Clinical trial NCT04232657: Romosozumab to Improve Bone Mineral Density and Architecture in Chronic SCI
Official title: Romosozumab to Improve Bone Mineral Density and Architecture in Chronic SCI
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Spinal Cord Injury (=3 Years)
Sublesional Bone Loss Secondary to SCI
Keywords: Spinal Cord Injury
Veterans Affairs RR&D
Sublesional Bone Loss
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
Collaborators: name: Kessler Institute for Rehabilitation
First posted: 2020-01-18
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, double-blind, placebo-controlled, parallel group clinical trial
Primary purpose: PREVENTION

Brief summary: Treatment for sublesional bone loss (osteoporosis) in persons with chronic, motor-complete spinal cord injury (SCI) has been limited and unsuccessful to date. Romosozumab, a sclerostin antagonist, has potential to increase bone formation (anabolic) and decrease bone resorption (anti-catabolic) in persons with chronic SCI. Conventional anti-resorptive therapy alone would not be anticipated to reverse sublesional bone loss in a timely manner because the skeleton below the level of lesion in chronic SCI is assumed to be in a low turnover state. However, because there is a high likelihood that the bone accrued while on romosozumab will be lost once discontinued, denosumab, an anti-resorptive agent, will be administered after treatment with romosozumab, to maintain or, possibly, to continue to increase, bone mineral density (BMD).

The purpose of this study is to address the gap in the treatment of osteoporosis in individuals with chronic SCI by partially restoring BMD with romosozumab treatment for 12 months and then to maintain, or further increase, BMD with denosumab treatment for 12 months. A two group, randomized, double-blind, placebo-controlled clinical trial will be conducted in 39 participants who have chronic (\>3 years), motor-complete or incomplete SCI and areal BMD (aBMD) values at the distal femur of at the distal femur \<1.0 g/cm2 measured by dual photon X-ray absorptiometry (DXA). The intervention group will receive 12 months of romosozumab followed by 12 months of denosumab, and the control group will receive 12 months of placebo followed by 12 months denosumab.

Detailed description: Persons with chronic spinal cord injury (SCI) have markedly reduced bone mass and the loss of skeletal architectural integrity, which predisposes them to low-impact fractures. Currently, there is no practical treatment to reverse the severe bone loss in persons with chronic SCI. In the proposed study, a dual pharmacological intervention will be tested to improve bone health. Restoration of bone mass below the level of injury would be expected to reduce the morbidity associated with fractures and permit safer participation in upright activities. Quality of life would be substantially improved because of the ability to engage more securely in activities of daily living and to integrate into the community. Despite the depressed skeletal activity below the level of lesion in persons with chronic SCI, net bone loss occurs because resorption exceeds formation, with a difference between these rates in those with SCI being greater than that observed in the able-bodied population. Thus, it would be anticipated to be of value in persons with chronic SCI to increase bone turnover with the objective to increase bone formation over that of bone resorption. In a preclinical study that administered an anti-sclerostin antibody to rats 12 weeks after complete spinal cord transection bone, mineral density (BMD) was almost fully restored at the distal femoral metaphysis, with improved bone structure, and mechanical strength; in contrast, vehicle-treated animals after complete spinal transection had a marked reduction in distal femoral metaphysis BMD and a deterioration in bone structure and mechanical strength. When used to treat postmenopausal osteoporosis, romosozumab, a human monoclonal anti-sclerostin antibody, was more effective to increase bone mineral density (BMD) and to reduce fracture than any other anti-resorptive or bone-anabolic agent, and this effect was also evident for the appendicular skeleton, which is the site in individuals with chronic SCI of greatest bone loss and most frequent fracture. Because of the absence of clinical options available for the treatment of osteoporosis in individuals with chronic paralysis, the investigators have proposed to test an antagonist of sclerostin, which is a potent bone anabolic agent with proven efficacy in treating women with postmenopausal osteoporosis, to improve bone mass and reduce fragility fractures.

Thirty-nine male and female subjects with chronic, motor-complete or incomplete SCI (\>3 years post injury, American Spinal Injury Association Impairment Scale A \& B) between the ages of 18 and 55 years old (for females) or 65 years old (for males) who have aBMD at the distal femur at the distal femur \<1.0 g/cm2 will be recruited for participation in a randomized, double-blind, placebo-controlled, parallel group clinical trial. The outcome measures of the proposed study are bone mineral density (BMD) by peripheral quantitative computed tomography (pQCT) and dual energy x-ray absorptiometry (DXA), and biochemical markers of bone resorption and formation. This prospective, randomized, placebo controlled clinical trial will take place at the James J. Peters VA Medical Center (JJPVAMC) and Kessler Institute for Rehabilitation (KIR) (each facility will perform patient enrollment and study procedures).

Eligibility criteria: Inclusion Criteria:

* Motor-complete or incomplete SCI \[all levels of lesion\] classified using International Standards for Neurological Classification for Spinal Cord Injury (ISNCSCI) impairment scale\] as ISNCSCI score A-C
* Duration of injury \>3 years
* Males (18-65 years old) and females (premenopausal, between the ages of 18 and 55 years old).
* aBMD at the distal femur \<1.0 g/cm2 (determined at screening)

Exclusion Criteria:

* Long-bone fracture of the leg within the past year
* History of prior bone disease (Paget's hyperparathyroidism, etc.)
* Active and/or history of coronary heart disease or stroke within the past year
* Postmenopausal women
* Men with known hypogonadism prior to SCI
* Anabolic therapy longer than six months duration after SCI
* Glucocorticoid administration longer than three months duration within the last year, and/or prescribed moderate or high dose corticosteroids (\>40 mg/d prednisone or an equivalent dose of other corticosteroid medication) for longer than one week, not including drug administered to preserve neurological function at the time of acute SCI
* Endocrinopathies (hyperthyroidism, Cushing's disease or syndrome, etc.)
* Severe underlying chronic disease (e.g., COPD, end-stage heart disease, chronic renal failure)
* Heterotopic ossification (HO) of the knee region (the distal femoral epiphysis is the primary endpoint); HO to any other boney region will not prevent study participation as long as contraindicated medications have not been prescribed)
* Chronic alcohol abuse
* Hypocalcemia
* Pregnancy
* Prescribed a bisphosphonate for HO, or prescribed any other agent to treat osteoporosis other than calcium and vitamin D
* Electrical stimulation of the lower extremities
* Current diagnosis of cancer or history of cancer
* Osteosarcoma
* Life expectancy less than 5 years

Primary outcomes:
measure: Change in vBMD at the Distal Femur, measured by pQCT after 12 months of romosozumab treatment
timeFrame: Baseline (0), Month 6, Month 12
measure: Change in vBMD at the distal femur after an additional 12 months of denosumab treatment
timeFrame: Month 18, Month 24
Secondary outcomes:
Other outcomes:
measure: Additional variables by pQCT - vBMD Proximal Tibia
timeFrame: Baseline (0), Month 6, Month 12, Month 18, Month 24
measure: Additional variables by pQCT - tBMD Distal Femur
timeFrame: Baseline (0), Month 6, Month 12, Month 18, Month 24
measure: Additional variables by pQCT - tBMD Proximal Tibia
timeFrame: Baseline (0), Month 6, Month 12, Month 18, Month 24
measure: Additional variables by pQCT - cortical BMD of the tibia (38% of the tibial length)
timeFrame: Baseline (0), Month 6, Month 12, Month 18, Month 24
measure: Additional variables by pQCT - Distal Tibia Microarchitecture
timeFrame: Baseline (0), Month 6, Month 12, Month 18, Month 24
measure: Additional variables by DXA - aBMD Distal Femur and Proximal Tibia (i.e. knee)
timeFrame: Baseline (0), Month 6, Month 12, Month 18, Month 24
measure: Additional variables by DXA - aBMD Hip
timeFrame: Baseline (0), Month 6, Month 12, Month 18, Month 24
measure: Biomarkers for Bone Resorption (CTx)
timeFrame: Baseline (0), Month 1, Month 3, Month 6, Month 12, Month 18, Month 24
measure: Biomarkers for Bone Formation (osteocalcin, alkaline phosphatase, P1NP)
timeFrame: Baseline (0), Month 1, Month 3, Month 6, Month 12, Month 18, Month 24
measure: Calcium Metabolism Studies
timeFrame: Baseline (0), Month 1, Month 3, Month 6, Month 12, Month 18, Month 24
measure: General Endocrine Studies
timeFrame: Baseline (0), Month 12, Month 24
measure: Additional variables by pQCT - Distal Tibia Microarchitecture
timeFrame: Baseline (0), Month 6, Month 12, Month 18, Month 24
measure: Additional variables by pQCT - Distal Tibia Microarchitecture
timeFrame: Baseline (0), Month 6, Month 12, Month 18, Month 24
measure: Additional variables by pQCT - Distal Tibia Microarchitecture
timeFrame: Baseline (0), Month 6, Month 12, Month 18, Month 24
measure: Calcium Metabolism Studies
timeFrame: Baseline (0), Month 1, Month 3, Month 6, Month 12, Month 18, Month 24
measure: Calcium Metabolism Studies
timeFrame: Baseline (0), Month 1, Month 3, Month 6, Month 12, Month 18, Month 24
measure: Calcium Metabolism Studies
timeFrame: Baseline (0), Month 1, Month 3, Month 6, Month 12, Month 18, Month 24
measure: Calcium Metabolism Studies
timeFrame: Baseline (0), Month 1, Month 3, Month 6, Month 12, Month 18, Month 24
measure: Calcium Metabolism Studies
timeFrame: Baseline (0), Month 1, Month 3, Month 6, Month 12, Month 18, Month 24
measure: General Endocrine Studies
timeFrame: Baseline (0), Month 12, Month 24
measure: General Endocrine Studies
timeFrame: Baseline (0), Month 12, Month 24
measure: General Endocrine Studies
timeFrame: Baseline (0), Month 12, Month 24
measure: General Endocrine Studies
timeFrame: Baseline (0), Month 12, Month 24
measure: General Endocrine Studies
timeFrame: Baseline (0), Month 12, Month 24
measure: General Endocrine Studies
timeFrame: Baseline (0), Month 12, Month 24
measure: Biomarkers for Bone Formation
timeFrame: Baseline (0), Month 1, Month 3, Month 6, Month 12, Month 18, Month 24
measure: Biomarkers for Bone Formation
timeFrame: Baseline (0), Month 1, Month 3, Month 6, Month 12, Month 18, Month 24
Locations:
city: West Orange
country: United States
facility: Kessler Institute for Rehabilitation
state: New Jersey
city: Bronx
country: United States
facility: James J. Peters VA Medical Center, Bronx, NY
state: New York
Study officials:
affiliation: James J. Peters Veterans Affairs Medical Center
name: Christopher Cardozo, MD
role: PRINCIPAL_INVESTIGATOR
References: