Can Vitamin C Reduce the Risk of Postoperative Shoulder Stiffness?

Study Overview
=================
Brief Summary
-----------------
Postoperative shoulder stiffness is a common complication after shoulder surgery (incidence 10-15%). The symptoms consist primarily in a painful impairment of the mobility of the glenohumeral joint, usually after initially good course. Cause and origin are not clear. Vitamin C is known as an inactivator of free radicals and plays a key role in building collagen tissue. Vitamin C thus has a modulating role in inflammatory reactions. Injured and ill people have been shown to have significantly increased vitamin C needs, which underlines this role. Evidence was also found that vitamin C has a positive influence on similar diseases such as the complex regional pain syndrome (CRPS, Morbus Sudeck) on the wrist and postoperative arthrofibrosis on the knee joint. The Investigators want to investigate whether vitamin C intake can positively influence the incidence and / or severity of postoperative shoulder stiffness after shoulder surgery. The primary objective of this study is to investigate the effect of vitamin C on the external rotational ability of the operated shoulder in the glenohumeral joint compared to the opposite side at 12 weeks post surgery. Secondary objectives of this study are to investigate other shoulder mobility tests, patient-reported outcomes (level of pain, ability/return to work, smoking habits), patient-reported questionnaires (Constant Score, Oxford shoulder score, DASH score) and the incidence of a frozen shoulder at 6, 12, 26, and 52 weeks post surgery. Total duration of study: 2.5 years.

Detailed Description
-----------------
Participants will be randomly allocated to the two treatment arms, vitamin C or placebo, in a 1:1 ratio Study participants in the verum group receive one capsule of Burgerstein Vitamin C retard 500mg b.i.d. with treatment starting in the evening on the day of the operation for a total of 50 days. The placebo group receives one placebo capsule b.i.d. with treatment starting in the evening on the day of the operation for a total of 50 days. Vitamin C will be administered orally. Burgerstein Vitamin C Retard Capsules 500 mg (Pharmacode: 6739189) will be used for this study. Active substance: Ascorbic acid (Vitamin C, E 300). Since a known drug should be tested for a new indication, the exclusion of a bias by a placebo effect, the administration of a placebo to the control group is necessary. To exclude a detection bias and a performance bias, the study is performed double-blind. A randomization protects against a selection bias. The determination of the sample size is based on the following considerations. The primary endpoint is not expected to be normally distributed. Therefore the sample size determination is based on a Mann-Whitney test for the comparison of the two groups (placebo and treatment) assuming a logistic distribution. Based on a few data of comparable measurements the Investigators think that the standard deviation of the primary endpoint is 10(=SD) in each group. The treatment effect is expected to be Delta=10, a medically reasonable effect. To achieve a power of at least 80% for the 4 tested comparisons in the final analysis of the primary endpoint, a minimal sample size of 42 in each of the 4 patient groups (strata) is required. In expectation of a drop-out rate of 20%, the target sample size will be 50 patients in each stratum and 200 patients in total, with 100 in the placebo group and 100 in the treatment group.

Official Title
-----------------
Can Vitamin C Reduce the Risk of Postoperative Shoulder Stiffness? A Multi-center, Double-blinded, Randomized and Placebo-controlled Study

Conditions
-----------------
Shoulder Stiffness

Intervention / Treatment
-----------------
* Drug: Vitamin C
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Informed Consent as documented by signature 18 years or older at the time of informed consent signature Complication-free rotator cuff* or shoulder arthroscopy** with or without resection of the acromioclavicular joint at the orthopedics Sonnenhof. The rotator cuff operations are basically open or in mini-open technique, usually with additional tenotomy / tenodesis of the long biceps tendon. * rotator cuff surgery can include tenotomy/tenodesis of long biceps tendon, intra-articular debridement with or without resection of the coracoacromial ligament and/or acromioplasty, biopsies, diagnostic arthroscopy ** Arthroscopic procedures include subacromial debridement (including partial resection of the coracoacromial ligament & acromioplasty), diagnostic arthroscopy, tenotomy of the long biceps tendon, intra-articular debridement, resection of calcium depots for treatment of tendinitis calcarea, biopsies, stabilizations (only without postoperative immobilization) Sufficient knowledge of German to understand the patient information and informed consent, follow instructions by study personnel, and complete patient questionnaires & diary Exclusion Criteria: Contraindications to ascorbic acid or one of the excipients, e.g. known hypersensitivity or allergy to the investigational product Planned single or multiple intake of vitamin supplements during the study period, which results in an additional daily intake of > 50 mg ascorbic acid Known pregnancy or breast feeding Known or suspected non-compliance, for example drug or alcohol abuse Inability to follow the procedures of the study, e.g. due to psychological disorders, dementia, etc. Participation in another interventional study within the 30 days preceding and during the present study Previous enrollment into the current study Enrollment of the investigator, his / her family members, employees and other dependent persons Current or previous frozen shoulder (no matter on which side) Pre-surgery on the affected shoulder joint (preoperative procedures include all procedures examined in this study, including all other procedures involving the glenohumeral joint and / or acromioclavicular joint. In addition, all interventions, which as a result, negatively influence the mobility of the shoulder with great likelihood up to the current time) Known current unstable medical problem on the not-affected shoulder joint according to the judgment of the investigator Taking a cortisone preparation or an immunomodulatory drug (for example methotrexate or similar) Alcoholism (defined as intake of more than 12g (women) or 24g (men) alcohol per day) Regular hemodialysis Known diabetes mellitus Known Addison's disease Known not correctly adjusted thyroid metabolism Known Parkinson's disease and similar CNS disorders (Diffuse Lewy Body Disease, Corticobasal Degeneration, Multisystem Atrophy, Progressive Supranuclear Paralysis, Essential Tumor, Huntington's Disease, Multiple Sclerosis) Known diseases / injuries of the peripheral nerves (Isaac's Syndrome, Stiff-Person Syndrome, Guillain-Barré Syndrome, Chronic Inflammatory Demyelinating Polyneuropathy, Hereditary Neuropathies, Amyotrophic Lateral Sclerosis, Hereditary Motor Neuropathies Prone to Pressure Paralysis, Motor Neurone Diseases, Myasthenia Gravis, Spinal Muscular Atrophies, Thoracic Outlet Syndromes) Known infection in the shoulder joint to be operated Known Hyperlipidemia Known Uremia Known Thalassemia Known iron storage diseases Known Glucose-6-phosphate dehydrogenase (G6PD) deficiency Planned further operation of any kind within the next 50 days after shoulder surgery

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Participants will be randomly allocated to the two treatment arms, vitamin C or placebo, in a 1:1 ratio. The randomisation will be stratified by type of surgery performed. Allocation will be concealed using sequentially coded drug packs that are otherwise identical. Drug packs will be coded as 01-01 to 01-50 for stratum 1, 02-01 to 02-50 for stratum 2, 03-01 to 03-50 for stratum 3, and 04-01 to 04-50 for stratum 4. The 4 strata differ in the type of operation performed: Rotator cuff surgery with resection of the acromioclavicular joint Rotator cuff surgery without resection of the acromioclavicular joint Shoulder arthroscopy with resection of the acromioclavicular joint Shoulder arthroscopy without resection of the acromioclavicular joint Vitamin C will be administered orally at 1000 mg/day (500 mg b.i.d.) for 50 days post surgery.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vitamin C<br>Patients who are assigned to the experimental treatment group will be given extended release capsules with 500 mg of ascorbic acid orally two times daily, packed in PET/PP-bottles identical as used for the licenced product. | Drug: Vitamin C<br>* Study participants in the verum group receive one capsule of Burgerstein Vitamin C retard 500mg b.i.d. with treatment starting in the evening on the day of the operation for a total of 50 days.<br>|
| Placebo Comparator: Placebo<br>The control intervention of this study consists of treatment with no active substance (placebo) but in the same schedule as the experimental treatment (verum). | Drug: Placebo<br>* The placebo group receives one placebo capsule b.i.d. with treatment starting in the evening on the day of the operation for a total of 50 days.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference between the external glenohumeral joint rotations of the operated shoulder and the opposite shoulder | The primary endpoint of this study is the difference between the external glenohumeral joint rotations of the operated shoulder and the opposite shoulder (Delta ∆). The external glenohumeral joint rotation was chosen as primary measure for shoulder performance because this is the component of movement in the shoulder joint, which is the first and most severely impaired in postoperative shoulder stiffness and which normalizes as the last after the symptomatology subsides. Delta ∆ was chosen as an outcome measure, since the standard deviation of the external rotation capability in the population is very high. The external glenohumeral joint rotation of both shoulders is measured using a smartphone with the App GetMyROM. | 12 weeks post surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delta ∆ of the external glenohumeral joint rotation | The external glenohumeral joint rotation of both shoulders is measured using a smartphone with the App GetMyROM | after 6, 26, and 52 weeks post surgery | 
| Delta ∆ of abduction | - Abduction will be assessed using the GetMyROM-App. Abduction will be done passively with the glenohumeral joint fixed. | after 6, 26, and 52 weeks post surgery | 
| Delta ∆ of internal rotation | -Internal rotation will be assessed using typical landmarks in clinical practice (Trochanter major, Gluteus maximus/Buttocks, Belt, lumbar spine, thoracolumbar junction, breast spine, interscapular) | after 6, 26, and 52 weeks post surgery | 
| Delta ∆ of flexion | -Flexion will be assessed using the GetMyROM-App. Flexion will be done passively with the glenohumeral joint fixed. | after 6, 26, and 52 weeks post surgery | 
| Level of pain | Secondary endpoints include the Level of pain of the operated shoulder preoperatively and level of pain (at rest and in motion) will be assessed using the VAS pain scale | daily during the first 50 days post surgery, and at 12, 26, and 52 weeks post surgery as a criterion for the occurrence of postoperative frozen shoulder | 
| Work ability | Secondary endpoints include work ability (back-to-work ratio) post surgery. The (partial) ability to work is requested. | 6, 26, and 52 weeks post surgery | 
| Oxford shoulder score | Secondary endpoints include the Oxford shoulder score as a measure of the pain and the utilizability of the shoulder as well as the patient satisfaction. Will be recorded by the patient getting a questionnaire, which he or she fills out in the waiting room before the appointment with the doctor. The practical part of the Constant score is subsequently filled in by the doctor during the clinical follow-up examination. | preoperatively and after 6, 12, 26, and 52 weeks | 
| Constant Score | Secondary endpoints include the Constant Score as a measure of everyday utilizability of the shoulder and patient satisfaction. Will be recorded by the patient getting a questionnaire, which he or she fills out in the waiting room before the appointment with the doctor. The practical part of the Constant score is subsequently filled in by the doctor during the clinical follow-up examination. The Force measurement in the Constant score is performed with the following device: IsoForceControl®EVO2 - Dynamometer 10-400N. | preoperatively and depending on the procedure after 6 and 12 weeks (strata 3 & 4), and after 26 and 52 weeks (all strata) | 
| DASH score | Secondary endpoints include the DASH score as a measure of the pain and the utilizability of the shoulder as well as the patient satisfaction. Will be recorded by the patient getting a questionnaire, which he or she fills out in the waiting room before the appointment with the doctor. The practical part of the Constant score is subsequently filled in by the doctor during the clinical follow-up examination. | preoperatively and after 6, 12, 26, and 52 weeks | 
| Smoking habits | Secondary endpoints include the influence of smoking habits on the outcome and possibly on the effect of the study drug. The (current) smoking habits are documented. | end of the study, up to 2.5 years | 
| Frozen shoulder | Secondary endpoints include the incidence of frozen shoulder. There is no standard definition for frozen shoulder in the literature. The diagnosis is made clinically. The frozen shoulder in this study is defined as a further decrease in external rotation of the glenohumeral joint in the postoperative period. | end of the study, up to 2.5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Vitamin C, pain, mobility, rotation, glenohumeral joint