The Optimised Use of Romozosumab Study

Study Overview
=================
Brief Summary
-----------------
OPTIMIST is a two-year, randomised, active controlled, open-label, multicentre intervention trial. OPTIMIST includes 3 treatment groups each comprising combinations of romosozumab (ROMO) and zoledronate (ZOL) treatment used in standard doses (210 mg monthly (sc) and 5 mg yearly (iv), respectively). The study will investigate if it is possible to maximize the effect of romosozumab by giving it in 2 periods of 6 months interrupted by zoledronate for 12 months compared to romosozumab for 12 months uninterrupted followed by zoledronate for 12 months. The investigators will also evaluate if 6 months of romosozumab followed by 18 months of zoledronate is non-inferior to the standard regimen of romosozumab for 12 months followed by zoledronate for 12 months.

Detailed Description
-----------------
Recent clinical trials have demonstrated the benefit of bone anabolic treatment over no treatment or antiresorptive treatment in terms of increasing bone mineral density (BMD) and reducing fracture risk for patients with osteoporosis. However, the bone anabolic treatment is expensive and therefore restricted to a limited group of patients. This study is based on the hypothesis that treatment with romosozumab for 6 months, zoledronate for 12 months, and romosozumab for 6 months results in larger gains in bone mineral density than treatment regimens based on romosozumab treatment for 6 or 12 months followed by zoledronate for a total of 24 months of treatment due to reappearance of the bone anabolic effect of romosozumab upon retreatment. The OPTIMIST study is a two-year, randomised, active controlled, open-label, intervention trial. The study includes 270 postmenopausal women who will be randomised to 3 groups. Group 1 (n=90) will receive romosozumab for 12 months followed by zoledronate for 12 months. Group 2 (n=90) will receive romosozumab for 6 months followed by zoledronate for 12 months and romosozumab for 6 months. Group 3 (n=90 ) will receive romosozumab for 6 months followed by zoledronate for 18 months. The investigational drugs in this study are romosozumab 210 mg/2,34 mL and zoledronate 5 mg/100 mL This study will include 270 treatment naïve postmenopausal women. When inclusion and exclusion criteria have been reviewed, and the participant meets the requirements for study participation and continues to participate in the study, the patients will be randomized 1:1:1 Data will be registered in RedCAP (eCRF) and site monitoring assessed by the local Good Clinical Practice unit (GCP-unit). The patients will be recruited from the outpatient clinics and the Dual-Energy X-ray Absorptiometry (DXA) units to which patients are referred from their general practitioner or fracture liaison services (FLS) at: Department of Endocrinology, Odense University Hospital Department of Endocrinology and Internal Medicine, Aarhus University Hospital Department of Endocrinology, Køge Hospital Department of Endocrinology, Hvidovre Hospital Department of Endocrinology, Bispebjerg Hospital During the intervention phase, there will be obtained fasting blood test, high-resolution peripheral quantitative computed tomography (HR-pQCT),Oral Glucose Tolerance Test (OGTT), DXA, Vertebral fracture assessment (VFA) and biochemistry at different time stamps. From 105 patients there will be obtained bone marrow aspirates and performed jamshidi bone biopsies. The study will therefore show if it would be possible to treat twice as many patients for the same prize but also if the treatment for 12 months can be optimized. The knowledge about the optimal use of romosozumab will be included in an update of osteoporosis treatment guidelines. This will lead to optimized treatment of patients with severe osteoporosis.

Official Title
-----------------
The Optimised Use of Romozosumab Study

Conditions
-----------------
Osteoporosis

Intervention / Treatment
-----------------
* Drug: Romosozumab
* Drug: Zoledronate
* Drug: Romosozumab
* Drug: Zoledronate
* Drug: Romosozumab
* Drug: Zoledronate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Postmenopausal women (postmenopausal for at least two years) BMD T-score < -2.5 at lumbar spine, total hip, or femoral neck Osteoporotic fracture within the last 3 years at the spine, hip, pelvis, humerus or forearm after the age of 50 years. Exclusion Criteria: Osteoporosis treatment including hormone replacement therapy within the last 5 years Metabolic bone disease Known disorders affecting bone metabolism, e.g., uncontrolled thyrotoxicosis, liver dysfunction (baseline phosphatase higher than twice upper limit), rheumatism, severe COPD (chronic obstructive pulmonary disease), hypopituitarism, Cushing's disease Ongoing treatment with glucocorticoids (systemic) Estimated glomerular filtration rate (eGFR) < 35 mL/min Contraindications for zoledronate according to the Supplementary protection certificates (SPC) Contraindications for romosozumab according to the SPC For the subgroup with Jamshidi biopsies contraindications for local anaesthetics according to the SPC For the subgroup with Jamshidi biopsies contraindications for tetracycline or doxycykline according to the SPC

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group 1 - ROMO 12 months, ZOL 12 months<br>90 patients 12 months of romosozumab (ROMO) followed by 12 months of zoledronate (ZOL) | Drug: Romosozumab<br>* Romosozumab 210 mg/2.34 ml from baseline to month 11<br>* Other names: Evenity;Drug: Zoledronate<br>* 5 mg/100 ml at month 12<br>|
| Active Comparator: Group 2 - ROMO 6 months, ZOL 12 months, ROMO 6 months<br>90 patients 6 months of romosozumab followed by 12 months of zoledronate and lastly 6 months of romosozumab. | Drug: Romosozumab<br>* 210 mg/2.34 ml from baseline to month 5 and from month 18 to month 23<br>* Other names: Evenity;Drug: Zoledronate<br>* 5 mg/100 ml at month 6<br>|
| Active Comparator: Group 3 - ROMO 6 months, ZOL 18 months<br>90 patients 6 months of romosozumab followed by 18 months of zoledronate . | Drug: Romosozumab<br>* 210 mg/2.34 ml from baseline to month 5<br>* Other names: Evenity;Drug: Zoledronate<br>* 5 mg/100 ml at month 5 and month 18<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in total hip BMD | Change in total hip BMD | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in femoral neck BMD | Change in femoral neck BMD | 24 months | 
| Changes in trabecular bone volume fraction (bone volume/tissue volume, BV/TV) and cortical porosity measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) | Mean percent change in trabecular bone volume fraction and cortical porosity measured by HR-pQCT at the radius and tibia | 24 months | 
| Change in spine BMD | Change in spine BMD | 24 months |