Comparative Effectiveness of Particulate Versus Nonparticulate Corticosteroid Injections for the Treatment of Musculoskeletal Conditions
Phase: PHASE4
Conditions: Osteoarthritis, Tendinopathy, Impingement Shoulder
Sponsor: Stanford University

 
 
 
 
Comparative Effectiveness of Particulate Versus 
Nonparticulate Corticosteroid Injections for the Treatment 
of Musculoskeletal Conditions  
 
Study Protocol and Statistical Analysis Plan 
NCT04278833 
April 7, 2020 

1) Name of study:  
 
Comparative Effectiveness of Particulate versus Nonparticulate Steroid Injections for Treating 
Musculoskeletal Conditions  
  
  
2) PI and other key investigators or key study personnel 
PI: Eugene Y. Roh, MD  
Investigator: Anita Lowe Taylor, MD  
Research coordinator: Ma Agnes Ith, MD, CCRC 
 
3) Specific source of institutional funding (account number): None 
 
4) List of sources from whom you are seeking funds (or have sought funding) for this 
project 
AMSSM funding 
Stanford internal funding 
PM&R foundation 
Charity from donors 
  
5) Specific aims and basic hypothesis including an explicit primary hypothesis or goal 
  
Specific Aims:  
a. To determine if particulate or non-particulate corticosteroid injections are more effective 
at treating pain from musculoskeletal pathologies of the intra-articular hip, glenohumeral 
joint, biceps tendon, and subacromial bursa at 2 weeks, 3 months, or 6 months. 
b. To determine if there is a significantly different side effect profile between particulate 
and non-particulate corticosteroids when used for intra-articular hip, glenohumeral joint, 
biceps tendon, or subacromial bursa injections.  
 
Hypothesis: There will be no significant difference in pain reduction, number of injections 
received, conversion to surgery, or side effect profile at 2 weeks, 3 months, or 6 months between 
particulate and non-particulate corticosteroids in the treatment of musculoskeletal pathologies of 
the intra-articular hip, glenohumeral joint, biceps tendon, or subacromial bursa. 
 
  
6) General background 
 
Corticosteroid injections are commonly used for the treatment of painful musculoskeletal 
pathologies including hip and glenohumeral joint osteoarthritis, adhesive capsulitis, biceps 
tendinopathy, and impingement syndrome/subacromial bursitis (Lambert et al, 2007; Lee et al, 
1997; Yoon et al, 2013; Hong et al, 2011), yet there is no consensus on whether particulate or 
non-particulate steroids are superior.  Particulate steroids include betamethasone, triamcinolone, 
and methylprednisolone, while non-particulate steroids include dexamethasone (Derby et al, 
2008).  
 

While particulate steroids might have theoretical improved efficacy due to possible decreased 
dispersion from the intra-articular space, there is animal data to suggest that particulate steroids 
may decrease microvascular perfusion (Laemell et al, 2016). Moreover, during animal studies in 
which steroids were directly injected into the arterial circulation, particulate but not non-
particulate steroids resulted in permanent central nervous system damage (Dawdley et al, 2009; 
Okubadejo et al, 2008). Yet because there is no meaningful data to support one choice over 
another, there remains significant clinical equipoise.  
 
This is in contrast to spinal epidural corticosteroid injections, where dexamethasone is generally 
preferred due to comparable efficacy and improved safety profile of non-particulate steroids 
compared to particulate steroids (Kennedy et al, 2014; Mehta et al, 2017).   
 
While randomized controlled trials have been completed comparing particulate to non-particulate 
steroids in the treatment of spinal stenosis (Kennedy et al, 2014; Mehta et al, 2017), knee 
rheumatoid arthritis (Hajialilo et al, 2016), and idiopathic trigger finger (Ring et al, 2008) with 
conflicting results, there have been no studies comparing these two steroid types in the hip joint, 
glenohumeral joint, biceps tendon, or subacromial/subdeltoid bursa. 
 
7) Preliminary unpublished data: None  
  
  
8) Experimental design and data analysis, including inclusion and exclusion criteria, 
statistical basis for the number of subjects to be enrolled, the statistical plan for analyzing 
at least the primary hypothesis, matrix showing procedure plan for each study visit, data 
safety monitoring plan . 
 
Design 
 
This will be a single center, prospective, single blind, randomized controlled trial of hip, 
glenohumeral joint, peri-tendinous biceps brachii, and subacromial bursa injections comparing 
the efficacy of particulate (triamcinolone, betamethasone) versus non-particulate 
(dexamethasone) corticosteroids.  
 
Participants will be recruited for the study by trained physicians and physician extenders at 
Stanford orthopedic and PM&R clinics only after they have already opted for corticosteroid 
injection as a part of their routine medical care.  The initial decision to pursue steroid injection 
will be based entirely on joint decision making between the patient and their medical provider 
prior to mention of the study.  
 
After consenting, basic demographic data, average numeric pain score (NRS) over the past week, 
and information on other medical interventions tried for their pain (including medication use, 
physical therapy, chiropractic care, and massage) will be collected.  The participant will then be 
randomized to receive either a particulate (triamcinolone or betamethasone) or non-particulate 
(dexamethasone) corticosteroid, both of which are within current standards of care. Ultrasound 
or fluoroscopic guided injection will then be completed using sterile technique as per current 
clinic practice.   

