E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Paget's disease of the bone (PDB) |
Enfermedad ósea de Paget (PDB) |
|
E.1.1.1 | Medical condition in easily understood language |
Paget?s disease of bone (PDB) is a serious bone disease, which causes pain, arthritis and deafness and can lead to softening of the bones causing then to enlarge and become bent. |
|
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 | 14.1 |
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 | 10028395 - Musculoskeletal and connective tissue disorders |
|
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 if targeted intervention with Zoledronic acid can prevent
the development of raised bone turnover and/or focal bone lesions in
subjects who are genetically predisposed to develop PDB because they
carry mutations in SQSTM1 that have previously been associated with
PDB. |
Determinar si la intervención dirigida con acido zoledrónico puede evitar una elevada remodelación ósea y/o lesiones óseas localizadas en individuos que están genéticamente predispuestos a desarrollar PDB puesto que portan mutaciones que han sido previamente asociadas al PDB. |
|
E.2.2 | Secondary objectives of the trial |
1. investigate the effects of genetic testing and intervention on quality of
life and on anxiety or depression in subjects with SQSTM1 mutations
2. determine whether there is any difference in the biochemical makers
which are predictive of the disease in the group who do not have the
mutation compared to the group who have the mutation
3. determine if specialised biomarkers of bone turnover, gene
expression, the presence of antibodies and genetic profiling are of value
in predicting which patients develop PDB (or complications of PDB) as
compared with those who do not and if they are of value in predicting
treatment response and/or the development of side effects with
treatment. |
En este estudio se incluirá un grupo observacional que presente el mismo riesgo de desarrollar la enfermedad de Paget que la población general. El objetivo de este grupo será contestar las siguientes preguntas (dicho grupo no recibirá ningún tratamiento):
1. ¿Someterse a un análisis genético produce un aumento de la ansiedad y la depresión, incluso si no se ha encontrado ninguna mutación en el gen SQSTM1?
2. ¿Existen diferencias en los marcadores bioquímicos predictivos de la enfermedad en este grupo comparados con el grupo que presenta la mutación? |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria for genetic test - Patients with PDB (Probands):
Probands must be diagnosed with PDB
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 |
Criterios de inclusión en el análisis genético - Pacientes con PDB (Probandos)
Los probandos deben presentar un diagnóstico de PDB.
Deben tener al menos un familiar con 30 años de edad o mayor
Criterios de inclusión en el análisis genético - Familiares
Los familiares deben tener 30 años de edad o mayores.
Sin diagnóstico de PDB.
Criterios de inclusión en el estudio intervencional
Familiares de pacientes con mutaciones en SQSTM1 con 30 años de edad o mayores que presenten mutaciones en SQSTM1.
Todavía no diagnosticados de PDB al comienzo del estudio.
Criterios de inclusión en el estudio observacional
Familiares con 30 años de edad o mayores.
Familiares a los que no se les ha detectado mutaciones en SQSTM1 en el análisis. |
|
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
Severe liver or renal disease (bilirubin or transaminases elevated more than twice the upper limit of normal)
Osteonecrosis of the jaw (ONJ)
Estimated GFR (eGFR) < 35ml/min
Hypocalcaemia (serum adjusted caclium <2.2mmol/l)
Metastatic cancer or cancer diagnosed less than 2 years ago where treatment is still ongoing
Active history of uveitis, iritis, or episcleritis
Already taking part in another randomised controlled clinical trial
Female patients of child bearing potential are eligible only if they
are:
a. not pregnant - negative serum b-hCG pregnancy test done on the baseline screening visit and a negative urine pregnancy test on the day of infusion day, with results available, prior to infusion
b. consent to a pregnancy test prior to every dose administration
b. non-lactating
c. are sexually abstinent or are surgically sterile (tubal ligation or hysterectomy)
d. if sexually active:
must receive specific advice from their consultant about 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 |
Criterios de exclusión del análisis genético (Pacientes con PDB y familiares)
Los sujetos no desean someterse a un análisis de sangre.
Los sujetos no desean o no pueden firmar el consentimiento informado.
Criterios de exclusión del estudio intervencional
Ya diagnosticados de PDB
No desear o no poder firmar el consentimiento informado
Los bifosfonatos están contraindicados en ese paciente.
Recibir terapia con bifosfonatos por otra razón
Enfermedad de hígado o riñón grave (nivel de bilirrubina o transaminasas mayor del doble del límite superior normal)
Osteonecrosis mandibular (ONJ)
GFR (eGFR) estimada < 35ml/min
Hipocalcemia (niveles de calcio ajustados en suero <2.2 mmol/l)
Cáncer metastático o cáncer diagnosticado hace menos de 2 años con tratamiento todavía en curso
Uveitis, iritis, o episcleritis activas.
Ya participa en otro ensayo clínico aleatorio controlado.
Las pacientes con posibilidad de tener hijos se elegirán solo si:
a. no están embarazadas- prueba de embarazo en suero b-hCG negativa llevada a cabo en la visita de exploración inicial y prueba de embarazo negativa en orina el día de aplicación de la dosis, con resultados disponibles antes de la administración de la dosis
b. consentimiento de una prueba de embarazo antes de la administración de cada dosis
c. no encontrarse amamantando
d. presentar abstinencia sexual o ser estéril quirúrgicamente (ligación de trompas o histerectomía)
e. si es sexualmente activa:
debe recibir una advertencia específica de su médico sobre los posibles riesgos asociados al embarazo durante el ensayo y
debe estar de acuerdo en llevar a cabo un control de natalidad médicamente aceptable al menos durante los 12 meses posteriores a la administración de la dosis (se incluye en control de natalidad aceptable el uso de DIU, espermicidas, condones, implantes subdérmicos o contraceptivos orales)
Criterios de exclusión del estudio observacional
Sujetos diagnosticados de PDB |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The total number of subjects who develop new bone lesions after 5 years.
The development of elevated bone turnover over 3 years, as measured by ALP.
In the observational group, the primary endpoint will be anxiety / depression over 3 years, measured using the HAD scale. |
Número total de sujetos que desarrollan nuevas lesiones óseas al cabo de 5 años.
Desarrollo de una remodelación ósea elevada después de los 3 años, medida por la ALP.
En el grupo observacional, el punto final primordial será la ansiedad/depresión al cabo de 3 años, medida empleando la escala HDA. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The total number of subjects who develop new bone lesions after 5 years.
The development of elevated bone turnover over 3 years, as measured by ALP.
In the observational group, the primary endpoint will be anxiety / depression over 3 years, measured using the HAD scale. |
|
E.5.2 | Secondary end point(s) |
In the biochemical marker sub-study, patients will be followed up for 5 years and investigated for the development of bone lesions. At the end of the study, we will perform a pooled analysis of data from the bone lesion sub-study and biochemical marker sub-study to determine if there is an overall effect of treatment on bone lesions.
Quality of life, and anxiety and depression assessed by the SF-36, BPI and HADS questionnaires will be evaluated in the biochemical marker and bone-lesion sub-studies.
The development of elevated bone turnover, as measured by ALP and quality of life, assessed by the SF-36 questionnaire will be evaluated in the observational sub-study.
Specialised markers will be used to determine if it is possible to predict which patients develop PDB (or complications of PDB) as compared with those who do not and to determine if they are of value in predicting treatment response and/or the development of side effects with treatment. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
In the biochemical marker sub-study, patients will be followed up for 5 years and investigated for the development of bone lesions. |
|
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 | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 |
|
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
|
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. |
El final del estudio en términos de la relación de los participantes es la última revisión clínica de los mismos. El final del estudio se define con el final del periodo de la subvención. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |