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The main purpose of the study was to evaluate the efficacy of ALXN1840 (formerly WTX101) for 24 weeks on non-ceruloplasmin-bound copper (NCC) concentrations adjusted for molybdenum plasma concentration in participants newly diagnosed with Wilson Disease (WD) who were aged 18 and older and who had NCC concentrations within or above the reference range at the time of enrollment in the study. The study consisted of a 24-week Treatment Period, followed by a planned 36-month Extension Period.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| ALXN1840 | Experimental | Treatment Period: ALXN1840 at individualized doses ranging from 15 to 60 milligram (mg) per day. Dose increases or dose reductions were dependent on the individual NCC concentrations adjusted for Mo plasma concentration. ALXN1840 may have been administered every other day, once daily, or twice daily, depending on individualized dosing regimen, for 24 weeks. Extension Period: Participants continued the same ALXN1840 daily dose maintained at Week 24 of the Treatment Period and the same dosing regimen. During the Extension Period, no up-titration was made unless NCC concentrations adjusted for Mo plasma concentration did not remain stable within (or below) the reference range. ALXN1840 could have been received for up to 36 months in the Extension Period. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| ALXN1840 | Drug | Individualized oral doses of ALXN1840. |
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| Measure | Description | Time Frame |
|---|---|---|
| Percentage Of Participants With Normalized Concentrations Of NCC | Normalized concentrations of NCC was defined as who achieving or maintaining normalized levels of NCC (0.8 to 2.3 micromole [μmol]l/liter [L]]) adjusted for Mo plasma concentration or reaching a reduction of at least 25% in NCC corrected for Mo if above the normal reference range at the time of enrollment. NCC was calculated by subtracting the amount of copper (Cu) bound to ceruloplasmin (CP) from the total plasma Cu concentration. Post-baseline NCC values were adjusted (corrected) to account for Cu bound in tripartite complexes with ALXN1840 and albumin. Descriptive statistics are reported. | Week 24 |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline In NCC Concentrations Adjusted For Mo Plasma Concentration At Week 24 | The change from Baseline in NCC adjusted for Mo plasma concentration over 24 weeks were analyzed and descriptive statistics are reported. Change from Baseline = (Week 24 NCC concentrations adjusted for Mo plasma concentration) - (Baseline NCC concentrations). Least square means and their 95% confidence intervals (CIs) were calculated using a restricted maximum likelihood (REML)-based mixed model for repeated measures (MMRM) with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Eugene Swenson, MD, PhD | Alexion Pharmaceuticals, Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Clinical Trial Site | Los Angeles | California | 90095 | United States | ||
| Clinical Trial Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28988934 | Result | Weiss KH, Askari FK, Czlonkowska A, Ferenci P, Bronstein JM, Bega D, Ala A, Nicholl D, Flint S, Olsson L, Plitz T, Bjartmar C, Schilsky ML. Bis-choline tetrathiomolybdate in patients with Wilson's disease: an open-label, multicentre, phase 2 study. Lancet Gastroenterol Hepatol. 2017 Dec;2(12):869-876. doi: 10.1016/S2468-1253(17)30293-5. Epub 2017 Oct 5. |
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Participants meeting all inclusion and no exclusion criteria were enrolled into the study and studied as outpatients. Participants enrolled as pre-treated with other de-coppering agents were required to undergo a 48-hour washout from their previous Wilson Disease (WD) treatment just prior to initiation of study treatment. Participants who completed the 24-week treatment period and had favorable safety profiles and WD control were offered the opportunity to participate in the Extension Period.
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| ID | Title | Description |
|---|---|---|
| FG000 | ALXN1840 | Treatment Period: ALXN1840 at individualized doses ranging from 15 to 60 milligrams (mg) per day. Dose increases or dose reductions were dependent on the individual non-ceruloplasmin-bound copper (NCC) concentrations adjusted for molybdenum (Mo) plasma concentration. ALXN1840 may have been administered every other day, once daily, or twice daily, depending on individualized dosing regimen, for 24 weeks. Extension Period: Participants continued the same ALXN1840 daily dose maintained at Week 24 of the Treatment Period and the same dosing regimen. During the Extension Period, no up-titration was made unless NCC concentrations adjusted for Mo plasma concentration did not remain stable within (or below) the reference range. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 24-Week Treatment Period |
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| Extension Period |
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Participants who were enrolled and received at least 1 dose of study drug.
