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Treatment of Osteogenesis Imperfecta With Parathyroid Hormone and Zoledronic Acid (TOPaZ)

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ClinicalTrials.gov Identifier: NCT03735537
Recruitment Status : Recruiting
First Posted : November 8, 2018
Last Update Posted : November 8, 2018
Sponsor:
Collaborator:
NHS Lothian
Information provided by (Responsible Party):
University of Edinburgh

Brief Summary:

Osteogenesis imperfecta (OI) is an inherited skeletal disorder characterised by increased risk of fragility fractures. Bisphosphonates are frequently prescribed for adult patients with OI with the aim of preventing fractures but the evidence base for efficacy is poor. Recent evidence suggests that the bone anabolic agent teriparatide (TPTD) increases bone mineral density (BMD) and may have the potential to prevent fractures in OI.

The purpose of the TOPaZ Trial is to investigate if a a two-year course of teriparatide (TPTD) followed by antiresorptive therapy with a single infusion of zoledronic acid (ZA) in adults with OI reduces the proportion of patients who experience a fracture as compared with standard care

Adult patients with a clinical diagnosis of OI who are willing and able to give informed consent and who do not have contraindications to the study medications will be recruited from participating sites. Participants will be randomised 1:1 to receive either standard care for the duration of the trial or TPTD for 24 months followed by a single infusion of ZA, or another antiresorptive agent in the event that ZA is contraindicated.

Participants will attend recruiting centres for a Baseline/Screening visit, at 12 months, 24 months and at the end of the trial for formal study visits with telephone calls every 6 months from a site research nurse. Participants randomised to TPTD will also attend recruiting centre at regular intervals during the 24 month treatment period to collect new supplies of TPTD.


Condition or disease Intervention/treatment Phase
Osteogenesis Imperfecta Drug: Teriparatide Pen Injector Drug: Zoledronic Acid Phase 4

Detailed Description:

Osteogenesis imperfecta (OI) is an inherited skeletal disorder characterised by increased risk of fragility fractures. Bisphosphonates are frequently prescribed for adult patients with OI with the aim of preventing fractures but the evidence base for efficacy is poor. Recent evidence suggests that the bone anabolic agent teriparatide (TPTD) increases bone mineral density (BMD) and may have the potential to prevent fractures in OI.

The purpose of the TOPaZ Trial is to investigate if a a two-year course of teriparatide (TPTD) followed by antiresorptive therapy with a single infusion of zoledronic acid (ZA) in adults with OI reduces the proportion of patients who experience a fracture as compared with standard care.

The trial has a number of secondary objectives which aim to investigate if a two-year course of TPTD followed by antiresorptive therapy with a single infusion of ZA in adults with OI reduces the total number of fractures, reduces the risk of vertebral fractures; or affects bone pain, quality of life and functional status as compared with standard care. There is also a planned mechanistic analysis to understand which baseline characteristics of adults with OI, such as age, clinical subtype of OI, genetic diagnosis, bone turnover, BMD, and previous treatment influences the occurrence of fractures and/or the response to treatment

Adult patients with a clinical diagnosis of OI who are willing and able to give informed consent and who do not have contraindications to the study medications will be recruited from participating sites. Participants will be randomised 1:1 to receive either standard care for the duration of the trial or TPTD for 24 months followed by a single infusion of ZA, or another antiresorptive agent in the event that ZA is contraindicated. Exclusion criteria include: current or previous treatment with an investigational (non-licensed experimental) drug with effects on bone metabolism, contraindication to TPTD or ZA, women of childbearing potential not using highly effective methods of contraception, pregnancy, women that are breastfeeding or age <18 years.

Participants will attend recruiting centres for a Baseline/Screening visit, at 12 months, 24 months and at the end of the trial for formal study visits with telephone calls every 6 months from a site research nurse. Participants randomised to TPTD will also attend recruiting centre at regular intervals during the 24 month treatment period to collect new supplies of TPTD.

