Clinical trial NCT03479502
Conditions: Adhesive Capsulitis Adhesive Capsulitis of Unspecified Shoulder Frozen Shoulder
Sponsor: Vanderbilt University Medical Center
Start date: 2018-03-05; Completion date: 2022-02-08
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
We will recruit a total of 40 patients from the Vanderbilt Sports Medicine Clinics who have been diagnosed with adhesive capsulitis and have not undergone any previous treatment. The 40 patients will be randomized, with 20 in the control group of 3 intra-articular injections of 40mg Methylprednisolone spaced every two weeks, and 20 in the experimental group of 3 intra-articular injection of 50mg doxycycline spaced every two weeks. Both groups will begin a standardized physical therapy program within a pain-free range of motion 4 weeks after the initiation of treatment. We will prospectively follow patients for one year, with follow-up at 6 weeks, 12 weeks, 6 months, and 12 months after the initiation of treatment.

Outcomes will be measured using the American Shoulder and Elbow Score (ASES) and objective measurements of shoulder range of motion, which will be collected by the treating physician. Both the patients and physicians participating in the study will be blinded.

Detailed description:
Adhesive capsulitis, also known as frozen shoulder, is a common condition of the shoulder joint affecting 2-5% of the adult population and characterized by progressive, painful loss of both passive and active range of motion of shoulder \[1,2\]. Individuals affected by this condition find it increasingly difficult to perform activities of daily living that require overhead movement or rotation of the affected shoulder. The natural history of frozen shoulder follows a predictable progression of symptoms, lasting from 9-24 months before complete resolution, and results in significant loss of productivity and quality of life for those affected \[3\]. Despite the significant number of patients affected by adhesive capsulitis and the extensive literature focused on the progression and natural history of the condition, the true underlying etiology remains poorly understood. In light of this poor understanding of the condition, it is not surprising that a number of conservative and invasive modalities exist as accepted treatments. These include non-steroidal anti-inflammatory drugs (NSAIDS), oral steroids, intra-articular steroid injections, Physical Therapy (PT), and benign neglect as well as more invasive treatments such as hydroxylation, manipulation under anesthesia, and arthroscopic capsular release \[2\]. These treatments have all be shown to have short-term benefit in pain relief, but none have proven to be superior nor alter the long-term natural history of adhesive capsulitis.

Over the past decade, however, there has been a growing body of literature suggesting that Propionibacterium acnes infection may play a significant role in a variety of pathological conditions affecting the native shoulder, most notably frozen shoulder \[4,5\]. Our goal is to employ a treatment strategy focused on eradicating P acnes infection as a conservative treatment of adhesive capsulitis. Through this project, we aim to complete a prospective randomized pilot study to examine the hypothesis that administration of intra-articular antibiotics effective against P acnes will prove to be a superior treatment of adhesive capsulitis as compared to current gold standard of intraarticular steroid injection.

Arms: arm 1: Patients meeting the inclusion criteria will be randomized into either the control group of intra-articular injection of 40mg Methylprednisolone once every 2 two weeks for 4 weeks (day 1, week 2, week 4) with 20 patients in each group. Injections will be administered by the treating physician. arm 2: Patients meeting the inclusion criteria will be randomized or the experimental group of intraarticular injection of 50 mg doxycycline once every 2 two weeks for 4 weeks (day 1, week 2, week 4), with 20 patients in each group. Injections will be administered by the treating physician.
Interventions: intervention 1: Methylprednisolone Injectable Product intervention 2: Doxycycline Injection
Intervention descriptions: intervention 1: 3 intra-articular injections of Methylprednisolone Injectable Product spaced every two weeks intervention 2: 3 intra-articular injections of Doxycycline Injection spaced every two weeks

Protocol documents:
Prot_SAP_000.pdf: 
Intra-articular doxycylcine: A Novel Treatment of Adhesive Capsulitis 
NCT03479502 
Date:  08January 2018 
Version 2 
Nick Dantzker, MD 
Vanderbilt University Medical Center 
Department of Orthopaedic Surgery and Sports Medicine 
John Edward Kuhn, MD 
Vanderbilt University Medical Center 
Department of Orthopaedic Surgery and Sports Medicine 