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| ID | Title | Description |
|---|---|---|
| BG000 | ALXN1840 | Treatment Period: ALXN1840 at individualized doses ranging from 15 to 60 mg per day. Dose increases or dose reductions were dependent on the individual NCC concentrations adjusted for Mo plasma concentration. ALXN1840 may have been administered every other day, once daily, or twice daily, depending on individualized dosing regimen, for 24 weeks. Extension Period: Participants continued the same ALXN1840 daily dose maintained at Week 24 of the Treatment Period and the same dosing regimen. During the Extension Period, no up-titration was made unless NCC concentrations adjusted for Mo plasma concentration did not remain stable within (or below) the reference range. |
| Units | Counts |
|---|---|
| Participants |
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| 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 | Percentage Of Participants With Normalized Concentrations Of NCC | Normalized concentrations of NCC was defined as who achieving or maintaining normalized levels of NCC (0.8 to 2.3 micromole [μmol]l/liter [L]]) adjusted for Mo plasma concentration or reaching a reduction of at least 25% in NCC corrected for Mo if above the normal reference range at the time of enrollment. NCC was calculated by subtracting the amount of copper (Cu) bound to ceruloplasmin (CP) from the total plasma Cu concentration. Post-baseline NCC values were adjusted (corrected) to account for Cu bound in tripartite complexes with ALXN1840 and albumin. Descriptive statistics are reported. | Participants who were enrolled and received at least 1 dose of study drug. | Posted | Number | 95% Confidence Interval | percentage of participants | Week 24 |
|
Day 1 after dosing up to last assessment (up to Week 176), mean duration of treatment of 693.1 days
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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 | ALXN1840 | Treatment Period: ALXN1840 at individualized doses ranging from 15 to 60 mg per day. Dose increases or dose reductions were dependent on the individual NCC concentrations adjusted for Mo plasma concentration. ALXN1840 may have been administered every other day, once daily, or twice daily, depending on individualized dosing regimen, for 24 weeks. Extension Period: Participants continued the same ALXN1840 daily dose maintained at Week 24 of the Treatment Period and the same dosing regimen. During the Extension Period, no up-titration was made unless NCC concentrations adjusted for Mo plasma concentration did not remain stable within (or below) the reference range. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Agranulocytosis | Blood and lymphatic system disorders | MedDRA 21.1 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Leukopenia | Blood and lymphatic system disorders | 21.1 | Systematic Assessment |
Due to low chromatographic resolution of data, quantitative analysis for speciation profiling, as had been planned in the protocol, was not feasible.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Alexion Pharmaceuticals Inc. | Alexion Pharmaceuticals Inc. | 855-752-2356 | clinicaltrials@alexion.com |
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| ID | Term |
|---|---|
| D006527 | Hepatolenticular Degeneration |
| ID | Term |
|---|---|
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| D001480 | Basal Ganglia Diseases |
| D001927 | Brain Diseases |
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| Baseline, Week 24 |
| Time To Normalization Of NCC Adjusted For Mo Plasma Concentration In Participants With Elevated Baseline NCC | For time to normalization of NCC adjusted for Mo plasma concentration, a Kaplan-Meier approach was used where participants not normalized were censored at the latest observed time point. To achieve a normalized NCC concentration, participants must have demonstrated 2 consecutive measures within the normal range (0.8 to 2.3 μmol/L). Analyses includes all data up to the last assessment in the extension period for participants who reached the event of normalization of NCC corrected concentrations. Last Assessment is a summary of the last available post-baseline result for each participant. Analyses includes all data up to the last assessment in the extension period; up to Week 176. | Up to last assessment (up to Week 176) |
| Change From Baseline In Neurological Status Using The Unified Wilson's Disease Rating Scale (UWDRS) (Neurological Subscore; Part I) At Week 24 | The UWDRS is a clinical rating scale designed to evaluate the neurological manifestations of WD. Change from Baseline in the UWDRS I for consciousness is presented.
| Baseline, Week 24 |
| Change From Baseline In Neurological Status Using The UWDRS (Neurological Subscore; Parts II, III, And Total Score) At Week 24 | The UWDRS is a clinical rating scale designed to evaluate the neurological manifestations of WD. UWDRS comprises 3 parts: UWDRS I (consciousness), UWDRS II (disability), and UWDRS III (neurological status). Change from Baseline in the UWDRS II, III, and total score are presented.
| Baseline, Week 24 |
| Change From Baseline In Psychiatric Status Dimension Using Mini International Neuropsychiatric Interview (M.I.N.I.) Tracking Standardized Scores At Week 24 | The M.I.N.I. is a short structured diagnostic interview for the Diagnostic and Statistical Manual of Mental Disorders IV and the 10th revision of the International Statistical Classification of Diseases and Related Health Problems. It was used to "track" the severity of symptoms by using a combination of questions in 16 Psychiatric Status dimensions that are summarized using a single standardized score for each dimension, ranging from 0 (interpreted as "did not occur at all") to 4 (interpreted as "occurred extremely often"). The standardized score is an average of these responses. Change from Baseline = Week 24 standardized score - Baseline standardized score. Least square means and 95% CIs were calculated using an REML-based MMRM with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction. Decrease from Baseline (a lower score) is indicative of a decrease in symptoms and a better outcome. | Baseline, Week 24 |
| Clinical Global Impression-Improvement Scale (CGI-I) At Week 24 | The CGI-I is a 7-point scale where the clinician assessed how much participant's illness improved or worsened relative to a Baseline state at the beginning of the intervention and rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. Change from Baseline = Week 24 score - Baseline score. An increase in CGI-I score indicates improvement. | Week 24 |
| Change From Baseline In Clinical Global Impression Severity Scale (CGI-S) At Week 24 | The CGI-S is a 7-point scale where the investigator rated severity of participant's illness at the time of assessment, relative to the investigator's past experience with participants who have the same diagnosis. Considering total clinical experience, a participant was assessed on severity of illness at time of rating as: 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. Change from Baseline = Week 24 score - Baseline score. Decrease in CGI-S score and increase indicates improvement. | Baseline, Week 24 |
| Change From Baseline In Quality Of Life (QoL)/Patient Reported Outcome (PRO) Assessed By The European Quality Of Life 5 Dimensions (EQ-5D) Visual Analogue Scale (VAS) At Week 24 | The EQ-5D VAS records the participant's self-rated health as indicated on a scale from 0 to 100 with 0 being "the worst health you can imagine" and 100 being "the best health you can imagine, with higher scores for a higher quality of life. Change from Baseline = Week 24 score - Baseline score. An increase in score indicates improvement. The least-square means and their 95% CIs were calculated using a REML-based MMRM with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction. | Baseline, Week 24 |
| Change From Baseline In Quality Of Life (QoL)/Patient Reported Outcome (PRO) Assessed By The EQ-5D Descriptive System UK Health Index Scores At Week 24 | The EQ-5D-5L Descriptive System provides a simple descriptive profile and a single index value for health status (United Kingdom [UK] Health Index Score). The EQ-5D-5L consists of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each of which can have 1 of 5 responses that represent 5 levels of severity (no problems, slight problems, moderate problems, severe problems, extreme problems). The participant was asked to indicate his/her health state for each of the 5 dimensions. The 5-item index score was transformed into a utility score between 0 (worst health state) and 1 (best health state). Change from Baseline = Week 24 index score - Baseline index score. An increase in score indicates improvement. The least square means and their 95% CIs were calculated using a REML-based MMRM with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction. | Baseline, Week 24 |
| QoL/PRO Assessed By The 8-Item Medication Adherence Scale (MMAS-8) At Week 24 | The MMAS-8 is a scale used to evaluate adherence to medication. The MMAS-8 consists of 8 questions with a sum score ranging between 0 and 8 points, with 8 being the maximum adherence to medication. Mean adherence to medication is presented. | Week 24 |
| QoL/PRO Assessed By The Treatment Satisfaction Questionnaire For Medication (TSQM-9) At Week 24 | The TSQM-9 was used to assess the overall level of satisfaction or dissatisfaction with medication participants were taking. This composite scale is comprised of 2 items on the TSQM-9 survey: How satisfied are you that good things about this medication outweigh the bad things? Taking all things into account, how satisfied or dissatisfied are you with this medication? The TSQM-9 domain scores (effectiveness score, convenience score, global satisfaction score) range from 0 to 100 with higher scores representing greater satisfaction for the domain. | Week 24 |
| Change From Baseline In Hepatic Laboratory Measure Alanine Aminotransferase (ALT) At Week 24 | Assessed by laboratory measurements. Change from Baseline = Week 24 ALT level - Baseline ALT level. | Baseline, Week 24 |
| Change From Baseline In Hepatic Laboratory Measure Aspartate Aminotransferase (AST) At Week 24 | Assessed by laboratory measurements. Change from Baseline = Week 24 AST level - Baseline AST level. | Baseline, Week 24 |
| Change From Baseline In Hepatic Laboratory Measure International Normalized Ratio (INR) At Week 24 | Assessed by laboratory measurements. Change from Baseline = Week 24 INR - Baseline INR. | Baseline, Week 24 |
| Change From Baseline In Hepatic Laboratory Measure Bilirubin At Week 24 | Assessed by laboratory measurements. Change from Baseline = Week 24 bilirubin level - Baseline bilirubin level. | Baseline, Week 24 |
| Change From Baseline In Exchangeable Cu At Week 24 | Assessed by laboratory measurements. Change from Baseline = Week 24 Exchangeable Cu level - Baseline Exchangeable Cu level. | Baseline, Week 24 |
| Change From Baseline In Speciation Profiling (Mo, Cu, And Protein Complex Profiling Using Size Exclusion Chromatography) At Week 24 | Due to low chromatographic resolution of data, quantitative analysis for speciation profiling, as had been planned in the protocol, was not feasible. | Baseline, Week 24 |
| Change From Baseline In 24-Hour Urinary Mo And Cu At Week 24 | Assessed by laboratory measurements. Change from Baseline = Week 24 (24-hour) urinary Mo or Cu level - Baseline 24-hour urinary Mo or Cu level. | Baseline, Week 24 |
| Pharmacokinetics (PK): Area Under The Curve From Time 0 to 24 (AUC0-24) Of Plasma Total Mo | PK blood sampling occurred on Day 1, Week 12, and Week 24 at the following serial PK sampling time-points: 0, 1, 2, 3, 4, 5, 6, 8, and 12 (10 to 12) hours post-dose. | 0, 1, 2, 3, 4, 5, 6, 8, and 12 (10 to 12) hours post-dose on Day 1, Week 12, and Week 24 |
| PK: Maximum Concentration (Cmax) Of Plasma Total Mo | PK blood sampling occurred on Day 1, Week 12, and Week 24 at the following serial PK sampling time-points: 0, 1, 2, 3, 4, 5, 6, 8, and 12 (10 to 12) hours post-dose. | 0, 1, 2, 3, 4, 5, 6, 8, and 12 (10 to 12) hours post-dose on Day 1, Week 12, and Week 24 |
| Extension Period: Percentage Of Participants With Normalized Concentrations Of NCC | Normalized concentrations of NCC was defined as who achieving or maintaining normalized levels of NCC (0.8-2.3 μM) adjusted for Mo plasma concentration or reaching a reduction of at least 25% in NCC corrected for Mo if above the normal reference range at the time of enrollment. NCC was calculated by subtracting the amount of Cu bound to Cp from the total plasma Cu concentration. Post-baseline NCC values were adjusted (corrected) to account for Cu bound in tripartite complexes with ALXN1840 and albumin. Last Assessment is a summary of the last available post-baseline result for each participant. Analyses includes all data up to the last assessment in the extension period; up to Week 176. | Up to last assessment (up to Week 176) |
| Extension Period: Change From Baseline In NCC Levels Adjusted For Mo Plasma Concentration | The change from Baseline in NCC adjusted for Mo plasma concentration over 176 weeks were analyzed. Last Assessment is a summary of the last available post-baseline result for each participant. Analyses includes all data up to the last assessment in the extension period, up to Week 176. Change from Baseline = (Last assessment [up to Week 176] NCC concentrations adjusted for Mo plasma concentration) - (Baseline NCC concentrations). Least square means and their 95% CIs were calculated using an REML-based MMRM with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction. | Baseline, last assessment (up to Week 176) |
| New Haven |
| Connecticut |
| 06519 |
| United States |
| Clinical Trial Site | Chicago | Illinois | 60611 | United States |
| Clinical Trial Site | Ann Arbor | Michigan | 48109 | United States |
| Clinical Trial Site | Vienna | 1090 | Austria |
| Clinical Trial Site | Heidelberg | 69120 | Germany |
| Clinical Trial Site | Warsaw | 02-957 | Poland |
| Clinical Trial Site | Guildford | Surrey | GU27XX | United Kingdom |
| Clinical Trial Site | Birmingham | B15 2TH | United Kingdom |
| Physician Decision |
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| Protocol Deviation |
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| NOT COMPLETED |
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| Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Secondary | Change From Baseline In NCC Concentrations Adjusted For Mo Plasma Concentration At Week 24 | The change from Baseline in NCC adjusted for Mo plasma concentration over 24 weeks were analyzed and descriptive statistics are reported. Change from Baseline = (Week 24 NCC concentrations adjusted for Mo plasma concentration) - (Baseline NCC concentrations). Least square means and their 95% confidence intervals (CIs) were calculated using a restricted maximum likelihood (REML)-based mixed model for repeated measures (MMRM) with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction. | Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint. | Posted | Least Squares Mean | 95% Confidence Interval | μmol/L | Baseline, Week 24 |
