Clinical Trial Results:
A Phase 2, Multi-centre, Open-label, Study to Evaluate the Efficacy and Safety of WTX101 Administered for 24 Weeks in Newly Diagnosed Wilson Disease Patients Aged 18 and Older with an Extension Phase of 36 Months
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Summary
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EudraCT number |
2014-001703-41 |
Trial protocol |
DE AT PL GB |
Global end of trial date |
07 Nov 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
31 Jan 2021
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First version publication date |
31 Jan 2021
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
WTX101-201
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Alexion Pharmaceuticals, Inc.
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Sponsor organisation address |
121 Seaport Boulevard, Boston, MA, United States, 02210
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Public contact |
European Clinical Trial Information, Alexion Pharmaceuticals, Inc., 33 147100615, clinicaltrials.eu@alexion.com
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Scientific contact |
European Clinical Trial Information, Alexion Pharmaceuticals, Inc., 33 147100615, clinicaltrials.eu@alexion.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
30 Jun 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
07 Nov 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
07 Nov 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective was to evaluate the efficacy of ALXN1840 (formerly WTX101) for 24 weeks on non-ceruloplasmin-bound copper (NCC) concentrations adjusted for molybdenum (Mo) plasma concentration in participants newly diagnosed Wilson Disease (WD) who were aged 18 and older and who had NCC concentrations within or above the reference range at the time of enrolment in the study.
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Protection of trial subjects |
This study was conducted in accordance with International Council on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the countries in which the study was conducted.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Aug 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 8
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Country: Number of subjects enrolled |
United Kingdom: 2
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Country: Number of subjects enrolled |
Austria: 3
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Country: Number of subjects enrolled |
Germany: 4
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Country: Number of subjects enrolled |
United States: 12
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Worldwide total number of subjects |
29
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EEA total number of subjects |
17
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
29
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Participants meeting all inclusion and no exclusion criteria were enrolled into the study and studied as outpatients. 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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Pre-assignment
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Screening details |
Participants enrolled as pre-treated with other de-coppering agents were required to undergo a 48-hour washout from their previous WD treatment just prior to initiation of study treatment. | ||||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
29 | ||||||||||||||||||
Number of subjects completed |
28 | ||||||||||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Consent withdrawn by subject: 1 | ||||||||||||||||||
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Period 1
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Period 1 title |
24-Week Treatment Period
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
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Arms
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Arm title
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ALXN1840 24-Week Treatment Period | ||||||||||||||||||
Arm description |
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 Mo plasma concentration. ALXN1840 may have been administered every other day, once daily, or twice daily, depending on individualized dosing regimen, for 24 weeks. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
ALXN1840
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Investigational medicinal product code |
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Other name |
WTX101
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Pharmaceutical forms |
Capsule, Coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Individualized oral doses of ALXN1840. Initially, ALXN1840 was administered as uncoated capsules. Following a protocol amendment, ALXN1840 was administered as enteric coated tablets.
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: One participant was enrolled but not treated. |
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Period 2
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Period 2 title |
Extension Period
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Is this the baseline period? |
No | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
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Arms
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Arm title
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ALXN1840 Extension Period | ||||||||||||||||||
Arm description |
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. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
ALXN1840
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Investigational medicinal product code |
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Other name |
WTX101
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Pharmaceutical forms |
Coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Individualized oral doses of ALXN1840.
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Baseline characteristics reporting groups
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Reporting group title |
24-Week Treatment Period
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Reporting group description |
Participants who were enrolled and received at least 1 dose of study drug. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
ALXN1840 24-Week Treatment Period
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Reporting group description |
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 Mo plasma concentration. ALXN1840 may have been administered every other day, once daily, or twice daily, depending on individualized dosing regimen, for 24 weeks. | ||
Reporting group title |
ALXN1840 Extension Period
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Reporting group description |
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. | ||
Subject analysis set title |
ALXN1840 Every Other Day
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Participants who received at least 1 dose of ALXN1840 administered at 15 mg every other day and from whom pharmacokinetic (PK) parameters could be derived.
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Subject analysis set title |
ALXN1840 15 mg Daily
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Participants who received at least 1 dose of ALXN1840 administered at 15 mg per day and from whom PK parameters could be derived.
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Subject analysis set title |
ALXN1840 30 mg Daily
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Participants who received at least 1 dose of ALXN1840 administered at 30 mg per day and from whom PK parameters could be derived.
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Subject analysis set title |
ALXN1840 60 mg Daily
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Participants who received at least 1 dose of ALXN1840 administered at 60 mg per day and from whom PK parameters could be derived.
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End point title |
Percentage Of Participants With Normalized Concentrations Of NCC [1] | ||||||||
End point description |
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 molybdenum (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
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End point type |
Primary
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End point timeframe |
Week 24
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: As per protocol, statistical analysis was not performed. Descriptive statistics are included. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline In NCC Concentrations Adjusted For Mo Plasma Concentration At Week 24 | ||||||||
End point description |
The change from Baseline in NCC adjusted for Mo plasma concentration over 24 weeks were analyzed and descriptive statistics are reported. Change from baseline = (Baseline NCC concentrations) - (Week 24 NCC concentrations adjusted for Mo plasma concentration). 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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End point type |
Secondary
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End point timeframe |
Baseline, Week 24
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| Notes [2] - Had analyzable data at the specified timepoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Time To Normalization Of NCC Adjusted For Mo Plasma Concentration In Participants With Elevated Baseline NCC | ||||||||
End point description |
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. The analysis included participants who did not normalize. The values for these participants were censored to be the time of last observation in the Kaplan-Meier analysis.
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End point type |
Secondary
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End point timeframe |
Up to last assessment (up to Week 176)
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| Notes [3] - Subset of participants with elevated baseline NCC. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline In Neurological Status Using The Unified Wilson’s Disease Rating Scale (UWDRS) (Neurological Subscore; Part I) At Week 24 | ||||||||
End point description |
The UWDRS is a clinical rating scale designed to evaluate the neurological manifestations of WD that generally can be divided into 3 movement disorder syndromes: a) dystonic b) ataxic, c) Parkinsonian syndrome. The UWDRS is designed to comprise 3 parts:
• UWDRS I (consciousness, item 1): maximum score of 3
• UWDRS II (disability, items 2 to 11): maximum score of 40
• UWDRS III (neurological status, items 12 to 34): Maximum score of 175
The UWDRS total score is the sum of the 3 subscores. UWDRS I and III was assessed by a Neurologist, while UWDRS II was reported by the participant or caregiver.
Change from baseline was calculated as: Baseline score - Week 24 score. A decrease in score from baseline indicates an improvement in condition. The UWDRS Part 1 mean scores are reported.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24
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| Notes [4] - Had analyzable data at the specified timepoint |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline In Neurological Status Using The Unified Wilson’s Disease Rating Scale (UWDRS) (Neurological Subscore; Parts II, III, And Total Score) At Week 24 | ||||||||||||||
End point description |
The UWDRS is a clinical rating scale designed to evaluate the neurological manifestations of WD that generally can be divided into 3 movement disorder syndromes: a) dystonic b) ataxic, c) Parkinsonian syndrome. The UWDRS is designed to comprise 3 parts:
• UWDRS I (consciousness, item 1): maximum score of 3
• UWDRS II (disability, items 2 to 11): maximum score of 40
• UWDRS III (neurological status, items 12 to 34): Maximum score of 175
The UWDRS total score is the sum of the 3 subscores. UWDRS I and III was assessed by a Neurologist, while UWDRS II was reported by the participant or caregiver.
Change from baseline was calculated as: Baseline score - Week 24 score. A decrease in score from baseline indicates an improvement in condition.
The UWDRS Parts II and III and total score are reported.
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.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24
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| Notes [5] - Had analyzable data at the specified timepoint. |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change From Baseline In Psychiatric Status Using Mini International Neuropsychiatric Interview (M.I.N.I.) Tracking At Week 24 | ||||||||||||||||||||||||||||||||||||||||
End point description |
The M.I.N.I. is a psychiatric diagnostic interview instrument with only “yes” or “no” answers. The M.I.N.I. is designed to “track” severity of symptoms in relation to baseline data. The following components are presented: Major Depressive Episode (n=22), Suicidality Tracking Scale (n=23), Manic/Hypomanic Episode (n=21), Panic Disorder (n=23), Agoraphobia (n=22), Social Anxiety Disorder (n=22), Obsessive Compulsive Disorder (n=23), Post Traumatic Stress Disorder (n=22), Alcohol Use Disorder (n=22), Substance Use Disorder (n=23), Psychotic Disorders (n=22), Anorexia Nervosa (n=23), Bulimia Nervosa (n=23), Binge Eating Disorder (n=22), Generalized Anxiety Disorder (n=23), and Antisocial Personality Disorder (n=20).
Change from baseline = Baseline score - Week 24 score. Decrease in score indicates decrease in symptoms. 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.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24
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| Notes [6] - Had analyzable data at the specified timepoint. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||
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End point title |
Change From Baseline In Clinical Symptoms As Assessed By The Investigators On The Clinical Global Impression (CGI) Scale Items 1 (Severity Of Illness) And 2 (Global Improvement) At Week 24 | ||||||||||||
End point description |
CGI Severity scale (CGI-S) is a 7-point scale where the investigator rated the severity of the 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 the 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. The CGI Improvement scale (CGI-I) is a 7 point scale where the clinician assessed how much the 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 = Baseline score - Week 24 score. Decrease in CGI-S score and increase in CGI-I score indicates improvement.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24
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| Notes [7] - Had analyzable data at the specified timepoint. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
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 | ||||||||
End point description |
The EQ-5D VAS records the participant’s self-rated health as indicated on a 20 centimeter (cm) vertical VAS with endpoints labelled “the best health you can imagine” (20 cm) and “the worst health you can imagine” (0 cm) on a scale from 0 to 100, with higher scores for higher quality of life. Change from baseline = Baseline score - Week 24 score. An increase in score indicates improvement. 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.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24
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| Notes [8] - Had analyzable data at the specified timepoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline In Quality Of Life (QoL)/Patient Reported Outcome (PRO) Assessed By The EQ5D Descriptive System UK Health Index Scores At Week 24 | ||||||||
End point description |
The EQ-5D-5L Descriptive System provides a simple descriptive profile and a single index value for health status (UK Health Index Score) consisting 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. This decision resulted in a 1-digit number expressing the level selected for that dimension. Digits for the 5 dimensions were combined in a 5-digit number describing the participant’s health state.
Change from baseline = Baseline score - Week 24 score. An increase in score indicates improvement. 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.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24
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| Notes [9] - Had analyzable data at the specified timepoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
QoL/PRO Assessed By The 8-Item Medication Adherence Scale (MMAS-8) At Week 24 | ||||||||
End point description |
The MMAS-8 is a scale used to evaluate adherence to medication. The first 7 questions are yes or no questions. For Questions 1 through 4, 6, and 7, yes takes a value of 0 and no takes a value of 1. For Question 5, yes takes a value of 1 and no takes a value of 0. Question 8 has to be remapped as follows: 4 = 1, 3 = 0.75, 2 = 0.5, 1 = 0.25, 0 = 0. The total score was calculated by adding values for Questions 1 through 8 and thus has a maximum value of 8 (maximum adherence to medication). If 7 of the 8 questions were answered, the total score was pro-rated by dividing by 7 and multiplying by 8. If less than 7 questions were answered, the total score was not derived. 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.
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End point type |
Secondary
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End point timeframe |
Week 24
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| Notes [10] - Had analyzable data at the specified timepoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
QoL/PRO Assessed By The Treatment Satisfaction Questionnaire For Medication (TSQM-9) At Week 24 | ||||||||||||||
End point description |
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.
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End point type |
Secondary
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End point timeframe |
Week 24
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| Notes [11] - Had analyzable data at the specified timepoint. |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change From Baseline In Hepatic Laboratory Measure Alanine Aminotransferase (ALT) At Week 24 | ||||||||
End point description |
Assessed by laboratory measurements. Change from baseline = Baseline ALT level- Week 24 ALT level.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24
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| Notes [12] - Had analyzable data at the specified timepoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline In Hepatic Laboratory Measure Aspartate Aminotransferase (AST) At Week 24 | ||||||||
End point description |
Assessed by laboratory measurements. Change from baseline = Baseline AST level- Week 24 AST level.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24
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| Notes [13] - Had analyzable data at the specified timepoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline In Hepatic Laboratory Measure International Normalized Ratio (INR) At Week 24 | ||||||||
End point description |
Assessed by laboratory measurements. Change from baseline = Baseline INR - Week 24 INR.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 24
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| Notes [14] - Had analyzable data at the specified timepoint. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline In Hepatic Laboratory Measure Bilirubin At Week 24 | ||||||||
End point description |
Assessed by laboratory measurements. Change from baseline = Baseline bilirubin level- Week 24 bilirubin level.
