Clinical trial NCT03913702
Conditions: Subacromial Impingement Subacromial Impingement Syndrome
Keywords: Ketorolac Methylprednisolone Subacromial impingement syndrome
Sponsor: The University of Texas Medical Branch, Galveston
Start date: 2019-09-09; Completion date: 2022-11-02
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The investigators aim to compare subacromial ketorolac (non-steroidal anti-inflammatory drug) versus methylprednisolone (steroid) for the treatment of shoulder impingement syndrome.

Detailed description:
Because of the current conflicting evidence, the lack of long-term follow-up, and the multiple potential benefit benefits to the society, the investigators aim to compare subacromial ketorolac versus methylprednisolone for the treatment of shoulder impingement syndrome. The investigators hypothesize that patients with shoulder impingement treated with a subacromial methylprednisolone versus ketorolac have similar outcomes based on the ASES (American Shoulder and Elbow Surgeon) self-assessment score. The study will be performed at one institution, the University of Texas Medical Branch.

Arms: arm 1: Assigned patients will receive a subacromial injection of ketorolac 60mg (2ml + 8ml lidocaine 1%) arm 2: Assigned patients will receive a subacromial injection of methylprednisolone 80mg (1ml + 9ml lidocaine 1%)
Interventions: intervention 1: Ketorolac Tromethamine intervention 2: Methylprednisolone Acetate
Intervention descriptions: intervention 1: 2ml of injectable Ketorolac (30mg/ml) will be mixed with 8ml of lidocaine HCL (1% without epinephrine) and delivered into the subacromial joint (total of 60mg of active substance in 10ml). intervention 2: 1ml of injectable Methylprednisolone (80mg/ml) will be mixed with 9ml of lidocaine HCL (1% without epinephrine) and delivered into the subacromial joint (total of 80mg of active substance in 10ml)

Protocol documents:
Prot_SAP_001.pdf: 
 
 
                           
Protocol – Version 3 – June 17, 2019 
 
 
Subacromial injection of methylprednisolone versus ketorolac to treat shoulder 
impingement: a multicenter double-blind randomized controlled trial 
 
 
 
 
 
 
Principal Investigators 
Jeremy S. Somerson, MDa 
 
 
Research Coordinator 
Paul J. Weatherby, MDa 
 
Collaborators 
William I. Weiss, MDa 
Robert W. Lindeman, MDa 
Jessica J. Lamphere, NP-Ca 
Randal P. Morris, BSa 
 
Biostatistician 
Daniel C. Jupiter, PhDc 
 
a Department of Orthopaedic Surgery and Rehabilitation, The University of Texas 
Medical Branch, Galveston, Texas, USA  
b School of Medicine, The University of Texas Medical Branch, Galveston, Texas, USA 
c Department of Preventive Medicine and Community Health, The University of Texas 
Medical Branch, Galveston, Texas, USA  
 


Protocol – Version 2 – November 13, 2018 
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Table of Contents 
 
Study Schema 
 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Inclusion/Exclusion Criteria 
4.0 
Enrollment/Randomization 
5.0 
Study Procedures 
6.0 
Study Product Description 
7.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
8.0 
Study Withdrawal/Discontinuation 
9.0 
Statistical Considerations 
10.0 
Ethical Considerations and Privacy/Confidentiality Issues 
11.0 
Record Retention 
12.0 
References 
 
 
 


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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal regulations 
and ICH guidelines. 
 
Site Investigator:* 
 
Signed: 
 
Date: 
 
 
Name     Jeremy S. Somerson 
Title       MD 
 
 
 
* The protocol should be signed by the local investigator who is responsible for the study 
implementation at his/her specific site; i.e., if Investigational New Drug study, the 
individual who signs the Form FDA 1572. 


Protocol – Version 2 – November 13, 2018 
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1.0 
Background 
 
Subacromial impingement syndrome is a commonly encountered shoulder condition that 
consists of a constellation of symptoms, including pain with overhead activities. As the 
condition progresses, the pain may manifest at night, associated or not with progressive 
loss of motion and strength of the shoulder [1-3]. Impingement-related pain is thought to 
result from subacromial bursitis and tendonitis of the supraspinatus due to repetitive 
overhead activities impinging the coracoacromial arch [3, 4]. Many non-operative 
treatments have been advocated for subacromial impingement syndrome, beginning with 
rest, ice, oral non-steroidal anti-inflammatory drugs (NSAIDs), and physical therapy [5, 
6]. If patients fail to improve with conservative therapy, subacromial injections could be 
utilized to treat this condition [2, 7-11]. Although the exact mechanism(s) of corticosteroids 
and NSAIDs is/are not completely understood, it is hypothesized that symptom relief post 
subacromial injections is related to their local anti-inflammatory properties [2, 12]. 
 
While studies comparing subacromial injection of NSAIDs to steroids exist, they are low-
powered or lack long follow-up. Karthikeyan et al. conducted a randomized controlled trial 
in 2010 that compared subacromial injections of 40 mg methylprednisolone versus 20 mg 
of tenoxicam for subacromial impingement [13]. Their outcomes were the Disability of 
Arm, Shoulder, and Hand (DASH) score and the Oxford Shoulder Score (OSS). They 
concluded that corticosteroids are significantly better than tenoxicam for improving 
shoulder function in tendonitis of the rotator cuff, but their follow-up was only six weeks. 
Min et al., on the other hand, conducted a similar randomized controlled trial in 2013 using 
40 mg triamcinolone versus 60 mg ketorolac [3]. Their outcome measures were the visual 
analog (VAS) and the University of California Los Angeles (UCLA) shoulder rating scales. 
They showed greater improvements in the UCLA rating scale in the ketorolac arm, but 
their follow-up was only four weeks. Taheri et al. conducted a randomized controlled trial 
in 2017 to compare subacromial injections of 60 mg ketorolac and 40 mg 
methylprednisolone [14]. Their outcome measures were the VAS and Constant’s score. 
While the results did not show any significant difference between the two therapeutic arms 
at three months’ follow-up, the study included only 40 patients and an a priori power 
analysis was not performed. The lack of long-term follow-up and the inadequate power in 
the aforementioned studies point to the need for further investigation. 
 
If it can be shown that subacromial NSAIDs are superior or equivalent to steroids, the 
benefits to society could be multiple. Bellamy et al. studied the economic impact of using 
ketorolac instead of steroid for the treatment of knee osteoarthritis over a three-year period 
[15]. They found a total potential cost savings of approximately $12,000 if ketorolac was 
used in place of steroids at their institution. Furthermore, the local tissue reaction of 
steroids may be mitigated with the use of ketorolac. Shapiro et al. compared injections of 
methylprednisolone versus ketorolac in a rabbit model [16]. They found that the rabbits 
injected with steroids demonstrated greater peri-tendinous adhesions and cartilage necrosis 
compared to the rabbits injected with ketorolac and normal saline.  
 
2.0 
Rationale and Specific Aims 
 


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Because of the current conflicting evidence, the lack of long-term follow-up, and the 
multiple potential benefits to the society, we aim to compare subacromial ketorolac versus 
steroid for the treatment of shoulder impingement. We hypothesize that patients with 
external shoulder impingement who are treated with a subacromial injection of 80 mg 
methylprednisolone in 1% lidocaine versus 60 mg ketorolac in 1% lidocaine have similar 
outcomes based on the American Shoulder and Elbow Surgeon (ASES) self-assessment 
score (ranging between 0 and 100) at 2, 4, and 12 weeks post-injection. If the follow-up 
could not be performed exactly at 2, 4, or 12 weeks post-injection, investigators will allow 
examination and measurements at ±3 days. The study will be performed in The University 
of Texas Medical Branch (UTMB, coordinating center). This will help us determine the 
efficiency of either therapeutic modality in the management of patients with subacromial 
impingement syndrome. 
 
3.0 
Inclusion/Exclusion Criteria 
 
The center enrolling patients (UTMB) will obtain approval through its own institution 
review board (IRB). The study will be posted on clinicaltrials.gov. The subjects in this 
study will be recruited from the investigators’ private clinics. Prior to enrollment, the 
investigator will obtain informed written consent from the subjects. All of the investigators 
are CITI trained. They will review the consent form with patients and allow sufficient time 
for potential subjects to read the consent form and consider the risks and benefits of 
participation. Investigators will leave the clinic room to allow patients to consult with 
friends and family. If patients decide to defer the decision to enroll, they will be allowed 
to return at a later date. It will be emphasized to patients that they need not participate in 
the study to receive a subacromial injection. If they choose not to participate, they will be 
offered a subacromial injection that consists of the medication that is mutually agreed upon 
between their physician and them. No coercion to participate in the study will take place. 
 
Adults at least 18 years of age seen in clinic with a diagnosis of severe or recalcitrant 
shoulder impingement syndrome and to whom the investigator has offered a subacromial 
injection will be invited to participate.  
 
Subjects meeting any of the exclusion criteria at baseline will be excluded from study 
participation. Exclusion criteria are: allergy/intolerance to steroids or NSAIDs symptoms 
less than one month, pregnancy or breastfeeding, pre-existing asthma, uncontrolled 
psychiatric illness, previous shoulder injection within the past three months, evidence of 
other confounding shoulder pathology on plain radiographs such as calcific tendonitis, 
MRI evidence or history of a full-thickness rotator cuff tear, active comorbidities of the 
ipsilateral extremity such as cervical radiculopathy, moderate to severe glenohumeral 
arthritis, systemic inflammatory conditions, kidney or liver disease, gastrointestinal (GI) 
ulcers, bleeding disorders, pending litigation or work-related claims related to the shoulder, 
previous shoulder surgery on the affected shoulder, evidence of local infection, evidence 
of adhesive capsulitis, and evidence of shoulder instability. 
 
