Denosumab for Broken Bones in Dialysis Patients

(PREFERRED-1 Trial)

Not currently recruiting at 5 trial locations

Overseen By Jennifer Arnold

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Western University, Canada

Must not be taking: Osteoporosis medications

Disqualifiers: Kidney recovery, Palliative care, Childbearing, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 15 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the effectiveness of denosumab (also known as Prolia or Xgeva) in preventing bone fractures in individuals on hemodialysis. Participants will be divided into two groups: one receiving usual care and the other receiving denosumab injections every six months. The trial will assess the feasibility of organizing a larger study based on participant enrollment and retention. It is suitable for dialysis patients at high risk of bone fractures who are not currently using osteoporosis medications. As a Phase 4 trial, denosumab has already received FDA approval and proven effective, and this research aims to understand its benefits for more patients.

Will I have to stop taking my current medications?

If you are currently taking certain osteoporosis medications, including denosumab, bisphosphonates, or others listed in the trial's exclusion criteria, you will need to stop taking them to participate in this trial. The protocol does not specify a washout period, but you should discuss this with the trial team.

What is the safety track record for denosumab?

Research has shown that denosumab can pose safety concerns for people with chronic kidney disease. One study found that denosumab increases the risk of severe hypocalcemia, or very low calcium levels in the blood, particularly in those with advanced kidney problems. Another study noted that patients taking steroids or certain other medications might face a higher risk of infections when using denosumab.

However, evidence indicates that denosumab does not harm kidney function in patients with severe kidney disease, which is reassuring for those concerned about kidney health. The FDA has approved denosumab for various conditions, suggesting it is generally considered safe with proper monitoring.

Prospective trial participants should consider these risks and consult a healthcare provider to determine if denosumab is a suitable option. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Denosumab is unique because it offers a fresh approach to treating bone issues in dialysis patients by targeting a protein called RANKL. This mechanism is different from the standard treatment options like calcium supplements and vitamin D, which mainly focus on supporting bone health indirectly. Researchers are excited about denosumab because it directly inhibits the cells that break down bone, potentially leading to stronger bones and fewer fractures in a population that is highly vulnerable to bone damage. Additionally, its administration every six months during regular dialysis sessions makes it convenient for patients.

What evidence suggests that denosumab might be an effective treatment for fragility fractures in dialysis patients?

Research has shown that denosumab can reduce the risk of bone fractures and improve bone strength in people with chronic kidney disease (CKD), including those on dialysis. One study found that denosumab reduced fracture risk by 45% compared to oral bisphosphonates, another bone-strengthening medication. In this trial, some participants will receive denosumab to assess its effectiveness in dialysis patients. However, denosumab may increase the risk of serious heart problems, so discussing the benefits and risks with a healthcare provider is crucial. Overall, denosumab is one of the approved treatments in Canada for preventing fractures in CKD patients. ^{2 6 7 8 9}

Who Is on the Research Team?

Kristin K Clemens, MD, MSc

Principal Investigator

St. Joseph's Health Care London

Are You a Good Fit for This Trial?

This trial is for adults over 40 on outpatient maintenance hemodialysis with chronic kidney disease at high risk of bone fractures. They must have certain blood calcium, PTH, and ALP levels and be eligible for denosumab through Ontario's drug programs. Exclusions include current use of specific osteoporosis medications or treatments, planned major dental surgery, known allergy to denosumab, or expected changes in dialysis treatment within a year.

Inclusion Criteria

I am at high risk for breaking bones easily due to conditions like osteoporosis.

Your blood tests show high levels of calcium, PTH, or alkaline phosphatase.

I can get denosumab through my provincial drug benefits.

Exclusion Criteria

You are currently taking certain medications for osteoporosis, have certain planned dental surgeries, or have specific allergies or intolerances.

I am currently taking cinacalcet (Sensipar).

I am expected to start IV treatment with drugs like pamidronate or zoledronic acid.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 60 mg of denosumab every 6 months over a 15-month period, with monitoring of serum calcium and phosphate, and administration of vitamin D and calcium as needed.

15 months

In-person visits during regular hemodialysis sessions

Follow-up

Participants are monitored for safety and effectiveness after treatment, including monitoring of serum calcium and parathyroid hormone levels.

4 weeks

Monitoring visits following each denosumab injection

What Are the Treatments Tested in This Trial?

Interventions

• Denosumab

Trial Overview

The PREFERRED-1 study tests whether Denosumab can prevent fractures better than usual care in patients with kidney disease on dialysis. At least 60 participants from various centers will either follow a Denosumab care pathway including calcium and vitamin D supplements plus monitoring or receive the standard fracture prevention treatments.

How Is the Trial Designed?

Group I: Intervention Experimental Treatment 3 Interventions

60 mg of denosumab (Prolia) will be administered every 6 months over a 15 - month period. Monitoring of serum calcium and phosphate will occur and bloodwork will be drawn for 7 weeks following each denosumab injection. Correction of vitamin D deficiency (if required), the adjustment of calcium dialysate and the provision of intravenous (IV) or oral (po) calcitriol/calcidiol will be administered as needed following each denosumab injection as described in the Beside Protocol. Once the study monitoring period is over, serum calcium monitoring and management will occur as per routine care in the dialysis centre. All intervention activities will occur during regularly scheduled hemodyalisis sessions.

Group II: Usual care Active Control 1 Intervention

Usual care participants will continue to receive the typical standard of care in their dialysis unit which includes their routine dialysis monitoring and bloodwork. They will not receive denosumab, calcium and vitamin prophylaxis. There will be no extra monitoring or bloodwork.

Denosumab is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Prolia for:

• Osteoporosis in postmenopausal women
• Bone loss associated with hormone ablation therapy for prostate cancer
• Bone loss associated with hormone ablation therapy for breast cancer

Approved in United States as Prolia for:

• Treatment of postmenopausal women with osteoporosis at high risk for fracture
• Treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer
• Treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer

Approved in Canada as Prolia for:

• Treatment of osteoporosis in postmenopausal women at high risk for fracture
• Treatment to increase bone mass in men with osteoporosis at high risk for fracture

Approved in Japan as Prolia for:

• Treatment of osteoporosis in postmenopausal women
• Treatment of bone loss associated with hormone ablation therapy for prostate cancer

Who Is Running the Clinical Trial?

Western University, Canada

Lead Sponsor

Trials

270

Recruited

62,500+

ICES

Collaborator

Trials

4

Recruited

327,000+

Western University

Collaborator

Trials

31

Recruited

129,000+

ICES

Industry Sponsor

Trials

6

Recruited

534,000+

Academic Medical Organization of Southwestern Ontario

Collaborator

Trials

17

Recruited

1,600+

The Kidney Foundation of Canada

Collaborator

Trials

16

Recruited

3,200+

Published Research Related to This Trial

Denosumab, a drug used to prevent bone loss, was linked to a non-healing area in the lower jaw after a tooth extraction, highlighting a potential complication associated with its use.

After stopping denosumab, the non-healing area healed successfully, suggesting that discontinuation of the drug may be necessary to allow for healing in similar cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Denosumab: a case of MRONJ with resolution. Lyttle, CV., Patterson, H.[2018]

In a study of 75 patients with osteoporosis and decreased kidney function, treatment with denosumab (Prolia®) over an average of 5.3 years led to significant improvements in bone mineral density, with a 12% increase in the lumbar spine and a 7% increase in the hip T scores.

The treatment was generally well tolerated, although 20% of patients experienced new fractures and 21% had biochemical hypocalcemia, indicating the need for monitoring calcium levels during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of osteoporosis with denosumab in patients with decreased kidney function. Svendsen, OL.[2023]

Citations

1.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/39761590/

Cardiovascular Safety and Fracture Prevention ...

It was estimated that, compared with oral bisphosphonates, denosumab lowered the risk for fractures by 45% and increased the risk for MACE by 36%.

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10503558/

Denosumab Use in Chronic Kidney Disease Associated ...

The findings suggest that denosumab reduces the risk of fractures and improves bone mineral density in all stages of CKD.

3.

medpagetoday.com

medpagetoday.com/endocrinology/osteoporosis/113663

Denosumab May Offer Better Fracture Protection for ...

Denosumab may be more effective than oral bisphosphonates in reducing fracture risk, but it might also increase the risk of MACE.

4.

rheumatologyadvisor.com

rheumatologyadvisor.com/news/fracture-risk-in-dialysis-population-lower-with-denosumab-use/

Fracture Risk in Dialysis Population Lower With ...

Denosumab may reduce fracture risk better than oral bisphosphonates for treatment of osteoporosis in patients on dialysis, a new Japanese ...

5.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05096195

NCT05096195 | PRevEnting FracturEs in REnal Disease - 1

Denosumab (Prolia) is one of the only Health Canada approved medications for fragility fracture prevention across the CKD stages. While small clinical trials ...

6.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0006497124097970

Effects of Denosumab Therapy on Renal Function in ...

Conclusions: Our findings suggest that denosumab is safe in regard to renal function for MM patients with severe CKD (baseline CrCl < 30 ml/min) ...

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC7823314/

Denosumab Safety and Efficacy Among Participants in the ...

This post hoc analysis evaluates the long-term safety and efficacy of denosumab in individuals with mild-to-moderate chronic kidney disease (CKD) (stages 2 and ...

8.

fda.gov

fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-increased-risk-severe-hypocalcemia-patients-advanced-chronic-kidney-disease

FDA adds Boxed Warning for increased risk of severe ...

The results showed a significant increase in the risk of developing severe hypocalcemia with Prolia treatment compared to another class of ...

9.

journals.lww.com

journals.lww.com/sjkd/fulltext/2021/32050/safety_of_denosumab_in_patients_with_chronic.4.aspx

Safety of Denosumab in Patients with Chronic Kidney ...

Denosumab is associated with increased risk of infection in CKD patients on steroids or multiple immuno-suppressive medications.