Clinical trial NCT04472000: Can Vitamin C Reduce the Risk of Postoperative Shoulder Stiffness?
Official title: Can Vitamin C Reduce the Risk of Postoperative Shoulder Stiffness? A Multi-center, Double-blinded, Randomized and Placebo-controlled Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Shoulder Stiffness
Keywords: Vitamin C
pain
mobility
rotation
glenohumeral joint
Lead sponsor: Lindenhofgruppe AG
Sponsor class: INDUSTRY
First posted: 2020-07-15
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
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:

1. Rotator cuff surgery with resection of the acromioclavicular joint
2. Rotator cuff surgery without resection of the acromioclavicular joint
3. Shoulder arthroscopy with resection of the acromioclavicular joint
4. 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.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Difference between the external glenohumeral joint rotations of the operated shoulder and the opposite shoulder
timeFrame: 12 weeks post surgery
Secondary outcomes:
measure: Delta ∆ of the external glenohumeral joint rotation
timeFrame: after 6, 26, and 52 weeks post surgery
measure: Delta ∆ of abduction
timeFrame: after 6, 26, and 52 weeks post surgery
measure: Delta ∆ of internal rotation
timeFrame: after 6, 26, and 52 weeks post surgery
measure: Delta ∆ of flexion
timeFrame: after 6, 26, and 52 weeks post surgery
measure: Level of pain
timeFrame: 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
measure: Work ability
timeFrame: 6, 26, and 52 weeks post surgery
measure: Oxford shoulder score
timeFrame: preoperatively and after 6, 12, 26, and 52 weeks
measure: Constant Score
timeFrame: preoperatively and depending on the procedure after 6 and 12 weeks (strata 3 & 4), and after 26 and 52 weeks (all strata)
measure: DASH score
timeFrame: preoperatively and after 6, 12, 26, and 52 weeks
measure: Smoking habits
timeFrame: end of the study, up to 2.5 years
measure: Frozen shoulder
timeFrame: end of the study, up to 2.5 years
Other outcomes:
Locations:
city: Aarberg
country: Switzerland
facility: Spital Aaberg
state: Bern
city: Bern
country: Switzerland
facility: Orthopädie Sonnenhof
Study officials:
affiliation: Campus SLB, Lindenhof AG
name: Janine Antonov, Dr.
role: STUDY_CHAIR
References:
citation: Cho CH, Song KS, Kim BS, Kim DH, Lho YM. Biological Aspect of Pathophysiology for Frozen Shoulder. Biomed Res Int. 2018 May 24;2018:7274517. doi: 10.1155/2018/7274517. eCollection 2018.
citation: Wong CK, Levine WN, Deo K, Kesting RS, Mercer EA, Schram GA, Strang BL. Natural history of frozen shoulder: fact or fiction? A systematic review. Physiotherapy. 2017 Mar;103(1):40-47. doi: 10.1016/j.physio.2016.05.009. Epub 2016 Jun 21.
citation: Kim DH, Kim YS, Kim BS, Sung DH, Song KS, Cho CH. Is frozen shoulder completely resolved at 2 years after the onset of disease? J Orthop Sci. 2020 Mar;25(2):224-228. doi: 10.1016/j.jos.2019.03.011. Epub 2019 Apr 2.
citation: Aim F, Klouche S, Frison A, Bauer T, Hardy P. Efficacy of vitamin C in preventing complex regional pain syndrome after wrist fracture: A systematic review and meta-analysis. Orthop Traumatol Surg Res. 2017 May;103(3):465-470. doi: 10.1016/j.otsr.2016.12.021. Epub 2017 Mar 4.
citation: Kim JH, Kim YC, Nahm FS, Lee PB. The Therapeutic Effect of Vitamin C in an Animal Model of Complex Regional Pain Syndrome Produced by Prolonged Hindpaw Ischemia-Reperfusion in Rats. Int J Med Sci. 2017 Jan 15;14(1):97-101. doi: 10.7150/ijms.17681. eCollection 2017.
citation: Chen S, Roffey DM, Dion CA, Arab A, Wai EK. Effect of Perioperative Vitamin C Supplementation on Postoperative Pain and the Incidence of Chronic Regional Pain Syndrome: A Systematic Review and Meta-Analysis. Clin J Pain. 2016 Feb;32(2):179-85. doi: 10.1097/AJP.0000000000000218.
citation: Fukushima R, Yamazaki E. Vitamin C requirement in surgical patients. Curr Opin Clin Nutr Metab Care. 2010 Nov;13(6):669-76. doi: 10.1097/MCO.0b013e32833e05bc.
citation: Behrend H, Lengnick H, Zdravkovic V, Ladurner A, Rudin D, Erschbamer M, Joerger M, Kuster M. Vitamin C demand is increased after total knee arthroplasty: a double-blind placebo-controlled-randomized study. Knee Surg Sports Traumatol Arthrosc. 2019 Apr;27(4):1182-1188. doi: 10.1007/s00167-018-5030-3. Epub 2018 Jun 28.
