Treatment with zoledronate subsequent to denosumab in osteoporosis 2

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Aarhus University Hospital

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

11 May 2023 → ongoing

Decision date (initial)

2023-02-02

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Funding sources

Novo Nordisk

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

The aims of ZOLARMAB2 are fourfold. First, we want to investigate if multiple infusions of zoledronate can prevent the rebound activation of bone turnover and the subsequent bone loss in patients previously treated with denosumab and if there is difference between infusing zoledronate at fixed time-points after the last injection of denosumab or when bone turnover is increased.
Second, we want to investigate if bone loss will resume after controlling the rebound activation of bone turnover during the first year after denosumab discontinuation and if this can be prevented by yearly infusions of zoledronate.
Third, we want to investigate the underlying pathophysiological mechanisms by investigating biochemical markers, oste-oclast and osteoblast activation signals in the bone and bone marrow, and the pool of preosteoclasts/mature osteoclasts before and after treatment with zoledronate.
Fourth, we want to investigate the effect of denosumab discontinuation on muscle mass and muscle strength and on insulin sensitivity.

Conditions and MedDRA coding

Osteoporosis

Study design 2 periods

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Postmenopausal women (postmenopausal for at least two years)
2. Age ≥ 40 years
3. Treatment for at least two years with denosumab
4. Last denosumab injection less than five months ago
5. At least 2 lumbar vertebrae that can be evaluated by DXA

Exclusion criteria 16

1. Low-energy vertebral fracture within the last ten years
2. Metabolic bone disease (for example osteogenesis imperfecta, Paget's disease of bone)
3. Hormone replacement therapy
4. Active cancer within the last 5 years with the exception of basal cell skin cancer
5. Multiple low-energy vertebral fractures (>= 3) at any time
6. Low-energy hip fracture within the last 12 months
7. BMD T-score < -2.0 (lumbar spine, total hip or femoral neck)
8. Zoledronate treatment for more than three years prior to denosumab treatment within the last ten years
9. Alendronate treatment for more than three years prior to denosumab treatment within the last five years or for more than five years within the last the years
10. Treatment with other bisphosphonates (risedronate, ibandronate) for more than three years prior to denosumab treatment within the last five years
11. Diabetes Mellitus
12. Ongoing treatment with systemic glucocorticoids
13. Estimated glomerular filtration rate (eGFR) ≤ 35 mL/min
14. Contraindications for zoledronate according to the SPC
15. Unable to read and understand Danish
16. Immobility

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Change in lumbar spine BMD after 12 and 36 months.
2. The proportion of patients who fails to maintain BMD (total hip, femoral neck and spine) after 12 months. Failure is defined as ≥ 3 % BMD loss at the lumbar spine or ≥ 5 % BMD loss at the femoral neck or total hip.

Secondary endpoints 10

1. Changes in total hip and femoral neck BMD after 12 and 36 months.
2. 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) at the radius and tibia after 12 and 36 months.
3. Changes in CTX and procollagen type I N-terminal propeptide (PINP) after 3, 6, 12, 24 and 36 months.
4. Morphometric vertebral fractures assessed by vertebral fracture assessment (VFA) after 12 and 36 months or by spinal x-ray if clinical suspicion of vertebral fracture.
5. Serum RANKL/OPG, tartrate-resistant acid phosphatase type 5b (TRAcP-5b), sclerostin and Dickkopf-1 (Dkk-1) at 0, 1, 3, 6 and 12 months
6. Molecular bone histology of accumulating osteoclast activation sites and pre-osteoclasts as well as single-nucleus transcriptomics on jamshidi biopsies at baseline in a total of 100 patients from groups 1 and 2 and in up to 15 participants in groups 1 and 2 at month 3 with a strong rebound response (p-CTX > 0.6 ug/l).
7. Osteoclasts differentiation, fusion, function, and response to ZOL in cultures derived from peripheral blood at baseline from groups 1 and 2. 30 patients will be recruited from each group, hence 60 patients.
8. Epigenetic marker analysis with special focus on genes involved in osteoclast activation, differentiation, fusion, function and response to ZOL. Samples collected at baseline from all participants.
9. Muscle mass assessed by whole-body DXA and muscle strength assessed by handgrip strength and muscle strength over the knee and elbow joints. A total of 100 patients from groups 1 and 2 will be investigated at base-line month 3 and 12.
10. Insulin sensitivity assessed by Hb1Ac, HOMA-IR and OGTT. Accumulation of advanced glycation end products (AGEs) will also be evaluated.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Aarhus University Hospital

Sponsor organisation

Aarhus University Hospital

Address

Palle Juul-Jensens Boulevard 99

City

Aarhus N

Postcode

8200

Country

Denmark

Scientific contact point

Organisation

Aarhus University Hospital

Contact name

Anne Sophie Sølling

Public contact point

Organisation

Aarhus University Hospital

Contact name

Anne Sophie Sølling

Third parties 1

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

6 submissions — initial application plus substantial / non-substantial modifications