Prevention of Bone Loss After Acute SCI by Zoledronic Acid

• Sponsor: Northwestern University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02325414
• Collaborator: United States Department of Defense (U.S. Fed)
• Enrollment: 60
• Locations: 2
• Arms: 2
• Actual Duration (Months): 66.8
• Patients Per Site: 30
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The overall objective of this study is to define an effective therapeutic approach, using currently available medication, to prevent or mitigate the loss of bone mass and bone strength that occurs after acute spinal cord injury.

Condition or Disease	Intervention/Treatment	Phase
Spinal Cord Injury; Acute Spinal Cord Injury; Bone Loss; Osteoporosis	Drug: Zoledronic acid; Drug: Placebo	Phase 2

Detailed Description

This is a randomized, double-blind placebo-controlled study of zoledronic acid to evaluate its efficacy and safety over a 2 year period for the prevention of bone loss and maintenance of bone strength in individuals with recent onset SCI (see diagram below). Subjects will be randomized at the baseline visit to receive either zoledronic acid or placebo. At the end of the first year of the study, each treatment group will be re-randomized to either zoledronic acid or placebo to evaluate the durability of response to zoledronic acid and the utility of serum bone markers to guide therapeutic decision making. DXA imaging, CT imaging and bone markers will be obtained at baseline, 3 months, 6 months, 12 months, 18 months and 24 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Prevention of Bone Loss After Acute SCI by Zoledronic Acid: Durability, Effect on Bone Strength, and Use of Biomarkers to Guide Therapy
• Actual Study Start Date: Feb 1, 2015
• Actual Primary Completion Date: Aug 25, 2020
• Actual Study Completion Date: Aug 25, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Zol Intravenous infusion of zoledronic acid (zol) 5 mg at baseline.	Drug: Zoledronic acid; Intravenous infusion of zoledronic acid 5 mg.; Other Names: Reclast Zometa Bisphosphonate
Experimental: Placebo Intravenous infusion of placebo at baseline.	Drug: Placebo; Placebo (saline) infusion to match zoledronic acid; Other Names: Saline

Outcome Measures

Primary Outcome Measures

1. Percent Change in Bone Mass Density (BMD) in the Hip [0-12 months]

   Percent change of bone mass density (BMD) in the total hip (as measured by DXA)

2. Percent Change of Bone Mass Density (BMD) in the Femoral Neck [0-12 months]

   Percent change of bone mass density (BMD) in the femoral neck (as measured by DXA)

Secondary Outcome Measures

1. Percent Change in the Epiphyseal Integral Bone Mass Content (iBMC) of the Femur [0-12 months]

   Percent change in the epiphyseal integral bone mass content (iBMC) of the femur, as collected by CT.

2. Percent Change in the Metaphyseal Integral Bone Mass Content (iBMC) of the Femur [0-12 months]

   Percent change in the metaphyseal integral bone mass content (iBMC) of the femur, as collected by CT

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• In-patient at Rehabilitation Institute of Chicago (RIC) or an outpatient who was recently discharged from RIC

• Males and females

• Age >/=18 years

• Medically stable in the opinion of subject's physiatrist

• SCI at within 120 days inclusive at time of screening

• SCI with inability to ambulate independently

• ASIA Impairment Scale (AIS) A, B, or C, at time of study entry

• Capable of positioning to have DXA performed

• Able to tolerate acetaminophen

• No known endocrinopathies (diabetes type 1 or 2 can be included)

• Normal TSH levels

• Normal 25-OH vitamin D levels (>/= 20 ng/ml) at baseline (subjects may be repleted)

• Normal calcium levels

• Normal renal function (creatinine <2.0 mg/dl)

• Well hydrated with adequate intake of liquids

• Able to return for all follow-up visits

• Capable of reading and understanding informed consent document

• Males and females of childbearing potential must be willing and able to use double barrier method of contraception for 2 months after having received study drug

Exclusion Criteria:

• Have Paget's disease of the bone

• Malignancy as a cause of acute SCI

• Have unexplained high levels of alkaline phosphatase in blood

• Any active gastrointestinal condition that results in malabsorption

• Poor dental hygiene or requirement for invasive dental procedure within two months prior to enrollment

• History of bone metastasis and skeletal malignancies

• History of alcoholism or drug abuse within the 2 years prior to study screening

• Other medical conditions that in the opinion of the investigator would preclude the subject from completing the study

• Elevated liver function tests >2x normal

• Currently being prescribed anti-convulsants at a dose or frequency that is determined to interfere with bone metabolism as determined by the investigator

• Currently being prescribed glucocorticoids, other than inhaled glucocorticoids

• Current or recent use any bone-active agents, including any bisphosphonate, raloxifene, hormone therapy (estrogen and estrogen/progestin), calcitonin or strontium-containing compounds within 60 days of screening.

• Pregnant, planning to become pregnant, or lactating

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University Feinberg School of Medicine	Chicago	Illinois	United States	60611
2	Rehabilitation Institute of Chicago	Chicago	Illinois	United States	60611

Sponsors and Collaborators

• Northwestern University
• United States Department of Defense

Investigators

• Principal Investigator: Thomas J Schnitzer, MD, PhD, Northwestern University Feinberg School of Medicine

Study Documents (Full-Text)

• Study Protocol - Jun 28, 2020
• Statistical Analysis Plan - Jun 17, 2020

More Information

Publications

None provided.

• Responsible Party: Thomas J. Schnitzer, Professor, Northwestern University
• ClinicalTrials.gov Identifier: NCT02325414
• Other Study ID Numbers: STU00098239; A-18350
• First Posted: Dec 25, 2014
• Last Update Posted: Jun 29, 2021
• Last Verified: Jun 1, 2021

• Keywords provided by Thomas J. Schnitzer, Professor, Northwestern University: Osteoporosis; Spinal Cord Injury; Bone Diseases; Metabolic Bone Diseases; Musculoskeletal Diseases; Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Nervous System; Wounds and Injuries; Bone Density Conservation Agents; Physiological Effects of Drugs; Pharmacologic Actions; Department of Defense
• Additional relevant MeSH terms: Osteoporosis; Spinal Cord Injuries; Wounds and Injuries; Zoledronic Acid; Diphosphonates

Study Results

Participant Flow

Recruitment Details	Patients with acute SCI were recruited from the Shirley Ryan AbilityLab, formerly known as the Rehabilitation Institute of Chicago. Recruitment took place between February 2015 and February 2018.
Pre-assignment Detail	After meeting eligibility, participants were randomized in a blinded fashion and received study drug at the baseline visit.

Arm/Group Title	Zoledronic Acid	Placebo
Arm/Group Description	Intravenous infusion of zoledronic acid (zol) 5 mg at baseline.	Intravenous infusion of placebo (saline) at baseline.
Period Title: Overall Study
STARTED	30	30
COMPLETED	22	24
NOT COMPLETED	8	6

Baseline Characteristics

Arm/Group Title	Zoledronic Acid	Placebo	Total
Arm/Group Description	Intravenous infusion of zoledronic acid (Zol) 5 mg at baseline	Intravenous infusion of placebo (saline) at baseline.	Total of all reporting groups
Overall Participants	30	30	60
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	29 96.7%	28 93.3%	57 95%
>=65 years	1 3.3%	2 6.7%	3 5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.3 (15.9)	38.2 (15.2)	37.8 (15.4)
Sex: Female, Male (Count of Participants)
Female	9 30%	3 10%	12 20%
Male	21 70%	27 90%	48 80%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 13.3%	7 23.3%	11 18.3%
Not Hispanic or Latino	26 86.7%	23 76.7%	49 81.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 6.7%	1 3.3%	3 5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	8 26.7%	6 20%	14 23.3%
White	20 66.7%	21 70%	41 68.3%
More than one race	0 0%	2 6.7%	2 3.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	30 100%	30 100%	60 100%
Time Since Injury (Days) (days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [days]	68.7 (28.5)	62.7 (23.2)	65.7 (25.9)

Outcome Measures

1. Primary Outcome

Title	Percent Change in Bone Mass Density (BMD) in the Hip
Description	Percent change of bone mass density (BMD) in the total hip (as measured by DXA)
Time Frame	0-12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Zoledronic Acid	Placebo
Arm/Group Description	Intravenous infusion of zoledronic acid (zol) 5 mg at baseline. Zoledronic acid: Intravenous infusion of zoledronic acid 5 mg.	Intravenous infusion of placebo at baseline. Placebo: Placebo (saline) infusion to match zoledronic acid
Measure Participants	30	30
Median (Inter-Quartile Range) [percent change in bone mass density]	-2.21	-12.82

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	10.61
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		One-year data analysis were carried out using linear mixed-effects models. Covariate adjustments for baseline value of the corresponding outcome and ambulatory status (measured by WISCI) were performed by fitting these variables as fixed factors. The repeated measures were addressed using participant identification as random intercepts in the model.

2. Primary Outcome

Title	Percent Change of Bone Mass Density (BMD) in the Femoral Neck
Description	Percent change of bone mass density (BMD) in the femoral neck (as measured by DXA)
Time Frame	0-12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Zoledronic Acid (Zol)	Placebo (Pla)
Arm/Group Description	Intravenous infusion of the study drug zoledronic acid (Zol) 5 mg at baseline.	Intravenous infusion of placebo at baseline. Placebo (Pla): saline
Measure Participants	30	30
Median (Inter-Quartile Range) [percent change in bone mass density]	-1.72	-11.34

3. Secondary Outcome

Title	Percent Change in the Epiphyseal Integral Bone Mass Content (iBMC) of the Femur
Description	Percent change in the epiphyseal integral bone mass content (iBMC) of the femur, as collected by CT.
Time Frame	0-12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Zoledronic Acid (Zol)	Placebo (Pla)
Arm/Group Description	Intravenous infusion of the study drug zoledronic acid (Zol) 5 mg at baseline.	Intravenous infusion of placebo at baseline. Placebo (Pla): saline
Measure Participants	30	30
Median (Inter-Quartile Range) [percent change]	-9.6	-22.90

4. Secondary Outcome

Title	Percent Change in the Metaphyseal Integral Bone Mass Content (iBMC) of the Femur
Description	Percent change in the metaphyseal integral bone mass content (iBMC) of the femur, as collected by CT
Time Frame	0-12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Zoledronic Acid (Zol)	Placebo (Pla)
Arm/Group Description	Intravenous infusion of the study drug zoledronic acid (Zol) 5 mg at baseline.	Intravenous infusion of placebo at baseline. Placebo (Pla): saline
Measure Participants	30	30
Median (Inter-Quartile Range) [percent change]	-4.73	-8.88

