This study was designed according to the Consolidated Standards of Reporting Trials (CONSORT) guidelines.17) This clinical trial was prospective, randomized and blinded. The trial was registered at ClinicalTrials.gov (NCT02258295) before IRB approval. After meeting inclusion and exclusion criteria, patients were randomized in a 1:1 ratio into one of two treatment arms, HA injection (HA group) versus saline control (Saline group). All the patients were recruited and evaluated at a single center, an academic referral facility. Randomization was done using a table provided by our statistician created by a randomization program in blocks of thirty. All patients in the study were consented prior to randomization. The research assistant would reveal to the injecting physician the material to be used after consent was obtained. Each patient was given a full explanation of the procedure including the possibility of getting a saline injection. They were given a copy of the signed informed consent. Admission of the patient into the study was recorded in the medical records.
Inclusion/Exclusion Criteria:
The criteria for diagnosis included pain and tenderness at the lateral epicondyle worse with resisted wrist or finger extension (with the elbow in the extended position). Inclusion criteria were age over 18 years, chronic pain defined as six months or longer, and pain (average pain over the past week when using the hand) on the Visual Analogue Score (VAS) scale of 50 or greater (out of 100).
Exclusion criteria included elbow steroid injection less than three months prior to starting the study, prior elbow surgery, inflammatory condition like rheumatoid arthritis or lupus, and allergy to birds, feathers or egg products. If the patient had complaints of pain and significant tenderness on exam in the area of the radial neck, then a component of radial tunnel syndrome was assumed and those patients were excluded from study. Patients with pain from other areas such as the radio-capitellar joint or medial epicondyle were also excluded.
Blinding:
All injections were performed using syringes that were masked and numbered. The patient was blinded from knowing which material was used. Although the physician injecting was not blinded, a separate physician, blinded to the material, performed follow-up visits.
Injections:
Injections of HA or saline were the only treatment for the study duration. Patients were not referred for therapy and no other interventions or treatment were recommended. This study used Intragel (IBSA Institut Biochimique, Lugano, Switzerland). The formulation has a molecular weight averaging 800-1200 KDaltons and concentration of 16mg per 2cc.
The senior author (GZ) performed all injections. The injections were performed in a similar fashion for both HA and Saline groups. First, the point of maximum tenderness at the lateral epicondyle was identified and marked. After local preparation with alcohol, 1cc of lidocaine 1% was placed both superficially and deep into the tendon substance. Using a separate and pre-loaded syringe, 2cc of either HA or saline was injected using a fanning technique into the area of maximal tenderness approximately 1cm distal to the lateral epicondyle. Each participant was injected three times, two weeks apart. When planning the study, we reviewed all the clinical studies to date and the number of injections done were between one to six per patient. The primary reason we chose three was prior experience. We have been injecting patients since 2011 with HA. Before starting this study, we did a quality survey of the patients injected and found that nearly all patients had two to three injections each until their pain was essentially resolved. We chose two weeks apart because prior research had two to three week intervals.
Additional Treatment:
Patients were not referred for any additional treatment during the study period. Most had tried therapy and injections prior to enrollment. Patients were asked about other interventions during the follow-up period (six and 12 months after HA injections) and no additional treatment was reported.
Demographic Data:
General demographic data included age, sex, handedness, type of work, symptomatic side, and if they participated in racquet sports (Table 1).
Table 1
Categorical (Chi square test for Gender, Fishers test for others - for comparisons between groups) and Continuous (T-tests and Wilcoxon for normal and non-normal distributions) Baseline Characteristics by Group: HA versus Saline.
Parameter | Category | Group HA N (%) | Group Saline N (%) | P-Value |
Age (years)* | Age | 51.9 (SD 10.6) | 52.9 (SD 8.9) | 0.800 |
Gender | Female | 7 /17 (41.2) | 3 /13 (23.1) | 0.297 |
| Male | 10 /17 (58.8) | 10 /13 (76.9) | |
Handedness | Left | 1 /17 (5.9) | 1 /14 (7.1) | 1.00 |
| Right | 16 /17 (94.1) | 13 /14 (92.9) | |
Occupation | Manual | 3 /17 (17.6) | 4 /14 (28.6) | 0.115 |
| Office | 13 /17 (76.5) | 6 /14 (42.9) | |
| Retired | 1 /17 (5.9) | 4 /14 (28.6) | |
BMI | BMI | 25.9 (SD 3.2) | 27.1 (SD 4.1) | 0.463 |
Painful side | Left | 8 /16 (50.0) | 7 /14 (50.0) | 1.00 |
| Right | 8 /16 (50.0) | 7 /14 (50.0) | |
Pain Duration (months) | Pain Duration | 28.1 (SD 22.0) | 51.4 (SD 59.9) | 0.936 |
VAS Pain (In the past week how much pain do you feel when gripping something - on average?) | VAS Pain | 76.4 (SD 12.1) | 72.1 (SD 11.9) | 0.348 |
PRTEE Score | PRTEE | 67.0 (SD 14.6) | 71.9 (SD 14.5) | 0.357 |
QuickDASH | QuickDASH | 53.7 (SD 18.90 | 58.8 (SD 13.1) | 0.408 |
Racquet sports | No | 15 /17 (88.2) | 13 /14 (92.9) | 1.00 |
| Yes | 2 /17 (11.8) | 1 /14 (7.1) | |
* T Test |
HA – Hyaluronic Acid |
PRTEE – patient-rated tennis elbow evaluation |
QuickDASH – Quick Disabilities of the Arm, Shoulder and Hand Score |
VAS – Visual Analog Score |
Outcome Measures:
The primary outcome measure was the VAS for pain when asked, “What is the average pain you experienced the past week while gripping or actively using your hand?” Secondary outcome measures included the brief form of the disabilities of the arm, shoulder, and hand (QuickDASH)18) and the patient rated tennis elbow evaluation (PRTEE).19) Outcome measures were collected at baseline, three months, six months and one year from the initial injection. Patients were encouraged to return for clinical evaluation for each visit but some preferred to respond to telephone or email outcome questionnaires.
The QuickDASH is an 11-question short version of the longer 30-question DASH. The score ranges from 0 (no disability) to 100 (most severe disability). The PRTEE is a 15-question survey that evaluates pain and function on a 10-point VAS. The score ranges from 0 (no pain and maximum function) to 100 (maximum pain and minimum function). Therefore, the best score for the QuickDASH and the PRTEE are both 0.
Primary endpoint:
The primary endpoint was reduction of the VAS pain at three months from the initial injection.
Secondary endpoints:
Secondary outcomes included differences for HA for VAS pain at six and 12 months and for PRTEE and QuickDASH at 3-, 6- and 12-months post-injection. We also calculated 25% reduction in VAS pain from baseline for HA versus saline to allow comparison to Peerbooms et al. 201020) results from PRP injection.
Power of study and statistical analysis:
One of the few prospective studies on HA done to date was performed by Petrella et al.15) They evaluated treatment of chronic HA in racquet sport athletes using a total of two HA injections one week apart. They used pain VAS as their primary endpoint. Using standard deviation data from their study we calculated the sample size needed to power this study. With the null hypothesis that the HA group would improve relative to the control (by VAS 18 or greater) at 3 months post-injection, the significance level, \(\propto\) set at 0.05 and power at 80% (1-\(\beta\))=0.20, computed 29 patients per group to allow comparison to the saline placebo. Unfortunately, the inclusion and exclusion criteria were so restrictive that enrollment was slower than anticipated. Specifically, the requirement for only chronic, no component of radial tunnel syndrome and no recent steroid injections limited the number of suitable patients. In the end, we stopped the study at 35 patients, with 18 in the HA group.
Differences in baseline characteristics were assessed with Fisher’s test for categorical variables and T-test or Wilcoxon tests for continuous variables, depending on the distribution of the data. The T-test was used to t for differences in outcome measures.