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End point type |
Secondary
|
||||||||
End point timeframe |
Baseline, Week 24
|
||||||||
|
|||||||||
| Notes [15] - Had analyzable data at the specified timepoint. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change From Baseline In Exchangeable Cu At Week 24 | ||||||||
End point description |
Assessed by laboratory measurements. Change from baseline = Baseline Exchangeable Cu level- Week 24 Exchangeable Cu level.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline, Week 24
|
||||||||
|
|||||||||
| Notes [16] - Had analyzable data at the specified timepoint. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change From Baseline In Speciation Profiling (Mo, Cu, And Protein Complex Profiling Using Size Exclusion Chromatography) At Week 24 | ||||||||
End point description |
Due to low chromatographic resolution of data, quantitative analysis for speciation profiling, as had been planned in the protocol, was not feasible.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline, Week 24
|
||||||||
|
|||||||||
| Notes [17] - Quantitative analysis for speciation profiling was not feasible. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||
End point title |
Change From Baseline In 24-Hour Urinary Mo And Cu At Week 24 | ||||||||||||
End point description |
Assessed by laboratory measurements. Change from baseline = Baseline 24-hour urinary Mo or Cu level - Week 24 24-hour urinary Mo or Cu level.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 24
|
||||||||||||
|
|||||||||||||
| Notes [18] - Had analyzable data at the specified timepoint |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||||||||||||||
End point title |
PK: Area Under The Curve From Time 0 to 24 (AUC0-24) Of Plasma Total Mo On Day 1 And Week 12 | ||||||||||||||||||||||||||||||
End point description |
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.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
0, 1, 2, 3, 4, 5, 6, 8, and 12 (10 to 12) hours post-dose on Day 1 and Week 12
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
| Notes [19] - No participants had analyzable PK data. [20] - n=3 for Day 1 and n=4 for Week 12 [21] - n=16 for Day 1 and n=12 for Week 12 [22] - n=2 for Day 1 and n=6 for Week 12 |
|||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
|||||||||||||||||||||
End point title |
PK: Area Under The Curve From Time 0 to 24 (AUC0-24) Of Plasma Total Mo On Week 24 | ||||||||||||||||||||
End point description |
PK blood sampling occurred on 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.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
0, 1, 2, 3, 4, 5, 6, 8, and 12 (10 to 12) hours post-dose on Week 24
|
||||||||||||||||||||
|
|||||||||||||||||||||
| Notes [23] - Note: Since only 1 participant was analyzed, standard deviation was unable to be calculated. |
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
End point title |
PK: Maximum Concentration (Cmax) Of Plasma Total Mo On Day 1 And Week 12 | ||||||||||||||||||||||||||||||
End point description |
PK blood sampling occurred on Day 1 and Week 12 at the following serial PK sampling time-points: 0, 1, 2, 3, 4, 5, 6, 8, and 12 (10 to 12) hours post-dose.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
0, 1, 2, 3, 4, 5, 6, 8, and 12 (10 to 12) hours post-dose on Day 1 and Week 12
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
| Notes [24] - No participants had analyzable PK data. [25] - n=19 for Day 1 and n=13 for Week 12 [26] - n=3 for Day 1 and n=6 for Week 12 |
|||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
|||||||||||||||||||||
End point title |
PK: Maximum Concentration (Cmax) Of Plasma Total Mo At Week 24 | ||||||||||||||||||||
End point description |
PK blood sampling occurred on 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.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
0, 1, 2, 3, 4, 5, 6, 8, and 12 (10 to 12) hours post-dose on Week 24
|
||||||||||||||||||||
|
|||||||||||||||||||||
| Notes [27] - Note: Since only 1 participant was analyzed, standard deviation was unable to be calculated. |
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||
End point title |
Extension Period: Percentage Of Participants With Normalized Concentrations Of NCC | ||||||||
End point description |
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.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Up to last assessment (up to Week 176)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Extension Period: Change From Baseline In NCC Levels Adjusted For Mo Plasma Concentration | ||||||||
End point description |
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 = (Baseline NCC concentrations) - (last assessment [up to Week 176] NCC concentrations adjusted for Mo plasma concentration). 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.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline, last assessment (up to Week 176)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
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Timeframe for reporting adverse events |
Day 1 after dosing up to last assessment (up to Week 176), mean duration of treatment of 693.1 days
|
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Adverse event reporting additional description |
Participants who were enrolled and received at least 1 dose of study drug.
