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Clinical Trial Details — Status: Terminated

Administrative data

NCT number NCT03403205
Other study ID # WTX101-301
Secondary ID 2017-004135-36
Status Terminated
Phase Phase 3
First received
Last updated
Start date February 22, 2018
Est. completion date June 30, 2023

Study information

Verified date June 2024
Source Alexion Pharmaceuticals, Inc.
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

The study will evaluate the efficacy and safety of ALXN1840 (formerly called WTX101) administered for 48 weeks compared to standard of care (SoC) in Wilson Disease (WD) participants aged 12 and older in the Primary Evaluation Period. In addition, efficacy and safety will be evaluated during an optional 60-month Extension Period.


Description:

The study consists of 2 cohorts. Cohort 1: Participants who have received SoC therapy for > 28 days and Cohort 2: Participants who are treatment-naïve or who have received SoC therapy for ≤ 28 days. All enrolled participants were randomized by cohort in a 2:1 ratio to treatment with ALXN1840 or SoC (either as continued therapy in Cohort 1 or as continued or initial therapy in Cohort 2).


Recruitment information / eligibility

Status Terminated
Enrollment 214
Est. completion date June 30, 2023
Est. primary completion date June 30, 2023
Accepts healthy volunteers No
Gender All
Age group 12 Years and older
Eligibility Key Inclusion Criteria: - Established diagnosis of WD by Leipzig-Score = 4 - Female participants of childbearing potential, if heterosexually active, must be willing to follow protocol-specified guidance for highly effective contraception starting at least 6 weeks before the Day 1 visit and continuing through 28 days after the last dose of either ALXN1840 or SoC - Male participants, if heterosexually active, must be willing to follow protocol-specified guidance for highly effective contraception beginning at Day 1 visit and continuing through 90 days after last dose of either ALXN1840 or SoC Key Exclusion Criteria: - Decompensated hepatic cirrhosis - MELD score > 13 - Modified Nazer score > 7 - Clinically significant gastrointestinal bleed within past 3 months - Alanine aminotransferase > 2 X upper limit of normal (ULN) for participants treated for > 28 days with WD therapy (Cohort 1) - Alanine aminotransferase > 5 X ULN for treatment-naïve participants or participants who have been treated for = 28 days (Cohort 2) - Marked neurological disease requiring either nasogastric feeding or intensive inpatient medical care - Hemoglobin < 9 grams/deciliter - History of seizure activity within 6 months prior to informed consent - Pregnant (or women who are planning to become pregnant) or breastfeeding women - Active infection with hepatitis B virus (positive hepatitis B surface antigen) or C virus or seropositivity for human immunodeficiency virus (HIV) - Previous treatment with tetrathiomolybdate - Participants with end-stage renal disease on dialysis (chronic kidney disease stage 5) or creatinine clearance < 30 milliliter/minute

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
ALXN1840
ALXN1840 administered orally in 15 mg tablets
SoC Therapy
Depending on the site/region, participants randomized to receive SoC treatment will receive trientine, penicillamine, Zinc, or a combination of these medicines, administered according to standard regimens.

Locations

Country Name City State
Australia Research Site Adelaide
Australia Research Site Concord
Australia Research Site Parkville
Australia Research Site Parkville
Austria Research Site Graz
Austria Research Site Innsbruck
Austria Research Site Vienna
Canada Research Site Toronto Ontario
Czechia Research Site Praha 2
Denmark Research Site Århus N
France Research Site Bron
France Research Site Paris
Germany Research Site Hamburg
Germany Research Site Heidelberg
Germany Research Site Leipzig
Hong Kong Research Site Hong Kong
Hungary Research Site Budapest
Israel Research Site Jerusalem
Israel Research Site Ramat Gan
Japan Research Site Chiba
Japan Research Site Kumamoto-shi
Japan Research Site Kurume-shi
Japan Research Site Matsuyama-city
Japan Research Site Meguro-ku
Japan Research Site Sapporo-shi
Japan Research Site Takatsuki-shi
Japan Research Site Yokohama-shi
Korea, Republic of Research Site Daegu
New Zealand Research Site Grafton
Poland Research Site Warsaw
Poland Research Site Warszawa
Russian Federation Research Site Moscow
Russian Federation Research Site Moscow
Russian Federation Research Site Moscow
Russian Federation Research Site Nizhniy Novgorod
Russian Federation Research Site St. Petersburg
Serbia Research Site Belgrade
Singapore Research Site Singapore
Spain Research Site Barcelona
Spain Research Site Málaga
Spain Research Site Sabadell
Taiwan Research Site Taipei
Taiwan Research Site Taoyuan City
Turkey Research Site Ankara
Turkey Research Site Istanbul
Turkey Research Site Istanbul
Turkey Research Site Izmir
United Kingdom Research Site Edgbaston
United Kingdom Research Site Guildford
United Kingdom Research Site London
United States Research Site Ann Arbor Michigan
United States Research Site Chicago Illinois
United States Research Site Houston Texas
United States Research Site Los Angeles California
United States Research Site New Haven Connecticut
United States Research Site Seattle Washington

Sponsors (1)

Lead Sponsor Collaborator
Alexion Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Canada,  Czechia,  Denmark,  France,  Germany,  Hong Kong,  Hungary,  Israel,  Japan,  Korea, Republic of,  New Zealand,  Poland,  Russian Federation,  Serbia,  Singapore,  Spain,  Taiwan,  Turkey,  United Kingdom, 

Outcome

Type Measure Description Time frame Safety issue
Primary Daily Mean Area Under The Effect-time Curve (AUEC) of Directly Measured Non-ceruloplasmin-bound Copper (dNCC) From 0 to 48 Weeks (dNCC AUEC0-48W) dNCC is the directly quantified copper not bound to ceruloplasmin, obtained by inductively coupled plasma mass spectrometry after immunocapture and removal of ceruloplasmin. Baseline was defined as last non-missing value on or before first study drug administration. Least square (LS) mean and standard error (SE) was calculated using analysis of covariance (ANCOVA). Baseline to Week 48
Secondary Number of Participants With Treatment-emergent Adverse Events (TEAEs) An AE was any untoward medical occurrence in a participant administered the study drug and which did not necessarily have a causal relationship with this treatment. TEAEs were defined as those AEs with onset after the first dose of randomized treatment or existing events that worsened in severity after the first dose of randomized treatment. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. Baseline up to Week 48
Secondary Change From Baseline in the Unified Wilson Disease Rating Scale (UWDRS) Part II Total Score at Week 48 The UWDRS comprises 3 parts: UWDRS Part I (level of consciousness, item 1), UWDRS Part II (a patient-reported review of daily activity items [disability], items 2 to 11 [10 items in total]), and UWDRS Part III (a detailed neurological examination, items 12 to 34 [23 items in total]). The UWDRS Part II total score was calculated as the sum of Question 2 to Question 11 (each question has range 0 [none] to 4 [severe]). The UWDRS Part II total score ranges from 0 (no disability) to 40 (severe disability), with lower score indicating improvement in condition and a better outcome. Change from baseline was calculated as: postbaseline assessment value - baseline assessment value when both values were not missing. Baseline, Week 48
Secondary Change From Baseline in UWDRS Part III Total Score at Week 48 The UWDRS comprises 3 parts: UWDRS Part I (level of consciousness, item 1), UWDRS Part II (a patient-reported review of daily activity items [disability], items 2 to 11 [10 items in total]), and UWDRS Part III (a detailed neurological examination, items 12 to 34 [23 items in total]). The UWDRS Part I and III was assessed by a neurologist who was blinded to the treatment randomization. The UWDRS Part III total score was calculated as the sum of Question 12 to Question 34. The UWDRS Part III total score ranges from 0 (normal) to 175 (severe disease), with lower score indicating improvement in condition and a better outcome. Change from baseline was calculated as: postbaseline assessment value - baseline assessment value when both values were not missing. Baseline, Week 48
Secondary Change From Baseline in UWDRS Part III Functional Subscale Score at Week 48 UWDRS Part III Functional Subscale consists of speech, handwriting, arising from chair, and gait from UWDRS Part III. The standardized score of the first 3 items ranges from 0 (normal) to 10 (worst), and standardized transformed score of gait ranges from 0 (normal) to 10 (worst). The average of these scores was used to create the Part III Functional Subscale with a range of 0 (normal) - 10 (worst) with higher scores indicating more functional disability. Baseline, Week 48
Secondary Change From Baseline in UWDRS Part III Individual Items/Subscales (Speech, Handwriting, Arising From a Chair, and Gait) Score at Week 48 UWDRS Part III individual items speech, handwriting, arising from chair, and gait are reported here. For speech (Question 12), original score ranges from 0 (normal) to 4 (unintelligible). For handwriting (Question 20), original score ranges from 0 (normal) to 4 (cannot hold a pen). For arising from chair (Question 27), original score ranges from 0 (normal) to 4 (unable to arise without help). For gait (Question 29), the original score (range: 0 [normal] to 10 [severe condition]) was calculated by summing subscores (0 [normal] to 4 [severe]) of Part A (Right and Left Leg dystonia), B (Ataxia), and C (Parkinsonism). Baseline, Week 48
Secondary Clinical Global Impression-Improvement Scale (CGI-I) Score at Week 48 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. Week 48
Secondary Change From Baseline in Clinical Global Impression Severity Scale (CGI-S) Score at Week 48 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. Baseline, Week 48
Secondary Change From Baseline in Model for End-Stage Liver Disease (MELD) Score at Week 48 The MELD score uses the participant's values for bilirubin, creatinine, and the international normalized ratio (INR). The initial MELD score (MELD[i]) is calculated according to the following formula: MELD(i) = 3.78*ln[serum bilirubin (mg/dL)] + 11.2*ln[INR] + 9.57*ln[serum creatinine (mg/dL)] + 6.43. Creatinine, bilirubin, and INR values less than 1.0 are set to 1.0 and creatinine values greater than 4.0 are set to 4.0 when calculating MELD(i). Additionally, creatinine, bilirubin, and INR are rounded to the 10th decimal place prior to performing the calculation. The initial MELD score is then rounded to the nearest integer. The MELD score ranges from 6 (least sick) - 40 (most sick), with higher values indicating more advanced disease. Baseline, Week 48
Secondary Absolute Change From Baseline in Calculated Non-Ceruloplasmin Bound Copper (cNCC) or Calculated Non-Ceruloplasmin Bound Copper Corrected (cNCCcorrected) in Plasma at Week 48 cNCC = Plasma Total Copper (Cu) [micrograms (µg)/L]-(3.15*ceruloplasmin [milligrams (mg)/L])/63.5 [µg/µmol] For ALXN1840-treated participants, cNCC in plasma corrected for amount of Cu bound to ALXN1840 tripartite complex (TPC) cNCCcorrected = (vcNCC- 0.993)2vMo, (Mo= molybdenum). In calculation of cNCC and cNCCcorrected following rules apply: - For plasma total Cu concentration Baseline, Week 48
Secondary Percent Change From Baseline in cNCC or cNCCcorrected in Plasma at Week 48 cNCC [µmol/L] = Plasma Total Cu [µg/L]-(3.15*ceruloplasmin [mg/L])/63.5 [µg/µmol] For ALXN1840-treated participants, cNCC in plasma was corrected for amount of Cu bound to the ALXN1840 TPC using square root-based cNCC correction method: cNCCcorrected = (vcNCC- 0.993)2vMo, where Mo = molybdenum. In calculation of cNCC and cNCCcorrected following rules apply: - For plasma total Cu concentration values Baseline, Week 48
Secondary cNCC/cNCCcorrected Responder at Week 48 cNCC/cNCCcorrected responder was defined as participants who achieved or maintained normalized cNCC/cNCCcorrected concentration (0.8-2.3 µmol) within (at or before) 48 weeks or reached a reduction of at least 25% in cNCC/cNCCcorrected within 48 weeks. Thus, a participant was considered a cNCC/cNCCcorrected responder if they met at least 1 of the following criteria: - Achieved normalized cNCC/cNCCcorrected concentration for 2 consecutive measurements within 48 weeks, for participants who had elevated cNCC concentrations at baseline; - Maintained normalized cNCC/cNCCcorrected concentration within 48 weeks, for participants who had normal cNCC concentrations at baseline; - Reached a reduction of at least 25% in cNCC/cNCCcorrected for 2 consecutive measurements within 48 weeks. Week 48
See also
  Status Clinical Trial Phase
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Completed NCT03539952 - Trientine Tetrahydrochloride (TETA 4HCL) for the Treatment of Wilson's Disease Phase 3
Active, not recruiting NCT04884815 - Study of UX701 Gene Transfer for the Treatment of Wilson Disease Phase 1/Phase 2
Not yet recruiting NCT03659331 - A Controlled Study of Potential Therapeutic Effect of Oral Zinc in Manifesting Carriers of Wilson Disease N/A
Recruiting NCT05687474 - Baby Detect : Genomic Newborn Screening
Completed NCT04965571 - Clinical Features and Outcome of Wilson's Disease With Generalized Epilepsy in Chinese Patients
Terminated NCT05047523 - Study of ALXN1840 Versus Standard of Care in Pediatric Participants With Wilson Disease Phase 3
Completed NCT04526210 - Study of ALXN1840 on the Metabolism of a CYP2B6 Substrate in Healthy Participants Phase 1
Completed NCT00004338 - Study of Zinc for Wilson Disease Phase 4
Enrolling by invitation NCT03655223 - Early Check: Expanded Screening in Newborns
Completed NCT02273596 - Efficacy and Safety Study of WTX101 (ALXN1840) in Adult Wilson Disease Patients Phase 2
Completed NCT02763215 - The Assessment of Copper Parameters in Wilson Disease Participants on Standard of Care Treatment
Recruiting NCT05444127 - Oral Health and Wilson's Disease: SOMAWI
Completed NCT04408300 - Study of Retinal Vascular Parameters in Patients With Wilson's Disease N/A
Active, not recruiting NCT05783687 - Real World Evidence Study in Subjects With Wilson's Disease
Terminated NCT04909346 - Adeno-Associated Virus (AAV) Antibody Study in Subjects OTC Deficiency, GSDIa, and Wilson Disease
Completed NCT03867526 - Establishment of Human Cellular Disease Models for Wilson Disease
Enrolling by invitation NCT03589820 - Plasma Exchange and Continuous Hemodiafiltration in Treatment of Wilson's Disease-related Liver Failure N/A
Completed NCT04526197 - Phase 1 Study of ALXN1840 on the Metabolism of a CYP2C9 Substrate in Healthy Participants. Phase 1
Not yet recruiting NCT06430359 - Circadian Variation of Urinary Copper Excretion in Wilson Disease Patients

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