Treatment of osteogenesis imperfecta with parathyroid hormone and zoledronic acid
| ISRCTN | ISRCTN15313991 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN15313991 |
| EudraCT/CTIS number | 2016-003228-22 |
| ClinicalTrials.gov number | NCT03735537 |
| Secondary identifying numbers | EME 14/200/18; AC16092 |
- Submission date
- 25/07/2016
- Registration date
- 10/08/2016
- Last edited
- 24/10/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Musculoskeletal Diseases
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 study 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 and some other drugs used in the treatment of osteoporosis. Participants in both groups are reviewed at 12 months, 24 months and again at the end of the study. At each time point, patients have a sample of blood taken and complete a number of questionnaires. In addition, a DEXA scan (scan to measure bone density) is done at 12 and 24 months and at the end of the study. A spine x-ray is done at the start of the study and at the end of the study.
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 21 other study centres in Scotland, Wales, England and Northern Ireland (UK) as well as four centres in Europe including Amsterdam, Paris, Dublin and Aarhus
When is the study starting and how long is it expected to run for?
November 2016 to April 2025
Who is funding the study?
Medical Research Council, Efficacy and Mechanism Evaluation Programme (UK)
Who is the main contact?
Prof. Stuart H Ralston, topaz.trial@ed.ac.uk
Contact information
Scientific
Edinburgh Clinical Trials Unit
Usher Institute
University of Edinburgh
Level 2, Nine Edinburgh BioQuarter
9 Little France Road
Edinburgh
EH16 4UX
United Kingdom
 ORCID ID |
0000-0002-2804-7586 |
|---|---|
| Phone | +44 (0) 131 651 9915 |
| topaz.trial@ed.ac.uk |
Public
Edinburgh Clinical Trials Unit
Usher Institute
University of Edinburgh
Level 2, Nine Edinburgh BioQuarter
9 Little France Road
Edinburgh
EH16 4UX
United Kingdom
| Phone | +44 (0)131 651 9972 |
|---|---|
| topaz.trial@ed.ac.uk |
Study information
| Study design | Prospective open-label randomised multi-centre controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | ISRCTN15313991_PIS_18Apr18.pdf |
| Scientific title | Treatment of Osteogenesis Imperfecta with Parathyroid hormone and Zoledronic acid |
| Study 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(s) |
Approved 15/09/2016, East of Scotland Research Ethics Service (EoSRES) (Tayside medical Science Centre, Residency Block Level 3, George Pirie Way, Ninewells Hospital and Medical School, Dundee, DD1 9SY, United Kingdom; +44 (0)1382 383878; eosres.tayside@nhs.net), ref: 16/ES/0110 |
| Condition | Osteogenesis imperfecta |
| Intervention | Current interventions as of 14/07/2023: Participants are randomised to one of two groups in a 1:1 ratio 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. Bone anabolic drugs such as teriparatide and romosozumab will be prohibited in the standard care group. In the active group, romosozumab will be prohibited. Investigational drugs will be prohibited in both groups. 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 an average of 60 months after the patient has enrolled on the study. Participants are reviewed at 12 months, 24 months and again at the end of the study. This will on average be 60 months after enrollment but it may vary between 24 and 84 months. At each visit, the patient will get blood checked and complete questionnaires. At baseline, 24 months and the study end, a DEXA will be done. At baseline and the study end a spine-x-ray will be done. Previous interventions: 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 |
| Pharmaceutical study type(s) | Not Applicable |
| Phase | Phase III/IV |
| Drug / device / biological / vaccine name(s) | Teriparatide, Zoledronic acid |
| Primary outcome measure | 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 | Current secondary outcome measures: 1. Total number of clinical fractures experienced by participants validated by x-ray or other imaging at the final study visit. 2. Number of incident vertebral fractures assessed by imaging of the thoracic and lumbar spine at the final study visit. 3. Total number of fractures experienced by participants defined as the combination of 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. 4. Bone pain is assessed by the brief pain inventory (BPI) at 12 months, 24 months and at the end of the study visit. 5. Quality of life is assessed by the SF36 questionnaire at 12 months, 24 months and at the end of the study visit. 6. Functional status is assessed by the health assessment questionnaire (HAQ) and EuroQol5D (EQ5D) assessment tools at 12 months, 24 months and at the end of the study visit. 7. Adverse events reported by participants at 12 months, 24 months and at the end of the study visit. Previous 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 study start date | 01/11/2016 |