4.0 
Treatment Assignment/Randomization 
 


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The following measures will be taken to ensure double-blinded randomization. Prior to the 
initiation of the study, computer-generated tables will be created in Excel to assign each 
patient a randomization number. This master list will be kept with a statistician and 
research coordinators, who do not have any patient contact. Based on his/her corresponding 
generated number (even or odd), the patient will be assigned to his/her therapeutic arm 
(methylprednisolone and ketorolac, respectively). The statistician will use an equally 
weighted random number generator to create these assignments. Therefore subjects will 
have an equal chance of being assigned to either treatment arm. Separate lists for male and 
female participants will also be generated to ensure equal gender participation. The 
statistician will then prepare an opaque envelope for each subject number. The unique 
subject number will be written on the visible outside surface of each envelope. The 
corresponding treatment arm assignment will be inside the envelope. The statistician will 
seal each envelope individually and send all of the envelopes to the research coordinator 
(Marc El Beaino) prior to patient enrollment. The sealed opaque envelopes will be divided 
equally among the clinics and kept in locked containers in the research coordinator’s office. 
The study staff will not have access to the envelopes. After ensuring that the patient has 
completed the ASES questionnaire (to establish a baseline prior to the injection), the study 
staff will contact Marc El Beaino or Safee Ahmed to provide them with the patient’s first 
and last names as well as the MRN. The research coordinator will open one of the 
sequentially numbered envelopes to assign each patient the corresponding subject number 
(written on the outside of the envelope), and a member of the clinic staff will prepare the 
appropriate injection (see below) for the assigned treatment arm. The syringe will be 
covered with opaque tape prior to being given to the surgeon for administration. The 
injection will take place in a private clinic room in compliance with the Health Insurance 
Portability and Accountability Act (HIPAA) guidelines. The blinded surgeon will 
administer the injection into the subacromial space using standard bony landmarks from 
the posterolateral approach. The clinic staff will file the drug accountability log after 
preparing the injection and they will not disclose the treatment arm assignment to the 
patient nor the provider. This will maintain the blinding for both the patient and research 
surgeons. Patients' subject number will be recorded on their consent form and in their 
electronic medical record. Envelopes will be destroyed at the end of the study by the 
research coordinators. The statistician will unlock the master list only after patient 
enrollment and follow-up are complete, or if mandated by any regulatory body. Blinding 
will also be uncovered in case of a patient developing an adverse event while being 
followed in the trial. 
 
 
5.0 
Study Procedures 
 
Shoulder impingement is a syndrome characterized by shoulder pain that is exacerbated by 
passive and/or active elevation, with positive provocative testing for impingement such as 
Neer and Hawkins tests, and/or the diagnosis of subacromial bursitis based on tenderness 
to palpation of the acromion. Generally, patients who present with shoulder impingement 
will be treated initially with non-invasive measures such as activity modification, ice, 
physical therapy, and a trial of oral NSAIDs. If those measures do not provide adequate 
relief, then patients will be offered a therapeutic subacromial injection. The investigators 
will follow these principles of conservative management except when the patients’ pain is 


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severely limiting their activities of daily living and their ability to work and provide for 
themselves or when patients are having pain at night that interferes with sleep. In those 
situations, a subacromial injection may be offered prior to attempting less invasive 
measures. Ultimately, the decision to offer a subacromial injection will be made in clinic 
by the investigators based on their clinical judgment. All of the investigators are 
fellowship-trained orthopedic surgeons who subspecialize in shoulder diseases. Their 
decision to offer patients a subacromial injection will be independent of whether the 
patients wish to participate in the study. Patients will be given the opportunity to participate 
in the study only after the decision to offer an injection is made by the clinician. Patients 
will not be solicited outside of a regularly scheduled clinic visit to participate in this study. 
 
Investigational Drug Service (IDS) staff will not be directly involved with the handling of 
the study drugs; however, a plan has been documented and agreed upon by both parties 
regarding study drug supply, storage, randomization, preparation, administration, and 
accountability (Study Drug Management Form). Therefore, the clinic staff will maintain 
the blinding of the surgeons, who are licensed by the medical board of Texas to perform 
the injection.  
 
Drugs that will be injected will be dispended to medically-licensed research personnel by 
the clinic staff to be delivered to the treating surgeon. For the methylprednisolone treatment 
arm, the injection will consist of 9 mL of lidocaine HCl (1% without epinephrine) and 1 
mL of methylprednisolone acetate (80 mg/mL). For the ketorolac treatment arm, the 
injection will consist of 8 mL of lidocaine HCl (1% without epinephrine) and 2 mL of 
injectable ketorolac tromethamine (30 mg/mL). The total injection volume in each 
treatment arm will be 10 mL. After the clinic encounter, a blinded member of the research 
staff will call or email the patient to complete the ASES questionnaire at 2, 4, and 12 weeks 
post-injection. If the follow-up could not be performed exactly at 2, 4, or 12 weeks post-
injection, investigators will allow examination and measurements at ±3 days. 
 