The baseline assessment will include dual energy x-ray absorptiometry (DEXA), spine x-rays, safety bloods, medical and fracture history, pain (brief pain inventory, BPI) and quality of life (SF36, HAQ, EQ5D, PSQI). Blood will be taken for genetic analysis and for analysis of biochemical markers of bone turnover. In some centres, a high resolution quantitative CT scan (HRQCT) of the wrist and tibia will be performed. Participants will be seen after 12 months when bloods, questionnaires and HRQTC will be repeated; at 24 months when bloods, questionnaires, DEXA and HRQCT will be repeated. At the end of the study participants will undergo DEXA, spine x-rays, HRQCT and bloods and questionnaires will be repeated. Information on adverse events and fractures will be collected throughout the study and participants suspected to have fractures will have x-ray or other imaging to confirm the presence of fractures.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 380 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Multicentre, parallel arm, open-label, phase IV randomised controlled trial
Masking: Single (Outcomes Assessor)
Masking Description: Images of incident fractures and vertebral fractures will be assessed by an independent clinical adjudicator blinded to treatment allocation.
Primary Purpose: Treatment
Official Title: Treatment of Osteogenesis Imperfecta With Parathyroid Hormone and Zoledronic Acid
Actual Study Start Date : November 1, 2016
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : April 1, 2023


Arm Intervention/treatment
Active Comparator: Teriparatide and zoledronic acid
Teriparatide (TPTD) 20mcg daily using Teriparatide Pen Injector, given subcutaneously using a self-administered injection device for two years (24 months) followed by a single intravenous 5mg infusion of zoledronic acid.
Drug: Teriparatide Pen Injector
Other Names:
  • Forsteo
  • Forteo

Drug: Zoledronic Acid
Any brand or preparation may be used to deliver the required dose of 5mg
Other Names:
  • Aclasta 5mg solution for infusion
  • Zoledronic acid 5mg/100ml solution for infusion

No Intervention: Standard Care
Continuation of existing bone modifying treatment (i.e. bisphosphonate treatment) or no active bone modifying treatment according to the clinical judgement of the local investigator.



Primary Outcome Measures :
  1. Incident clinical fractures validated by x-ray or other imaging [ Time Frame: Through study completion, approximately 5 years ]
    Proportion of participants experiencing a clinical fracture validated by x-ray or other imaging as compared to standard care


Secondary Outcome Measures :
  1. Total number of incident vertebral fractures [ Time Frame: Baseline (0) and Final Trial Visit (5 years after baseline) ]
    Incident vertebral fractures assessed by imaging of the thoracic and lumbar spine and reviewed by an independent masked adjudicator using two spine x-rays collected at the start and end of the trial

  2. Total number of fractures [ Time Frame: Through study completion, approximately 5 years ]
    Total number of fractures experienced by participant defined as combination of validated clinical fractures, vertebral fractures and fractures reported by participants where imaging was not performed, was not feasible or where results were inconclusive

  3. Pain assessed by the Brief Pain Inventory (BPI) Short Form measure [ Time Frame: Baseline (0), 12 months, 24 months and Final Trial Visit (5 years after baseline) ]

    Bone pain assessed by the Brief Pain Inventory (BPI) Short Form, a Patient Reported Outcome Measure completed at 4 time-points throughout the trial. The BPI gives two main scores - a pain severity score and a pain interference score. The pain severity score is calculated from the four questions (3-6) about pain intensity. Each item is rated from 0 (no pain) to 10 (pain as bad as you can imagine). The scores from the 4 questions are added together and then divided by 4, giving a severity score out of 10.

    The pain interference score corresponds to Question 9 responses. The seven sub-items are rated from 0 (does not interfere) to 10 (completely interferes). The scores are added together and divided by 7, giving an interference score out of 10.

    Question 2 (pain drawing diagram), Question 7 and Question 8 (pain relief treatment or medication) do not contribute to the scoring.


  4. Quality of life assessed by the SF-36 (v1) Quality of Life [ Time Frame: Baseline, 12 months, 24 months and Final Trial Visit (5 years after baseline ]
    The SF-36 questionnaire consists of 36 generic health questions: 8 health domains of the questionnaire, each of which are summarised (Physical functioning score (10 items), Role-physical score (4 items), Bodily pain (2 items), General health score (5 items), Vitality score (4 items), Social functioning score (2 items), Role-emotional score (3 items), and Mental health score (5 items)). The resulting score for each domain is standardized, to obtain values ranging from 0 to 100, with higher values indicating a better quality of life.Two overall summary measures (physical and mental component scores) are calculated.

  5. Sleep quality assessed by the Pittsburgh Sleep Quality Index (PSQI) measure [ Time Frame: Baseline (0), 12 months, 24 months and Final Trial Visit (5 years after baseline) ]

    Sleep quality as assessed by the Pittsburgh Sleep Quality Index, a Patient Reported Outcome Measure completed at 4 time-points throughout the trial. The Pittsburgh Sleep Quality Index contains 19 self-rated questions. The questions are combined to form seven 'component' scores, each of which has a range of 0-3 points.

    In all cases, a score of 0 indicates no difficulty while a score of 3 indicates severe difficulty. The seven component scores are added to yield one global score, ranging from 0-21 points, 0 indicating no difficulty and 21 indicating severe difficulties in all areas.


  6. Functional status assessed by the Health Assessment Questionnaire (HAQ) measure [ Time Frame: Baseline (0), 12 months, 24 months and Final Trial Visit (5 years after baseline) ]
    The HAQ includes 8 blocks of questions covering difficulties performing simple daily activities. There are 20 questions in total. A 4 point grading system is used to denote degree of difficulty (0=none, 1=some difficulty, 2=great difficulty, 3=not able to perform at all). Each item has a companion aids-devices variable used to record types of assistance the subject uses for his/her usual activities. These variables are coded from 0 to 3 (0 = No assistance is needed, 1 = A special device is used by the subject in his/her usual activities, 2 = The subject usually needs help from another person, 3 = The subject usually needs BOTH a special device AND help from another person). The highest score reported for any component question of the 8 categories determines the score for that category. A global score is calculated by summing the scores for each of the categories and dividing by the number of categories answered.

  7. Adverse events [ Time Frame: Through study completion, approximately 5 years ]
    All adverse events reported throughout the duration of the trial. Summarised by treatment and by severity, causality and seriousness, reporting both the number of events and the number of patients experiencing a given event.

  8. Mechanistic analyses (ITT) [ Time Frame: Biological samples collected at Baseline (0), 12 months, 24 months and Final Trial Visit (5 years after baseline) ]

    Relationship between gender, clinical OI subtype, lowest Bone Mineral Density T score at spine or hip (≤ -2.5 or > -2.5)), type of genetic mutation (mutations of COLIA1 or COLIA2 and biochemical markers of bone turnover with fracture occurrence and response to treatment. Descriptive statistics by treatment group for each subgroup will be presented.

    The primary outcome, defined as the proportion of participants experiencing a clinical fracture validated by x-ray or other imaging, will be analysed for these subgroups. The interaction between subgroup and treatment will be included in the primary and secondary analysis models to determine if the treatment effect differs by subgroup.




Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult patients aged 18 years and over with a clinical diagnosis of Osteogenesis Imperfecta (OI)
  • Patients willing and able to consent and comply with the study protocol

Exclusion Criteria:

  • Current or previous treatment with an investigational (non-licensed experimental) drug with effects on bone metabolism
  • Contraindication to teriparatide or zoledronic acid
  • Women of childbearing potential not using highly effective methods of contraception
  • Pregnancy
  • Women that are breastfeeding
  • Age < 18 years

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03735537


Contacts
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Contact: Holly Ennis, PhD 00 44 131 651 9915 holly.ennis@ed.ac.uk
Contact: Vikki Young, PhD 00 44 131 242 3353 resgov@accord.scot

Locations
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Ireland
St Vincent's Hospital Not yet recruiting
Dublin, Ireland, 4
Contact: Holly Ennis, PhD    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Rachel Crowley, MD         
United Kingdom
Aberdeen Royal Infirmary Recruiting
Aberdeen, United Kingdom, AB25 2ZR
Contact: Holly Ennis, PhD         
Principal Investigator: Rosemary Hollick, MD         
Royal Victoria Hospital Recruiting
Belfast, United Kingdom, BT12 6BA
Contact: Holly Ennis, PhD    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: John Lindsay, MD         
Queen Elizabeth Hospital Not yet recruiting
Birmingham, United Kingdom, B15 2TH
Contact: Holly Ennis, PhD    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Neil Gittoes, MD         
Bristol Royal Infirmary Not yet recruiting
Bristol, United Kingdom, NS2 8HW
Contact: Holly Ennis, PhD    0044 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Shane Clarke, MD         
Addenbrooke's Hospital Not yet recruiting
Cambridge, United Kingdom, CB2 0QQ
Contact: Holly Ennis, PhD    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Ken Poole, MD         
Ninewells Hospital Recruiting
Dundee, United Kingdom, DD1 9SY
Contact: Holly Ennis, PhD    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Ellen Malcolm, MD         
Western General Hospital Recruiting
Edinburgh, United Kingdom, EH4 2XU
Contact: Holly Ennis, PhD    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Stuart Ralston, MD         
Queen Elizabeth University Hospital Recruiting
Glasgow, United Kingdom, G51 4TF
Contact: Holly Ennis, PhD    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Stephen Gallacher, MD         
Leicester Royal Infirmary Not yet recruiting
Leicester, United Kingdom, LE1 5WW
Contact: Holly Ennis, PhD    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Prashanath Patel, MD         
Royal Liverpool Hospital Not yet recruiting
Liverpool, United Kingdom, L7 8XP
Contact: Holly Ennis, PhD    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Fadil Hannan, MD         
Llandough University Hospital Not yet recruiting
Llandough, United Kingdom, CF64 2XX
Contact: Holly Ennis, PhD    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Mike Stone, MD         
Guy's and St Thomas' Hospital Not yet recruiting
London, United Kingdom, SE1 9RT
Contact: Holly Ennis, PhD    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Geeta Hampson, MD         
Manchester Royal Infirmary Not yet recruiting
Manchester, United Kingdom, M13 9WL
Contact: Holly Ennis    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Peter Selby, MD         
James Cook University Hospital Not yet recruiting
Middlesbrough, United Kingdom, PS4 3BW
Contact: Holly Ennis    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Steven Tuck, MD         
Freeman Hospital Recruiting
Newcastle Upon Tyne, United Kingdom, NE7 7DN
Contact: Holly Ennis, PhD    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Terry Aspray, MD         
Norfolk and Norwich University Hospital Not yet recruiting
Norwich, United Kingdom, NR4 7UQ
Contact: Holly Ennis, PhD    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: William Fraser, MD         
Nottingham City Hospital Not yet recruiting
Nottingham, United Kingdom, NG5 1PD
Contact: Holly Ennis, PhD    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Peter Prinsloo, MD         
Nuffield Orthopaedic Centre Not yet recruiting
Oxford, United Kingdom, OX3 7HE
Contact: Holly Ennis, PhD    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Kassim Javaid, MD         
Queen Alexandria Hospital Not yet recruiting
Portsmouth, United Kingdom, P06 3LY
Contact: Holly Ennis, PhD    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Steven Young Min, MD         
Northern General Hospital Not yet recruiting
Sheffield, United Kingdom, S5 7AU
Contact: Holly Ennis, PhD    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Jennifer Walsh, MD         
University Hospital Southampton Not yet recruiting
Southampton, United Kingdom, S016 6YD
Contact: Holly Ennis, PhD    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Nick Harvey, MD         
Royal National Orthopaedic Hospital Not yet recruiting
Stanmore, United Kingdom, HA7 4LP
Contact: Holly Ennis, PhD    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Richard Keen, MD         
Haywood Community Hospital Not yet recruiting
Stoke-on-Trent, United Kingdom, ST6 7AG
Contact: Holly Ennis, PhD    00 44 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Zoe Paskins, MD         
Wishaw General Hospital Not yet recruiting
Wishaw, United Kingdom, ML2 0DP
Contact: Holly Ennis, PhD    0044 131 651 9915    holly.ennis@ed.ac.uk   
Principal Investigator: Robin Munro, MD         
Sponsors and Collaborators
University of Edinburgh
NHS Lothian
Investigators
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Principal Investigator: Stuart Ralston, MD University of Edinburgh and NHS Lothian
  Study Documents (Full-Text)

Documents provided by University of Edinburgh:
Study Protocol  [PDF] February 13, 2018
Statistical Analysis Plan  [PDF] June 22, 2018


Additional Information:
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Responsible Party: University of Edinburgh
ClinicalTrials.gov Identifier: NCT03735537     History of Changes
Other Study ID Numbers: AC16092
2016-003228-22 ( EudraCT Number )
First Posted: November 8, 2018    Key Record Dates
Last Update Posted: November 8, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Anonymised aggregate data only will be shared.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Edinburgh:
Fracture
Teriparatide

Additional relevant MeSH terms:
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Osteogenesis Imperfecta
Osteochondrodysplasias
Bone Diseases, Developmental
Bone Diseases
Musculoskeletal Diseases
Genetic Diseases, Inborn
Collagen Diseases
Connective Tissue Diseases
Pharmaceutical Solutions
Hormones
Zoledronic Acid
Teriparatide
Parathyroid Hormone
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Bone Density Conservation Agents
Calcium-Regulating Hormones and Agents