Wilson Disease
Conditions
Keywords
Wilson Disease, Pediatric
Brief summary
This study is being conducted to evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics of ALXN1840 versus standard of care in pediatric participants with Wilson disease (WD).
Detailed description
Participants who complete the 48 weeks of treatment in Period 1 will have the option to receive ALXN1840 for 24 weeks in Period 2 (open-label extension). Safety will be monitored throughout the study.
Interventions
DRUGALXN1840
Administered as an oral tablet.
DRUGStandard of Care
Depending on the site/region, participants randomized to receive Standard of Care treatment will receive trientine, penicillamine, zinc, or a combination of these medicines, administered according to standard regimens.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
This study is rater-blinded for the Unified Wilson Disease Rating Scale (UWDRS) assessment only.
Eligibility
Sex/Gender
ALL
Age
3 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Diagnosis of Wilson Disease by Leipzig Score ≥ 4. 2. Adequate venous access to allow collection of required blood samples. 3. Able to swallow intact ALXN1840 tablets or mini-tablets. 4. Willing to avoid intake of foods and drinks with high contents of copper. 5. Willing and able to follow protocol-specified contraception requirements. Key
Exclusion criteria
1. Decompensated hepatic cirrhosis or MELD score \> 13 (ages 12 to \<18) or PELD score \> 13 (ages 3 to \< 12). 2. Modified Nazer score \> 7. 3. Clinically significant gastrointestinal bleed within past 3 months. 4. Alanine aminotransferase (ALT) \> 2 × upper limit of normal (ULN) for participants treated for \> 28 days with WD therapy or ALT \> 5 × ULN for treatment-naïve participants or participants who have been treated for ≤ 28 days. 5. Marked neurological disease requiring either nasogastric feeding tube or intensive inpatient medical care. 6. Hemoglobin less than lower limit of the reference range for age and sex. 7. History of seizure activity within 6 months prior to informed consent/assent. 8. Participants in renal failure, defined as in end-stage renal disease on dialysis (chronic kidney disease stage 5) or estimated glomerular filtration rate \< 30 milliliters/minute/1.73 meter squared.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to Week 48 in Non-ceruloplasmin-bound Copper in Plasma | Baseline, Week 48 | Plasma samples were planned to be collected to measure ceruloplasmin-bound copper. Due to the early termination of the study, data for this Outcome Measure were not collected for any of the cohorts. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) During the Primary Evaluation Period | Baseline up to Week 48 | An adverse event (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 AEs with onset after the first dose of study intervention or existing events that worsened in severity after the first dose of study intervention. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. |
| Area Under the Effect Versus Time Curve (AUEC) for Plasma Total Copper and Direct NCC | Week 48 | — |
| Maximum Observed Concentration (Cmax) of ALXN1840 for Plasma Total Molybdenum and Plasma Ultrafiltrate Molybdenum Concentrations | Week 48 | — |
| Area Under the Plasma Concentration Versus Time Curve From Time 0 to the End of the Dosing Interval (AUCtau) of ALXN1840 for Plasma Total Molybdenum and Plasma Ultrafiltrate Molybdenum | Week 48 | — |
Countries
Australia, France, Germany, Japan, Poland, South Korea, Spain
Participant flow
Recruitment details
The study consisted of 2 periods: Primary Evaluation Period (PEP) and Open-label Extension (OLE) Period. Participants who completed the 48-week PEP were offered the opportunity to continue treatment in an up to 24-week OLE Period.
Pre-assignment details
Per prespecified analysis, participants were randomized, stratified by cohort, in 1:1 ratio to ALXN1840 or continued treatment with Standard of Care (SoC) in Cohort 1 or as continued or initial therapy in Cohort 2 for the PEP. The stratification was not applicable to the OLE Period. Data was collected for the OLE Period by dose received irrespective of the cohort assigned during randomization.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: ALXN1840 Participants in Cohort 1 (who received SoC therapy, that is, chelation therapy with penicillamine or trientine, zinc therapy, or a combination of both chelation and zinc therapy for \>28 days) received titrated doses of ALXN1840 orally for up to 48 weeks in PEP. | 15 |
| Cohort 1: SoC Therapy Participants in Cohort 1 (who received SoC therapy, that is, chelation therapy with penicillamine or trientine, zinc therapy, or a combination of both chelation and zinc therapy for \>28 days) continued to receive SoC therapy according to the local package label for up to 48 weeks in PEP. | 16 |
| Cohort 2: ALXN1840 Participants in Cohort 2 (who were treatment naïve or who received SoC therapy for ≤28 days) received titrated doses of ALXN1840 orally for up to 48 weeks in PEP. | 4 |
| Cohort 2: SoC Therapy Participants in Cohort 2 (who were treatment naïve or who received SoC therapy for ≤28 days) received SoC therapy according to the local package label for up to 48 weeks in PEP. | 5 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Extension Period (24 Weeks) | Adverse Event | 0 | 0 | 0 | 0 | 1 | 1 |
| Extension Period (24 Weeks) | Study Terminated by Sponsor | 0 | 0 | 0 | 0 | 8 | 8 |
| Primary Evaluation Period (48 Weeks) | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 |
| Primary Evaluation Period (48 Weeks) | Physician Decision | 0 | 0 | 1 | 0 | 0 | 0 |
| Primary Evaluation Period (48 Weeks) | Study Terminated by Sponsor | 2 | 4 | 3 | 4 | 0 | 0 |
| Primary Evaluation Period (48 Weeks) | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Cohort 1: ALXN1840 | Cohort 1: SoC Therapy | Cohort 2: ALXN1840 | Cohort 2: SoC Therapy |
|---|---|---|---|---|---|
| Age, Customized Adolescents (12-17 years) | 22 Participants | 9 Participants | 10 Participants | 1 Participants | 2 Participants |
| Age, Customized Children (2-11 years) | 18 Participants | 6 Participants | 6 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 5 Participants | 4 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 10 Participants | 11 Participants | 4 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 15 Participants | 5 Participants | 6 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 20 Participants | 9 Participants | 9 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Female | 15 Participants | 5 Participants | 4 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Male | 25 Participants | 10 Participants | 12 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 16 | 0 / 4 | 0 / 5 | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 13 / 15 | 12 / 16 | 2 / 4 | 4 / 5 | 6 / 12 | 8 / 12 |
| serious Total, serious adverse events | 0 / 15 | 2 / 16 | 0 / 4 | 0 / 5 | 0 / 12 | 0 / 12 |
Outcome results
Primary
Percent Change From Baseline to Week 48 in Non-ceruloplasmin-bound Copper in Plasma
Plasma samples were planned to be collected to measure ceruloplasmin-bound copper. Due to the early termination of the study, data for this Outcome Measure were not collected for any of the cohorts.
Time frame: Baseline, Week 48
Population: FAS included all participants who received at least 1 dose of ALXN1840 or SoC treatment. Due to the early termination of the study, data for this Outcome Measure were not collected for any of the cohorts.
Secondary
Area Under the Effect Versus Time Curve (AUEC) for Plasma Total Copper and Direct NCC
Time frame: Week 48
Population: Pharmacodynamic (PD) analysis set included all participants who had sufficient plasma samples to enable the calculation of pharmacokinetic (PK) parameters and provide PK/PD profiles. Here, 'Overall number of participants analyzed' = participants evaluable for this Outcome Measure. No participants were evaluable for this Outcome Measure for Cohort 2: ALXN1840.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: ALXN1840 | Area Under the Effect Versus Time Curve (AUEC) for Plasma Total Copper and Direct NCC | Total Copper | 6342.909 nanograms (ng)*hours (hr)/milliliter(mL) | Standard Deviation 3038.3317 |
| Cohort 1: ALXN1840 | Area Under the Effect Versus Time Curve (AUEC) for Plasma Total Copper and Direct NCC | Direct NCC | 3882.473 nanograms (ng)*hours (hr)/milliliter(mL) | Standard Deviation 1716.4565 |
| Cohort 1: SoC Therapy | Area Under the Effect Versus Time Curve (AUEC) for Plasma Total Copper and Direct NCC | Total Copper | 7528.864 nanograms (ng)*hours (hr)/milliliter(mL) | Standard Deviation 4167.211 |
| Cohort 1: SoC Therapy | Area Under the Effect Versus Time Curve (AUEC) for Plasma Total Copper and Direct NCC | Direct NCC | 3067.864 nanograms (ng)*hours (hr)/milliliter(mL) | Standard Deviation 1524.9183 |
| Cohort 2: SoC Therapy | Area Under the Effect Versus Time Curve (AUEC) for Plasma Total Copper and Direct NCC | Total Copper | 16369.000 nanograms (ng)*hours (hr)/milliliter(mL) | — |
| Cohort 2: SoC Therapy | Area Under the Effect Versus Time Curve (AUEC) for Plasma Total Copper and Direct NCC | Direct NCC | 4214.000 nanograms (ng)*hours (hr)/milliliter(mL) | — |
Secondary
Area Under the Plasma Concentration Versus Time Curve From Time 0 to the End of the Dosing Interval (AUCtau) of ALXN1840 for Plasma Total Molybdenum and Plasma Ultrafiltrate Molybdenum
Time frame: Week 48
