VitC: Can Vitamin C Reduce the Risk of Postoperative Shoulder Stiffness?

Sponsor

Lindenhofgruppe AG (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04472000

Collaborator

(none)

200

Enrollment

Location

Arms

25.1

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Shoulder Stiffness	Drug: Vitamin C Drug: Placebo	Phase 4

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

200 participants

Allocation:

Randomized

Intervention Model:

Single Group Assignment

Intervention 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.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 (Participant, Care Provider, Investigator)

Masking Description:

All study participants and trial personnel but the persons generating the randomization list and preparing the blinded drug packs at the Inselapotheke and Spitalapotheke Lindenhof will be blinded to the assigned treatment. Blinding will be upheld until all analyses are completed. Vitamin C and placebo will be provided in identical looking capsules in drug packs, which will also look identical except for the consecutive code number which is unique on each pack.

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Apr 27, 2021

Anticipated Primary Completion Date :

Jun 1, 2023

Anticipated Study Completion Date :

Jun 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Vitamin C 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 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.
Placebo Comparator: Placebo 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 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.

Arm

Intervention/Treatment

Experimental: Vitamin C

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

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.

Placebo Comparator: Placebo

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

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.

Outcome Measures

Primary Outcome Measures

Difference between the external glenohumeral joint rotations of the operated shoulder and the opposite shoulder [12 weeks post surgery]
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".

Secondary Outcome Measures

Delta ∆ of the external glenohumeral joint rotation [after 6, 26, and 52 weeks post surgery]
The external glenohumeral joint rotation of both shoulders is measured using a smartphone with the App "GetMyROM"
Delta ∆ of abduction [after 6, 26, and 52 weeks post surgery]
- Abduction will be assessed using the GetMyROM-App. Abduction will be done passively with the glenohumeral joint fixed.
Delta ∆ of internal rotation [after 6, 26, and 52 weeks post surgery]
-Internal rotation will be assessed using typical landmarks in clinical practice (Trochanter major, Gluteus maximus/Buttocks, Belt, lumbar spine, thoracolumbar junction, breast spine, interscapular)
Delta ∆ of flexion [after 6, 26, and 52 weeks post surgery]
-Flexion will be assessed using the GetMyROM-App. Flexion will be done passively with the glenohumeral joint fixed.
Level of pain [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]
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
Work ability [6, 26, and 52 weeks post surgery]
Secondary endpoints include work ability (back-to-work ratio) post surgery. The (partial) ability to work is requested.
Oxford shoulder score [preoperatively and after 6, 12, 26, and 52 weeks]
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.
Constant Score [preoperatively and depending on the procedure after 6 and 12 weeks (strata 3 & 4), and after 26 and 52 weeks (all strata)]
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.
DASH score [preoperatively and after 6, 12, 26, and 52 weeks]
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.
Smoking habits [end of the study, up to 2.5 years]
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.
Frozen shoulder [end of the study, up to 2.5 years]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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