Alpha-1-antitrypsin Deficiency, Liver Cirrhosis
Conditions
Keywords
Carbamazepine (Tegretol) use, severe liver disease, alpha-1-antitrypsin deficiency
Brief summary
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 .
Detailed description
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.
Interventions
DRUGDrug-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..
DRUGCarbamazepine (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.
Sponsors
Novartis
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Pittsburgh
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
14 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Age greater than or equal to 14 years to less than or equal to 80 years of age. * Alpha-1-Antitrypsin deficiency confirmed by ZZ or SZ phenotype & serum level * \< 83mg/dl. * HVPG greater than or equal to 10 mmHg unless collateral vessels are visualized via transvenous biopsy.
Exclusion criteria
* Child Pugh Score greater than or equal to 12. Serum total bilirubin \> 5 mg/dl. INR \> 2.2.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Outcome Will be to Determine the Effect of Carbamazepine on Hepatic ATZ Load. | 52 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| For the Secondary Outcomes we Will Determine the Effect of Carbamazepine Treatment on Hepatic Fibrosis. | 52 weeks | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 13 |
| 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. | 7 |
| Total | 20 |
Baseline characteristics
| Characteristic | Drug-Carbamazepine (Tegretol XR) Placebo | Total | Drug-Carbamazepine (Tegretol XR) |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 1 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 3 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 16 Participants | 13 Participants |
| Age, Continuous | 53.7 years STANDARD_DEVIATION 19.6 | 51.75 years STANDARD_DEVIATION 13.38 | 50.7 years STANDARD_DEVIATION 9.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 20 Participants | 13 Participants |
| Region of Enrollment United States | 7 participants | 20 participants | 13 participants |
| Sex: Female, Male Female | 3 Participants | 8 Participants | 5 Participants |
| Sex: Female, Male Male | 4 Participants | 12 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 2 / 7 |
| other Total, other adverse events | 13 / 13 | 7 / 7 |
| serious Total, serious adverse events | 6 / 13 | 4 / 7 |
Outcome results
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.
Time frame: 52 weeks
Population: 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.
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.
Time frame: 52 weeks
Population: 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.