 
After the injection, patients will follow up in clinic or over the phone at 2 weeks, 3 months, and 6 
months and will be asked their average NRS over the past week, functional questionnaires 
appropriate to pertinent body parts (WOMAC, ASES, QDASH), other treatments they have tried 
in the interim, and for any side effects they have experienced. In addition to obtaining outcome 
measures, the treating physicians may order repeat injections, medications, or refer the subject to 
surgery, at their discretion based upon the patient’s pain and functional limitations. Up to a total 
of three injections to the same musculoskeletal structure are allowed during the 6 month study 
period. Any injection into a separate space (i.e. glenohumeral joint followed by subdeltoid bursa) 
will be considered different structures, and follow up for the new anatomical site will begin at 
the time of that injection.  Data collection and follow up on the previous anatomical injection site 
will continue on the same timeline. Data on number and timing of repeat injections, surgeries, 
side effects, and medications will be recorded as part of the study. 
  
  
Data analysis 
Patients receiving injections to the intra-articular hip, glenohumeral joint, peri-tendinous biceps, 
and subdeltoid bursa will be analyzed separately. Depending on normality and cell counts, 
baseline measures between the particulate and non-particulate injection groups will be compared 
using two-sample t-tests or Mann-Whitney U-tests for continuous variables and chi-squared tests 
or Fisher’s exact tests for categorical variables.  
 
Within each joint/structure, a mixed-effects model will be used to compare differences in pain 
(NRS), function (WOMAC, ASES, QDASH), and the number of subsequent injections. These 
models will include adjustments for repeated measures and potential covariates as determined by 
the previous univariate tests. A power analysis determined that a sample size of 50 (25/group) 
will provide at least 80% power to detect 10% differences in pain and 25% differences in 
function between patients receiving particulate and non-particulate corticosteroids in the 
subdeltoid bursa and intra-articular hip, while a sample size of 36 (18/group) achieves the same 
power for patients receiving treatment in the glenohumeral joint, and a sample size of 62 
(31/group) achieves this power in the biceps brachii group.  
 
The time until a repeat injection was administered will be analyzed using a Cox proportional 
hazards survival model and chi-squared tests will be used to analyze repeat injections, repeat 
surgeries, and side effects between groups. All statistical analyses will be completed using a two-
sided level of significance of 0.05.  
 
  
Inclusion Criteria 
-Age greater than or equal to 18 
-Ability to provide informed consent 
-Capable of complying with the outcome instruments used 
-Capable of attending all planned follow up visits 
-Patient is deemed appropriate for intra-articular hip, glenohumeral, peri-tendinous biceps, or 
subdeltoid bursa corticosteroid injection by their treating physician for the treatment of a painful 
musculoskeletal condition 

-Average pain of greater than or equal to 4/10 over the last 7 days 
 
Exclusion Criteria 
-Unclear diagnosis 
-Pregnancy 
-Incarcerated patients 
-Prior corticosteroid injection into the anatomical structure within the past 3 months  
-Prior prosthetic surgery on the joint 
-Any condition that increases injection risk such as bleeding tendencies, uncontrolled diabetes, 
current active infection, or infection requiring antibiotics within the last 7 days 
-Chronic opioid use to control pain 
-Workers compensation and litigation. 
-BMI > 40 
 
  
Data safety monitoring  
Redcap will be used as a secure database in which to compile and capture all data. All data will 
be entered directly to the Redcap database. Data will be de- identified and coded through Redcap 
prior to exportation to spreadsheet form for data analysis. Devices that contain identifiable 
subject information will be password protected and encrypted. Access to the data will be limited 
exclusively to members of the research team until after de-identification. Thereafter, files may be 
shared electronically via encrypted, password protected email.  
 
Participants will be asked to report all adverse events at the time of occurrence to the principal 
investigator, and information on minor side effects will be elicited via phone or appointment at 2 
weeks, 3 months, and 6 months.  As the procedures and medications used in this trial are current 
standard of care, we do not anticipate significant adverse events.  
  
Procedure Plan 
  
Time of Visit 
Questionnaires 
X-Ray or 
Ultrasound 
Baseline 
N/A 
Standard care 
Injection 
Study 
Standard care 
2 weeks (±1w) 
Study 
 
N/A 
3months (±4w) 
Study 
N/A 
6 months (±4w) 
Study 
N/A 
 
  
  
  
 
 
 

9) Significance:  
 
Currently there is no data to support the injection of one type of corticosteroid over another in 
the treatment of many musculoskeletal conditions. We hope that the results of this study will aide 
clinicians in selecting the most effective medication for musculoskeletal injections and resolve 
the clinical equipoise surrounding this question. 
  
10) Key References 
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saline and steroid improves function and reduces pain in patients with painful stiff 
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Daniels EW, Cole D, Jacobs B, Phillips SF. Existing Evidence on Ultrasound-Guided 
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Dawley J, Moeller-Bertram T, Wallace M, Patel P. Intra-arterial injection in the rat brain: 
Evaluation of steroids used for transforaminal epidurals. Spine (Phila Pa 1976). 
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5.  
Derby R, Lee S, Date ES, Lee J, Lee C. Size and Aggregation of Corticosteroids Used for 
Epidural Injections. Pain Med (United States). 2008;9(2):14–7.  
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8.  
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