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.1
|
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Reporting groups
|
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Reporting group title |
ALXN1840
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
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 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
12 Dec 2014 |
• The 8-item Medication Adherence Questionnaire was replaced with the MMAS-8.
• Number of planned study sites was increased.
• Clarified that over the counter medication also had to be recorded as concomitant medication on the CRF.
• Clarified that UWDRS (Parts I, II, and III), M.I.N.I. Tracking, CGI scale item 1, and EQ-5D had to be filled in within 24 hours prior to the first dose of study drug on Day 1.
• Copper endpoints for serial assessment were changed from NCC, Mo, and exchangeable Cu to Cp, total and exchangeable Cu, and Mo.
• Window periods for PK sampling were further specified.
• Planned volume of blood to be collected by Week 24 was markedly decreased.
• Creatinine phosphokinase was added to the laboratory measures.
• Lactate dehydrogenase measurement, hematology parameters, coagulation parameters, pregnancy testing, follicle stimulating hormone, urinalysis, and analyses for Cp, total and exchangeable Cu, and total Mo were added to Screening.
• A urine pregnancy test was added to Day 1 (prior to dosing).
• Investigators’ obligations in relation to AE intensity assessment were further specified.
• In relation to the informed consent form process, clarified that under certain circumstances, the signature of an impartial witness could be accepted.
• Time windows for scheduled visits were defined. |
||
27 Feb 2015 |
• Dosing of ALXN1840 during the Initiation Period was changed to 30 mg once daily (QD) from Day 1 for the first 6 weeks with the option to up-titrate to 30 mg twice daily (BID) upon review of the Day 43 NCC concentrations adjusted for Mo plasma concentration.
• Dosing of ALXN1840 upon entry into the Maintenance Period was changed to 30 mg QD.
• Dosing of ALXN1840 during the Maintenance Period in case NCC concentrations adjusted for Mo plasma concentration did not remain stable within the reference range was changed from re-initiation of BID daily dosing with the current dose (eg, 120 mg QD was increased to 120 mg BID) with potential, subsequent increases by 30 mg BID up to a maximum dose of 150 mg BID to up-titration to a maximum dose of 30 mg BID.
• Off-site Visits were added in Weeks 7, 9, and 11.
• Number of drug kits dispensed was reduced at some time points.
• 24-hour urinary Mo was added as an evaluation criterion.
• Planned volume of blood to be collected by Week 28 was increased by approximately 100 mL.
• Time frame for reporting and follow-up of serious adverse events that were suspected to be drug-related was increased from the participant's study termination to up to 30 days after the participant's study termination. |
||
22 May 2015 |
• A 12-month Extension Period was added to the study.
• Primary objective was changed to “to evaluate the efficacy of ALXN1840 administered for 24 weeks on NCC concentrations adjusted for Mo plasma concentration in newly diagnosed WD patients aged 18 and older with NCC
concentrations above the reference range at the time of enrollment”.
•Secondary objective/efficacy endpoint was added: Evaluate the durability, and establish long-term safety and efficacy of ALXN1840 in a 12-month Extension Period.
• Long term safety and tolerability of ALXN1840 obtained in the Extension Period was added as a safety endpoint.
• Minimum starting dose of ALXN1840 was changed from 30 mg QD to 15 mg QD.
• Formulation of study drug was changed from uncoated capsules containing 30 mg of bis-choline tetrathiomolybdate to enteric coated tablets containing 15 mg of bis-choline tetrathiomolybdate.
• Mode of administration of study drug was changed from fed state to fasted state.
• Number of drug kits dispensed was increased at some time points.
• Clarified that, during the Extension Period, no up-titration was to be made unless NCC concentrations adjusted for Mo plasma concentration did not remain stable within (or below) the reference range. If the NCC concentration was above the reference range, up-titration of study drug might have been performed (ie, from 30 mg QD to 30 mg BID, or from 15 mg QD to 30 mg QD).
• Stopping rules/dose modification criteria were modified.
• Blood samples for the measurement of plasma concentrations of total and free Cu were added to the study.
• Definition of the Maintenance Period was changed
• Clarified that Off-site Visits could either be conducted by a visiting nurse or at the primary institution.
• Safety monitoring guidelines were revised. |
||
11 Sep 2015 |
• Primary objective was changed to “to evaluate the efficacy of ALXN1840 for 24 weeks on NCC adjusted for Mo plasma concentration in newly diagnosed WD patients aged 18 and older with NCC concentrations within or above the reference range at the time of enrollment in the study”.
• Primary endpoint was changed to “the proportion of successful patients who achieve or maintain normalized concentrations of NCC (0.8 - 2.3 μM) adjusted for Mo plasma concentration or reach a reduction of at least 25% in NCC corrected for Mo if above the reference range at the time of enrollment”.
• Primary efficacy variable was changed to “change from Baseline in NCC adjusted for Mo plasma concentration over 24 weeks”.
• Clarified that, as the objective of the trial was going to be analyzed using primarily descriptive statistics, no formal power calculations had been done.
• Clarified that, for participants with normal Cu concentration at Baseline, maintenance within the reference range was considered a success.
• Inclusion Criterion 5 was changed to “NCC concentrations within or above the reference range (0.8 – 2.3 μM)”.
• Exclusion Criterion 1 was changed to “Treatment for greater than 24 months for WD with chelation therapy … or Zn therapy”.
• Starting dose of ALXN1840 in the Initiation Period was clarified.
• Clarified that doses of ALXN1840 15 mg QD could be reduced to 15 mg QOD throughout the study.
• Participants no longer had to be symptomatic with neurological, hepatic, or combined neurological and hepatic presentation to be eligible for enrollment.
• Clarified that participants could enter the study into the Maintenance Period (ie, without participating in the Initiation Period), if their Screening NCC concentrations were within the reference range.
• Reference range for NCC concentrations adjusted for Mo plasma concentration was specified to be 0.8 – 2.3 μM. |
||
18 Mar 2016 |
• Extension Period was extended from 12 months to 36 months and clarified, for each participant, that the main study would end approximately 28 weeks after initiation of treatment on study Day 1.
• Dosing scheme for ALXN1840 was changed from QD dosing in the morning and BID dosing (in the morning and in the evening) to QD dosing (in the morning) during the Initiation Period, because previous work in oncology with bis-choline tetrathiomolybdate had shown that both BID and QD dosing were effective in de-coppering and maintaining a de-coppered status and QD dosing was considered easier for the participants.
• Clarified that, after review of NCC concentrations in Week 6, ALXN1840 might have been up-titrated as soon as in Week 8.
• Clarified that participants remained in the Initiation Period until they met the criteria for the Maintenance Period (meaning that the length of the Initiation Period was individualized).
• Exclusion Criterion 9 was corrected from “Severe anemia with a hemoglobin
< 9 mg/dL” to “Severe anemia with a hemoglobin < 9 g/dL”.
• Clarified that, at each Clinic Visit, participants did not only have to return unused medication, but also empty kits so that compliance could be calculated.
• A urine sample for measurement of urinary creatinine was added to Screening, Day 1, all Clinic Visits (prior to dosing), and the End of Study Visit.
• Laboratory tests for all periods of the study were further specified.
• It was further specified what did not constitute an AE. |
||
27 Oct 2017 |
• A description of the calculation of NCC concentrations adjusted for Mo plasma concentration was added based on a proposal by the American Association for the study of Liver Diseases and European WD practice guidelines. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| Due to low chromatographic resolution of data, quantitative analysis for speciation profiling, as had been planned in the protocol, was not feasible. | |||
Online references |
|||
| http://www.ncbi.nlm.nih.gov/pubmed/28988934 |
|||