| Overall study end date | 30/04/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 350 |
| Total final enrolment | 350 |
| 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 exclusion criteria | Current exclusion criteria as of 07/02/2017: 1. Current or previous treatment with an investigational (non-licensed) drug with effects on bone metabolism 2. Contraindication to TPTD or ZA 3. Women of childbearing potential not using highly effective methods of contraception 4. Pregnancy 5. Women that are breastfeeding 6. Age < 18 years Previous 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 | 30/11/2022 |
Locations
Countries of recruitment
- Denmark
- England
- France
- Ireland
- Netherlands
- Northern Ireland
- Scotland
- United Kingdom
- Wales
Study participating centres
Edinburgh
EH4 2XU
United Kingdom
4
Ireland
AB25 2ZR
United Kingdom
BT12 6BA
United Kingdom
B15 2TH
United Kingdom
BS2 8HW
United Kingdom
CB2 0QQ
United Kingdom
DD1 9SY
United Kingdom
G51 4TF
United Kingdom
LE1 5WW
United Kingdom
L7 8XP
United Kingdom
CF64 2XX
United Kingdom
SE1 9RT
United Kingdom
M13 9WL
United Kingdom
PS4 3BW
United Kingdom
NE7 7DN
United Kingdom
NR4 7UQ
United Kingdom
NG5 1PD
United Kingdom
OX3 7HE
United Kingdom
P06 3LY
United Kingdom
S5 7AU
United Kingdom
S016 6YD
United Kingdom
HA7 4LP
United Kingdom
ST6 7AG
United Kingdom
ML2 0DP
United Kingdom
Aarhus
800 Aarhus C
Denmark
Amsterdam
1081 HV Amsterdam
Netherlands
2 Rue Ambroise Paré
Paris
75010 Paris
France
Sponsor information
University/education
The Queen’s Medical Research Institute
47 Little France Crescent
Edinburgh
Edinburgh
EH16 4TJ
Scotland
United Kingdom
| Phone | +44 131 242 9262 |
|---|---|
| Fiach.o'mahoney@ed.ac.uk | |
| Website | www.ed.ac.uk |
"ROR" |
https://ror.org/01nrxwf90 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- NIHR Efficacy and Mechanism Evaluation Programme, EME
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/04/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | The results of the trial will be published in peer reviewed scientific journals |
| IPD sharing plan | The current data sharing plans for the current study are unknown and will be made available at a later date |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | 18/04/2018 | 18/04/2018 | No | Yes | |
| HRA research summary | 28/06/2023 | No | No | ||
| Protocol article | 22/11/2023 | 23/11/2023 | Yes | No |
Additional files
- ISRCTN15313991_PIS_18Apr18.pdf
- Uploaded 18/04/2018
Editorial Notes
24/10/2024: The study contact information was amended.
23/11/2023: Publication reference added.
14/07/2023: The following changes were made to the study record and the plain English summary was updated accordingly:
1. Ethics approval added.
2. The interventions were changed.
3. The secondary outcome measures were changed.
4. The total final enrolment was added.
5. Denmark, France, and the Netherlands were added, and United States Minor Outlying Islands were removed from the countries of recruitment.
6. Aarhus University Hospital, Amsterdam University Medical Centre and Hôpital Lariboisiére were added as study participating centres.
28/11/2022: The following changes were made to the trial record:
1. The target number of participants has been changed from 380 to 350.
2. The recruitment end date was changed from 31/10/2022 to 30/11/2022.
12/07/2022: The following changes were made to the trial record:
1. The recruitment end date was changed from 30/06/2020 to 31/10/2022.
2. The overall end date was changed from 02/03/2023 to 30/04/2025.
3. The intention to publish date was changed from 01/06/2023 to 01/04/2026.
4. The plain English summary was updated to reflect these changes.
18/05/2020: Due to current public health guidance, recruitment for this study has been paused.
09/08/2019: The recruitment end date was changed from 31/07/2019 to 30/06/2020.
04/07/2019: The following changes were made to the trial record:
1. ClinicalTrials.gov number added.
2. 24 trial participating centres were added.
18/04/2018: The following changes have been made:
1. The patient information sheet, previously available at http://www.ed.ac.uk/files/atoms/files/pil_v2.0_130916.pdf, has been uploaded.
2. The recruitment end date has been changed from 31/01/2019 to 31/07/2019.
3. Ireland has been added as a country of recruitment.
07/02/2017: The overall trial start date was changed from 29/01/2015 to 01/11/2016.
