E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Paget's disease of the bone (PDB) |
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E.1.1.1 | Medical 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. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033363 |
E.1.2 | Term | Paget's disease of bone |
E.1.2 | System Organ Class | 100000004859 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary 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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 |
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E.4 | Principal 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 |
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E.5 End points |
E.5.1 | Primary 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary outcomes will be assessed following the final follow up visit for the last patient. |
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E.5.2 | Secondary 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. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary outcomes will be assessed following the final follow up visit for the last patient. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial 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
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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. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 9 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 18 |
E.8.9.2 | In all countries concerned by the trial years | 11 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 22 |