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    Summary
    EudraCT Number:2008-005667-34
    Sponsor's Protocol Code Number:G0701625
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-02-15
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedIreland - HPRA
    A.2EudraCT number2008-005667-34
    A.3Full title of the trial
    Randomised Trial of Genetic Testing and Targeted Zoledronic acid therapy to Prevent SQSTM1 Mediated Paget's Disease (Zoledronate in the Prevention of Paget's).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A research study to determine if a drug called Zoledronic Acid prevents a serious bone disease (Paget's disease) in people who are known to have a change in a gene which has been linked to the disease.
    A.3.2Name or abbreviated title of the trial where available
    ZiPP study
    A.4.1Sponsor's protocol code numberG0701625
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN11616770
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity of Edinburgh
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMedical Research Council
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEdinburgh Clinical Trials Unit
    B.5.2Functional name of contact pointAnna Heye
    B.5.3 Address:
    B.5.3.1Street AddressEdinburgh Clinical Trials Unit, Usher Institute
    B.5.3.2Town/ cityEdinburgh
    B.5.3.3Post codeEH16 4UX
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+441316519917
    B.5.6E-mailzipptri1@exseed.ed.ac.uk
    B.Sponsor: 2
    B.1.1Name of SponsorNHS Lothian
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMedical Research Council
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportArthritis Research UK
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEdinburgh Clinical Trials Unit
    B.5.2Functional name of contact pointAnna Heye
    B.5.3 Address:
    B.5.3.1Street AddressEdinburgh Clinical Trials Unit, Usher Institute
    B.5.3.2Town/ cityEdinburgh
    B.5.3.3Post codeEH16 4UX
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+441316519917
    B.5.6E-mailzipptri1@exseed.ed.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Aclasta
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis EuroPharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAclasta
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNZoledronic Acid
    D.3.9.1CAS number 165800-06-6
    D.3.9.3Other descriptive nameZOLEDRONIC ACID MONOHYDRATE
    D.3.9.4EV Substance CodeSUB21645
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.05
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous drip use (Noncurrent)
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Paget's disease of the bone (PDB)
    E.1.1.1Medical condition in easily understood language
    Paget's disease of bone (PDB) is a serious bone disease, which causes pain, arthirtis and deafness and can lead to softening of the bones causing them to enlarge and become bent.
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10033363
    E.1.2Term Paget's disease of bone
    E.1.2System Organ Class 100000004859
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine whether targeted intervention with Zoledronic acid can prevent the development of new focal bone lesions in carriers of SQSTM1 gene mutations.

    There will be an observational group in this study who have the same risk of developing paget's disease as the general population. The primary objective of the Observational study will be to determine if genetic testing impacts on quality of life or depression in participants who do not have SQSTM1 gene mutations.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study will be to determine whether targeted intervention with Zoledronic acid:
    a) can modify the activity of existing bone lesions in carriers of SQSTM1 gene mutations,
    b) can reduce or prevent PDB-related skeletal events (PRSE) in carriers of SQSTM1 mutations.
    c) can reduce or prevent increases in bone turnover in carriers of SQSTM1 gene mutations.
    d) can modify quality of life, bone pain and anxiety or depression.

    For the observational study, the secondary objectives will be to determine if:
    a) bone turnover changes with time in non-gene carriers,
    b) alterations in the quality of life occur in non-gene carriers.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion criteria for a Genetic Test - Patients with PDB (Probands):
    Probands must be diagnosed with PDB AND
    Have at least one relative aged 30 years old or greater

    Inclusion criteria for a Genetic Test - Relatives:
    Relatives are aged 30 years old or greater.
    Relatives not yet been diagnosed with PDB.

    Inclusion Criteria for the Intervention Study:
    Relatives of patients with SQSTM1 mutations aged 30 years old or greater who carry SQSTM1 mutations.
    Not already diagnosed with PDB at study entry.

    Inclusion Criteria for the Observational Study:
    Relatives aged between 30 years old or greater
    Relatives who on screening are found NOT to have SQSTM1 mutations
    E.4Principal exclusion criteria
    Exclusion Criteria for Genetic Test (Patient with PDB and Relatives)
    Subjects not willing to have a blood sample taken.
    Subjects who are unwilling or unable to consent.

    Exclusion Criteria for the Intervention Study
    Already diagnosed with PDB.
    Unwilling or unable to consent.
    Bisphosphonates contraindicated.
    Receiving bisphosphonate therapy for another reason.
    Osteonecrosis of the jaw (ONJ).
    Estimated GFR (eGFR) < 35ml/min.
    Hypocalcaemia
    Metastatic cancer or cancer diagnosed less than 2 years ago where treatment is still ongoing.
    Active uveitis, iritis, or episcleritis.
    Already taking part in another randomised controlled clinical trial.
    Pregnancy.
    Lactation.

    Exclusion waivers will not be permitted.
    1 Female patients of child bearing potential should have a negative pregnancy test on the day of, or the day before, the infusion of study drug. The preferred method of testing for pregnancy is serum beta-hCG, but a urine beta-hCG is also acceptable for centres that are unable to obtain a serum beta-hCG within 1-2 days. Participants who are sexually active must receive specific advice about the possible risks associated with getting pregnant whilst on the trial and must agree to practice a medically acceptable form of birth control for at least 12 months post infusion (acceptable birth control defined as the use of an IUD, a barrier method with spermicide, condoms, subdermal implant or oral contraceptives)

    Exclusion Criteria for the Observational Study
    Subjects diagnosed with PDB or SQSTM1 mutation positive
    E.5 End points
    E.5.1Primary end point(s)
    In the intervention study, the primary outcome will be the total number of subjects who develop new bone lesions on radionuclide bone scans with the characteristics of PDB between the baseline visit and the final follow up visit. The presence of lesions will be assessed by an imaging expert blinded to treatment allocation. A new bone lesion will be defined as evidence of involvement of a new bone or part of an existing bone at the end-of-study visit which was not thought to be involved at the baseline visit”.

    In the observational study, the primary outcome measure will be anxiety / depression, measured using the HADS scale.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary outcomes will be assessed following the final follow up visit for the last patient.
    E.5.2Secondary end point(s)
    In the interventional study, the secondary outcome measures will be:
    a) number of new bone lesions on radionuclide bone scan,
    b) change in activity of existing bone lesions that were present at the baseline assessed by semiquantitative analysis of radionuclide bone scans,
    c) the development of PDB-related skeletal events (PRSE) in carriers of SQSTM1 mutations, defined as any one of the following:
    - development of new bone lesions thought to be due to PDB on imaging
    - development of complications thought to be due to the development or progression of PDB including pathological fractures, bone deformity, deafness, deafness, joint replacement surgery or other orthopaedic procedures
    - administration of treatment for PDB with an antiresorptive drug because of the development of signs or symptoms thought to be due to PDB such as pain localised to an affected site or neurological symptoms
    d) the development of increased bone turnover, as assessed by measurement of biochemical markers of bone resorption (NTX) and bone formation (ALP, BSALP, P1NP),
    e) quality of life, and anxiety and depression assessed by the SF-36, BPI and HADS questionnaires,
    f) presence and severity of localised bone pain as assessed by the BPI pain manikin,
    g) presence and severity of pain assessed by the BPI pain questionnaire.

    In the observational study, the secondary outcomes will be:
    a) the development of increased bone turnover, as assessed by measurement of biochemical markers of bone resorption (NTX) and bone formation (ALP, BSALP, P1NP),
    b) quality of life, assessed by the SF-36 questionnaire.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The secondary outcomes will be assessed following the final follow up visit for the last patient.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA17
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    New Zealand
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study in terms of the participant's involvement is the last participant's final clinical follow up. The end of study is defined as the end of the funding period.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years9
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days18
    E.8.9.2In all countries concerned by the trial years11
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days22
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 194
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 63
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state18
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 103
    F.4.2.2In the whole clinical trial 357
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Due to the nature of this study, longer term follow up of these subjects may well be an option. This will depend on end of trial analysis or results and continuing funding. If this occurs, intervention will continue.

    If this does not occur, participants will need to speak to their local doctor/clinician to determine if this is something they would consider doing.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-04-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-04-14
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-05-31
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