 
6.0 
Study Product Description 
 
The following information has all been retrieved from the methylprednisolone acetate and 
the ketorolac tromethamine package inserts. 
Formulation, Packaging, and Labeling 
Ketorolac tromethamine is a member of the NSAIDs. The chemical name for the drug is: 
(±)-5-benzoyl2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, compound with 2-amino-2-
(hydroxymethyl)-1,3-propanediol (1:1). Its structural formula is presented below. 
 


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Ketorolac tromethamine is a racemic mixture of [-]S and [+]R ketorolac tromethamine. It 
is soluble in water. Injectable ketorolac tromethamine is available for intravenous (IV) 
administration as 15 mg in 1 mL and 30 mg in 1 mL in sterile solution. For intramuscular 
(IM) administration, ketorolac tromethamine is available only as 60 mg in 2 mL (30 
mg/mL) in sterile solution. In this case, the latter contains 10% alcohol and 8.70 mg of 
sodium chloride in sterile water. The pH range is 6.9 to 7.9 and is adjusted with sodium 
hydroxide and/or hydrochloric acid. The sterile solutions are clear and slightly yellow in 
color. 
 
Injectable methylprednisolone acetate is an anti-inflammatory glucocorticoid. The 
chemical name for the drug is: pregna-1,4-diene-3,20-dione, 21-(acetyloxy)-11,17-
dihydroxy-6-methyl-,(6α,11ß)-. Its structural formula is presented below. 
 
 
Injectable methylprednisolone acetate is used for intramuscular, intra-articular, soft-tissue 
or intralesional injection. It is available in three strengths: 20 mg/mL, 40 mg/mL, and 80 
mg/mL. In this study, the latter (80 mg/mL) will be used as indicated for large joints in the 
FDA brochure of this medication. Each mL of this preparation contains 80 mg of 
methylprednisolone acetate, 28.2 mg of polyethylene glycol 3350, 1.88 mg of polysorbate 
80, 6.59 mg of monobasic sodium phosphate, 1.37 mg of dibasic sodium phosphate, and 
8.88 mg of benzyl alcohol (as a preservative). The pH range is 3.5 to 7.0 and is adjusted 
with sodium hydroxide and/or hydrochloric acid. 
Product Storage and Stability 
 
Injectable ketorolac tromethamine must be stored between 15oC (59oF) and 30oC (86oF). 
Injectable methylprednisolone acetate must be stored between 20oC (68oF) and 25oC 
(77oF). They both should be kept at controlled room temperature while being protected 
from light. 
 


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Dosage, Preparation and Administration of Study Intervention/Investigational 
Product 
 
The sealed envelopes that contain each patient’s therapeutic arm assignment will be equally 
distributed to the study staff prior to the enrollment. They will be kept in locked containers 
in each investigator’s clinic. Only study staff will have access to the envelopes. After 
patient enrollment and informed consent completion, the study staff will open one of the 
sequentially numbered envelopes and the patient assigned the corresponding subject 
number written on the outside of the envelope. The study staff will prepare the appropriate 
injection (see below) for the assigned treatment arm. The syringe will be covered with 
opaque tape prior to being given to the surgeon for administration. The injection will take 
place in a private clinic room in compliance with HIPAA guidelines. The surgeon will 
administer the injection into the subacromial space using standard bony landmarks from 
the posterolateral approach. After the injection is given by the research MD, the clinic staff 
will then dispose of the syringe without  disclosing the treatment arm assignment to the 
patient nor the provider. Patients' subject number will be recorded on their consent form 
and in their electronic medical record. The statistician will unlock the master list only after 
patient enrollment and follow-up are complete, or if mandated by any regulatory bodies. 
Blinding will also be uncovered in case of a patient developing an adverse event while 
being followed in the trial. 
 
Both drugs will be intra-articularly delivered through a single subacromial injection within 
30 to 45 minutes. For the methylprednisolone treatment arm, the injection will consist of 9 
mL of lidocaine HCl (1% without epinephrine) and 1 mL of methylprednisolone acetate 
(80 mg/mL). For the ketorolac treatment arm, the injection will consist of 8 mL of lidocaine 
HCl (1% without epinephrine) and 2 mL of injectable ketorolac tromethamine (30 mg/mL). 
The total injection volume in each treatment arm will be 10 mL. These drugs are not 
suitable for multi-dose use. Following administration of the desired dose, any remaining 
suspension will be returned to IDS. 
 
Modification of Study Intervention/Investigational Product for a Participant 
 
The study consists of a subacromial single dose injection of either methylprednisolone 
acetate (80 mg) or ketorolac tromethamine (60 mg). Patients will then be followed-up for 
12 weeks and ASES data will be recorded at 2, 4, and 12 weeks post-injection. If the follow-
up could not be performed exactly at 2, 4, or 12 weeks post-injection, investigators will 
allow examination and measurements at ±3 days. No additional injections will be needed, 
and therefore, no dose modification will be required. Patients meeting any of the exclusion 
criteria will not be initially enrolled in the study. 
 
Accountability Procedures for the Study Intervention/Investigational Product(s) 
 
Drugs that will be injected will be prepared by clinic staff and will then be delivered to the 
treating surgeon. The clinic staff will be responsible of maintaining the drug accountability 
at each enrollment site.  There will be an inventory accountability log kept by the clinic 
staff at each location. For the methylprednisolone treatment arm, the injection will consist 


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of 9 mL of lidocaine HCl (1% without epinephrine) and 1 mL of methylprednisolone 
acetate (80 mg/mL). For the ketorolac treatment arm, the injection will consist of 8 mL of 
lidocaine HCl (1% without epinephrine) and 2 mL of injectable ketorolac tromethamine 
(30 mg/mL). The total injection volume in each treatment arm will be 10 mL. Treatment 
will be administered once and patients will be evaluated afterwards at 2, 4, and 12 weeks 
post-injection. Injectable drugs administered in this study are not suitable for multi-dose 
use.  
 
Assessment of Subject Compliance with Study Intervention/Investigational Product  
 
The responsible investigator will administer the treatment in a double-blinded fashion to 
the patient, who will be examined and followed at 2, 4, and 12 weeks by the same 
investigator. At enrollment and at 12 weeks, the follow-ups will be performed in the clinic, 
whereas at 2 and 4 weeks, this will be performed by phone contact/email. The ASES 
questionnaire will be completed prior to the injection, and then at those time points (2, 4, 
and 12 weeks). If the follow-up could not be performed exactly at 2, 4, or 12 weeks post-
injection, investigators will allow examination and measurements at ±3 days. 
 
Risks 
 
The risks associated with this study include the risks of randomization, loss of 
confidentiality, and the burden associated with answering a questionnaire. Also, 
administration of methylprednisolone or ketorolac into the subacromial space is associated 
with certain risks; however, eligible subjects of this study would receive one of these 
medications regardless of their participation in this research. The ASES questionnaire at 
follow up will take approximately four minutes to fill out at each of the three follow-up 
time points (2, 4, and 12 weeks post-injection). The risk of loss of confidentiality will be 
minimized by storing all protected health information in locked filing cabinets in the 
orthopedic offices of UTMB, accessible only to those study staff that have a need to access. 
All digital health information will be de-identified with research-specific subject numbers 
and it will be stored on password protected and encrypted computers on the secure 
institution’ network. Only serious and unanticipated problems associated with the 
injectable product will be reported to the IRB. 
 
Minor side effects of steroid injections include post-injection flare, uterine bleeding, and 
facial erythema; major toxicities include Cushing syndrome and radiologic deterioration of 
joints and osteonecrosis [12, 17]. Local adverse effect of steroid injection includes 
permanent skin depigmentation, infection, tendon rupture, and fat necrosis or calcification. 
Systemic side effects of ketorolac include increased risk for cardiovascular thrombotic 
events including myocardial infarction and stroke, GI bleeding, ulceration and perforation, 
renal failure, and risk of bleeding. 
 
Benefits 
 
There are no foreseeable benefits to the subjects for participation in this study. If ketorolac 
is shown to be equivalent or superior to methylprednisolone, then the potential benefits to 


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the society are multiple. These include health care cost savings, standardization of care, 
and the furthering of orthopedic knowledge. 
 
Concomitant Medications/Treatments 
 
The information below report mainly drug interactions with other medications on the 
package insert of the agent of interest. This also included the current literature pertaining 
to each medication. In either arm, the drug is delivered intra-articularly (locally), which 
mitigates its systemic absorption and therefore its potential side effects.  
 
Modern evidence do not indicate a significant interaction between ketorolac tromethamine 
and warfarin, heparin, aspirin, digoxin, diuretics, probenecid, lithium, methotrexate, ACE 
inhibitors, and angiotensin II receptor antagonists. Sporadic cases of epilepsy and 
hallucinations have been reported when combining ketorolac with antiepileptic or 
psychoactive drugs, respectively. When administered with SSRI, an increased risk of 
bleeding was noted. However, all of these adverse events occurred with IV (systemic) 
rather than intra-articular (local) administration of the drug. No teratogenicity or 
tumorigenicity were reported to date. 
 
Recent evidence indicates an interaction between corticosteroids and either antifungals or 
antibiotics. However, patients with any sign or symptom of infection will be screened, and 
therefore excluded, prior to the injection in case an infection is suspected. Corticosteroids 
have been shown to interact with anticoagulants. Nonetheless, bleeding problems are also 
screened for prior to the injection, and if present, patients will be excluded from the trial. 
Corticosteroids may also intervene with hepatic enzyme inducers/inhibitors, and patients 
with liver diseases will be excluded. No adequate studies have been conducted to evaluate 
the tumorigenic effect of corticosteroids. These agents may exhibit teratogenic effects, 
which is the reason why pregnant women will be take part of the study. 
 
7.0 
Adverse Events or Unanticipated Problems involving Risk to Participants or 
Others 
 
Most of these contra-indications are retrieved from the medications package inserts. Due 
to the randomization and blinding design of the study, a contra-indication to either drug 
(methylprednisolone acetate or ketorolac tromethamine) is considered an absolute contra-
indication for the patient to be enrolled in the study. Subjects meeting any of these 
conditions at baseline will be excluded from study participation. These conditions include: 
allergy/intolerance to steroids or NSAIDs symptoms less than one month, pregnancy or 
breastfeeding, pre-existing asthma, psychiatric illness, previous shoulder injection within 
the past three months, evidence of other confounding shoulder pathology on plain 
radiographs such as calcific tendonitis, MRI evidence or history of rotator cuff tear, active 
comorbidities of the ipsilateral extremity such as lateral epicondylitis and cervical 
radiculopathy, moderate to severe glenohumeral arthritis, systemic inflammatory 
conditions, kidney or liver disease, gastrointestinal (GI) ulcers, bleeding disorders, pending 
litigation or work-related claims related to the shoulder, previous shoulder surgery on the 


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affected shoulder, evidence of local infection, evidence of adhesive capsulitis, evidence of 
shoulder instability, and bilateral shoulder pain. 
 
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) defines an adverse event (AE) as any untoward 
medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product regardless of its causal relationship to the study treatment. An AE 
can therefore be any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of medicinal product. The occurrence of an AE may come to the 
attention of study personnel during study visits and interviews of a study recipient 
presenting for medical care, or upon review by a study monitor.  
 
All AEs including local and systemic reactions not meeting the criteria for “serious adverse 
events” should be captured on the appropriate case report form. Information to be collected 
includes event description, time of onset, clinician’s assessment of severity, relationship to 
study product (assessed only by those with the training and authority to make a diagnosis, 
which would include MD, PA, Nurse Practitioner, DO, or DDS), and time of 
resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution.  
 
Any medical condition that is present at the time that the patient is screened should be 
considered as baseline and not reported as an AE. However, if it deteriorates at any time 
during the study, it should be recorded as an AE. 
 
All AEs must be graded for severity and relationship to study product. In such cases, the 
statistician will uncovering the patient blinding and randomization process to reveal the 
medication that was administered to the patient. 
 
Severity of Event 
 
All AEs will be assessed by the clinician using a protocol defined grading system. For 
events not included in the protocol defined grading system, than the following guidelines 
will be used to quantify intensity.  
Mild – Events require minimal or no treatment and do not interfere with the patient’s daily 
activities; Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures; Moderate – Events may cause some interference with functioning; 
Severe – Events interrupt a patient’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually incapacitating; and Life threatening 
– Any adverse drug experience that places the patient or subject, in the view of the 
investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction that had it occurred in a more severe form, might have caused death. 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. Adverse events 
characterized as intermittent require documentation of onset and duration of each episode. 
 


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Relationship to Study Products 
 
The clinician’s assessment of an AE's relationship to test article is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE, the event should 
be reported. All AEs must have their relationship to study product assessed using the terms: 
associated or not associated. In a clinical trial, the study product must always be suspect. 
To help assess, the following guidelines are used: Associated – Event temporally related 
to the administration of the study product and no other etiology explains the event; and Not 
Associated – Event temporally independent of study product and/or the event appears to 
be explained by another etiology. 
 
Serious Adverse Event (SAE) 
 
An SAE is defined as an AE that meets one of the following conditions: (1) Death during 
the period of protocol defined surveillance; (2) Life threatening event (defined as a subject 
at immediate risk of death at the time of the event); (3) An event requiring inpatient 
hospitalization or prolongation of existing hospitalization during the period of protocol 
defined surveillance, results in congenital anomaly or birth defect, results in a persistent or 
significant disability/incapacity; or (4) Any other important medical event that may not 
result in death, be life threatening, or require hospitalization, may be considered a serious 
adverse experience when, based upon appropriate medical judgment, the event may 
jeopardize the subject and may require medical or surgical intervention to prevent one of 
the outcomes listed above.  
 
All SAEs will be recorded on the appropriate SAE case report form, followed through 
resolution by a study clinician, and reviewed and evaluated by a study clinician. 
Reporting Procedures for Serious Adverse Events 
 
Any AE considered serious by the principal investigator or co-investigators or which meets 
the aforementioned criteria must be submitted on the SAE form to the IRB in accordance 
with IRB policies and procedures. 
 
