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| ID | Type | Description | Link |
|---|---|---|---|
| 1R21DK092567-01 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| Novartis | INDUSTRY |
| National Institutes of Health (NIH) | NIH |
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
| University of Pittsburgh |
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The primary objective is to determine if the medication Carbamazepine, can be used as a therapy for patients with severe liver disease due to Alpha-1-Antitrypsin Deficiency .
The primary objective is to determine if Carbamazepine therapy in patients with severe liver disease due to Alpha-1-Antitrypsin Deficiency leads to a significant reduction in the hepatic accumulation of ATZ.
The other objectives are:
To determine whether Carbamazepine treatment reduces hepatic fibrosis in alpha-1-antitrypsin deficient patients with severe liver disease. To determine whether Carbamazepine treatment reduces portal pressure in alpha-1-antitrypsin deficient patients with severe liver disease. To determine whether Carbamazepine treatment is safe and tolerated by patients with severe liver disease caused by alpha-1-deficiency. To determine whether Carbamazepine treatment leads to stabilization in disease severity as measured by the MELD scores.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Drug-Carbamazepine (Tegretol XR) | Active Comparator | One arm receives Drug-Carbamazepine (Tegretol XR).All subjects have severe liver disease due to alpha-1-antitrypsin deficiency. |
|
| Drug-Carbamazepine (Tegretol XR) Placebo | Placebo Comparator | One arm receives Carbamazepine (Tegretol-XR) placebo.All subjects have severe liver disease due to alpha-1-antitrypsin deficiency. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Drug-Carbamazepine (Tegretol XR) | Drug | To reduce the likelihood of hypersensitivity reactions the subjects will be started on 400 mg/day in 2 doses and the dose will be increased weekly by 200mg/day until reaching a stable therapeutic concentration with a dose not exceeding 1200mg/day(or 1000mg/day in subjects less than 15 years of age). The CBZ tablets will be encapsulated.. |
| Measure | Description | Time Frame |
|---|---|---|
| The Primary Outcome Will be to Determine the Effect of Carbamazepine on Hepatic ATZ Load. | The effect of Carbamazepine on hepatic ATZ load will be measured by the number of hepatocytes with PAS+/diastase-resistant globules and/or steady state levels of ATZ by immunoblot analysis. | 52 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| For the Secondary Outcomes we Will Determine the Effect of Carbamazepine Treatment on Hepatic Fibrosis. | For the secondary outcomes we will determine the effect of Carbamazepine treatment on hepatic fibrosis on the basis of sirius red staining and hydroxyproline concentration and whether Carbamazepine treatment changes portal pressure as determined by Hepatic Venous Pressure Gradient. | 52 weeks |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| David H. Perlmutter, M.D. | Washington University School of Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Washington University in St. Louis School of Medicine | St Louis | Missouri | 63110 | United States | ||
| Children's Hospital of Pittsburgh, UPMC |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| Background | Perlmutter D.H., Alpha-1-Antitrypsin Deficiency, in Schiff's Disease of Liver, Schiff E.R., Maddrey W.C., Editor. 2007; Lippincott-Raven: Philadelphia. 1063-1084. | ||
| 16864711 | Background | Perlmutter DH. Pathogenesis of chronic liver injury and hepatocellular carcinoma in alpha-1-antitrypsin deficiency. Pediatr Res. 2006 Aug;60(2):233-8. doi: 10.1203/01.pdr.0000228350.61496.90. | |
| 18617899 |
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We will share data and liver tissue with other researchers. They may be doing research in areas similar to this research or in other unrelated areas. These researchers may be at Washington University, at other research centers and institutions, or industry sponsors of research. We may also share research data with large data repositories (a repository is a database of information) for broad sharing with the research community. If individual research data is placed in one of these repositories only qualified researchers, who have received prior approval from individuals that monitor the use of the data, will be able to look at the information.
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| ID | Title | Description |
|---|---|---|
| FG000 | Drug-Carbamazepine (Tegretol XR) | One arm receives Drug-Carbamazepine (Tegretol XR).All subjects have severe liver disease due to alpha-1-antitrypsin deficiency. Drug-Carbamazepine (Tegretol XR): To reduce the likelihood of hypersensitivity reactions the subjects will be started on 400 mg/day in 2 doses and the dose will be increased weekly by 200mg/day until reaching a stable therapeutic concentration with a dose not exceeding 1200mg/day(or 1000mg/day in subjects less than 15 years of age). The CBZ tablets will be encapsulated. |
| FG001 | Drug-Carbamazepine (Tegretol XR) Placebo | One arm receives Carbamazepine (Tegretol-XR) placebo.All subjects have severe liver disease due to alpha-1-antitrypsin deficiency. Carbamazepine (Tegretol XR) Placebo: Carbamazepine (Tegretol XR)Placebo-the subjects will be started on 400mg/day in 2 doses and the dose will be increased weekly by 200 mg/day until reaching a dose not exceeding 1200 mg/day (or 1000 mg/day in subjects less than 15 years of age). The placebo group will receive encapsulated tables without Carbamazepine. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Drug-Carbamazepine (Tegretol XR) | One arm receives Drug-Carbamazepine (Tegretol XR).All subjects have severe liver disease due to alpha-1-antitrypsin deficiency. Drug-Carbamazepine (Tegretol XR): To reduce the likelihood of hypersensitivity reactions the subjects will be started on 400 mg/day in 2 doses and the dose will be increased weekly by 200mg/day until reaching a stable therapeutic concentration with a dose not exceeding 1200mg/day(or 1000mg/day in subjects less than 15 years of age). The CBZ tablets will be encapsulated, and the placebo group will receive encapsulated tablets without CBZ. |
| 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 | The Primary Outcome Will be to Determine the Effect of Carbamazepine on Hepatic ATZ Load. | The effect of Carbamazepine on hepatic ATZ load will be measured by the number of hepatocytes with PAS+/diastase-resistant globules and/or steady state levels of ATZ by immunoblot analysis. | The primary outcome was not assessable because the number of subjects with available pre & post PAS+/diastase stained liver biopsies & tissue for immunoblot was insufficient in subject number and sample quality. To elaborate only 3 subjects had both pre & post biopsies stained for PAS, 2 from the placebo & 1 from the Carbamazepine arms & the available histology quality was insufficient for histomorphormetry. Frozen liver samples were also of insufficient number & mass for immunoblot. | Posted | 52 weeks |
|
Serious Adverse Events and Adverse Events were collected for 52 weeks.
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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 | Drug-Carbamazepine (Tegretol XR) | One arm receives Drug-Carbamazepine (Tegretol XR).All subjects have severe liver disease due to alpha-1-antitrypsin deficiency. Drug-Carbamazepine (Tegretol XR): To reduce the likelihood of hypersensitivity reactions the subjects will be started on 400 mg/day in 2 doses and the dose will be increased weekly by 200mg/day until reaching a stable therapeutic concentration with a dose not exceeding 1200mg/day(or 1000mg/day in subjects less than 15 years of age). The CBZ tablets will be encapsulated, and the placebo group will receive encapsulated tablets without CBZ. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastrointestinal | Gastrointestinal disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cardiac | Cardiac disorders | Systematic Assessment |
The primary & secondary outcomes could not be assessed because the number of subjects with available pre & post biopsies was insufficient in subject number and sample quality to conduct the analyses. As described in more detail in Outcome Measures.
.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| David Rudnick MD, PhD- Associate Professor | Washington University School of Medicine | 314-286-2832 | rudnick_d@wustl.edu |
Not provided
| 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 | Feb 19, 2016 | Oct 20, 2020 | Prot_SAP_000.pdf |
Not provided
| ID | Term |
|---|---|
| D019896 | alpha 1-Antitrypsin Deficiency |
| D008103 | Liver Cirrhosis |
| D008107 | Liver Diseases |
| ID | Term |
|---|---|
| D004066 | Digestive System Diseases |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D030342 | Genetic Diseases, Inborn |
Not provided
Not provided
| ID | Term |
|---|---|
| D002220 | Carbamazepine |
| ID | Term |
|---|---|
| D003984 | Dibenzazepines |
| D006575 | Heterocyclic Compounds, 3-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
Not provided
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| OTHER |
Not provided
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|
|
| Carbamazepine (Tegretol XR) Placebo | Drug | Carbamazepine (Tegretol XR)Placebo-the subjects will be started on 400mg/day in 2 doses and the dose will be increased weekly by 200 mg/day until reaching a dose not exceeding 1200 mg/day (or 1000 mg/day in subjects less than 15 years of age). The placebo group will receive encapsulated tables without Carbamazepine. |
|
|
| Pittsburgh |
| Pennsylvania |
| 15201 |
| United States |
| University of Pittsburgh Medical Center, Presbyterian Hospital | Pittsburgh | Pennsylvania | 15213 | United States |
| Background |
| Perlmutter DH. Autophagic disposal of the aggregation-prone protein that causes liver inflammation and carcinogenesis in alpha-1-antitrypsin deficiency. Cell Death Differ. 2009 Jan;16(1):39-45. doi: 10.1038/cdd.2008.103. Epub 2008 Jul 11. |
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| 23664631 | Derived | Silverman GA, Pak SC, Perlmutter DH. Disorders of protein misfolding: alpha-1-antitrypsin deficiency as prototype. J Pediatr. 2013 Aug;163(2):320-6. doi: 10.1016/j.jpeds.2013.03.077. Epub 2013 May 8. No abstract available. |
| BG001 | Drug-Carbamazepine (Tegretol XR) Placebo | One arm receives Carbamazepine (Tegretol-XR) placebo.All subjects have severe liver disease due to alpha-1-antitrypsin deficiency. Carbamazepine (Tegretol XR) Placebo: Carbamazepine (Tegretol XR)Placebo-the subjects will be started on 400mg/day in 2 doses and the dose will be increased weekly by 200 mg/day until reaching a dose not exceeding 1200 mg/day (or 1000 mg/day in subjects less than 15 years of age). The placebo group will receive encapsulated tables without Carbamazepine. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Drug-Carbamazepine (Tegretol XR) Placebo | One arm receives Carbamazepine (Tegretol-XR) placebo.All subjects have severe liver disease due to alpha-1-antitrypsin deficiency. Carbamazepine (Tegretol XR) Placebo: Carbamazepine (Tegretol XR)Placebo-the subjects will be started on 400mg/day in 2 doses and the dose will be increased weekly by 200 mg/day until reaching a dose not exceeding 1200 mg/day (or 1000 mg/day in subjects less than 15 years of age). The placebo group will receive encapsulated tables without Carbamazepine. |
|
| Secondary | For the Secondary Outcomes we Will Determine the Effect of Carbamazepine Treatment on Hepatic Fibrosis. | For the secondary outcomes we will determine the effect of Carbamazepine treatment on hepatic fibrosis on the basis of sirius red staining and hydroxyproline concentration and whether Carbamazepine treatment changes portal pressure as determined by Hepatic Venous Pressure Gradient. | The secondary outcome was also not assessable because the number of subjects with available pre & post trichrome stained liver biopsies & tissue for hydroxyproline was also insufficient in subject number and sample quality. Again only 3 subjects had both pre & post biopsies stained for trichrome, 2 placebo- & 1 Carbamazepine treated. Available histology quality was also insufficient here for histomorphormetry &.frozen liver samples insufficient for hydroxyproline determination. | Posted | 52 weeks |
|
|
| 0 |
| 13 |
| 6 |
| 13 |
| 13 |
| 13 |
| EG001 | Drug-Carbamazepine (Tegretol XR) Placebo | One arm receives Carbamazepine (Tegretol-XR) placebo.All subjects have severe liver disease due to alpha-1-antitrypsin deficiency. Carbamazepine (Tegretol XR) Placebo: Carbamazepine (Tegretol XR)Placebo-the subjects will be started on 400mg/day in 2 doses and the dose will be increased weekly by 200 mg/day until reaching a dose not exceeding 1200 mg/day (or 1000 mg/day in subjects less than 15 years of age). The placebo group will receive encapsulated tables without Carbamazepine. | 2 | 7 | 4 | 7 | 7 | 7 |
| Pain | General disorders | Systematic Assessment |
|
| Pulmonary | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Cardiac | Cardiac disorders | Systematic Assessment |
|
| Infection | Infections and infestations | Systematic Assessment |
|
| Vascular | Vascular disorders | Systematic Assessment |
|
| Constitutional | General disorders | Systematic Assessment |
|
| Hematologic | Blood and lymphatic system disorders | Systematic Assessment |
|
| Metabolic/Laboratory | Metabolism and nutrition disorders | Systematic Assessment |
|
| Child-Pugh Score Increase | Hepatobiliary disorders | Systematic Assessment |
|
| Constitutional | General disorders | Systematic Assessment |
|
| Dermatologic | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Endocrine | Endocrine disorders | Systematic Assessment |
|
| Gastrointestinal | Gastrointestinal disorders | Systematic Assessment |
|
| Genitourological | Renal and urinary disorders | Systematic Assessment |
|
| Gynecological | Reproductive system and breast disorders | Systematic Assessment |
|
| Hematologic | Blood and lymphatic system disorders | Systematic Assessment |
|
| Infection | Infections and infestations | Systematic Assessment |
|
| Metabolic/Laboratory | Metabolism and nutrition disorders | Systematic Assessment |
|
| Musculoskeletal | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Neurologic | Nervous system disorders | Systematic Assessment |
|
| Pain | General disorders | Systematic Assessment |
|
| Pulmonary | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Vascular | Vascular disorders | Systematic Assessment |
|
Not provided
Not provided
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D013352 | Subcutaneous Emphysema |
| D004646 | Emphysema |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D005355 | Fibrosis |