Adverse Events

Time Frame	Baseline - 12 month visit
Adverse Event Reporting Description	Adverse event collection began at the baseline visit, as soon as the participant received the first year study drug infusion. At each study visit, participants were asked about any changes to their health.
Arm/Group Title	Zoledronic Acid		Placebo
Arm/Group Description	Intravenous infusion of the study drug zoledronic acid (Zol) 5 mg at baseline.		Intravenous infusion of placebo at baseline. Placebo (Pla): saline
All Cause Mortality
	Zoledronic Acid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/30 (0%)
Serious Adverse Events
	Zoledronic Acid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/30 (26.7%)		9/30 (30%)
Blood and lymphatic system disorders
Immune Thrombocytopenic Purpura	1/30 (3.3%)	1	0/30 (0%)	0
Eye disorders
Exophoria with Intermittent Exotropia	1/30 (3.3%)	1	0/30 (0%)	0
General disorders
Acute Phase Response	2/30 (6.7%)	2	0/30 (0%)	0
Infections and infestations
C. difficile Infection	1/30 (3.3%)	1	0/30 (0%)	0
Septic Shock	1/30 (3.3%)	1	1/30 (3.3%)	1
Injury, poisoning and procedural complications
Traumatic Catheterization	0/30 (0%)	0	1/30 (3.3%)	1
Metabolism and nutrition disorders
Dehydration	0/30 (0%)	0	1/30 (3.3%)	1
Musculoskeletal and connective tissue disorders
Gas (Incidental finding on X-ray)	1/30 (3.3%)	1	0/30 (0%)	0
Osteomyelitis	0/30 (0%)	0	1/30 (3.3%)	1
Muscle pain (Back)	0/30 (0%)	0	1/30 (3.3%)	1
Nervous system disorders
Autonomic Dysreflexia	0/30 (0%)	0	2/30 (6.7%)	2
Epilepsy	1/30 (3.3%)	1	0/30 (0%)	0
Neuropathy, new or worsened	0/30 (0%)	0	1/30 (3.3%)	1
Psychiatric disorders
Altered Mental Status	1/30 (3.3%)	2	0/30 (0%)	0
Panic Attack	1/30 (3.3%)	1	0/30 (0%)	0
Worsened Psychiatric Symptoms	0/30 (0%)	0	1/30 (3.3%)	1
Renal and urinary disorders
Pyelonephritis	0/30 (0%)	0	1/30 (3.3%)	1
Urinary Tract Infection	3/30 (10%)	4	5/30 (16.7%)	5
Respiratory, thoracic and mediastinal disorders
Shortness of Breath	1/30 (3.3%)	1	0/30 (0%)	0
Skin and subcutaneous tissue disorders
Pressure Ulcer	0/30 (0%)	0	1/30 (3.3%)	1
Vascular disorders
Thrombus	0/30 (0%)	0	1/30 (3.3%)	1
Other (Not Including Serious) Adverse Events
	Zoledronic Acid		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/30 (93.3%)		22/30 (73.3%)
Gastrointestinal disorders
Constipation	2/30 (6.7%)	2	0/30 (0%)	0
General disorders
Acute Phase Response	20/30 (66.7%)	20	3/30 (10%)	3
Chills	2/30 (6.7%)	2	1/30 (3.3%)	1
Cough	3/30 (10%)	3	0/30 (0%)	0
Fatigue/Weakness	1/30 (3.3%)	1	2/30 (6.7%)	2
Fever	2/30 (6.7%)	2	3/30 (10%)	3
Headache	0/30 (0%)	0	2/30 (6.7%)	2
Injury, poisoning and procedural complications
Fall	0/30 (0%)	0	2/30 (6.7%)	2
Metabolism and nutrition disorders
Hypocalcemia	2/30 (6.7%)	2	0/30 (0%)	0
Musculoskeletal and connective tissue disorders
Heterotopic Ossification, new or worsened	3/30 (10%)	3	2/30 (6.7%)	2
Joint Pain	2/30 (6.7%)	2	4/30 (13.3%)	4
Myalgia	2/30 (6.7%)	2	1/30 (3.3%)	1
Nervous system disorders
Autonomic Dysreflexia	3/30 (10%)	4	1/30 (3.3%)	1
Neuropathy, new or worsened	0/30 (0%)	0	2/30 (6.7%)	3
Spasticity, new or worsened	2/30 (6.7%)	2	2/30 (6.7%)	2
Psychiatric disorders
Worsened Depression Symptoms	2/30 (6.7%)	2	0/30 (0%)	0
Renal and urinary disorders
Urinary Tract Infection	15/30 (50%)	26	10/30 (33.3%)	19
Respiratory, thoracic and mediastinal disorders
Flu	2/30 (6.7%)	2	2/30 (6.7%)	2
Upper Respiratory Infection	2/30 (6.7%)	4	8/30 (26.7%)	8
Skin and subcutaneous tissue disorders
Burn	1/30 (3.3%)	1	2/30 (6.7%)	2
Fungal Infection	0/30 (0%)	0	2/30 (6.7%)	2
Pressure Ulcer	3/30 (10%)	3	4/30 (13.3%)	4
Vascular disorders
Hypertension	3/30 (10%)	3	2/30 (6.7%)	2

Limitations/Caveats

The number of participants in the trial was limited, particularly during the second year in each subgroup. Additionally, the number of women studied was limited but was representative of the general sex distribution observed in people with spinal cord injury.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.