Clinical trial NCT03735537: Treatment of Osteogenesis Imperfecta With Parathyroid Hormone and Zoledronic Acid
Official title: Treatment of Osteogenesis Imperfecta With Parathyroid Hormone and Zoledronic Acid
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Osteogenesis Imperfecta
Keywords: Fracture
Teriparatide
Lead sponsor: University of Edinburgh
Sponsor class: OTHER
Collaborators: name: NHS Lothian
First posted: 2018-11-08
Enrollment: 350
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicentre, parallel arm, open-label, phase IV randomised controlled trial
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Incident clinical fractures validated by x-ray or other imaging
timeFrame: Through study completion, approximately 5 years
Secondary outcomes:
measure: Total number of incident vertebral fractures
timeFrame: Baseline (0) and Final Trial Visit (5 years after baseline)
measure: Total number of fractures
timeFrame: Through study completion, approximately 5 years
measure: Pain assessed by the Brief Pain Inventory (BPI) Short Form measure
timeFrame: Baseline (0), 12 months, 24 months and Final Trial Visit (5 years after baseline)
measure: Quality of life assessed by the SF-36 (v1) Quality of Life
timeFrame: Baseline, 12 months, 24 months and Final Trial Visit (5 years after baseline
measure: Sleep quality assessed by the Pittsburgh Sleep Quality Index (PSQI) measure
timeFrame: Baseline (0), 12 months, 24 months and Final Trial Visit (5 years after baseline)
measure: Functional status assessed by the Health Assessment Questionnaire (HAQ) measure
timeFrame: Baseline (0), 12 months, 24 months and Final Trial Visit (5 years after baseline)
measure: Adverse events
timeFrame: Through study completion, approximately 5 years
measure: Mechanistic analyses (ITT)
timeFrame: Biological samples collected at Baseline (0), 12 months, 24 months and Final Trial Visit (5 years after baseline)
Other outcomes:
Locations:
city: Dublin
country: Ireland
facility: St Vincent's Hospital
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Belfast
country: United Kingdom
facility: Royal Victoria Hospital
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Bristol
country: United Kingdom
facility: Bristol Royal Infirmary
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Dundee
country: United Kingdom
facility: Ninewells Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: Liverpool
country: United Kingdom
facility: Royal Liverpool Hospital and Aintree Hospital
city: Llandough
country: United Kingdom
facility: Llandough University Hospital
city: London
country: United Kingdom
facility: Guy's and St Thomas' Hospital
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
city: Middlesbrough
country: United Kingdom
facility: James Cook University Hospital
city: Newcastle Upon Tyne
country: United Kingdom
facility: Freeman Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
city: Oxford
country: United Kingdom
facility: Nuffield Orthopaedic Centre
city: Sheffield
country: United Kingdom
facility: Northern General Hospital
city: Southampton
country: United Kingdom
facility: University Hospital Southampton
city: Stanmore
country: United Kingdom
facility: Royal National Orthopaedic Hospital
city: Stoke-on-Trent
country: United Kingdom
facility: Haywood Community Hospital
city: Wishaw
country: United Kingdom
facility: Wishaw General Hospital
Study officials:
affiliation: University of Edinburgh
name: Stuart Ralston, MD
role: PRINCIPAL_INVESTIGATOR
References: