Back to resultsCopper Concentration & Histopathologic Changes in Liver Biopsy in Participants With Wilson Disease Treated With ALXN1840
Primary Purpose
Wilson Disease
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Bis-Choline Tetrathiomolybdate
Sponsored by
About this trial
This is an interventional treatment trial for Wilson Disease focused on measuring Copper, ALXN1840, Histology, Liver Biopsy
Eligibility Criteria
Inclusion Criteria:
- Diagnosis of WD by Leipzig Criteria ≥ 4 or by historical test results.
- Continuous treatment for WD with penicillamine, trientine or zinc for at least 1 year prior to screening.
- Body mass index < 30 kilograms/meter squared.
- Able to cooperate with a percutaneous liver biopsy.
- Willing and able to follow protocol-specified contraception requirements.
- Capable of giving signed informed consent.
Exclusion Criteria:
- Decompensated cirrhosis or Model for End Stage Liver Disease score > 13.
- Modified Nazer score > 7.
- Clinically significant gastrointestinal bleed within past 3 months.
- Alanine aminotransferase > 2 × upper limit of normal.
- History of bleeding abnormality or known coagulopathy, including platelet count < 100,000, and international normalized ratio for prothrombin time ≥ 1.5.
- Participant unwilling to accept blood products, if required.
- Marked neurological disease requiring either nasogastric feeding tube or intensive inpatient medical care.
- Hemoglobin less than lower limit of the reference range for age and sex.
- Participants in renal failure, defined as in end-stage renal disease on dialysis (chronic kidney disease 5) or creatinine clearance < 30 milliliters/minute.
- Lymphoma, leukemia, or any malignancy within the past 5 years.
- Current or chronic history of liver disease not associated with WD.
Sites / Locations
- Clinical Trial Site
- Clinical Trial Site
- Clinical Trial Site
- Clinical Trial Site
- Clinical Trial Site
- Clinical Trial Site
- Clinical Trial Site
- Clinical Trial Site
- Clinical Trial Site
- Clinical Trial Site
- Clinical Trial Site
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
ALXN1840
Arm Description
Participants will receive ALXN1840.
Outcomes
Primary Outcome Measures
Change From Baseline in Liver Cu Concentration at Week 48 (Treatment Period)
Liver biopsy samples were taken for the assessment of liver Cu concentration. Multiple imputation was used to impute missing data at Week 48 due to any reason based on Baseline values.
Secondary Outcome Measures
Number of Participants With Change From Baseline in Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) Fibrosis Stage at Week 48 (Treatment Period)
Fibrosis from histology was evaluated by NASH CRN Fibrosis Stage, which was scaled from 0 to 4 stages where Score 0: None; Score 1: Perisinusoidal or periportal - 1a - mild, zone 3, perisinusoidal; Score 1: Perisinusoidal or periportal - 1b - moderate, zone 3, perisinusoidal; Score 1: Perisinusoidal or periportal - 1c - portal/periportal; Score 2: Both perisinusoidal and portal/periportal; Score 3: Bridging fibrosis; and Score 4: Cirrhosis. Higher scores indicated greater fibrosis.
Number of Participants With Change From Baseline in Metavir Fibrosis Score at Week 48 (Treatment Period)
Fibrosis from histology was evaluated by Metavir Fibrosis Score, which was ranged from 0 to 4 where Score 0: No fibrosis; Score 1: Stellate enlargement of portal tract but without septa formation; Score 2: Enlargement of portal tract with rare septa formation; Score 3: Numerous septa without cirrhosis; and Score 4: Cirrhosis. Higher scores indicated greater fibrosis.
Number of Participants With Change From Baseline in Ishak Fibrosis Score at Week 48 (Treatment Period)
Fibrosis from histology was evaluated by Ishak Fibrosis Score, which was ranged from 0 to 6 where Score 0: No fibrosis; Score 1: Fibrous expansion of some portal areas, with or without short fibrous septa; Score 2: Fibrous expansion of most portal areas, with or without short fibrous septa; Score 3: Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; and Score 4: Fibrous expansion of portal areas with marked bridging (P-P) as well as portal central (P-C); Score 5: Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); and Score 6: Cirrhosis, probable or definite. Higher scores indicated greater fibrosis.