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| Secondary | Time To Normalization Of NCC Adjusted For Mo Plasma Concentration In Participants With Elevated Baseline NCC | For time to normalization of NCC adjusted for Mo plasma concentration, a Kaplan-Meier approach was used where participants not normalized were censored at the latest observed time point. To achieve a normalized NCC concentration, participants must have demonstrated 2 consecutive measures within the normal range (0.8 to 2.3 μmol/L). Analyses includes all data up to the last assessment in the extension period for participants who reached the event of normalization of NCC corrected concentrations. Last Assessment is a summary of the last available post-baseline result for each participant. Analyses includes all data up to the last assessment in the extension period; up to Week 176. | This analysis was only performed on the subset of participants with elevated Baseline NCC who reached the event of normalization of NCC corrected concentrations. | Posted | Median | Inter-Quartile Range | days | Up to last assessment (up to Week 176) |
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| Secondary | Change From Baseline In Neurological Status Using The Unified Wilson's Disease Rating Scale (UWDRS) (Neurological Subscore; Part I) At Week 24 | The UWDRS is a clinical rating scale designed to evaluate the neurological manifestations of WD. Change from Baseline in the UWDRS I for consciousness is presented.
| Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint. | Posted | Mean | Standard Deviation | score on a scale | Baseline, Week 24 |
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| Secondary | Change From Baseline In Neurological Status Using The UWDRS (Neurological Subscore; Parts II, III, And Total Score) At Week 24 | The UWDRS is a clinical rating scale designed to evaluate the neurological manifestations of WD. UWDRS comprises 3 parts: UWDRS I (consciousness), UWDRS II (disability), and UWDRS III (neurological status). Change from Baseline in the UWDRS II, III, and total score are presented.
| Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint. | Posted | Least Squares Mean | 95% Confidence Interval | score on a scale | Baseline, Week 24 |
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| Secondary | Change From Baseline In Psychiatric Status Dimension Using Mini International Neuropsychiatric Interview (M.I.N.I.) Tracking Standardized Scores At Week 24 | The M.I.N.I. is a short structured diagnostic interview for the Diagnostic and Statistical Manual of Mental Disorders IV and the 10th revision of the International Statistical Classification of Diseases and Related Health Problems. It was used to "track" the severity of symptoms by using a combination of questions in 16 Psychiatric Status dimensions that are summarized using a single standardized score for each dimension, ranging from 0 (interpreted as "did not occur at all") to 4 (interpreted as "occurred extremely often"). The standardized score is an average of these responses. Change from Baseline = Week 24 standardized score - Baseline standardized score. Least square means and 95% CIs were calculated using an REML-based MMRM with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction. Decrease from Baseline (a lower score) is indicative of a decrease in symptoms and a better outcome. | Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint. | Posted | Least Squares Mean | 95% Confidence Interval | score on a scale | Baseline, Week 24 |
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| Secondary | Clinical Global Impression-Improvement Scale (CGI-I) At Week 24 | The CGI-I is a 7-point scale where the clinician assessed how much participant's illness improved or worsened relative to a Baseline state at the beginning of the intervention and rated as: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. Change from Baseline = Week 24 score - Baseline score. An increase in CGI-I score indicates improvement. | Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint. | Posted | Least Squares Mean | 95% Confidence Interval | score on a scale | Week 24 |
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| Secondary | Change From Baseline In Clinical Global Impression Severity Scale (CGI-S) At Week 24 | The CGI-S is a 7-point scale where the investigator rated severity of participant's illness at the time of assessment, relative to the investigator's past experience with participants who have the same diagnosis. Considering total clinical experience, a participant was assessed on severity of illness at time of rating as: 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. Change from Baseline = Week 24 score - Baseline score. Decrease in CGI-S score and increase indicates improvement. | Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint. | Posted | Least Squares Mean | 95% Confidence Interval | score on a scale | Baseline, Week 24 |
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| Secondary | Change From Baseline In Quality Of Life (QoL)/Patient Reported Outcome (PRO) Assessed By The European Quality Of Life 5 Dimensions (EQ-5D) Visual Analogue Scale (VAS) At Week 24 | The EQ-5D VAS records the participant's self-rated health as indicated on a scale from 0 to 100 with 0 being "the worst health you can imagine" and 100 being "the best health you can imagine, with higher scores for a higher quality of life. Change from Baseline = Week 24 score - Baseline score. An increase in score indicates improvement. The least-square means and their 95% CIs were calculated using a REML-based MMRM with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction. | Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint. | Posted | Least Squares Mean | 95% Confidence Interval | score on a scale | Baseline, Week 24 |
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| Secondary | Change From Baseline In Quality Of Life (QoL)/Patient Reported Outcome (PRO) Assessed By The EQ-5D Descriptive System UK Health Index Scores At Week 24 | The EQ-5D-5L Descriptive System provides a simple descriptive profile and a single index value for health status (United Kingdom [UK] Health Index Score). The EQ-5D-5L consists of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each of which can have 1 of 5 responses that represent 5 levels of severity (no problems, slight problems, moderate problems, severe problems, extreme problems). The participant was asked to indicate his/her health state for each of the 5 dimensions. The 5-item index score was transformed into a utility score between 0 (worst health state) and 1 (best health state). Change from Baseline = Week 24 index score - Baseline index score. An increase in score indicates improvement. The least square means and their 95% CIs were calculated using a REML-based MMRM with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction. | Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint. | Posted | Least Squares Mean | 95% Confidence Interval | EQ-5D-5L index score | Baseline, Week 24 |
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| Secondary | QoL/PRO Assessed By The 8-Item Medication Adherence Scale (MMAS-8) At Week 24 | The MMAS-8 is a scale used to evaluate adherence to medication. The MMAS-8 consists of 8 questions with a sum score ranging between 0 and 8 points, with 8 being the maximum adherence to medication. Mean adherence to medication is presented. | Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint. | Posted | Mean | 95% Confidence Interval | score on a scale | Week 24 |
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| Secondary | QoL/PRO Assessed By The Treatment Satisfaction Questionnaire For Medication (TSQM-9) At Week 24 | The TSQM-9 was used to assess the overall level of satisfaction or dissatisfaction with medication participants were taking. This composite scale is comprised of 2 items on the TSQM-9 survey: How satisfied are you that good things about this medication outweigh the bad things? Taking all things into account, how satisfied or dissatisfied are you with this medication? The TSQM-9 domain scores (effectiveness score, convenience score, global satisfaction score) range from 0 to 100 with higher scores representing greater satisfaction for the domain. | Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint. | Posted | Mean | 95% Confidence Interval | score on a scale | Week 24 |
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| Secondary | Change From Baseline In Hepatic Laboratory Measure Alanine Aminotransferase (ALT) At Week 24 | Assessed by laboratory measurements. Change from Baseline = Week 24 ALT level - Baseline ALT level. | Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint. | Posted | Mean | Standard Deviation | U/L | Baseline, Week 24 |
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| Secondary | Change From Baseline In Hepatic Laboratory Measure Aspartate Aminotransferase (AST) At Week 24 | Assessed by laboratory measurements. Change from Baseline = Week 24 AST level - Baseline AST level. | Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint. | Posted | Mean | Standard Deviation | U/L | Baseline, Week 24 |
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| Secondary | Change From Baseline In Hepatic Laboratory Measure International Normalized Ratio (INR) At Week 24 | Assessed by laboratory measurements. Change from Baseline = Week 24 INR - Baseline INR. | Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint. | Posted | Mean | Standard Deviation | ratio | Baseline, Week 24 |
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| Secondary | Change From Baseline In Hepatic Laboratory Measure Bilirubin At Week 24 | Assessed by laboratory measurements. Change from Baseline = Week 24 bilirubin level - Baseline bilirubin level. | Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint. | Posted | Mean | Standard Deviation | μmol/L | Baseline, Week 24 |
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| Secondary | Change From Baseline In Exchangeable Cu At Week 24 | Assessed by laboratory measurements. Change from Baseline = Week 24 Exchangeable Cu level - Baseline Exchangeable Cu level. | Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint. | Posted | Mean | Standard Deviation | ng/mL | Baseline, Week 24 |
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| Secondary | Change From Baseline In Speciation Profiling (Mo, Cu, And Protein Complex Profiling Using Size Exclusion Chromatography) At Week 24 | Due to low chromatographic resolution of data, quantitative analysis for speciation profiling, as had been planned in the protocol, was not feasible. | Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint. | Posted | Baseline, Week 24 |
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| Secondary | Change From Baseline In 24-Hour Urinary Mo And Cu At Week 24 | Assessed by laboratory measurements. Change from Baseline = Week 24 (24-hour) urinary Mo or Cu level - Baseline 24-hour urinary Mo or Cu level. | Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint. | Posted | Mean | 95% Confidence Interval | μg/day | Baseline, Week 24 |
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|
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| Secondary | Pharmacokinetics (PK): Area Under The Curve From Time 0 to 24 (AUC0-24) Of Plasma Total Mo | PK blood sampling occurred on Day 1, Week 12, and Week 24 at the following serial PK sampling time-points: 0, 1, 2, 3, 4, 5, 6, 8, and 12 (10 to 12) hours post-dose. | Participants who were enrolled and received at least 1 dose of study drug and had any Baseline and post-Baseline measurable concentration data reported. | Posted | Mean | Standard Deviation | h*ng/mL | 0, 1, 2, 3, 4, 5, 6, 8, and 12 (10 to 12) hours post-dose on Day 1, Week 12, and Week 24 |
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|
|
| Secondary | PK: Maximum Concentration (Cmax) Of Plasma Total Mo | PK blood sampling occurred on Day 1, Week 12, and Week 24 at the following serial PK sampling time-points: 0, 1, 2, 3, 4, 5, 6, 8, and 12 (10 to 12) hours post-dose. | Participants who were enrolled and received at least 1 dose of study drug and had any Baseline and post-Baseline measurable concentration data reported. | Posted | Mean | Standard Deviation | ng/mL | 0, 1, 2, 3, 4, 5, 6, 8, and 12 (10 to 12) hours post-dose on Day 1, Week 12, and Week 24 |
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| Secondary | Extension Period: Percentage Of Participants With Normalized Concentrations Of NCC | Normalized concentrations of NCC was defined as who achieving or maintaining normalized levels of NCC (0.8-2.3 μM) adjusted for Mo plasma concentration or reaching a reduction of at least 25% in NCC corrected for Mo if above the normal reference range at the time of enrollment. NCC was calculated by subtracting the amount of Cu bound to Cp from the total plasma Cu concentration. Post-baseline NCC values were adjusted (corrected) to account for Cu bound in tripartite complexes with ALXN1840 and albumin. Last Assessment is a summary of the last available post-baseline result for each participant. Analyses includes all data up to the last assessment in the extension period; up to Week 176. | Participants who were enrolled and received at least 1 dose of study drug. | Posted | Number | 95% Confidence Interval | percentage of participants | Up to last assessment (up to Week 176) |
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| Secondary | Extension Period: Change From Baseline In NCC Levels Adjusted For Mo Plasma Concentration | The change from Baseline in NCC adjusted for Mo plasma concentration over 176 weeks were analyzed. Last Assessment is a summary of the last available post-baseline result for each participant. Analyses includes all data up to the last assessment in the extension period, up to Week 176. Change from Baseline = (Last assessment [up to Week 176] NCC concentrations adjusted for Mo plasma concentration) - (Baseline NCC concentrations). Least square means and their 95% CIs were calculated using an REML-based MMRM with fixed effects for Baseline, cohort, visit, Baseline-by-visit, and cohort-by-visit interaction. | Participants who were enrolled and received at least 1 dose of study drug and had analyzable data at the specified timepoint. | Posted | Least Squares Mean | 95% Confidence Interval | μmol/L | Baseline, last assessment (up to Week 176) |
|
|
|
| 0 |
| 28 |
| 11 |
| 28 |
| 26 |
| 28 |
| Neutropenia | Blood and lymphatic system disorders | MedDRA 21.1 | Systematic Assessment |
|
| Hepato-lenticular degeneration | Congenital, familial and genetic disorders | MedDRA 21.1 | Systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | MedDRA 21.1 | Systematic Assessment |
|
| Gait disturbance | General disorders | MedDRA 21.1 | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA 21.1 | Systematic Assessment |
|
| Hepatic enzyme increased | Investigations | MedDRA 21.1 | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 21.1 | Systematic Assessment |
|
| Neurological decompensation | Nervous system disorders | MedDRA 21.1 | Systematic Assessment |
|
| Syncope | Nervous system disorders | MedDRA 21.1 | Systematic Assessment |
|
| Abnormal behaviour | Psychiatric disorders | MedDRA 21.1 | Systematic Assessment |
|
| Adjustment disorder | Psychiatric disorders | MedDRA 21.1 | Systematic Assessment |
|
| Affective disorder | Psychiatric disorders | MedDRA 21.1 | Systematic Assessment |
|
| Mania | Psychiatric disorders | MedDRA 21.1 | Systematic Assessment |
|
| Personality disorder | Psychiatric disorders | MedDRA 21.1 | Systematic Assessment |
|
| Psychotic disorder | Psychiatric disorders | MedDRA 21.1 | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | 21.1 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 21.1 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | 21.1 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 21.1 | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA 21.1 | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
|
| Sinusitis | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
|
| Influenza | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
|
| Tonsillitis | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA 21.1 | Systematic Assessment |
|
| Fall | Injury, poisoning and procedural complications | MedDRA 21.1 | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA 21.1 | Systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA 21.1 | Systematic Assessment |
|
| Gamma-glutamyltransferase increased | Investigations | MedDRA 21.1 | Systematic Assessment |
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| Hepatic enzyme increased | Investigations | MedDRA 21.1 | Systematic Assessment |
|
| Blood alkaline phosphatase increased | Investigations | 21.1 | Systematic Assessment |
|
| Blood creatine phosphokinase increased | Investigations | MedDRA 21.1 | Systematic Assessment |
|
| Liver function test increased | Investigations | MedDRA 21.1 | Systematic Assessment |
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| Decreased appetite | Metabolism and nutrition disorders | MedDRA 21.1 | Systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 21.1 | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 21.1 | Systematic Assessment |
|
| Dupuytren's contracture | Musculoskeletal and connective tissue disorders | 21.1 | Systematic Assessment |
|
| Muscle spasms | Musculoskeletal and connective tissue disorders | 21.1 | Systematic Assessment |
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| Myalgia | Musculoskeletal and connective tissue disorders | 21.1 | Systematic Assessment |
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| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA 21.1 | Systematic Assessment |
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| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 21.1 | Systematic Assessment |
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| Plantar fasciitis | Musculoskeletal and connective tissue disorders | MedDRA 21.1 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 21.1 | Systematic Assessment |
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| Tremor | Nervous system disorders | MedDRA 21.1 | Systematic Assessment |
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| Dysgeusia | Nervous system disorders | MedDRA 21.1 | Systematic Assessment |
|
| Paraesthesia | Nervous system disorders | MedDRA 21.1 | Systematic Assessment |
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| Anxiety | Psychiatric disorders | MedDRA 21.1 | Systematic Assessment |
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| Depression | Psychiatric disorders | MedDRA 21.1 | Systematic Assessment |
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| Insomnia | Psychiatric disorders | MedDRA 21.1 | Systematic Assessment |
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| Sleep disorder | Psychiatric disorders | MedDRA 21.1 | Systematic Assessment |
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| Depressed mood | Psychiatric disorders | MedDRA 21.1 | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 21.1 | Systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | MedDRA 21.1 | Systematic Assessment |
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| Dry skin | Skin and subcutaneous tissue disorders | MedDRA 21.1 | Systematic Assessment |
|
| Erythema | Skin and subcutaneous tissue disorders | MedDRA 21.1 | Systematic Assessment |
|
Not provided
Not provided
| D002493 |
| Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D020739 | Brain Diseases, Metabolic, Inborn |
| D001928 | Brain Diseases, Metabolic |
| D009069 | Movement Disorders |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D008661 | Metabolism, Inborn Errors |
| D008664 | Metal Metabolism, Inborn Errors |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| Title | Measurements |
|---|---|
|
|
| Manic/Hypomanic Episode Standardized |
|
|
| Panic Disorder Standardized |
|
|
| Agoraphobia Standardized |
|
|
| Social Anxiety Disorder Standardized |
|
|
| Obsessive Compulsive Disorder Standardized |
|
|
| Post Traumatic Stress Disorder Standardized |
|
|
| Alcohol Use Disorder Standardized |
|
|
| Substance Use Disorder Standardized |
|
|
| Psychotic Disorders Standardized |
|
|
| Anorexia Nervosa Standardized |
|
|
| Bulimia Nervosa Standardized |
|
|
| Binge Eating Disorder Standardized |
|
|
| Generalized Anxiety Disorder Standardized |
|
|
| Antisocial Personality Disorder Standardized |
|
|
| Title | Measurements |
|---|---|
|
|
| Week 12 |
|
|
| Week 24 |
|
|
|
| Week 12 |
|
|
| Week 24 |
|
|