citation: Giladi AM, Dossett LA, Fleming SB, Abumrad NN, Cotton BA. High-dose antioxidant administration is associated with a reduction in post-injury complications in critically ill trauma patients. Injury. 2011 Jan;42(1):78-82. doi: 10.1016/j.injury.2010.01.104. Epub 2010 Feb 10.
citation: Rizzo JA, Rowan MP, Driscoll IR, Chung KK, Friedman BC. Vitamin C in Burn Resuscitation. Crit Care Clin. 2016 Oct;32(4):539-46. doi: 10.1016/j.ccc.2016.06.003. Epub 2016 Aug 2.
citation: Kleszczewski T, Modzelewska B, Lisowska A, Buzun L, Kleszczewska E. Levels of vitamin C In the blood plasma patients treated with coronary artery bypass grafting increases significantly after surgery. Biomed Pharmacother. 2017 Jan;85:527-530. doi: 10.1016/j.biopha.2016.11.060. Epub 2016 Nov 24.
citation: Lee GW, Yang HS, Yeom JS, Ahn MW. The Efficacy of Vitamin C on Postoperative Outcomes after Posterior Lumbar Interbody Fusion: A Randomized, Placebo-Controlled Trial. Clin Orthop Surg. 2017 Sep;9(3):317-324. doi: 10.4055/cios.2017.9.3.317. Epub 2017 Aug 4.
citation: Zollinger PE, Tuinebreijer WE, Breederveld RS, Kreis RW. Can vitamin C prevent complex regional pain syndrome in patients with wrist fractures? A randomized, controlled, multicenter dose-response study. J Bone Joint Surg Am. 2007 Jul;89(7):1424-31. doi: 10.2106/JBJS.F.01147.
citation: Zollinger PE, Tuinebreijer WE, Kreis RW, Breederveld RS. Effect of vitamin C on frequency of reflex sympathetic dystrophy in wrist fractures: a randomised trial. Lancet. 1999 Dec 11;354(9195):2025-8. doi: 10.1016/S0140-6736(99)03059-7.
citation: Traxer O, Huet B, Poindexter J, Pak CY, Pearle MS. Effect of ascorbic acid consumption on urinary stone risk factors. J Urol. 2003 Aug;170(2 Pt 1):397-401. doi: 10.1097/01.ju.0000076001.21606.53.
citation: Thomas LD, Elinder CG, Tiselius HG, Wolk A, Akesson A. Ascorbic acid supplements and kidney stone incidence among men: a prospective study. JAMA Intern Med. 2013 Mar 11;173(5):386-8. doi: 10.1001/jamainternmed.2013.2296. No abstract available.
citation: Prier M, Carr AC, Baillie N. No Reported Renal Stones with Intravenous Vitamin C Administration: A Prospective Case Series Study. Antioxidants (Basel). 2018 May 21;7(5):68. doi: 10.3390/antiox7050068.
citation: Mitch WE, Johnson MW, Kirshenbaum JM, Lopez RE. Effect of large oral doses of ascorbic acid on uric acid excretion by normal subjects. Clin Pharmacol Ther. 1981 Mar;29(3):318-21. doi: 10.1038/clpt.1981.42.
citation: Auer BL, Auer D, Rodgers AL. The effect of ascorbic acid ingestion on the biochemical and physicochemical risk factors associated with calcium oxalate kidney stone formation. Clin Chem Lab Med. 1998 Mar;36(3):143-7. doi: 10.1515/CCLM.1998.027.
citation: Levine M, Conry-Cantilena C, Wang Y, Welch RW, Washko PW, Dhariwal KR, Park JB, Lazarev A, Graumlich JF, King J, Cantilena LR. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3704-9. doi: 10.1073/pnas.93.8.3704.
citation: Padayatty SJ, Levine M. Vitamin C: the known and the unknown and Goldilocks. Oral Dis. 2016 Sep;22(6):463-93. doi: 10.1111/odi.12446. Epub 2016 Apr 14.
citation: Zhang M, Jativa DF. Vitamin C supplementation in the critically ill: A systematic review and meta-analysis. SAGE Open Med. 2018 Oct 19;6:2050312118807615. doi: 10.1177/2050312118807615. eCollection 2018.
citation: Gerster H. No contribution of ascorbic acid to renal calcium oxalate stones. Ann Nutr Metab. 1997;41(5):269-82. doi: 10.1159/000177954.
citation: Zuckerman JD, Rokito A. Frozen shoulder: a consensus definition. J Shoulder Elbow Surg. 2011 Mar;20(2):322-5. doi: 10.1016/j.jse.2010.07.008. Epub 2010 Nov 4.
citation: Mejia-Hernandez K, Chang A, Eardley-Harris N, Jaarsma R, Gill TK, McLean JM. Smartphone applications for the evaluation of pathologic shoulder range of motion and shoulder scores-a comparative study. JSES Open Access. 2018 Mar 13;2(1):109-114. doi: 10.1016/j.jses.2017.10.001. eCollection 2018 Mar.