Change From Baseline in Hepatic Collagen Content at Week 48 (Treatment Period)
Fibrosis from histology was evaluated by morphometric quantification of hepatic collagen content.
Change From Baseline in a-SMA Content at Week 48 (Treatment Period)
Fibrosis from histology was evaluated by morphometric quantification of hepatic a-SMA content.
Number of Participants With Change From Baseline in NAS Steatosis Grading Score at Week 48 (Treatment Period)
Steatosis from histology was evaluated by the steatosis component of the NAS, which was ranged from 0 to 3 where Score 0: < 5% (minimal); Score 1: 5 - 33% (mild); Score 2: 34 - 66% (moderate); and Score 3: > 66% (severe). Higher scores indicated greater steatosis.
Change From Baseline in Hepatic Fat Content at Week 48 (Treatment Period)
Steatosis from histology was evaluated by morphometric quantification of hepatic fat content.
Change From Baseline in NAS Total Score at Week 48 (Treatment Period)
Inflammation was quantified by the NAS total score. The score is defined as the unweighted sum of the scores for steatosis (0 [minimal] to 3 [severe]), lobular inflammation (0 [none] to 3 [>4 foci / 200x field]), and hepatocellular ballooning (0 [none] to 2 [many]), thus ranging from 0 (no inflammation) to 8 (severe inflammation), with higher scores indicating more severe disease.
Treatment Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An SAE was an AE that met at least 1 of the following criteria: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization for the AE, persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug), important medical event or reaction. The TEAEs were AEs with onset on or after the first study drug dose. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
Extension Period: Number of Participants With TEAEs
An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An SAE was an AE that met at least 1 of the following criteria: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization for the AE, persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug), important medical event or reaction. The TEAEs were AEs with onset on or after the first study drug dose. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
Treatment Period: Predose Trough Plasma Total Mo Concentration
Treatment Period: Predose Trough Plasma Total PUF Mo Concentration
Change From Baseline in Mo in Liver Biopsy Specimen at Week 48 (Treatment Period)
Clinical Global Impression-Improvement (CGI-I) Scale Score at Week 48 (Treatment Period)
The CGI-I is a 7-point scale clinician assessment where 1= very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; or 7 = very much worse. Higher scores indicated worsening of disease.
Change From Baseline in CGI-S Scale Score at Week 48 (Treatment Period)
The CGI-S is a 7-point scale clinician assessment. Participants were assessed on severity of illness at the time of rating/assessment as follows: 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; or 7 = extremely ill. Higher scores indicated worsening of disease.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04422431
Brief Title
Copper Concentration & Histopathologic Changes in Liver Biopsy in Participants With Wilson Disease Treated With ALXN1840
Official Title
A Phase 2, Single-arm Pathologist-blinded 48-week Study Using Liver Biopsy Specimens to Assess Copper Concentration and Histopathologic Changes in ALXN1840-treated Patients With Wilson Disease Followed by an up to 48-weeks Extension Period
Study Type
Interventional
2. Study Status
Record Verification Date
June 2023
Overall Recruitment Status
Completed
Study Start Date
December 2, 2020 (Actual)
Primary Completion Date
May 21, 2022 (Actual)
Study Completion Date
May 17, 2023 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Alexion
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The main objective of the study is to evaluate the change in liver copper (Cu) concentration following 48 weeks of treatment with ALXN1840 in adult participants with Wilson Disease (WD) who have been previously treated for at least 1 year with standard of care (that is, trientine, penicillamine, or zinc). In the Treatment Period, efficacy and safety of ALXN1840 will be assessed at Week 48.
Detailed Description
Participants who complete the 48-week Treatment Period will be offered the opportunity to continue their treatment in a 48-week Extension Period that will offer additional time for evaluation of long-term efficacy and safety of ALXN1840. There will be no liver biopsies during the Extension Period.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Wilson Disease
Keywords
Copper, ALXN1840, Histology, Liver Biopsy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Masking Description
This study is only pathologist-blinded for the assessments of liver histology samples.
Allocation
N/A
Enrollment
31 (Actual)
8. Arms, Groups, and Interventions
Arm Title
ALXN1840
Arm Type
Experimental
Arm Description
Participants will receive ALXN1840.
Intervention Type
Drug
Intervention Name(s)
Bis-Choline Tetrathiomolybdate
Other Intervention Name(s)
ALXN1840
Intervention Description
Participants will be initiated at 15 milligrams once daily, then the dose will be increased to 30 milligrams once daily at Week 6.
Primary Outcome Measure Information:
Title
Change From Baseline in Liver Cu Concentration at Week 48 (Treatment Period)
Description
Liver biopsy samples were taken for the assessment of liver Cu concentration. Multiple imputation was used to impute missing data at Week 48 due to any reason based on Baseline values.
Time Frame
Baseline, Week 48 (Treatment Period)
Secondary Outcome Measure Information:
Title
Number of Participants With Change From Baseline in Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) Fibrosis Stage at Week 48 (Treatment Period)
Description
Fibrosis from histology was evaluated by NASH CRN Fibrosis Stage, which was scaled from 0 to 4 stages where Score 0: None; Score 1: Perisinusoidal or periportal - 1a - mild, zone 3, perisinusoidal; Score 1: Perisinusoidal or periportal - 1b - moderate, zone 3, perisinusoidal; Score 1: Perisinusoidal or periportal - 1c - portal/periportal; Score 2: Both perisinusoidal and portal/periportal; Score 3: Bridging fibrosis; and Score 4: Cirrhosis. Higher scores indicated greater fibrosis.
Time Frame
Baseline, Week 48 (Treatment Period)
Title
Number of Participants With Change From Baseline in Metavir Fibrosis Score at Week 48 (Treatment Period)
Description
Fibrosis from histology was evaluated by Metavir Fibrosis Score, which was ranged from 0 to 4 where Score 0: No fibrosis; Score 1: Stellate enlargement of portal tract but without septa formation; Score 2: Enlargement of portal tract with rare septa formation; Score 3: Numerous septa without cirrhosis; and Score 4: Cirrhosis. Higher scores indicated greater fibrosis.
Time Frame
Baseline, Week 48 (Treatment Period)
Title
Number of Participants With Change From Baseline in Ishak Fibrosis Score at Week 48 (Treatment Period)
Description
Fibrosis from histology was evaluated by Ishak Fibrosis Score, which was ranged from 0 to 6 where Score 0: No fibrosis; Score 1: Fibrous expansion of some portal areas, with or without short fibrous septa; Score 2: Fibrous expansion of most portal areas, with or without short fibrous septa; Score 3: Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; and Score 4: Fibrous expansion of portal areas with marked bridging (P-P) as well as portal central (P-C); Score 5: Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); and Score 6: Cirrhosis, probable or definite. Higher scores indicated greater fibrosis.
Time Frame
Baseline, Week 48 (Treatment Period)
Title
Change From Baseline in Hepatic Collagen Content at Week 48 (Treatment Period)
Description
Fibrosis from histology was evaluated by morphometric quantification of hepatic collagen content.
Time Frame
Baseline, Week 48 (Treatment Period)
Title
Change From Baseline in a-SMA Content at Week 48 (Treatment Period)
Description
Fibrosis from histology was evaluated by morphometric quantification of hepatic a-SMA content.
Time Frame
Baseline, Week 48 (Treatment Period)
Title
Number of Participants With Change From Baseline in NAS Steatosis Grading Score at Week 48 (Treatment Period)
Description
Steatosis from histology was evaluated by the steatosis component of the NAS, which was ranged from 0 to 3 where Score 0: < 5% (minimal); Score 1: 5 - 33% (mild); Score 2: 34 - 66% (moderate); and Score 3: > 66% (severe). Higher scores indicated greater steatosis.
Time Frame
Baseline, Week 48 (Treatment Period)
Title
Change From Baseline in Hepatic Fat Content at Week 48 (Treatment Period)
Description
Steatosis from histology was evaluated by morphometric quantification of hepatic fat content.
Time Frame
Baseline, Week 48 (Treatment Period)
Title
Change From Baseline in NAS Total Score at Week 48 (Treatment Period)
Description
Inflammation was quantified by the NAS total score. The score is defined as the unweighted sum of the scores for steatosis (0 [minimal] to 3 [severe]), lobular inflammation (0 [none] to 3 [>4 foci / 200x field]), and hepatocellular ballooning (0 [none] to 2 [many]), thus ranging from 0 (no inflammation) to 8 (severe inflammation), with higher scores indicating more severe disease.
Time Frame
Baseline, Week 48 (Treatment Period)
Title
Treatment Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Description
An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An SAE was an AE that met at least 1 of the following criteria: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization for the AE, persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug), important medical event or reaction. The TEAEs were AEs with onset on or after the first study drug dose. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
Time Frame
Day 1 (Treatment Period) up to Week 48 (Treatment Period)
Title
Extension Period: Number of Participants With TEAEs
Description
An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An SAE was an AE that met at least 1 of the following criteria: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization for the AE, persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug), important medical event or reaction. The TEAEs were AEs with onset on or after the first study drug dose. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
Time Frame
Day 1 (Extension Period) up data cutoff date of 29 Jul 2022 (up to Week 86)
Title
Treatment Period: Predose Trough Plasma Total Mo Concentration
Time Frame
Predose up to 4 hours postdose at Week 6 (Day 43) and Week 36 (Day 253)
Title
Treatment Period: Predose Trough Plasma Total PUF Mo Concentration
Time Frame
Predose up to 4 hours postdose at Week 6 (Day 43) and Week 36 (Day 253)
Title
Change From Baseline in Mo in Liver Biopsy Specimen at Week 48 (Treatment Period)
Time Frame
Baseline, Week 48 (Treatment Period)
Title
Clinical Global Impression-Improvement (CGI-I) Scale Score at Week 48 (Treatment Period)
Description
The CGI-I is a 7-point scale clinician assessment where 1= very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; or 7 = very much worse. Higher scores indicated worsening of disease.
Time Frame
Week 48 (Treatment Period)
Title
Change From Baseline in CGI-S Scale Score at Week 48 (Treatment Period)
Description
The CGI-S is a 7-point scale clinician assessment. Participants were assessed on severity of illness at the time of rating/assessment as follows: 1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; or 7 = extremely ill. Higher scores indicated worsening of disease.
Time Frame
Baseline, Week 48 (Treatment Period)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Diagnosis of WD by Leipzig Criteria ≥ 4 or by historical test results.
Continuous treatment for WD with penicillamine, trientine or zinc for at least 1 year prior to screening.
Body mass index < 30 kilograms/meter squared.
Able to cooperate with a percutaneous liver biopsy.
Willing and able to follow protocol-specified contraception requirements.
Capable of giving signed informed consent.
Exclusion Criteria:
Decompensated cirrhosis or Model for End Stage Liver Disease score > 13.
Modified Nazer score > 7.
Clinically significant gastrointestinal bleed within past 3 months.
Alanine aminotransferase > 2 × upper limit of normal.
History of bleeding abnormality or known coagulopathy, including platelet count < 100,000, and international normalized ratio for prothrombin time ≥ 1.5.
Participant unwilling to accept blood products, if required.
Marked neurological disease requiring either nasogastric feeding tube or intensive inpatient medical care.
Hemoglobin less than lower limit of the reference range for age and sex.
Participants in renal failure, defined as in end-stage renal disease on dialysis (chronic kidney disease 5) or creatinine clearance < 30 milliliters/minute.
Lymphoma, leukemia, or any malignancy within the past 5 years.
Current or chronic history of liver disease not associated with WD.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Eugene S. Swenson, MD, PhD
Organizational Affiliation
Alexion
Official's Role
Study Director
Facility Information:
Facility Name
Clinical Trial Site
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Facility Name
Clinical Trial Site
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Clinical Trial Site
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Facility Name
Clinical Trial Site
City
Aarhus
Country
Denmark
Facility Name
Clinical Trial Site
City
Auckland
Country
New Zealand
Facility Name
Clinical Trial Site
City
Moscow
Country
Russian Federation
Facility Name
Clinical Trial Site
City
St. Petersburg
Country
Russian Federation
Facility Name
Clinical Trial Site
City
Singapore
ZIP/Postal Code
169608
Country
Singapore
Facility Name
Clinical Trial Site
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Facility Name
Clinical Trial Site
City
Valencia
ZIP/Postal Code
46026
Country
Spain
Facility Name
Clinical Trial Site
City
London
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Copper Concentration & Histopathologic Changes in Liver Biopsy in Participants With Wilson Disease Treated With ALXN1840
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