In addition, SAE’s should be de-identified and anonymously reported to all investigators 
to emphasize on the possibility of other patients exhibiting a similar problem. The 
investigators are responsible of transmitting this information to their respective IRBs, who 
will then report the events that are serious, unexpected, and associated with the study 
product(s) to the Food and Drug Administration (FDA) within the required timelines as 
specified in 21 CFR Part 312.32: fatal and life-threatening events within 7 calendar days 
(by phone or fax) and all other SAEs in writing within 15 calendar days. All serious events 
designed as “not associated” to study product(s), will be reported to the FDA at least 
annually in a summary format. 
 
The study clinician will complete a sponsor provided Serious Adverse Event Form within 
the following timelines:  (1) All deaths and immediately life-threatening events, whether 


Protocol – Version 2 – November 13, 2018 
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related or unrelated, will be recorded on the Serious Adverse Event Form and sent by fax 
within 24 hours of site awareness; and (2) Serious adverse events other than death and 
immediately life-threatening events, regardless of relationship, will be reported via fax by 
the site within 72 hours of becoming aware of the event.  
 
All SAEs will be followed until satisfactory resolution or until the principal investigator or 
co-investigator deems the event to be chronic or the patient to be stable.  
 
8.0 
Study Withdrawal/Discontinuation 
 
Reasons for Withdrawal 
 
A study subject will be discontinued from participation in the study if any of the following 
occur: (1) Unacceptable AE; (2) Development of any exclusion criteria; and (3) Subject 
withdrawals consent to continue in the research for any reason. The development of an 
inter-current illness, or other medical condition or situation would not risk the continued 
participation in the study since the injection occurs once, after the patient has been entirely 
screened based upon the inclusion and exclusion criteria.  
 
Handling of Withdrawals 
 
Subjects who withdraw from the study will still be followed-up since they are receiving 
the same therapeutic modality whether they were enrolled in the trial or not. Safety data on 
any subject discontinued because of an AE or SAE will be collected and reported to the 
investigators, who will then communicate it to their corresponding IRBs. If voluntary 
withdrawal occurs, the subject should be asked to continue scheduled evaluations, 
complete an end-of-study evaluation, and be given appropriate care under medical 
supervision until the symptoms of any AE resolve or the subject’s condition becomes 
stable.  
 
Termination of Study  
The study will be terminated if: (1) the patients target number has been achieved and a 
complete follow-up has been accomplished; or (2) similar SAE patterns occur (5 consistent 
events in patients receiving the same therapy). In the first case, statistical analysis will be 
performed, whereas in the second, recruitment will be halted and AEs/SAEs reported to all 
investigators, IRBs, and if unexpected and deemed associated with the drug injected, to the 
FDA (via the IRB). 
 
9.0 
Statistical Considerations 
 
This study is a non-inferiority multicenter randomized controlled double-blinded trial that 
evaluates the efficacy of injectable methylprednisolone acetate monotherapy and ketorolac 
monotherapy in the treatment of patients with subacromial impingement syndrome in the 
outpatient setting. Therapeutic arms consist of two groups (groups 1 and 2 receiving 
injectable methylprednisolone acetate and ketorolac, respectively). Patients will be 
evaluated and compared based on the ASES self-assessment score (ranging between 0 and 


Protocol – Version 2 – November 13, 2018 
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100). Our main outcome is ASES score at the 12-week time-point, with details of analysis 
provided in the next paragraph. We will also, as exploratory analysis, compare the 
functional outcome at 2 and 4 weeks post-injection. We will report summary statistics 
containing means and standard deviations of ASES scores for each treatment arm at each 
time point. We will determine whether there is non-inferiority of ketorolac at each time 
point. 
 
Based on historical data (at 12 weeks post injection), the mean ASES score in the control 
(steroid) group is expected to be about 68.7, and the standard deviation about 12.3 [18]. 
The ASES patient self-assessment is a validated questionnaire that can quantify pain and 
decreased function of the affected shoulder, and it is usually filled out by patients as part 
of routine care for shoulder pain [19, 20]. Based on a review of the literature, the minimum 
clinically relevant effect size was determined to be ranged between 12 and 17 [21]. We 
therefore chose to use the lower value as reference. We calculated the minimum sample 
size (n) that would be required in order to ensure that the study has an 80% power with an 
enrollment ratio of 1, using the following formula:  
 
