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Efficacy and Safety of WTX101 Administered for 48 Weeks Versus Standard of Care in Wilson Disease Subjects

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ClinicalTrials.gov Identifier: NCT03403205
Recruitment Status : Recruiting
First Posted : January 18, 2018
Last Update Posted : September 3, 2018
Sponsor:
Information provided by (Responsible Party):
Wilson Therapeutics AB

Brief Summary:
Wilson Disease (WD) is an autosomal recessive disorder of impaired copper (CU) transport caused by mutations in the ATP7B gene. WTX101 (bis-choline tetrathiomolybdate) is a first-in-class copper-protein-binding agent with a unique mechanism of action, under investigation as a novel therapy for WD. It is formulated as an enteric coated tablet (15 mg strength) for oral administration. The purpose of this study is to evaluate the efficacy of WTX101 administered for 48 weeks compared to standard of care (SOC) in WD subjects aged 18 and older.

Condition or disease Intervention/treatment Phase
Wilson Disease Drug: WTX101 Drug: SOC Therapy Phase 3

Detailed Description:

This study is a randomized, rater-blinded, multi-center study assessing the efficacy and safety of an individualized WTX101 dosing regimen administered for 48 weeks, compared to SoC, in WD subjects aged 18 and older. Approximately 100 subjects will be enrolled at approximately 5 to 10 North American sites and 15 to 25 sites in the rest of the world. Subjects who complete the 48-week treatment period will be offered to participate in an Extension Phase of the study to evaluate the long-term safety and durability of treatment effect of WTX101.

The primary objective is to evaluate the efficacy of WTX101 administered for 48 weeks, compared to SOC, on Cu control in WD subjects aged 18 and older. Copper control will be assessed in terms of the percentage change from baseline (Day 1) to 48 weeks in non-ceruloplasmin-bound copper (NCC) levels. For WTX101-treated subjects, the NCC level will be corrected for the amount of Cu bound to the WTX101 tripartite complex (TPC) (NCCcorrected).


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 102 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Masking Description: This study is rater-blinded for the Unified Wilson Disease Rating Scale (UWDRS) assessment only. The rater will be blinded and will have no knowledge of the subject's treatment assignment and no access to systems that could result in potential unblinding of treatment assignment. Both raters and subjects will be instructed to avoid lines of inquiry, questions, and responses that could potentially lead to unblinding of the subject's treatment. The blinding will be documented by the rater after each UWDRS assessment. The rater assessments will be strictly limited to administration of the protocol specified instruments and assessments.
Primary Purpose: Treatment
Official Title: A Phase 3, Randomised, Rater-Blinded, Multi-Centre Study to Evaluate the Efficacy and Safety of WTX101 Administered for 48 Weeks Versus Standard of Care in Wilson Disease Subjects Aged 18 and Older With an Extension Phase of up to 60 Months
Actual Study Start Date : February 15, 2018
Estimated Primary Completion Date : December 18, 2019
Estimated Study Completion Date : February 14, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Wilson Disease

Arm Intervention/treatment
Experimental: 15-60 mg WTX101 to subjects treated >28 days with SOC
Subjects treated for >28 days with chelation or zinc (Zn) therapy or a combination of both chelation and Zn therapy will be treated with 15 mg every other day (QOD) to 60 mg once daily (QD) of WTX101 by oral administration.
Drug: WTX101
WTX101 administered orally in 15 mg tablets

Active Comparator: SOC for subjects treated with SOC >28 days prior
Subjects treated for >28 days with chelation or Zn therapy or a combination of both chelation and Zn therapy will continue to receive the SOC therapy.
Drug: SOC Therapy
Subjects randomized to receive SOC treatment will continue their current therapy or initiate therapy with chelation, Zn, or a combination of both chelation and Zn therapy. Depending on the site/region enrolling the subject, this treatment will be trientine hydrochloride, penicillamine, or Zn, or a combination of both chelation and Zn therapy, administered according to standard regimens.

Experimental: 15-60 mg WTX101 to subjects treated ≤28 days with SOC
Subjects who are treatment naïve or have been previously treated with chelation or Zn therapy or a combination of both chelation and Zn therapy for ≤28 days will be treated with 15 mg QOD to 60 mg QD of WTX101 by oral administration.
Drug: WTX101
WTX101 administered orally in 15 mg tablets

Active Comparator: SOC for subjects treated with SOC ≤28 days prior
Subjects who are treatment naïve or have been previously treated with chelation or Zn therapy or a combination of both chelation and Zn therapy for ≤28 days will initiate or continue SOC therapy.
Drug: SOC Therapy
Subjects randomized to receive SOC treatment will continue their current therapy or initiate therapy with chelation, Zn, or a combination of both chelation and Zn therapy. Depending on the site/region enrolling the subject, this treatment will be trientine hydrochloride, penicillamine, or Zn, or a combination of both chelation and Zn therapy, administered according to standard regimens.




