Kidney Transplant; Complications, Osteoporosis, Renal Osteodystrophy
Conditions
Keywords
Denosumab, Bone density, Kidney transplant, Prolia
Brief summary
This is a Phase 2 Multi-Center Clinical Trial (safety and effectiveness trial) in 60 patients (40 denosumab; 20 placebo) who have had a kidney transplant for 12-months or longer with more than 30% of kidney function. The investigators will test whether denosumab safely improves bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) and improves bone strength by high resolution peripheral quantitative computed tomography (HR-pQCT) in the subset of patients recruited at Columbia University Irving Medical Center. These data will inform the development and execution of a larger trial to test if denosumab prevents fractures in kidney transplant recipients.
Detailed description
Bone fractures are 3-times more common in kidney transplant recipients than in the general population and risk of dying after a hip fracture is 60% higher compared to kidney transplant recipients without a fracture. Unfortunately, there are no anti-fracture strategies that have been proven to be effective in double blinded randomized clinical trials for kidney transplant recipients. This is because some anti-fracture medications that are commonly used to treat osteoporosis and prevent fractures in the general population (i.e., bisphosphonates), may be harmful to the skeleton when kidney function is less than 30% of normal. In addition, intravenous bisphosphonates may be toxic to the kidneys, which further limits their utility in patients with a kidney transplant. Denosumab, a monoclonal antibody against RANKL, inhibits osteoclast function and is not harmful to the kidney. Denosumab prevents fractures in men and women with age-related and glucocorticoid-induced osteoporosis. Recently, a non-blinded randomized trial of denosumab versus usual care during the first year of kidney transplantation in 90 patients reported the bone mineral density (BMD) measured by dual energy X-ray absorptiometry (DXA) increased at the spine and hip and that bone strength measured by high resolution peripheral quantitative computed tomography (HR-pQCT) increased in patients treated with denosumab. Adverse events in denosumab-treated patients included greater risk of urinary tract infections, diarrhea, and transient levels of low serum calcium that were asymptomatic. This study demonstrated that denosumab safely increased BMD at the spine and hip in new kidney transplant recipients. However, long-term kidney recipients, who comprise the vast majority of patients living with a transplanted kidney and who are also at increased risk of fracture, were not included.
Interventions
Treatment will be administered by study personnel as a subcutaneous injection every 6-months for one year.
OTHERPlacebo
Placebo will be administered by study personnel as a subcutaneous injection every 6-months for one year.
Sponsors
Thomas Nickolas, MD MS
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
The investigators and clinical research coordinators will be blinded to treatment assignment for the duration of the study.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Men and women 2. All race-ethnicities 3. Age ≥ 18 years 4. ≥ 12-months after kidney transplantation (living or deceased donor recipient) 5. Stable allograft function over the previous year defined as: 1. No rejections 2. No more than a 15% decline in Glomerular filtration rate (GFR) over the prior year 6. Allograft GFR ≥ 30 mL/minute/1.73 m2 (MDRD or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) per local lab reporting) 7. 25OHD ≥ 30 ng/mL (determined at screening visit) 8. Serum calcium ≥ 9.0 mg/dL (determined at screening visit) 9. T-Score at the spine including and between -1.0 and -3.5 (determined at screening visit) 10. Must have had a routine dental exam within 6-months of study recruitment 11. Must agree to continue with routine dental exams over the course of the study 12. Has not undergone an invasive dental procedure (i.e., tooth extraction, dental implants, oral surgery) within ≤ 3-months of recruitment 13. Must agree to referral to metabolic bone disease specialist at the end of the study 14. Women of child bearing potential must be willing to use one form of effective contraception over the course of the study
Exclusion criteria
1. Allograft GFR \< 30 mL/minute/1.73 m2 (MDRD or CKD-EPI per local lab reporting) 2. Within 24-months of starting renal replacement therapy 3. Prevalent or occult vertebral fractures 4. History of post-transplantation non-basal cell carcinoma cancers 5. Non-ambulatory 6. Malignancy requiring chemotherapy or metastatic to bone 7. Non-transplant related metabolic bone diseases that alter bone mineral density, including but not limited to Primary hyperparathyroidism, Paget's, Osteogenesis Imperfecta 8. Within one-year of parathyroidectomy 9. Untreated hyperthyroidism for 6-months or longer 10. Untreated hypothyroidism for 6-months of longer 11. Medical diseases (end stage liver, lung or heart, intestinal malabsorption) 12. Use within the prior year of bisphosphonates, teriparatide, selective estrogen receptor modulators, testosterone, estrogen, denosumab, abaloparatide, calcitonin, and romosozumab 13. Allergy to components within the denosumab preparation or to denosumab 14. Weight \> 300 pounds 15. Parathyroid hormone (PTH) \> 450 pg /mL 16. Will undergo an invasive dental procedure (i.e., tooth extraction, dental implants, oral surgery) within the next 12-months 17. Pregnant 18. Planned pregnancy during the course of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bone Mineral Density (BMD) Measured by Dual Energy X-ray Absorptiometry (DXA) | 12 months | BMD will be measured to determine if 1-year of treatment with denosumab changes BMD as measured by DXA. |
| Estimated Bone Strength Measured by High Resolution Peripheral Quantitative Computed Tomography (HR-pQCT) Imaging | 12 months | Estimated bone mechanical competence will be measured by HR-pQCT. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Active Drug Denosumab 60 mg subcutaneous injection every 6 months for 12 months (i.e., 2 injections)
Denosumab Inj 60 mg/ml: Treatment will be administered by study personnel as a subcutaneous injection every 6-months for one year. | 4 |
| Placebo Placebo subcutaneous injection every 6 months for 12 months (i.e., 2 injections)
Placebo: Placebo will be administered by study personnel as a subcutaneous injection every 6-months for one year. | 4 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Due to the pandemic, this study was terminated early | 4 | 4 |
Baseline characteristics
| Characteristic | Active Drug | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 3 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 4 Participants | 1 Participants | 5 Participants |
| Region of Enrollment United States | 4 participants | 4 participants | 8 participants |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Male | 4 Participants | 1 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 4 |
| other Total, other adverse events | 1 / 4 | 2 / 4 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 |
Outcome results
Primary
Bone Mineral Density (BMD) Measured by Dual Energy X-ray Absorptiometry (DXA)
BMD will be measured to determine if 1-year of treatment with denosumab changes BMD as measured by DXA.
Time frame: 12 months
Population: Data was not collected due to termination of the study.
Primary
Estimated Bone Strength Measured by High Resolution Peripheral Quantitative Computed Tomography (HR-pQCT) Imaging
Estimated bone mechanical competence will be measured by HR-pQCT.
Time frame: 12 months
Population: Data was not collected due to termination of the study.