Conditions: Spinal Cord Injury Acute Spinal Cord Injury Bone Loss Osteoporosis
Keywords: 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
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 60
Healthy volunteers: no

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.

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.

Arms:
arm 1: Intravenous infusion of zoledronic acid (zol) 5 mg at baseline. arm 2: Intravenous infusion of placebo at baseline.

Interventions: intervention 1: Zoledronic acid intervention 2: Placebo
Intervention descriptions: intervention 1: Intravenous infusion of zoledronic acid 5 mg. intervention 2: Placebo (saline) infusion to match zoledronic acid

Protocol document:
SAP_002.pdf: 
   
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Prevention of Bone Loss after Acute SCI by Zoledronic Acid: 
Durability, Effect on Bone Strength, and Use of Biomarkers to 
Guide Therapy. NCT02325414 
 
 
 
 
 
 
 
 
Principal Investigator: Thomas J. Schnitzer, MD, PhD 
 
 
 
Sites: Northwestern University 
 
 
 
 
 
 
 


Version 2.2; 17Jun2020 
 
2
Table of Contents 
 
Overview .............................................................................................................................................................................. 3 
Study Objectives/Statistical Hypotheses ........................................................................................................................ 3 
Endpoints ............................................................................................................................................................................. 4 
Statistical Methods .............................................................................................................................................................. 4 
Missing Data .................................................................................................................................................................... 5 
Primary analyses .............................................................................................................................................................. 5 
Secondary analyses ......................................................................................................................................................... 5 
Sensitivity analyses .......................................................................................................................................................... 6 
Analysis of Safety ........................................................................................................................................................... 6 
Analysis Plan Summary ................................................................................................................................................. 7 
References ............................................................................................................................................................................ 8 
 
 
 


Version 2.2; 17Jun2020 
 
3
Overview 
This is a 2-year, randomized, double-blind placebo-controlled study of zoledronic acid 
to evaluate its efficacy and safety for the prevention of bone loss and maintenance of 
bone strength in individuals with recent onset SCI (see protocol). Subjects were 
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 was 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 of knee and bone markers were obtained at baseline, 3 months, 6 months, 
12 months, 18 months and 24 months. CT imaging of the hip was obtained at baseline, 
6 months, 12 months, and 24 months. 
 
Study Objectives/Statistical Hypotheses 
Hypothesis 1a. In participants treated shortly after acute SCI with a single infusion of 
zoledronic acid, the mean loss of bone after one year at skeletal sites in the lower 
extremity will be less than that determined for participants who received placebo. Hip 
areal bone mass density (aBMD) will be assessed as the primary endpoint. 
 
Hypothesis 1b: In participants treated shortly after acute SCI with a single infusion of 
zoledronic acid (zol/placebo) as well as those receiving a second treatment with 
zoledronic acid (zol/zol), the mean loss of bone after two years at skeletal sites in the 
lower extremity will be less than that determined for participants who received placebo 
for two years (placebo/placebo). 
 
Hypothesis 1c: The effects of a single infusion of zoledronic acid after acute SCI will 
wane over time; retreatment with zoledronic acid after one year will result in greater 
maintenance of bone than a single infusion with zoledronic acid.   
 
Hypothesis 1d: Initiation of treatment with zoledronic acid at one year after acute SCI 
in people not previously treated (placebo/zol) will still result in preventing further bone 
loss compared to no active bone-specific treatment (placebo/placebo); loss of bone 
mass that has occurred during the initial year without treatment will not be reversed, 
however.  
 
 
 
 
 


Version 2.2; 17Jun2020 
 
4
Endpoints 
Primary endpoints. The primary endpoints in this study are the percent-change in 
aBMD, evaluated by DXA, in the non-dominant (1) total hip and (2) femoral neck 
skeletal sites. If data on the non-dominant hip are unavailable, we will use aBMD for 
the dominant hip. Percent-change will be calculated as ((aBMDfollow-up - aBMDbaseline) / 
aBMDbaseline) × 100%. 
 
Key secondary endpoints. Secondary endpoints include: (1) integral volumetric bone 
mineral content (Int.vBMC) distal femoral epiphysis, (2) Int. vBMC tibial epiphysis, and 
(3) Int.vBMC distal femoral metaphysis measured by QCT. Percent-change will again 
be calculated for each outcome.  
 
Additional secondary endpoints.  CT biomarkers: Trabecular volumetric bone 
mineral density (Tb.vBMD; g/cm3) and cortical volumetric bone mineral content 
(Ct.vBMC; g) and bone volume (Ct.vBV; cm3) at epiphyseal and metaphyseal regions. 
For the diaphyseal region, Ct.vBMC and Ct.vBV.  WISCI. 
Exploratory endpoints. Torsional strength index (TSI; cm3) for each skeletal region. 
Stiffness and strength at the hip, distal femur, and proximal tibia determined by CT-
based finite element analysis.  Serum markers of bone metabolism:  P1NP, BSAP (bone 
formation markers), and CTX (bone resorption marker).  
 
 
 
 
Statistical Methods 
 
Diagnostics 
All variables will be plotted to examine distribution shapes as well as percentage of 
missing values. The mixed modelling proposed below uses both all available 
observations without deleting cases and imputed data. Residuals will be examined for 
each model fitted in case of unexpected violations of assumptions. Analysis will be 
performed as ITT (intention to treat): patients will be analyzed according to the 
treatment arm to which they were randomized.  
 


Version 2.2; 17Jun2020 
 
5
Missing Data 
 
Missing data will primarily be inputed by maximum likelihood estimation using a mixed 
effects model. A sensitivity analysis will be done latter, by using a multiple imputation 
methodology before modelling. Here, imputation of missing data will be based on 
sampling from a normal distribution using a mean value of the subjects’ last observed 
value and standard deviation (over treatment groups) of the observed data at the 
missing endpoint (3, 6, or 12 months). This is a multiple imputation version of Last 
Observation Carried Forward (LOCF) single imputation method. Note, a subject’s last 
observation may be the Baseline observation. One hundred imputed datasets will be 
used in this analysis. The linear mixed-effects model described below will be used for 
each imputation dataset, and the overall results will be calculated to take account of the 
variability both within and between imputation datasets using standard methods (Little 
& Rubin, 2002).  
 
 
Primary analyses 
Group comparisons will be tested with a linear mixed-effects model with the 
percentage-change from baseline to months 6 and 12 in aBMD at the total hip and 
femoral neck. Baseline aBMD at the total hip and femoral neck, study visit, ambulatory 
status measured by WISCI and interaction of WISCI with visit will be fitted as random 
factors. aBMD by group interaction will be considered statistically significant at p < 
0.05.  Raw effect sizes will be calculated as differences between groups at each time 
point.  Multiplicity will be handled by utilizing a fixed-sequence approach to testing, 
with initial analysis of total hip (α=0.05) and if successful followed by femoral neck 
(α=0.05). 
Secondary analyses 
Secondary analysis will be divided into three main sections: 
a) Effect of functional capacity (WISCI) on aBMD of total hip and femoral neck 
percent-change;  A secondary interaction analysis will be performed for the primary 
endpoint, exploring the effect of WISCI. The interaction of treatment with WISCI 
score will be fitted as a fixed effect (in addition to the WISCI score itself), with the 
resulting estimated treatment differences being shown for continuous scores of the 
WISCI scale. 
 
b) Secondary endpoint analysis at 12 months; 


Version 2.2; 17Jun2020 
 
6
The primary analysis described above will be applied for the all the three key secondary 
endpoints at 6, and 12 months visits, with the fixed sequence order described above. 
Appropriate p-values adjustments to compensate for a possible increased risk in Type 
I errors due to multiple secondary outcomes measurements will be done using a 
stepwise Dunnett procedure. All reporting will include both adjusted p values and raw 
effect sizes. 
 
c) Primary and secondary endpoint analysis at 24 months.   
 
Primary endpoint (total hip and femoral neck aBMD, measured by DXA) and 
secondary endpoints will be analyzed at 24 months. Here, we will study 4 groups of 
patients: 24 months of treatment, 24 months of no-treatment, switch from treatment 
to placebo at 12 months, switch from placebo to treatment at 12 months. A linear mixed 
model with the four groups, controlling for Baseline aBMD at the hip and ambulatory 
status measured by WISCI will be fitted to predict percent-change from baseline for 
each endpoint.  
Exploratory Analyses 
Serum bone markers (i.e., P1NP, BSAP, CTX) and additional CT bone biomarkers, 
measured at 3, 6, 12 and 24 months will be evaluated using a similar approach as for 
the primary analyses – linear mixed effects model. A compressive strength index (CSI; 
g2/cm4) and a torsional strength index (TSI; cm3) will be computed for each skeletal 
region. Finally, CT-based finite element analysis will be used to predict stiffness and 
strength at the hip, distal femur, and proximal tibia. 
 
Sensitivity analyses 
This analysis will assess the robustness of the efficacy conclusions regarding the choice 
of maximum likelihood estimation as the primary method for accounting for missing 
data. The primary mixed effects model described above will be repeated after multiple 
imputation, as described above.  
Analysis of Safety 
Analysis of safety will include all participants who underwent randomization and 
received at least one dose of the study drug. Safety endpoints will include incidence and 
severity of adverse events and laboratory blood chemical values. Adverse events will be 
characterized by system, organ, and class designation. Raw number of events and 
number of participants experiencing reported serious adverse events and adverse events 
will be reported. 


Version 2.2; 17Jun2020 
 
7
 
 
 
Analysis Plan Summary 
 
Endpoint 
Statistical 
Method 
Model/Covariates 
Missing Data 
Objective 
% Change from 
Baseline at 6,12 
months with total 
hip and femoral 
neck aBMD, 
DXA 
MEM 
Baseline total hip/ 
femoral 
neck 
aBMD, visit, WISCI 
score; (subjects as 
random effects) 
MLE 
Primary Analysis 
 
 
 
 
 
% Change from 
Baseline at 6,12 
months with total 
hip aBMD, DXA 
MEM 
Baseline total hip 
aBMD, visit, WISCI 
score; (subjects as 
random effects) 
Multiple 
Imputation 
Sensitivity Analysis 
 
 
 
 
 
% Change from 
Baseline at 6,12 
months with total 
hip aBMD, DXA 
(a) 
MEM 
Baseline total hip 
aBMD, visit, WISCI 
score, (subjects as 
random effects) 
MLE 
Secondary, 
Interaction Analysis 
% Change from 
Baseline at 6, 12 
months with 
femoral neck 
aBMD, DXA (b) 
MEM 
Baseline total hip 
aBMD, visit, WISCI 
score; (subjects as 
random effects)  
MLE 
Secondary Analysis 
% Change from 
Baseline at 6,12, 
months with QCT 
Int.vBMC 
Femoral 
Epiphysis (b) 
MEM 
Baseline total hip 
aBMD, visit, WISCI 
score; (subjects as 
random effects)  
MLE 
Secondary Analysis 
% Change from 
Baseline at 6,12, 
QCT Int.vBMC 
Femoral 
Methaphysis (b) 
MEM 
Baseline total hip 
aBMD, visit, WISCI 
score; (subjects as 
random effects) 
MLE 
Secondary Analysis 
% Change from 
Baseline 
at 
24 
months with total 
hip aBMD, DXA 
(c) 
MEM 
Baseline total hip 
aBMD, visit, WISCI 
score; (subjects as 
random effects) 
MLE 
Secondary Analysis 
% Change from 
Baseline 
at 
24 
months 
with 
MEM 
Baseline total hip 
aBMD, visit, WISCI 
MLE 
Secondary Analysis 


Version 2.2; 17Jun2020 
 
8
femoral 
neck 
aBMD, DXA (c) 
score; (subjects as 
random effects) 
% Change from 
Baseline 
at 
24 
months with QCT 
Int.vBMC 
Femoral 
Epiphysis (c) 
MEM 
Baseline total hip 
aBMD, visit, WISCI 
score; (subjects as 
random effects) 
MLE  
Secondary Analysis 
% Change from 
Baseline 
at 
24 
months with QCT 
Int.vBMC 
Femoral 
Methaphysis (c) 
MEM 
Baseline total hip 
BMD,  visit, WISCI 
score; (subjects as 
random effects) 
MLE 
Secondary Analysis 
(a) Secondary analysis phase 1: Interaction Analysis for primary endpoint with WISCI; (b) Secondary analysis 
phase 2: Secondary endpoints at 12 months; (c) Secondary analysis phase 3: Primary and Secondary endpoints 
at 24 months. aBMD (areal bone mineral density); MEM (mixed effects model); MLE (maximum likelihood 
estimates); WISCI (walking index for spinal cord injury). 
References 
 
Senn, S., & Julious, S. (2009). Measurement in clinical trials: a neglected issue for statisticians? 
Statistics in medicine, 28(26), 3189-3209. 
 
Little RJ & Rubin DB (2002). Statistical Analysis with Missing Data. New Jersey:Wiley. 
 
 

Prot_001.pdf: 
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