2n ൌ 4൫𝑧ଵି𝛼൅𝑧ଵିఉ൯
ଶ𝜎ଶ 
Δଶ
ൌ 4ሺ1.64 ൅0.84ሻଶ. 12.32
12ଶ
ൌ25.8 ൎ26 
 
In this formula, Δ represents the absolute difference between the means (μ) of groups 1 and 
2 (Δ=|μ2 – μ1|); σ, the variance of the mean; n, the sample size per arm; α, the probability 
of type 1 error (0.05); β, the probability of type II error (0.2); and z, the critical z value for 
a given α or β. To this end, 13 individuals per arm (26 in total) should have been enrolled 
and completed the trial. Assuming that 20% of patients will be lost to follow-up [3], we 
will attempt to enroll 26/0.8 = 33 patients. For this end, we would aim at including a total 
of 40 patients in the study, which correspond to 20 patients per therapeutic arm. We will 
also assess whether there are differences in baseline scores between the 2 groups. In the 
case that the ASES scores differ, we will control for baseline value for each patient by 
including it as a covariate in a linear regression analysis, with covariates being baseline 
value and treatment group.  
 
10.0 
Ethics and the Protection of Human Subjects 
The investigator will ensure that this study is conducted in full conformity with the 
principles set forth in The Belmont Report: Ethical Principles and Guidelines for the 
Protection of Human Subjects of Research of the US National Commission for the 
Protection of Human Subjects of Biomedical and Behavioral Research (April 18, 1979) 
and codified in 45 CFR Part 46 and/or the ICH E6; 62 Federal Regulations 25691 (1997).   
The investigator must provide for the review and approval of this protocol and the 
associated informed consent documents and recruitment material by an appropriate IRB 
registered with the OHRP. Any amendments to the protocol or consent materials must also 
be approved before they are placed into use. In the United States, only institutions holding 
a current US Federal-wide Assurance issued by OHRP may participate (UTMB). 


Protocol – Version 2 – November 13, 2018 
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Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continuing throughout the individual’s study participation. 
Extensive discussion of risks and possible benefits of this therapy will be provided to the 
subjects and their families. Consent forms describing in detail the study 
interventions/products, study procedures, and risks are given to the subject and written 
documentation of informed consent is required prior to starting intervention/administering 
study product. Consent forms will be IRB-approved and the subject will be asked to read 
and review the document. Upon reviewing the document, the investigator will explain the 
research study to the subject and answer any questions that may arise. The subjects will 
sign the informed consent document prior to any procedures being done specifically for the 
study. The subjects should have the opportunity to discuss the study with their surrogates 
or think about it prior to agreeing to participate. The subjects may withdraw consent at any 
time throughout the course of the trial. A copy of the informed consent document will be 
given to the subjects for their records. The rights and welfare of the subjects will be 
protected by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study. 
 
Privacy/Confidentiality Issues 
 
A confidentiality breach is a risk associated with chart review research. To this end, only 
personnel from UTMB designated by the Principal Investigator(s) will have access to study 
records. These personnel will be fully trained to maintain confidential nature of patient 
health information. Each research member will have taken the institutional human subjects 
protection and confidentiality training courses. Patient information and relevant data will 
be stored on password-protected institutional computers behind the institution firewall. 
Data will not be transferred to laptop computers that are removed from the institution. 
Paper records will be stored in locked files inside a locked office. External storage, if used, 
will be password-protected and encrypted. Study data will not be shared with any 
individual or entity that are not involved in the study. These data will be used only for 
research purposes and for this research study. Patients will be reassured that no personal 
identifiable or identity information will be published once the results of the study are available. 
 
In accordance with the FDA Amendment Act of 2007 (FDAAA) and The International 
Committee of Medical Journal Editors (ICMJE) member journals trials-registration policy 
as a condition for publication, this study will be registered in the public trials registry 
ClinicalTrials.gov, which is sponsored by the National Library of Medicine.  Results will 
be published to clinicalTrial.gov when available but will not identify individual subjects. 
 
11.0 
Record Retention 
 
Study data will not be shared with any individual or entity that are not involved in the 
study. These data will be used only for research purposes and for this research study. Study 
data and paper records will be destroyed within 5 years after publication of the findings. 
 
 
12.0 
References 


Protocol – Version 2 – November 13, 2018 
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3. 
Min, K.S., et al., A double-blind randomized controlled trial comparing the effects 
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4. 
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5. 
van der Windt, D.A., et al., The efficacy of non-steroidal anti-inflammatory drugs 
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injections for shoulder and elbow tendonitis: a meta-analysis of randomised 
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Cole, B.J. and H.R. Schumacher, Jr., Injectable corticosteroids in modern practice. 
J Am Acad Orthop Surg, 2005. 13(1): p. 37-46. 
13. 
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subacromial injection of tenoxicam or methylprednisolone in patients with 
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Bellamy, J.L., B.J. Goff, and S.A. Sayeed, Economic Impact of Ketorolac vs 
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Shapiro, P.S., et al., The effect of local corticosteroid or ketorolac exposure on 
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local anesthetic preparations: a review for radiologists. Radiology, 2009. 252(3): 
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18. 
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