Condition category
Musculoskeletal Diseases
Date applied
25/07/2016
Date assigned
10/08/2016
Last edited
10/08/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Background and study aims
Osteogenesis imperfect (OI) or brittle bone disease is an inherited condition in which the bones of the skeleton break (fracture) more easily than normal, often in response to a minor injury and sometimes for no reason at all. There is no cure for OI and no treatment has been convincingly shown to reduce the risk of breaking bones. Many doctors treat OI patients with drugs called bisphosphonates, such as zoledronic acid, which are also used in osteoporosis (gradual bone loss that leads to weakened bones), but it’s not clear if they are effective at preventing fractures in OI. Teriparatide (TPTD) is a form of parathyroid hormone, which works by activating bone building cells in the body. The aim of this trial is to determine if it is possible to reduce the risk of fractures occurring in OI by using a combination of treatments which will strengthen the skeleton as compared with standard care.

Who can participate?
Men and women aged 18 years and over who have been diagnosed with OI.

What does the study involve?
Participants are randomly allocated to one of two groups. Those in the first group are given a two year course teriparatide (TPTD) given by daily injections and this will be followed by an infusion (through a drip) of zoledronic acid (ZA). Those in the second group receive standard care, which may involve no treatment or treatment with bisphosphonates. Participants in both groups are reviewed at 12 months, 24 months and again at the end of study (between 36-60 months). At each timepoint, patients have a sample of blood taken and complete a number of questionnaires. In addition, a DEXA scan (scan to measure done density) is done at 12 and 24 months and a spine x-ray is done at the start of the study and then at the end of the study (between 36-60 months).

What are the possible benefits and risks of participating?
Participants benefit from being regularly reviewed and having the chance to be treated with parathyroid hormone which cannot normally be prescribed to patients with osteogenesis imperfecta. There is a small risk of side effects with teriparatide, zoledronic acid and the other treatments that might be used as part of standard care.

Where is the study run from?
NHS Lothian and at least 24 other study centres in Scotland, Wales, England and Northern Ireland (UK)

When is the study starting and how long is it expected to run for?
January 2015 to March 2023

Who is funding the study?
Medical Research Council, Efficacy and Mechanism Evaluation Programme (UK)

Who is the main contact?
Professor Stuart H Ralston

Trial website

Contact information

Type

Scientific

Primary contact

Prof Stuart Ralston

ORCID ID

http://orcid.org/0000-0002-2804-7586

Contact details

Centre for Genomic and Experimental Medicine
The University of Edinburgh
Western General Hospital
Crewe Road
Edinburgh
EH4 2XU
United Kingdom

Additional identifiers

EudraCT number

ClinicalTrials.gov number

2016-002928-85

Protocol/serial number

14/200/18

Study information

Scientific title

Treatment of Osteogenesis Imperfecta with Parathyroid hormone and Zoledronic acid

Acronym

TOPAZ

Study hypothesis

The aim of this study is to determine if treatment with parathyroid hormone followed by a single infusion of zoledronic acid is superior to standard care in reducing the risk of fractures in adults with osteogenesis imperfecta.

Ethics approval

Not provided at time of registration

Study design

Prospective open label randomised multi-centre controlled 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 use contact details to request a participant information leaflet

Condition

Osteogenesis Imperfecta

Intervention

Participants are randomised to one of two groups using minimisation to balance the groups for the following prognostic variables:
1. Clinical fracture during the two years prior to randomisation
2. Clinical subtype of OI (type I or others)
3. Gender
4. Lowest BMD T score at spine or hip (or Z-score aged 18-21) ≤-2.5; or >-2.5.
5. Age (≤50; >50)
6. Bisphosphonate at entry or within 2 years prior to randomisation

Intervention group: Participants will receive a 2-year course of teriparatide 20mcg daily by subcutaneous injection. At the end of this period, participants will be given a single intravenous infusion of zoledronic acid 5mg.

Control group: Participants will receive standard care, which may involve no bone specific treatment or treatment with bisphosphonates, depending on what the specialist that is normally responsible for treating participants’ osteogenesis imperfecta feels is most appropriate.

This is an event driven study which will go on until 149 clinical fractures have occurred. Based on published data, this is expected to have occurred after an average of 48 months after the patient has enrolled into the study.

Participants are reviewed at 12 months, 24 months and again at the end of study (this will on average be 48 months but it may vary between 36 and 60 months since the design is an event drive trial with a variable duration of follow up). At each visit the patient will get bloods checked and complete questionnaires. At baseline and 24 months a DEXA will be done. At baseline and 48 months (or study end) a spine-x-ray will be done.

Intervention type

Drug

Phase

Phase III/IV

Drug names

1. Teriparatide
2. Zoledronic acid

Primary outcome measures

Proportion of participants experiencing a clinical fracture validated by x-ray or other imaging at the final study visit (between 36-60 months).

Secondary outcome measures

1. Total number of clinical fractures experienced by participants validated by x-ray or other imaging at the final study visit (between 36-60 months)
2. Number of incident vertebral fractures assessed by imaging of the thoracic and lumbar spine at the final study visit (between 36-60 months)
3. Total number of fractures experienced by participants defined as the combination validated clinical fractures and vertebral fractures and fractures reported by participants, where imaging was not performed, not feasible or where the results were inconclusive at the final study visit (between 36-60 months)
4. Bone pain is assessed by the brief pain inventory (BPI) at 12 months, 24 months and at the end of study visit (between 36-60 months)
5. Quality of life is assessed by the SF36 questionnaire at at 12 months, 24 months and at the end of study visit (between 36-60 months)
6. Functional status is assessed by the health assessment questionnaire (HAQ) and EuroQol5D (EQ5D) assessment tools at at 12 months, 24 months and at the end of study visit(between 36-60 months)
7. Adverse events reported by participants at 12 months, 24 months and at the end of study visit (between 36-60 months)

Overall trial start date

29/01/2015

Overall trial end date

02/03/2023

Reason abandoned

Eligibility

Participant inclusion criteria

1. Adult patients age 18 years and over with a clinical diagnosis of osteogenesis imperfecta
2. Patients willing and able to consent and comply with the study protocol

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

380

Participant exclusion criteria

1. Contraindication to TPTD or ZA
2. Current or previous treatment with an investigational drug with effects on bone metabolism.
3. Women of childbearing potential not using adequate contraception
4. Pregnancy

Recruitment start date

01/02/2017

Recruitment end date

31/01/2019

Locations

Countries of recruitment

United Kingdom

Trial participating centre

NHS Lothian
Western General Hospital
Edinburgh
EH4 2XU
United Kingdom

Sponsor information

Organisation

University of Edinburgh

Sponsor details

The Queen’s Medical Research Institute
47 Little France Crescent
Edinburgh
Edinburgh
EH16 4TJ
United Kingdom
+44 131 242 9262
Ellie.Mcmaster@ed.ac.uk

Sponsor type

University/education

Website

www.ed.ac.uk

Funders

Funder type

Government

Funder name

Efficacy and Mechanism Evaluation Programme

Alternative name(s)

NIHR Efficacy and Mechanism Evaluation programme, EME

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

The results of the trial will be published in peer reviewed scientific journals

Intention to publish date

01/06/2023

Participant level data

To be made available at a later date

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes