Condition category
Musculoskeletal Diseases
Date applied
16/09/2008
Date assigned
17/10/2008
Last edited
04/03/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Paget's disease is caused by a problem with bone regeneration that causes bone to be replaced at a faster rate than usual, leading to enlarged bones that are weak and brittle. People who inherit a mutation in a gene called SQSTM1 have an increased chance of developing Paget's disease. The aim of this study is to determine whether the drug zoledronic acid can prevent Paget's disease in people with SQSTM1 mutations. We also wish to find out whether having a genetic test increases anxiety and depression even if the patient is found not to have the SQSTM1 mutation, and whether there any differences in the markers of Paget’s disease in people with and without the mutation.

Who can participate?
Patients diagnosed with Paget's disease and their relatives who have not yet been diagnosed with Paget's disease.

What does the study involve?
Genetic tests are carried out to identify patients with the SQSTM1 mutation, who are then randomly allocated to be treated with either zoledronic acid or placebo (salt solution) via intravenous infusion (i.e., delivered into a vein). All participants (with and without the SQSTM1 mutation) are asked to give blood samples and complete health questionnaires.

What are the possible benefits and risks of participating?
Not provided at time of registration

Where is the study run from?
Edinburgh Clinical Trials Unit (UK)

When is the study starting and how long is it expected to run for?
January 2009 to January 2020

Who is funding the study?
1. Medical Research Council (MRC) (UK)
2. Arthritis Research Council (ARC) (UK)

Who is the main contact?
ZiPP Trial Office
zipptri1@exseed.ed.ac.uk

Trial website

http://www.clinicaltrials.ed.ac.uk/trials/zipp/default.asp

Contact information

Type

Scientific

Primary contact

Dr ZiPP Trial Office

ORCID ID

Contact details

ZiPP Trial Office
Edinburgh Clinical Trials Unit
University of Edinburgh
Outpatients Building
Level 2
Room D71
Western General Hospital
Crewe Road
Edinburgh
EH4 2XU
United Kingdom
+44 (0)131 537 2552
zipptri1@exseed.ed.ac.uk

Additional identifiers

EudraCT number

2008-005667-34

ClinicalTrials.gov number

Protocol/serial number

MRC ref: G0701625

Study information

Scientific title

Randomised trial of genetic testing and targeted zoledronic acid therapy to prevent SQSTM1-mediated Paget's disease

Acronym

ZiPP study

Study hypothesis

Main aim of the interventional component 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 Paget's disease of bone (PDB) because they carry mutations in SQSTM1 that have previously been associated with PDB.

An observational sub-study will be carried out in participants who have the same risk of developing paget's disease as the general population. The sub-study will aim to answer the following two questions:

1. Does having a genetic test cause increased anxiety and depression, even if found not to have the SQSTM1 gene mutation?
2. Is there any difference in the biochemical makers which are predictive of the disease in this group compared to the group who have the mutation?

Genetic tests will be carried out to identify patients with a mutation in the SQSTM1 gene as part of the screening of potential participants.

Ethics approval

Fife and Forth Valley Research Ethics Committee, 22/12/2008, ref: 08/S0501/84

Study design

Multi-site double-blind placebo-controlled randomised trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please contact zipptri1@exseed.ed.ac.uk to request a patient information sheet.

Condition

Paget's disease of the bone (PDB)

Intervention

Current interventions as of 26/06/2012:
Participants will be randomised to either infusions of zoledronic acid (Aclasta®) 5 mg by intravenous infusion over 15 minutes or placebo (0.9% saline) at baseline.

In the observational study participants will have blood samples taken at a baseline and end of study visit and will be asked to complete health questionnaires.

Previous interventions:
Participants will be randomised to either infusions of zoledronic acid (Aclasta®) 5 mg by intravenous infusion over 15 minutes or placebo (0.9% saline) at baseline. Repeat infusions will be given after 30 months in both treatment arms. Patients in the placebo arm will receive a further placebo infusion at 30 months.

In the zoledronic acid group, a second 5 mg infusion will be given only if the serum bone specific alkaline phosphatase value taken at the routine review visit at 24 months lies above the reference range or has risen by 30% of the bone specific alkaline phosphatase (BSAP) level at baseline. If values lie below this a placebo infusion will be given to maintain blinding of the study.

In the observational sub-study participants will have blood and urine samples taken annually and will be asked to complete health questionnaires.

Intervention type

Drug

Phase

Not Applicable

Drug names

Zoledronic acid

Primary outcome measures

Current primary outcome measure (s):
In the intervention study, the primary outcome will be the total number of subjects who develop new bone lesions between the baseline visit and the final follow up visit.
In the observational study, the primary outcome measure will be anxiety / depression, measured using the HADS scale.

Previous primary outcome measure (s):
1. Bone-lesion sub-study: total number of subjects who develop new bone lesions after 5 years
2. Biochemical marker sub-study: the development of elevated bone turnover over 3 years, as measured by alkaline phosphatase (ALP)
3. Observational study: anxiety/depression over 3 years, measured using the Hospital Anxiety and Depression Scale (HADS)

Secondary outcome measures

Current secondary outcome measure (s):
In the interventional study, the secondary outcome measures will be:
1. The development of elevated bone turnover, as measured by ALP and other biochemical markers of bone turnover.
2. Quality of life, and anxiety and depression assessed by the SF-36, BPI and HADS questionnaires.
In the observational study, the secondary outcomes will be:
1. The development of elevated bone turnover, as measured by ALP and other biochemical markers of bone turnover.
2. Quality of life, assessed by the SF-36 questionnaire.

Previous secondary outcome measure (s):
1. Biochemical marker study:
1.1. Patients will be followed up for 5 years and investigated for the development of bone lesions. At the end of study, we will perform a pooled analysis of data from the bone lesion sub-study and biochemical markers sub-study to determine if there is an overall effect of treatment on bone lesions
2. Biochemical and bone-lesion sub-study:
2.1. Quality of life, anxiety and depression assessed by the 36-item short form health survey (SF-36), Brief Pain Inventory (BPI) and HADS questionnaires at baseline and annually for 5 years
3. Observational sub-study:
3.1. Development of elevated bone turnover, as measured by ALP (blood sample) at baseline and once a year for 5 years
3.2. Quality of life, assessed by the SF-36 questionnaire at baseline and annually for 5 years

Overall trial start date

12/01/2009

Overall trial end date

31/01/2020

Reason abandoned

Eligibility

Participant inclusion criteria

Both males and females are eligible for participation in this study.

Genetic test:
1. Patients with PDB (probands):
1.1. Diagnosed with PDB
1.2. Have relatives older than 30 years who have not yet been diagnosed with PDB
2. Relatives:
2.1. Relatives are aged 30 years old or greater
2.2. Relatives not yet been diagnosed with PDB

Intervention study:
1. Relatives of patients with SQSTM1 mutations
2. Aged 30 years old or greater
3. Carry SQSTM1 mutations
4. Not already diagnosed with PDB at study entry

Observational study:
1. Relatives aged between 30 years old or greater
2. Relatives who on screening are found NOT to have SQSTM1 mutations

Participant type

Mixed

Age group

Adult

Gender

Both

Target number of participants

510 in total (260 participants in the interventional study; 250 participants in the observational study)

Participant exclusion criteria

Current exclusion criteria as of 26/06/2012:
Genetic test:
For patients with PDB and relatives:
1. Subjects not willing to have a blood sample taken
2. Subjects who are unwilling or unable to consent.

Intervention study:
1. Already diagnosed with PDB
2. Unwilling or unable to consent
3. Bisphosphonates contraindicated
4. Receiving bisphosphonate therapy for another reason
5. Severe liver or renal disease
6. Osteonecrosis of the jaw (ONJ)
7. If creatine clearance levels are less than 35 ml/min
8. Metastatic cancer or cancer diagnosed less than 2 years ago where treatment is still ongoing
9. Active history of uveitis, iritis, or episcleritis
10. Already taking part in another randomised controlled clinical trial
11. Female patients of child bearing potential are eligible only if they are:
11.1. Not pregnant - negative pregnancy test on the day of or the day prior to the infusion
11.2. Consent to a pregnancy test prior to the inufsion
11.3. Non-lactating
11.4. Are sexually abstinent or are surgically sterile (tubal ligation or hysterectomy)
11.5. If sexually active:
11.5.1. Must receive specific advice from their consultant about possible risks associated with getting pregnant whilst on the trial, and
11.5.2. 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 intrauterine device [IUD], a barrier method with spermicide, condoms, subdermal implant or oral contraceptives)

Previous exclusion criteria
Genetic test:
For patients with PDB and relatives:
1. Subjects not willing to have a blood sample taken
2. Subjects who are unwilling or unable to consent.

Intervention study:
1. Already diagnosed with PDB
2. Unwilling or unable to consent
3. Bisphosphonates contraindicated
4. Receiving bisphosphonate therapy for another reason
5. Severe liver or renal disease
6. Osteonecrosis of the jaw (ONJ)
7. If creatine clearance levels are less than 35 ml/min
8. Metastatic cancer or cancer diagnosed less than 2 years ago where treatment is still ongoing
9. Active history of uveitis, iritis, or episcleritis
10. Already taking part in another randomised controlled clinical trial
11. Female patients of child bearing potential are eligible only if they are:
11.1. Not pregnant - negative serum beta-human chorionic gonadotropin (b-hCG) pregnancy test done on the day, with results available, prior to infusion
11.2. Consent to a pregnancy test prior to every dose administration
11.3. Non-lactating
11.4. Are sexually abstinent or are surgically sterile (tubal ligation or hysterectomy)
11.5. If sexually active:
11.5.1. Must receive specific advice from their consultant about possible risks associated with getting pregnant whilst on the trial, and
11.5.2. 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 intrauterine device [IUD], a barrier method with spermicide, condoms, subdermal implant or oral contraceptives)

Recruitment start date

12/01/2009

Recruitment end date

16/04/2015

Locations

Countries of recruitment

Australia, Belgium, Ireland, Italy, Spain, United Kingdom

Trial participating centre

Edinburgh Clinical Trials Unit
Edinburgh
EH4 2XU
United Kingdom

Sponsor information

Organisation

University of Edinburgh (UK)

Sponsor details

The Queen's Medical Research Institute
47 Little France Crescent
Edinburgh
EH16 4TJ
United Kingdom

Sponsor type

University/education

Website

http://www.clinicaltrials.ed.ac.uk

Organisation

Lothian NHS Board (UK)

Sponsor details

Deaconess House
148 Pleasance
Edinburgh
EH8 9RS
United Kingdom

Sponsor type

Hospital/treatment centre

Website

www.nhslothian.scot.nhs.uk

Funders

Funder type

Research organisation

Funder name

Medical Research Council (MRC) (UK) (ref: G0701625; 85281)

Alternative name(s)

MRC

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Funder name

Arthritis Research Council (ARC) (UK) (ref: 18163)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

2010 results in http://www.ncbi.nlm.nih.gov/pubmed/20499339

Publication citations

  1. Results

    Visconti MR, Langston AL, Alonso N, Goodman K, Selby PL, Fraser WD, Ralston SH, Mutations of SQSTM1 are associated with severity and clinical outcome in paget disease of bone., J. Bone Miner. Res., 2010, 25, 11, 2368-2373, doi: 10.1002/jbmr.132.

Additional files

Editorial Notes

04/03/2016: Plain English summary added. On 26/06/2012 the following changes were made to the trial record. 1. The target number of participants was changed from 870 in total (620 participants in the interventional study; 250 participants in the observational study) to 510 in total (260 participants in the interventional study; 250 participants in the observational study). 2. The overall trial end date has been updated from 01/08/2014 to 31/01/2020. On 20/12/2011 the countries of recruitment were updated. Canada was removed and Belgium and Ireland were added.