systematic Assessment |
|
| Staphylococcus test positive | Investigations | MedDRA 16.1 | Non-systematic Assessment |
|
| Total lung capacity decreased | Investigations | MedDRA 16.1 | Non-systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Pneumonitis | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Interstitial lung disease | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Productive cough | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Rhinorrhea | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Asthma | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Bronchial wall thickening | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Bronchospasm | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Nasal turbinate hypertrophy | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Pulmonary calcification | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Pulmonary mass | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Rhinitis allergic | Respiratory, thoracic and mediastinal disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Skin lesion | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Dermatitis | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Dermatitis atopic | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Skin ulcer | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Dermatitis diaper | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Drug eruption | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Dry skin | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Eczema | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Eczema nummular | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Erythema multiforme | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Lichen planus | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Petechiae | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Scab | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Urticaria | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Phimosis | Congenital, familial and genetic disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Cryptorchism | Congenital, familial and genetic disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Congenital genital malformation | Congenital, familial and genetic disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Micropenis | Congenital, familial and genetic disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Reproductive tract hypoplasia, male | Congenital, familial and genetic disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Enteritis | Gastrointestinal disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Gastroesophageal reflux disease | Gastrointestinal disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Dental caries | Gastrointestinal disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Oral disorder | Gastrointestinal disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Developmental delay | General disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Adverse drug reaction | General disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Device occlusion | General disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Cerebral hematoma | Nervous system disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Psychomotor hyperactivity | Nervous system disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Speech disorder | Nervous system disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Hepatomegaly | Hepatobiliary disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Autoimmune hepatitis | Hepatobiliary disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Gallbladder cholesterolosis | Hepatobiliary disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Hepatic fibrosis | Hepatobiliary disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Hepatic lesion | Hepatobiliary disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Bone development abnormal | Musculoskeletal and connective tissue disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Hypothyroidism | Endocrine disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Tibia fracture | Injury, poisoning and procedural complications | MedDRA 16.1 | Non-systematic Assessment |
|
| Wound | Injury, poisoning and procedural complications | MedDRA 16.1 | Non-systematic Assessment |
|
| Food aversion | Psychiatric disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Deafness bilateral | Ear and labyrinth disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Deafness | Ear and labyrinth disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Middle ear inflammation | Ear and labyrinth disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Amblyopia | Eye disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Hypermetropia | Eye disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Myopia | Eye disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Refraction disorder | Eye disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Pericardial effusion | Cardiac disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Pulmonary valve stenosis | Cardiac disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Sinus arrhythmia | Cardiac disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Wandering pacemaker | Cardiac disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Acquired phimosis | Reproductive system and breast disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Perineal erythema | Reproductive system and breast disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Hemangioma of liver | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 16.1 | Non-systematic Assessment |
|
| Lipofibroma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 16.1 | Non-systematic Assessment |
|
| Pyogenic granuloma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 16.1 | Non-systematic Assessment |
|
| Anaphylactic reaction | Immune system disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Hypertonic bladder | Renal and urinary disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Acidosis | Metabolism and nutrition disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Aspergillis infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Campylobacter infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Candida infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Catheter site infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Clostridium difficile colitis | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Clostridium difficile infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Ear infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Escherichia sepsis | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Fungal skin infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Sinusitis | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Staphylococcal sepsis | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Iron deficiency anaemia | Blood and lymphatic system disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Anaemia | Blood and lymphatic system disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Autoimmune thrombocytopenia | Blood and lymphatic system disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Pyrexia | General disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Epstein-Barr virus infection | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Respiratory Tract Infection, bacterial | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Urinary Tract Infection (bacterial) | Infections and infestations | MedDRA 16.1 | Non-systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA 16.1 | Non-systematic Assessment |
|
| Skin exfoliation | Skin and subcutaneous tissue disorders | MedDRA 16.1 | Non-systematic Assessment |
|
Not provided
| D008919 |
| Investigative Techniques |
| D002072 | Butylene Glycols |
| D006018 | Glycols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
| D008698 | Mesylates |
| D000476 | Alkanesulfonates |
| D017738 | Alkanesulfonic Acids |
| D000473 | Alkanes |
| D006839 | Hydrocarbons, Acyclic |
| D006838 | Hydrocarbons |
| D013451 | Sulfonic Acids |
| D013456 | Sulfur Acids |
| D013457 | Sulfur Compounds |
|
| Year 2 |
|
|
| Year 3 |
|
|
| <0.001 |
P value related to geometric mean ratio at 2 years post gene therapy compared to baseline |
| Geometric mean ratio |
| 5.4 |
| 2-Sided |
| 95 |
| 2.63 |
| 11.25 |
| Superiority |
| Mixed Model Repeated Measures | <0.001 | P value related to geometric mean ratio at 3 years post gene therapy compared to baseline | Geometric mean ratio | 6.5 | 2-Sided | 95 | 3.08 | 13.64 | Superiority |