Phase 3, open-label study of ALXN1840 versus standard of care in pediatric participants with Wilson disease

• Register: EUCTR
• Last refreshed on: 6 December 2021
• Main ID: EUCTR2021-001015-82-ES
• Date of registration: 23/08/2021
• Prospective Registration: Yes
• Primary sponsor: Alexion Pharmaceuticals, Inc.
• Public title: Phase 3, open-label study of ALXN1840 versus standard of care in pediatric participants with Wilson disease
• Scientific title: A multicenter, randomized, controlled, open-label, rater-blinded study to evaluate efficacy, safety, pharmacokinetics, and pharmacodynamics of ALXN1840 versus standard of care in pediatric participants with Wilson disease.
• Date of first enrolment: 22/11/2021
• Target sample size: 48
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2021-001015-82
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: yes; Other trial design description: Rater Blinded; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: yes; Other specify the comparator: Standard of Care (Penicillamine, Trientine, and Zinc); Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Austria, Canada, Czechia, Denmark, France, Germany, Hungary, Japan, Korea, Republic of, Netherlands, Poland, Russian Federation, Serbia, Spain, Turkey, United Kingdom, United States

Contacts

• Name: Anna Anguera
• Affiliation: Alexion Pharma Spain S.L.

• Name: Anna Anguera
• Affiliation: Alexion Pharma Spain S.L.

Key inclusion & exclusion criteria

Inclusion criteria:
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participants must be aged 3 to <18 years at time of signing the informed consent/assent.
Type of Participants and Disease Characteristics
2. Established diagnosis of WD by Leipzig-Score = 4 documented by testing as outlined in the 2012 European Association for the Study of Liver WD Clinical Practice Guidelines (Ferenci, 2003; EASL, 2012). Note: Historical test results for WD, including some or all of the following: presence of KF rings, neurologic symptoms, serum ceruloplasmin below the reference range, Coombs-negative hemolytic anemia, elevated liver or urinary copper, presence of mutations in the ATP7B gene, or other, as considered appropriate, may be used instead to confirm the diagnosis of Wilson disease.
3. Participant's parent/proxy must be willing and able to give written informed consent and the participant must be willing to give written informed assent (if applicable as determined by the central or local Institutional Review Board [IRB]/Institutional [or Independent] Ethics Committee [IEC]). If allowable per local regulations, a participant’s Legally Acceptable Representative (LAR) may provide informed consent if a participant is unable to do so.
4. Adequate venous access to allow collection of required blood samples.
5. Able to swallow intact ALXN1840 tablets or mini-tablets. Participants who require gastrostomy devices for feeding or medications may be enrolled upon agreement by the Medical Monitor.
6. Willing to avoid intake of foods and drinks with high contents of copper throughout the study duration
Sex
7. Female participants of childbearing potential and male participants must follow protocol-specified contraception guidance as described in Section 10.4 of the protocol.
Informed Consent
8. Capable of giving signed informed consent or assent as described in Section 10.1.3 of the protocol, which includes compliance with the requirements and restrictions listed in the informed consent or assent form and in this protocol.
Are the trial subjects under 18? yes
Number of subjects for this age range: 48
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Decompensated hepatic cirrhosis.
2. MELD score > 13 (ages 12 to <18) or PELD score > 13 (ages 3 to < 12).
3. Modified Nazer score > 7.
4. Clinically significant gastrointestinal (GI) bleed within past 3 months
5. Alanine aminotransferase (ALT) > 2 × upper limit of normal (ULN) for participants treated for > 28 days with WD therapy (Cohort 1).
6. ALT > 5 × ULN for treatment naïve participants or participants who have been treated for = 28 days (Cohort 2)
7. Marked neurological disease requiring either nasogastric feeding tube or intensive inpatient medical care.
8. Hemoglobin less than lower limit of the reference range for age and sex.
9. History of seizure activity within 6 months prior to informed consent/assent.
Prior/Concomitant Therapy
10. Previous use of ALXN1840 or ammonium tetrathiomolybdate; concomitant use of penicillamine, trientine, or zinc (for participants randomized to ALXN1840).
Prior/Concurrent Clinical Study Experience
11. The use of an investigational drug within 30 days before initiation of the first dose of study intervention.
Diagnostic assessments
12. Participants in renal failure, defined as in end-stage renal disease on dialysis (chronic kidney disease stage 5 [CKD 5]) or estimated glomerular filtration rate < 30 mL/min/1.73m2.
13. Active infection with hepatitis B virus (positive hepatitis B surface antigen) or C virus (participants with positive hepatitis C antibody result would require confirmation of active disease with a positive hepatitis C polymerase chain reaction test), or seropositivity for HIV.
14. Any disability acquired from trauma or another illness that, in the opinion of the Investigator, could interfere with evaluation of disability due to WD.
15. Systemic disease or other illness, or any deviation in laboratory values that are confirmed on re-examination to be clinically significant by the Investigator that would, in the opinion of the Investigator, compromise participant safety or interfere with the collection or interpretation of study results.
Other Exclusions
16. Pregnant (or females who are planning to become pregnant) or breastfeeding females.
17. Known sensitivity to ALXN1840, ALXN1840 excipients (anhydrous di-calcium phosphate, anhydrous sodium carbonate), or any of the ingredients contained in ALXN1840 or related compounds.
18. Regular alcohol consumption within 6 months prior to the study defined as > 14 units for males or > 7 units for females per week. One unit is equivalent to 14 g of alcohol: a half pint (approx. 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
19. Abuse of illicit or prescribed drugs.
20. In the opinion of the Investigator, the participant and/or their parent/proxy is likely to be non-compliant or uncooperative during the study.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Wilson Disease
MedDRA version: 20.0 Level: LLT Classification code 10047988 Term: Wilson's disease System Organ Class: 100000004850

Therapeutic area: Body processes [G] - Metabolic Phenomena [G03]

Intervention(s)

Product Name: ALXN1840
Product Code: ALXN1840
Pharmaceutical Form: Tablet
INN or Proposed INN: tiomolibdic acid
CAS Number: 649749-10-0
Current Sponsor code: ALXN1840
Other descriptive name: BIS-CHOLINE TETRATHIOMOLYBDATE, bis[(2-Hydroxyethyl)trimethylammonium] tetrathiomolybdate
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 15-

Product Name: ALXN1840
Product Code: ALXN1840
Pharmaceutical Form: Tablet
INN or Proposed INN: tiomolibdic acid
CAS Number: 649749-10-0
Current Sponsor code: ALXN1840
Other descriptive name: BIS-CHOLINE TETRATHIOMOLYBDATE, bis[(2-Hydroxyethyl)trimethylammonium] tetrathiomolybdate
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1.25-

Primary Outcome(s)

Main Objective: To evaluate the efficacy of ALXN1840 administered for 48 weeks, compared to SoC, on copper control in participants with WD aged 3 to < 18 years of age at the time of enrollment

Secondary Objective: - Evaluate the safety and tolerability of ALXN1840 administered for up to 48 weeks.
- Evaluate PD and biomarkers of ALXN1840 vs SoC administered for 48 weeks.
- Evaluate the effects of ALXN1840 and SoC on the NCC responder rate.
- Evaluate the effects of ALXN1840 and SoC on participant reported disability status.
- Evaluate the effects of ALXN1840 and SoC on rater-blinded neurological status.
- Evaluate PK of ALXN1840 administered for 48 weeks.
- Evaluate the effects of ALXN1840 and SoC on global clinical symptoms as assessed by the Investigator.
- Evaluate the effects of ALXN1840 and SoC on hepatic status.

Primary end point(s): Percentage change from baseline (Day 1) to 48 weeks in NCC in plasma. For ALXN1840-treated participants, the NCC in plasma will be corrected for the amount of copper bound to the ALXN1840 TPC (NCCcorrected)

Timepoint(s) of evaluation of this end point: 48 weeks

Secondary Outcome(s)

Secondary end point(s): • Incidence of adverse AEs/SAEs, AESIs, tolerability, clinical laboratory test data (including liver function tests), neurological and physical examination findings, 12-lead ECG data, and vital signs.
• AUEC for NCC
• AUEC for plasma total copper
• Biomarkers: observed, absolute and percentage changes of ceruloplasmin-bound copper and ceruloplasmin
• NCC responder rate
• Change from baseline to Week 48 in the UWDRS Part II total score
• Change from baseline in UWDRS Part III total score or individual items/subscales, as appropriate
• PK: Cmax, tmax, AUCtau and t1/2 on Day 1, Day 43 (Week 6), and Day 337 (Week 48) for plasma total molybdenum and plasma ultrafiltrate
molybdenum concentrations, accumulation ratio of Day 43 to Day 1 and Day 337 to Day 1 based on Cmax and AUCtau
• Derived population PK parameters such as apparent total body clearance (CL/F) and apparent volume of distribution (Vd/F)
• CGI-I
• Change from Baseline to Week 48 in CGI-S
• Change from Baseline to Week 48 in MELD score (ages 12 years and older) or PELD score (ages 3 to < 12 years)
• Change from Baseline to Week 48 in Modified Nazer score

Timepoint(s) of evaluation of this end point: 48 weeks

Secondary ID(s)

ALXN1840-WD-302

2021-001015-82-DE

Source(s) of Monetary Support

Alexion Pharmaceuticals, Inc

Ethics review

Status: Approved
Approval date: 06/10/2021
Contact: