Clinical trial NCT02216812
Conditions: Finger Stiffness Distal Radius Fracture
Keywords: Finger stiffness Range of motion Distal radius fracture Vitamin C
Sponsor: Massachusetts General Hospital
Start date: 2014-08-01; Completion date: 2017-12-22
Enrollment: 134 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The reported prevalence of disproportionate pain and disability among patients recovering from a fracture of the distal radius varies widely. Literature reports numbers between 1% and 37%, perhaps in part because it is poorly defined, known by so many different names, subjective, and unverifiable.

The investigators are interested in the effect of vitamin C after distal radius fractures on objective measurement of finger motion, patient reported outcome measures, and pain intensity, instead of the previously used, subjective and imprecise criteria for complex regional pain syndrome.

Patients presenting to the Hand and Orthopaedic Trauma Services of MGH with a distal radius fracture will be asked to participate in this clinical trial. Patient will be randomly assigned to take either placebo or vitamin C 500 mg until full finger motion is attained as regarded by the treating physician at follow-up or for 6 weeks.

The investigators hypothesize no difference in finger stiffness at 6 weeks measured by distance to palmar crease of the index through little finger between patients taking vitamin C or placebo after a distal radius fracture. Additionally, the investigators assess finger stiffness by range of motion and stiffness of the thumb, and difference in PROMIS upper extremity function and pain score both measured at six months.

Detailed description:

Arms: arm 1: Arm will take 1 pill of 500 mg vitamin C per day for 6 weeks arm 2: Arm will take 1 placebo pill per day for 6 weeks
Interventions: intervention 1: 500 mg vitamin c, 1 pill per day for 6 weeks intervention 2: 1 placebo pill for 6 weeks
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
Does Vitamin C Reduce Finger Stiffness after 
Distal Radius Fractures: a Placebo Randomized 
Controlled Trial. 
 
NCT02216812 
 
Version Date of the Document:  22 February 
2017


2 
 
PARNTERS HUMAN RESEARCH 
DETAILED PROTOCOL 
 
Does Vitamin C Reduce Finger Stiffness after Distal Radius Fractures: a 
Placebo Randomized Controlled Trial. 
 
Version 4 
2-22-2017 
 
BACKGROUND & SIGNIFICANCE 
 
The reported prevalence of disproportionate pain and disability among patients 
recovering from a fracture of the distal radius varies widely, between 1% and 37% 
in published series,1-7 perhaps in part because it is poorly defined, known by so 
many different names, subjective, and unverifiable. In general, physicians ascribe 
disproportionate pain and disability to a poorly understood pathophysiologic 
process currently labeled “complex regional pain syndrome”, while psychologists 
understand this as ineffective coping strategies.8 Studies consistently identify 
psychological factors (catastrophic thinking in particular) as the most important 
determinants of pain intensity, finger stiffness, and magnitude of disability after 
distal radius fractures. 8,9  
Along these lines, it is difficult to interpret the trials suggesting that vitamin C limits 
the occurrence of complex regional pain syndrome, given that the diagnosis is 
subjective and variably defined, and the only published trials were performed by 
advocates of vitamin C.6,10  We see this reflected in clinical practice, as only 11% of 
the orthopaedic surgeons always prescribes vitamin C after a distal radius fracture, 
making it one of the least adhered to recommendations of the AAOS clinical practice 
guidelines.11. In addition, there is a lack of clarity regarding the mechanism by which 
vitamin C would decrease the incidence of complex regional pain syndrome.12  
We are interested in the effect of vitamin C after distal radius fractures on objective 
measurement of finger motion, patient reported outcome measures, and pain 
intensity, instead of the previously used, subjective and imprecise Veldman criteria 
for complex regional pain syndrome13, i.e., (i) unexplained diffuse pain, or (ii) 
edema, (iii) difference in skin color, or (iv) temperature, or (v) limited active range 
of motion.  
 
SPECIFIC AIMS 
 
Primary null hypothesis 
There is no difference in finger stiffness (distance to palmar crease) between 
patients taking vitamin C or placebo after six weeks after a distal radius fracture.  
 
Secondary null hypotheses 
There is no difference in PROMIS upper extremity function and pain score between 
patients taking vitamin C or placebo after a distal radius fracture.  
 


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There are no factors associated with finger stiffness, PROMIS upper extremity 
function, and pain intensity after fracture of the distal radius. 
 
SUBJECT SELECTION 
 
Patients will be enrolled in the outpatient clinic at the Hand & Trauma Services at 
Massachusetts General Hospital.  
 
Inclusion Criteria:  
 All adult (age 18 or greater) patients presenting to the Hand and Orthopaedic 
Trauma Services of the Massachusetts General Hospital (MGH) within two 
weeks of a fracture of the distal radius, either operatively or nonoperatively 
treated. 
 
Exclusion criteria: 
 Patients with severe kidney failure or kidney stones, known allergy for 
vitamin C or pregnancy, or patients who are not fluent in either English or 
Spanish. 
 Wrist fracture within the last year on the newly fractured side 
 Confounders (baseline characteristics): fracture on the dominant side, 
current vitamin C supplements. 
 
 
SUBJECT ENROLLMENT 
 
The treating surgeon at the Hand or Orthopedic Trauma service will determine if the 
patient is eligible to participate in the study.  The surgeon will introduce the study to 
the patient and answer any questions that the patient may have about the study or 
about randomization. If the patient agrees to participate, a trained research 
coordinator (pre-med student) or trained research assistant (PhD or medical 
student) not involved in clinical care, will obtain consent and begin enrollment 
procedures.  As with the other research studies in this department, there will be no 
coercion. The research coordinator or research assistant will explain to the patient 
that participation in this study is completely voluntary and that the patient may 
withdraw at any time. The research coordinator or research assistant will offer all 
subjects the opportunity to speak with a licensed physician Investigator during the 
consent process. 
Subjects will be given a copy of the informed consent form, and be informed 
that their participation is voluntary and that they can withdraw at any time during 
the study.  Subjects make take as long as they like to consider participation, 
provided they still meet all enrollment criteria. 
Study staff will provide the patient with a box of medication, containing 
either vitamin C or placebo (both completely similar in appearance, taste and smell). 
The pharmacist involved in preparing the placebo will randomize the boxes of 
medication according to a list of generated random numbers (Stata 13). The 


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pharmacist will be the only person with access to the code until conclusion of the 
trial.  
 
STUDY PROCEDURES 
 
 
Eligible patient, after informed consent, will be randomly assigned, double-blind, to 
take either placebo or vitamin C 500 mg for 6 weeks.  
At enrollment and 6 weeks (5-8 weeks acceptable) after fracture we will measure: 
DPC (dig II-V), PROMIS UE CAT, PROMIS pain interference and VAS score; all 
questionnaires will be filled out in REDCap.  If the researcher misses the subject at 
the 6 week follow-up or if their appointment is outside of the 5-8 week timeframe, 
three attempts will be made to contact each patient via email and via telephone to 
complete the 6 week follow-up questionnaires. To address, one of the secondary 
hypotheses, patients will be contacted 6 months after injury by email; unresponsive 
patients will be contacted by telephone to assist them with filling out the 
questionnaires. Three attempts will be made to contact each patient via email and 
via telephone to complete the follow-up. 
 
Measured variables 
At enrollment and 6 weeks (5 to 8 weeks acceptable) after fracture: 
 Finger tip distance to palmar crease of fingers II-V (DPC) 
 PROMIS Upper Extremity Function (Short form) 
 PROMIS Pain Interference Short form 
 0-10 ordinal rating of pain intensity  
 
At 6 months (5 to 8 months acceptable) after fracture: 
 PROMIS UE – Short form 
 0-10 ordinal rating of pain intensity 
 
BIOSTATISTICAL ANALYSES 
 
Difference in DPC, function, pain interference and pain will be assessed by 
Wilcoxon-Mann-Whitney test.  
 
Assuming an effect size of similar magnitude to previous studies10, power analysis 
suggests 134 patients provide 80% power to detect a difference with an alpha of 
0.05 (effect size 0.50, two tailed Wilcoxon-Mann-Whitney test). As trauma patients 
are notoriously hard to track, halfway through the study we will assess enrollment 
and adjust sample size accordingly to account for lost to follow-up. 
 
RISKS AND DISCOMFORTS 
 
Although controversy exists regarding the value of prescribing vitamin C to patients 
with distal radius fractures, there appears to be limited downside with its use. 


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Adverse effects of vitamin C are dose-dependent and occur at doses well above the 
recommended daily dose of 60 mg. Generally, adverse side effects can be avoided 
with doses below 1000 mg daily in healthy people.14 In this study, patients who 
receive the vitamin C treatment will only take 500 mg daily. When several grams of 
vitamin C are taken at once, diarrhea and abdominal bloating are the most frequent 
side effects. In addition, renal calculi can precipitate as a result of the ingestion of 
excess vitamin C. Oxalic acid is produced and renally excreted during vitamin C 
metabolism. In patients with underlying hyperoxaluria, oxalate excretion is 
accelerated with vitamin C doses above 1000 mg daily and can contribute to 
formation of renal calculi. Similarly, hyperuricosuria can occur with large doses of 
vitamin C, also leading to formation of renal calculi. In patients requiring dialysis, 
hyperoxalemia can occur with doses as low as 500 mg daily. Therefore, these 
patients are excluded from our study. 
 
The subject will be inconvenienced by having to complete study related 
questionnaires and physical examination (about 20 minutes). 
 