Primary Outcome Measures :
  1. Evaluate the efficacy of WTX101 using standard of care as comparator and copper as the control assessed in terms of the percentage change from baseline (Day 1) to 48 weeks in non-ceruloplasmin-bound copper levels [ Time Frame: Change from baseline (Day 1) to 48 weeks ]
    Evaluate the efficacy of WTX101 administered for 48 weeks, compared to standard of care, on copper control in Wilson Disease subjects aged 18 and older. Copper control will be assessed in terms of the percentage change from baseline (Day 1) to 48 weeks in non-ceruloplasmin-bound copper levels. For WTX101-treated subjects, the non-ceruloplasmin-bound copper level will be corrected for the amount of copper bound to the WTX101 tripartite complex.


Secondary Outcome Measures :
  1. Safety and tolerability of individualized dosing of WTX101 by descriptive statistics via the Safety Analysis Set dataset [ Time Frame: Change from baseline (Day 1) to 48 weeks ]
    Safety and tolerability will be determined over the course of the study period by descriptive statistics via the Safety Analysis Set dataset. This dataset includes all subjects who received at least 1 dose of randomized treatment. Subjects will be summarized according to the treatment actually received.

  2. Effects of WTX101 on hepatic status [ Time Frame: Change from baseline (Day 1) to 48 weeks ]

    Evaluate the effects of WTX101 on hepatic status assessed by the Model for End-Stage Liver Disease (MELD) score. The MELD uses the subject's values for serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time (INR) to predict survival. It is calculated according to the following formula:

    MELD = 3.78×ln[serum bilirubin (mg/dL)] + 11.2×ln[INR] + 9.57×ln[serum creatinine (mg/dL)] + 6.43.


  3. Effects of WTX101 on disability status [ Time Frame: Change from baseline (Day 1) to 48 weeks ]
    Evaluate the effects of WTX101 on disability status assessed by the Unified WD Rating Scale (UWDRS) Part II which consists of a historical review of daily activity items and is reported by the subject or family.

  4. Effects of WTX101 on neurological status [ Time Frame: Change from baseline (Day 1) to 48 weeks ]
    Evaluate the effects of WTX101 on neurological status assessed by the Unified WD Rating Scale (UWDRS) Part III which consists of a neurological examination performed by a blinded neurologist.

  5. Global effects of WTX101 on clinical symptoms as assessed by the Investigator on the Clinical Global Impression-Improvement Scale (CGI-I) and the Clinical Global Impression-Severity Scale (CGI-S) [ Time Frame: Change from baseline (Day 1) to 48 weeks ]
    Evaluate the global effects of WTX101 on clinical symptoms performed by the Investigator using a composite assessment which include the Clinical Global Impression-Improvement Scale (a 7-point scale that assess how much the subject's illness has improved or worsened relative to a baseline and rated from 1 to 7) and the Clinical Global Impression-Severity Scale (a 7-point scale that assess severity of a subject's illness relative to a baseline and rated from 1 to 7).

  6. Effects of WTX101 on NCC responder rate [ Time Frame: Change from baseline (Day 1) to 48 weeks ]
    Evaluate the effects of WTX101 on the NCC responder rate



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Subjects who meet all of the following criteria will be eligible to participate in the study:

  • 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;
  • Treatment for >28 days for WD with chelation therapy (ie, penicillamine, trientine hydrochloride), Zn therapy, or a combination of a chelator and Zn; OR Treatment naïve or treatment for ≤28 days for WD with chelation therapy (ie, penicillamine, trientine hydrochloride), Zn therapy, or a combination of a chelator and Zn;
  • Willing and able to give informed consent for participation in the study;
  • Male or female subjects, aged 18 years or older as of signing the informed consent form (ICF);
  • Able to understand and willing to comply with study procedures, restrictions, and requirements, as judged by the Investigator;
  • Willing to undergo ≥48-hour washout from current WD treatment;
  • Adequate venous access to allow collection of required blood samples;
  • Willing to avoid use of vitamins and/or minerals containing Cu, Zn, or Mo throughout the study duration;
  • Willing to avoid intake of foods and drinks with high contents of Cu throughout the study duration;
  • Females of childbearing potential will be included if they are either sexually inactive (abstinent) for 14 days prior to the first WTX101 dose and continuing through 28 days after the last WTX101 dose, or using 1 of the following highly effective birth control methods (ie, results in <1% failure rate when used consistently and correctly):

    1. Intrauterine device (without Cu) in place for at least 3 months prior to the first WTX101 dose and throughout the study;
    2. Surgical sterilization of the partner (vasectomy for 6 months minimum);
    3. Combined (estrogen or progestogen containing) hormonal contraception associated with the inhibition of ovulation (either oral, intravaginal, or transdermal) for at least 3 months prior to the first WTX101 dose and throughout the study;
    4. Progestogen only hormonal contraception associated with the inhibition of ovulation (either oral, injectable, or implantable) for at least 3 months prior to the first WTX101 dose and throughout the study;
    5. Intrauterine hormone releasing system for at least 3 months prior to the first WTX101 dose and throughout the study; or
    6. Bilateral tubal occlusion for at least 6 months prior to the first WTX101 dose;

      • Note: Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. In this trial, abstinence is only acceptable if in line with the subject's preferred and usual lifestyle; and
      • Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method are not acceptable methods of contraception. As well, female condom and male condom should not be used together;
  • Females of childbearing potential agree to remain sexually inactive or to keep the same birth control method for at least 28 days following the last dose;
  • A female of non-childbearing potential must have undergone 1 of the following sterilization procedures at least 6 months prior to the first WTX101 dose:

    1. Hysteroscopic sterilization;
    2. Bilateral tubal ligation or bilateral salpingectomy;
    3. Hysterectomy; or
    4. Bilateral oophorectomy; OR be postmenopausal with amenorrhoea for at least 1 year prior to the first WTX101 dose and follicle stimulating hormone serum levels consistent with postmenopausal status;
  • A non-vasectomized male subject agrees to use a condom with spermicide or abstain from sexual intercourse during the study until 90 days beyond the last dose of study drug. For a vasectomized male who has had his vasectomy 6 months or more prior to study start, it is required that they use a condom during sexual intercourse. A male who has been vasectomized less than 6 months prior to study start must follow the same restrictions as a non-vasectomized male;

    • Note: Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. In this trial, abstinence is only acceptable if in line with the subject's preferred and usual lifestyle; and
    • Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method are not acceptable methods of contraception. As well, female condom and male condom should not be used together; and
  • If male, agrees not to donate sperm from the first WTX101 dose until 90 days after dosing.

Exclusion Criteria:

Subjects who meet any of the following criteria will be excluded from participation in the study:

  • Decompensated hepatic cirrhosis;
  • MELD score >13;
  • Modified Nazer score >7;
  • Clinically significant gastrointestinal bleed within past 3 months;
  • Alanine aminotransferase >2 × upper limit of normal (ULN) for subjects treated for >28 days with WD therapy (Cohort 1);
  • Alanine aminotransferase >5 × ULN for treatment naïve subjects or subjects who have been treated for ≤28 days (Cohort 2);
  • Marked neurological disease requiring either nasogastric feeding or intensive inpatient medical care;
  • Severe anaemia with a hemoglobin <9 g/dL;
  • Participation in a clinical study of an experimental or unapproved/unlicensed therapy at the same time or within the 4 weeks prior to this Screening Visit;
  • History of seizure activity within 6 months of study start;
  • Pregnant (or women who are planning to become pregnant) or lactating women;
  • Known sensitivity to WTX101, WTX101 excipients (anhydrous di-calcium phosphate, anhydrous sodium carbonate), or any of the ingredients contained in WTX101 or related compounds;
  • Active infection with hepatitis B virus (positive hepatitis B surface antigen) or C virus (subjects with positive hepatitis C antibody result would require confirmation of active disease with a positive hepatitis C polymerase chain reaction test), or seropositivity for human immunodeficiency virus;
  • Any disability acquired from trauma or another illness that, in the opinion of the Investigator, could interfere with evaluation of disability due to WD;
  • Previous treatment with tetrathiomolybdate;
  • Major systemic disease or other illness that would, in the opinion of the Investigator, compromise subject safety or interfere with the collection or interpretation of study results;
  • In the opinion of the Investigator, the subject is likely to be non-compliant or uncooperative during the study; or
  • Any deviation in laboratory values that are confirmed on re-examination to be clinically significant by the Investigator that would jeopardize the safety of the subject or impact the validity of the study results.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03403205


  Show 32 Study Locations
Sponsors and Collaborators
Wilson Therapeutics AB
Investigators
Study Director: Eugene Swenson, MD, PhD Alexion Pharmaceuticals

Responsible Party: Wilson Therapeutics AB
ClinicalTrials.gov Identifier: NCT03403205     History of Changes
Other Study ID Numbers: WTX101-301
First Posted: January 18, 2018    Key Record Dates
Last Update Posted: September 3, 2018
Last Verified: August 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Hepatolenticular Degeneration
Liver Diseases
Digestive System Diseases
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Movement Disorders
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Metabolic Diseases
Metabolism, Inborn Errors
Metal Metabolism, Inborn Errors