                       
  Principal Investigator (Last, First, Middle) Dantzker, Nicholas James 
 
 
 
2 
RESEARCH PLAN 
 
Specific Aims: 
 
Adhesive capsulitis, also known as frozen shoulder, is a common condition of the shoulder joint affecting 2-
5% of the adult population, and characterized by progressive, painful loss of both passive and active range 
of motion of shoulder1, 2. Individuals affected by this condition find it increasingly difficult to perform activities 
of daily living that require overhead movement or rotation of the affected shoulder. The natural history of 
frozen shoulder follows a predictable progression of symptoms, lasting from 9-24 months before complete 
resolution and resulting in significant loss of productivity and quality of life for those affected3. Despite the 
significant number of patients affected by adhesive capsulitis and the extensive literature focused on the 
progression and natural history of the condition, the true underlying etiology remains poorly understood. In 
light of this poor understanding of the condition, it is not surprising that a number of conservative and 
invasive modalities exist as accepted treatments. These include NSAIDS, oral steroids, intra-articular steroid 
injections, PT, and benign neglect as well as more invasive treatments such as hyrdodilation, manipulation 
under anesthesia, and arthroscopic capsular release2. These treatments have all be shown to have short-
term benefit in pain relief, but none have proven to be superior nor alter the long-term natural history of 
adhesive capsulitis. 
Over the past decade, however, there has been a growing body of literature suggesting that 
Propionibacterium acnes infection may play a significant role in a variety of pathological conditions affecting 
the native shoulder, most notably frozen shoulder4, 5. Our goal is to employ a treatment strategy focused on 
eradicating P acnes infection as a conservative treatment of adhesive capsulitis. Through this proposal, 
we aim to complete a prospective randomized trial to examine the hypothesis that administration of 
intra-articular antibiotics effective against P acnes will prove to be a superior treatment of adhesive 
capsulitis as compared to current gold standard of intraarticular steroid injection.  
Specific Aim 1: Determine if intra-articular doxycycline is superior to intraarticular corticosteroid in 
the treatment of adhesive capsulitis.  
We hypothesize that intra-articular doxycycline injection will be a more effective treatment of adhesive 
capsulitis than the current gold standard of intraarticular steroid injection. Methods: We will recruit a total of 
40 patients from the Vanderbilt Sports Medicine Clinics who have been diagnosed with adhesive capsulitis 
and have not undergone any previous treatment. The 40 patients will be randomized, with 20 in the control 
group of 3 intra-articular injections of 40mg Methylprednisolone spaced every two weeks, and 20 in the 
experimental group of 3 intra-articular injection of 50mg doxycycline spaced every two weeks.Both groups 
will begin a standardized physical therapy program within a pain-free range of motion 4 weeks after the 
initiation of treatment. We will prospectively follow patients for one year, with follow-up at 6 weeks, 12 
weeks, 6 months, and 12 months after the initiation of treatment. Outcomes will be measured using the 
American Shoulder and Elbow Score (ASES), which will be administered by the treating physician. Both the 
patients and physicians participating in the study will be blinded. Anticipated Outcome: We anticipate that 
patients treated with intra-articular doxycycline will have significantly higher ASES scores at each time point 
of follow-up as compared to patients treated with intra-articular corticosteroid injections. 
The proposed study has the potential to make a significant and long-term impact on not only the treatment 
of adhesive capsulitis, but on the treatment of wide array of destructive joint disease. Over the past decade, 
there has been a growing body of literature suggesting a potential infectious etiology in an array of articular 
pathologies. Although classically thought to be the result of genetics and biomechanical forces, there is 
growing evidence that many pathological conditions, including osteoarthritis, degenerative disc disease, 
and adhesive capsulitis, may have an infectious origin4-6. In recent literature, Propionibacterium acnes has 
been identified as the potential infective pathogen underlying these conditions. This project could not only 
add significant evidence to support the role of P acnes in native joint dysfunction, but also introduce a 
potential novel treatment for these conditions, spurring new research opportunities across orthopaedic 
specialties. 
 
 


                       
  Principal Investigator (Last, First, Middle) Dantzker, Nicholas James 
 
 
 
3 
Research Strategy 
Significance: Adhesive capsulitis is a common condition of the shoulder joint affecting 2-5% of the adult 
population1. For shoulder experts, sports medicine specialists, or general orthopaedists, adhesive capsulitis 
is a frequent diagnosis for which patients seek care. The condition often remains symptomatic for over a 
year despite treatment and results in significant morbidity and loss of function for those affected2 Despite the 
significant number of patients affected by adhesive capsulitis and the extensive literature focused on the 
natural history and treatment of the condition, the true etiology remains poorly understood and no currently 
accepted treatment has proven to alter its natural history.   
Over the past decade, however, there has been a growing body of literature suggesting that 
Propionibacterium acnes infection may play a significant role in a variety of pathological conditions of the 
shoulder4, 5. P acnes is a gram-positive anaerobic bacillus that is closely associated with sebum-producing 
hair follicles and has been shown to preferentially colonize the shoulder and upper back7.  Much of this 
literature has focused on the role of P acnes in post-operative infections, especially PJI after shoulder 
replacement and several authors have reported it to be the most common infecting organism after rotator 
cuff repair8-10. Recently and most significantly, however, there has been emerging evidence that P acnes 
may play a role in other conditions affecting the native shoulder, most notably osteoarthritis and adhesive 
capsulitis4, 5. Levy et al found that joint fluid cultures were positive for P acnes in 23 of 55 patients 
undergoing primary shoulder joint replacement for osteoarthritis or cuff arthropathy and who did not have 
previous shoulder surgery of any kind5. Schneeberger et al reviewed 7 patients who initially presenting with 
diffuse, non-localized shoulder pain and were found to have undiagnosed low-grade infections at the time of 
surgery11. None of these patients had ever undergone shoulder surgery. Of note, 3 of these 7 patients were 
had a pre-operative diagnosis of adhesive capsulitis and P acnes was found to be the infective organism in 
5 of the 7 patients. Most relevant to the discussion of adhesive capsulitis, Bunker et al cultured synovial 
tissue from the shoulders of 10 consecutive patients with adhesive capsulitis undergoing arthroscopic 
release and found that 8 of the 10 patients had positive cultures, 6 of which grew P acnes4. This emerging 
research suggests that indolent P acnes infection could be the underlying cause of adhesive capsulitis. 
To date, there have been no studies exploring whether empiric treatment of adhesive capsulitis with 
antibiotics effective against P acnes will lessen either the duration or severity of symptoms as compared to 
current treatment modalities.  This project could not only add significant evidence to support the role of P 
acnes in adhesive capsulitis, but also introduce the first treatment modality that has potential to alter the 
natural history of the condition. 
Innovation: There is a wide variety of currently accepted conservative and surgical options for the 
treatment of adhesive capsulitis. Unfortunately, none of these treatment options have been shown to 
shorten or alter the long-term natural history of the condition. Although some of these treatments are 
effective at reducing acute pain, patients must endure a prolonged course of pain, stiffness, and eventual 
resolution of their symptoms over the course of 12-24 months1. The lack of effective interventions for 
adhesive capsulitis can largely be explained by the illusive etiology underlying the condition.  Over the past 
decade, however, there has been mounting evidence suggesting that P acnes infection of the shoulder joint 
may play a role in the onset of adhesive capsulitis4-6. This project could not only provide further evidence of 
role of P acnes in adhesive capsulitis, but more importantly introduce a novel treatment for the condition that 
has the potential to shorten the duration of symptoms.  
Approach:  
Patient Selection: We will recruit a total of 40 patients from the Vanderbilt Sports Medicine Clinics who have 
a diagnosis of idiopathic stage II adhesive capsulitis of the shoulder, as determined by treating physician. 
Inclusion criteria will be 18 years of age and older, allergy to Doxycycline or Methylprednisolone, pregnancy, 
diagnosis of stage II adhesive capsulitis as determined by clinical examination of the treating physician, and 
absence of abnormal findings on X-ray. Exclusion criteria will be diagnosis. Inflammatory arthritis or 
diabetes, secondary adhesive capsulitis (history of significant trauma, RTC injury, stroke), evidence of 
arthritis on x-ray, current infectious disease, and any previous treatment for the for adhesive capsulitis of the 
affected shoulder. 
 


                       
  Principal Investigator (Last, First, Middle) Dantzker, Nicholas James 
 
 
 
4 
Materials and Methods: Patients meeting the inclusion criteria will be randomized into either the control 
group of 3 intra-articular injections of 40mg Methylprednisolone spaced every two weeks or the 
experimental group of 3 intra-articular injection of 50mg doxycycline spaced every two weeks, with 20 
patients in each group. Female participants will have a urine pregnancy test done prior to the first 
injections. Injections will be administered by the treating physician. Both groups will begin a standardized 
physical therapy program within a pain-free range of motion 4 weeks after the initiation of treatment. Both 
the patients and physicians participating in the study will be blinded to the treatment received. The 
Vanderbilt Investigational Pharmacy will provide the doxycycline and the steroid solutions and will be in 
charge of patient randomization. 
 
Doxycycline was select as the as the experimental intervention for this study as it is effective against P 
acnes and has been shown to be protective against joint damage in both in vitro and in vivo models12-16. 
Moreover, tetracylines have been shown to be safe and effective for intra-articular use in the treatment of 
hemophilic arthropathy in humans and in multiple animal models17. The decision to use doxycycline 50mg 
was based on the general acceptance of using 50% of the standard systemic dose for intraarticular 
injections of antibiotics and the known stability of the antibiotic at a concentration of 10mg/ml18. This dosage 
will provide intraarticular levels of doxycycline well above the typical minimum inhibitory concentration (MIC) 
for doxycycline-susceptible P. acnes.  
Data and Safety:  
  
An independent physician (Warne Fitch, MD) at VUMC will serve as the data safety monitor. The site will 
have monthly study meetings with the KSP to discuss number of eligible patients seen during the previous 
month, how many of them were approached for participation and how many of them consented or refused to 
participate. Protocol deviations and adverse events will be reviewed. The accumulative findings will be 
reported on an annual basis to the DSM. 
 
All adverse events will be recorded and reported upon finding them. All serious adverse events will be 
reported to the Data Safety Monitor (DSM) within 48 hours of identification. The DSM will then review them 
with the PI within 72 hours and will notify the VUMC IRB Department within 10 business days.  
 
Formal DSM reviews and reports will be conducted annually. 
 
Data Collection: Patients will be followed prospectively for one year, with follow-up at 6 weeks, 12 weeks, 6 
months,, and 12 months after the initiation of treatment. Outcomes will be measured using the American 
Shoulder and Elbow Score (ASES), which will be administered by the treating physician at each follow-up 
visit. The ASES questionnaire was developed to provide a standardized method for evaluating shoulder 
function and has been validated in patients with any array of shoulder pathologies19-23.    
 
Data Analysis: ASES scores at each time point in follow-up will be input into SPSS software (SPSS Inc, 
Chicago, IL) for statistical analysis. Statistical tests for nonparametric variables will be used. Paired t tests 
will be used to compare paired groups for continuous variables. Independent t tests will be used to compare 
different treatment regimens. Level of significance will be set at P ≤ .05.  
 
Potential Problems: Potential problems include possible allergic reactions to medications, or possibly 
introducing infection, which would be considered extremely rare.  Patients enrolled will be carefully followed. 


                       
  Principal Investigator (Last, First, Middle) Dantzker, Nicholas James 
 
 
 
5 
PROJECT TIMELINE 
 
0-6 Months 
6-12 Months 
12-18 Months 
18-24 Months 
24-26 Months 
Patient enrollment, randomization, initiation of 
treatment 
 
 
 
Data collection at each follow-up time point 
 
 
 
Data analysis 
 
 
 
 
Manuscript preparation 
 
 
HUMAN SUBJECTS 
 
Description of Study: 
We will recruit a total of 40 patients from the Vanderbilt Sports Medicine Clinics who have been 
diagnosed with adhesive capsulitis and have not undergone any previous treatmentThe 40 
patients will be randomized, with 20 in the control group of 3 intra-articular injections of 40mg 
Methylprednisolone spaced every two weeks, and 20 in the experimental group of 3 intra-
articular injection of 50mg doxycycline spaced every two weeks. Both groups will begin a 
standardized physical therapy program within a pain-free range of motion 4 weeks after the 
initiation of treatment.. Both groups will begin a standardized physical therapy program within a 
pain-free range of motion 4 weeks after the initiation of treatment. We will prospectively follow 
patients for one year, with follow-up at 6 weeks, 12 weeks, 6 months, and 12 months after the 
initiation of treatment. Outcomes will be measured using the American Shoulder and Elbow 
Score (ASES), which will be administered by the treating physician. Both the patients and 
physicians participating in the study will be blinded. 
 
Potential risks and complications: 
Because patient data is being collected there is a slight risk of a breach of confidentiality.  To 
reduce this risk, most study data will be maintained in a Vanderbilt REDCap database.  
Vanderbilt Redcap is a secure, web-based application for building and managing online 
databases and surveys.  The data obtained and stored in Redcap will only be accessible by 
research personnel.  All study data will be maintained for 6 years following study completion.  
Following this 6 year period, the Redcap database will be archived and all physical study forms 
will be disposed of in shred-it confidentiality bins provided by VUMC. 
 
The drugs used in this study are not narcotics or habit-forming but can have side effects.  The 
treating physician will screen for any condition that would increase the chance for the patient to 
have an unwanted side effect.  However, there is a small possibility that an injection of these 
medicines can be painful and cause bleeding or infection. 
 
Statement of confidentiality: 
During this study, every attempt will be made to keep the patient’s protected health information 
(PHI) private. Most study data will be maintained in a Vanderbilt REDCap database.  Vanderbilt 
Redcap is a secure, web-based application for building and managing online databases and 
surveys.  The data obtained and stored in Redcap will only be accessible by research 
personnel.  Any data sent to non-key study personnel for statistical analysis will be de-identified 
(dates will be shifted using a Redcap feature).   Any physical study forms (ex. consent 
documents, surveys) will be kept in a locked cabinet in the Vanderbilt Orthopaedic Institute 
Administrative Offices.  All study data will be maintained for 6 years following study completion.  


                       
  Principal Investigator (Last, First, Middle) Dantzker, Nicholas James 
 
 
 
6 
Following this 6 year period, the Redcap database will be archived and all physical study forms 
will be disposed of in shred-it confidentiality bins provided by VUMC. 
 
Allowance for non-prejudicial withdrawal for investigation:  
Participation in this study is completely voluntary.  If the study participant wishes to be 
withdrawn from the prospective portion of this study following consent, they may do so by letting 
the key study personnel know they withdraw their consent.  All data collected up to the point of 
the patient’s study withdrawal will be included in study analysis. 
 
 
Liability and hold harmless clause: 
If it is determined by Vanderbilt and the Investigator that an injury occurred as a direct result of 
the tests or treatments that are done for research, then the patients and/or their insurance will 
not have to pay for the cost of immediate medical care provided at Vanderbilt to treat the injury.  
 
There are no plans for Vanderbilt to pay for the costs of any additional care. There are no plans 
for Vanderbilt to give the patient money for the injury.  
 
 


                       
  Principal Investigator (Last, First, Middle) Dantzker, Nicholas James 
 
 
 
7 
APPENDIX 1:  ASES Shoulder Assessment (Patient Evaluation)