POTENTIAL BENEFIT 
 
There may or may not be any direct benefits to the individual subjects. Subjects may 
benefit from the Vitamin C treatment by experiencing reduced pain and reduced 
finger stiffness. It is also possible that the subjects will not directly benefit from the 
treatment, and will recover from their injury as they would under the standard of 
care treatment outside of this research. Either outcome will contribute to the 
understanding of the role of vitamin C in the healing of distal radius fractures.  
 
MONITORING AND QUALITY ASSURANCE 
 
Any adverse events will be recorded by a full time research coordinator involved in 
this project and discussed with the PI immediately.  An overview of all adverse 
events will be discussed at the monthly research meeting at which the PI will decide 
whether to continue or alter/stop the trial.  
 
The PI will have overall responsibility for the conduct and monitoring of the study 
and safety of subjects. The research coordinator has an assistive role and will monitor 
outcomes on a daily basis. The research coordinator will have an assistive role and 
will be responsible for monitoring outcomes on a daily basis and the research 
coordinator will discuss all outcomes with the PI on a monthly basis at the research 
meeting.  No independent monitoring will occur.  All investigators and study staff will 
be responsible for reporting adverse effects to the research coordinator. Should any 
adverse events occur, the research coordinator will report such events to the PI 
immediately.  The research coordinator will report adverse events to the IRB in 
accordance with the IRB adverse event reporting procedures. 
 
There will be a full-time research coordinator responsible for adherence to all IRB 
rules and guidelines and for the accuracy and completeness of all forms, entries, and 


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informed consent. The research coordinator is responsible for monitoring all data 
and adherence to the IRB-approved protocol on a daily basis, and all data and study 
details will be reviewed with the PI at the monthly research meeting. The research 
coordinator will report any deviations from the protocol to the PI immediately.  
 
All data from subjects will be filed in locked cabinets in the research office in 
individualized research folders, independent of clinical charts or any other medical 
record in electronic format.  Any magnetic or electronic information will be saved in 
password-protected computers to which only research coordinator and persons 
involved with the research project will have access. 
 
All participants are given a participation number/code at the time of enrollment 
matching with their received medication box.  This code is kept on all data sheets 
instead of the patient name.  Subject information is only accessible by Partners 
authorized investigators and will not be shared with outside entities.   The final 
results after statistical analysis will not be shared with the any institution. 
 
REFRENCES 
1. Atkins RM, Duckworth T, Kanis JA. Algodystrophy following Colles’ fracture. J Hand 
Surg Br 1989; 14(2):161–4. 
2. Atkins RM, Duckworth T, Kanis JA. Features of algo- dystrophy after Colles’ fracture. 
J Bone Joint Surg Br 1990;72(1):105–10. 
3. Dijkstra PU, Groothoff JW, ten Duis HJ, et al. Incidence of complex regional pain 
syndrome type I after frac- tures of the distal radius. Eur J Pain 2003;7(5):457–62. 
4. Field J, Warwick D, Bannister GC. Features of algodystrophy ten years after Colles’ 
fracture. J Hand Surg Br 1992;17(3):318–20. 
5. McKay SD, MacDermid JC, Roth JH, et al. Assessment of complications of distal radius 
fractures and development of a complication checklist. J Hand Surg Am 
2001;26(5):916–22. 
6. Zollinger PE, Tuinebreijer WE, Breederveld RS, et al. 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;89(7):1424–31. 
7. Bickerstaff DR, Kanis JA. Algodystrophy: an under recognized complication of minor 
trauma. Br J Rheumatol 1994;33(3):240–8. 
8. Ring D, Barth R, Barsky A. Evidence-based medicine: disproportionate pain and 
disability. J Hand Surg Am 2010;35(8):1345–7.  
9. T. Teunis, A.G. Bot, E.R. Thornton, D. Ring. ORIF Distal Radius: Catastrophic Thinking 
Leads to Stiff Fingers. Manuscript in preparation. 
10. Zollinger PE, Tuinebreijer WE, Kreis RW, et al. Effect of vitamin C on frequency of 
reflex sympathetic dystrophy in wrist fractures: a randomised trial. Lancet 
1999;354(9195):2025–8. 
11. J.L. Matzon, K.F. Lutsky, M. Maloney, P.K. Beredjiklian. Adherence to the AAOS 
Upper-extremity Clinical Practice Guidelines. Orthopaedics 2013;36:e1407-e1411. 
12. Amadio PC. Vitamin C reduced the incidence of reflex sympathetic dystrophy after 
wrist fracture. J Bone Joint Surg 2000;82A:873.  


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13. Veldman PH, Reynen HM, Arntz IE, Goris RJ. Signs and symptoms of reflex 
sympathetic dystrophy: prospective study of 829 patients.   Lancet 1993;342:1012–
1016.  
14. Levine M, Rumsey SC, Daruwala R, Park JB, Wang Y. Criteria and 
  recommendations for vitamin C intake. JAMA 1999;281:1415–1423.