Population: PK analysis set included all participants who had sufficient plasma samples to enable the calculation of PK parameters and provide PK/PD profiles. Here, 'Overall number of participants analyzed' = participants evaluable for this Outcome Measure. No participants were evaluable for this Outcome Measure for Cohort 2: ALXN1840.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: ALXN1840 | Area Under the Plasma Concentration Versus Time Curve From Time 0 to the End of the Dosing Interval (AUCtau) of ALXN1840 for Plasma Total Molybdenum and Plasma Ultrafiltrate Molybdenum | Plasma Total Molybdenum | 4498.082 ng*hr/mL | Standard Deviation 3054.83 |
| Cohort 1: ALXN1840 | Area Under the Plasma Concentration Versus Time Curve From Time 0 to the End of the Dosing Interval (AUCtau) of ALXN1840 for Plasma Total Molybdenum and Plasma Ultrafiltrate Molybdenum | Plasma Ultrafiltrate Molybdenum | 233.154 ng*hr/mL | Standard Deviation 145.796 |
| Cohort 1: SoC Therapy | Area Under the Plasma Concentration Versus Time Curve From Time 0 to the End of the Dosing Interval (AUCtau) of ALXN1840 for Plasma Total Molybdenum and Plasma Ultrafiltrate Molybdenum | Plasma Total Molybdenum | 2931.045 ng*hr/mL | Standard Deviation 1694.3512 |
| Cohort 1: SoC Therapy | Area Under the Plasma Concentration Versus Time Curve From Time 0 to the End of the Dosing Interval (AUCtau) of ALXN1840 for Plasma Total Molybdenum and Plasma Ultrafiltrate Molybdenum | Plasma Ultrafiltrate Molybdenum | 144.627 ng*hr/mL | Standard Deviation 88.671 |
| Cohort 2: SoC Therapy | Area Under the Plasma Concentration Versus Time Curve From Time 0 to the End of the Dosing Interval (AUCtau) of ALXN1840 for Plasma Total Molybdenum and Plasma Ultrafiltrate Molybdenum | Plasma Total Molybdenum | 4261.100 ng*hr/mL | — |
| Cohort 2: SoC Therapy | Area Under the Plasma Concentration Versus Time Curve From Time 0 to the End of the Dosing Interval (AUCtau) of ALXN1840 for Plasma Total Molybdenum and Plasma Ultrafiltrate Molybdenum | Plasma Ultrafiltrate Molybdenum | 129.370 ng*hr/mL | — |
Secondary
Maximum Observed Concentration (Cmax) of ALXN1840 for Plasma Total Molybdenum and Plasma Ultrafiltrate Molybdenum Concentrations
Time frame: Week 48
Population: PK analysis set included all participants who had sufficient plasma samples to enable the calculation of PK parameters and provide PK/PD profiles. Here, 'Overall number of participants analyzed' = participants evaluable for this Outcome Measure. No participants were evaluable for this Outcome Measure for Cohort 2: ALXN1840.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: ALXN1840 | Maximum Observed Concentration (Cmax) of ALXN1840 for Plasma Total Molybdenum and Plasma Ultrafiltrate Molybdenum Concentrations | Plasma Total Molybdenum | 183.150 ng/mL | Standard Deviation 110.4736 |
| Cohort 1: ALXN1840 | Maximum Observed Concentration (Cmax) of ALXN1840 for Plasma Total Molybdenum and Plasma Ultrafiltrate Molybdenum Concentrations | Plasma Ultrafiltrate Molybdenum | 13.733 ng/mL | Standard Deviation 8.6186 |
| Cohort 1: SoC Therapy | Maximum Observed Concentration (Cmax) of ALXN1840 for Plasma Total Molybdenum and Plasma Ultrafiltrate Molybdenum Concentrations | Plasma Total Molybdenum | 209.355 ng/mL | Standard Deviation 114.3741 |
| Cohort 1: SoC Therapy | Maximum Observed Concentration (Cmax) of ALXN1840 for Plasma Total Molybdenum and Plasma Ultrafiltrate Molybdenum Concentrations | Plasma Ultrafiltrate Molybdenum | 17.708 ng/mL | Standard Deviation 27.9548 |
| Cohort 2: SoC Therapy | Maximum Observed Concentration (Cmax) of ALXN1840 for Plasma Total Molybdenum and Plasma Ultrafiltrate Molybdenum Concentrations | Plasma Total Molybdenum | 307.000 ng/mL | — |
| Cohort 2: SoC Therapy | Maximum Observed Concentration (Cmax) of ALXN1840 for Plasma Total Molybdenum and Plasma Ultrafiltrate Molybdenum Concentrations | Plasma Ultrafiltrate Molybdenum | 9.910 ng/mL | — |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) During the Primary Evaluation Period
An adverse event (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 AEs with onset after the first dose of study intervention or existing events that worsened in severity after the first dose of study intervention. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
Time frame: Baseline up to Week 48
Population: Safety analysis set included all participants who received at least 1 dose of ALXN1840 or SoC treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: ALXN1840 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) During the Primary Evaluation Period | 13 Participants |
| Cohort 1: SoC Therapy | Number of Participants With Treatment-emergent Adverse Events (TEAEs) During the Primary Evaluation Period | 13 Participants |
| Cohort 2: ALXN1840 | Number of Participants With Treatment-emergent Adverse Events (TEAEs) During the Primary Evaluation Period | 3 Participants |
| Cohort 2: SoC Therapy | Number of Participants With Treatment-emergent Adverse Events (TEAEs) During the Primary Evaluation Period | 4 Participants |