Patients and protocol requirement
To be included in this study patients had to be 50 years of age or older and have an imaging-confirmed (radiograph or MRI) diagnosis of OA of the hip or knee. The use of an NSAID was not permitted in the 7 days prior to the enrollment visit, and intra-articular steroids could not have been administered within the previous 30 days. In addition, no enrolled patient had received intra-articular hyaluronate injections in the month prior to enrollment. One individual who had been treated with hyaluronate in the past had noted no benefit from the series of injections. Patients had to be able to ambulate sufficiently to complete a 25 foot walking time. Individuals with significant active medical conditions were excluded at the discretion of the principal investigator. The protocol and the case report forms were written entirely by the investigators (NO, VB and GJ). The protocol was approved by the University of Texas Southwestern Institutional Review Board and informed consent was obtained from all individuals prior to the baseline study visit activities. Clinicaltrials.gov identifier is NCT 01010919.
At the baseline visit, a medical history and physical exam were carried out. The patient completed the following self-assessment questionnaires:
McMaster Universities Osteoarthris Index (WOMAC)[
11,
12]
Brief Pain Inventory (BPI)[
13]
Modified health assessment questionnaire (MHAQ)[
14]
Visual analog scale (10 cm) for arthritis pain assessment (VAS)
Each patient also was timed for a 25 foot walk. The following laboratory tests were obtained and sent to the local clinical laboratory: complete blood count, AST, ALT and creatinine. Blinded medication provided by the study sponsor was dispensed. One batch of chicory, chemically verified for content by a third party laboratory, was used for all subjects. Randomization of the doses was pre-determined and built into the packaging, so that each numbered box of medication was dispensed in sequence to each enrolled patient. The dispensed capsules each contained either 200 mg of chicory extract or matching placebo.
Three study cohorts were enrolled. The first cohort took one 200 mg capsule three times daily (TID) for a total dose of 600 mg/day. The second cohort took 2 capsules TID for a total dose of 1200 mg/day and the third cohort took 3 capsules TID for a total daily dose of 1800 mg/day. Patients randomized to placebo took matching placebo capsules on the same schedule. To encourage enrollment, the ratio of active treatment to placebo was 5:3 in cohorts 1 and 2 and 16:8 in cohort 3. One patient assigned to cohort 3 (and randomized to placebo) took 1 capsule three times daily rather than 3 capsules three times daily and had 100% compliance with this regimen. Therefore, blinded data on this individual were analyzed with cohort 1. With this change in assignment, the final breakdown of treatment was as follows:
Cohort 1 - 9 Patients: 4 placebo, 5 chicory
Cohort 2 - 8 Patients: 3 placebo, 5 chicory
Cohort 3 - 23 Patients: 8 placebo, 15 chicory
Patients were given diaries to record dosing and use of the permitted rescue analgesics, acetaminophen alone or combined with either hydrocodone or codeine. The final visit was scheduled 4 weeks after the baseline and at this visit the same tests, instruments and assessments were carried out. Pill counts were completed and patients were discharged from the study.
Efficacy assessment and analysis
Efficacy was determined in three domains. The first was pain, measured as change from baseline in one of the following: WOMAC question #1, WOMAC question #2, or the mean of items 3,5 and 6 on the BPI. The second domain was stiffness, measured as change from baseline in at least one of the following: WOMAC question #3, #4 or #5. The third domain was global functional assessment measured as change from baseline in walking time, mHAQ score or the mean of BPI in questions 9a-9g. Improvement in each domain was defined as a change of at least 20% compared to the pretreatment baseline, analogous to the ACR20 response criteria for rheumatoid arthritis. The efficacy analyses were done with the blinded data; treatments were not unblinded until after each individual subject was assigned improved or unimproved status (by NO) and this status was confirmed (by MC). Only after this determination was complete were the treatment assignments unblinded.
Statistics
Analysis for efficacy was done using the per protocol population. Safety analyses included all patients who received any dose of blinded study medication. For continuous variables, data were expressed as the mean and standard error of the mean (SEM). Groups of continuous variables were compared using a t-test for 2 groups or a 1-way ANOVA for 3 or more groups. Baseline and final safety variables were compared using a paired t-test. Discontinuous variables were compared using a chi-square test. For all statistical analysis, P values < 0.05 were considered significant.