This study describes the results of a first pilot clinical trial of UP446 in OA subjects. UP446 is a novel dual pathway inhibitor of botanical origin. The effects of two different doses of this plant extract were evaluated on osteoarthritis and compared to placebo and Celecoxib. This study demonstrated that UP446 at both dose levels and Celecoxib were associated with significant reduction in pain, stiffness and functional incapacity as compared to placebo. Although the treatment groups were small, the results strongly suggest that UP446 at 500 mgs per day was significantly more effective than Celecoxib at 200 mgs for pain reduction and improvement in function as measured by the WOMAC. These findings offer an alternative way of dealing with the discomfort associated with osteoarthritis, there are many NSAIDs available but their major side effects are well known . There are some limitations and interesting findings in this pilot study. For example, the statistical findings in changes from baseline (p value < 0.05) were not consistent at the 30, 60 and 90 days time points for any of the study groups. For the pain the scores, the UP446 at both dose levels has significance at 30 and 90 days but not at 60 days in contrast the celecoxib group at 60 and 90 days but not at 30 days. Review of the study shows that the average change in WOMAC pain score (Figure 1) for UP446 at 250 mgs was remarkably close for the 30, 60 and 90 day measurement; mean -13 at 30 days, -14.64 at 60 days and -13.57 at 90 days. In fact the value at 60 days is if anything suggestive of a better result than the 30 day and 90 day values (Figure 1). We conclude that any "statistical" differences between the values are therefore due to differences in variance (standard deviation), which results in the 60 day value having marginally less statistical significance than the 30 day and 90 day values. Thus while only the 90 day value achieved p < =0.05, in fact the 30 day (p = 0.058) and the 60 day (p = 0.062) values are as meaningful and indicative of efficacy as the 90 day value (p = 0.045). For the UP446 500 mgs/day group statistical significance at p < 0.05 is achieved at 30 days (p = 0.001) and at 90 days (p = 0.001) but not a 60 days (p = 0.102), and for the Celecoxib group significance at p < 0.05 was observed at 60 days (p = 0.004) and at 90 days (p = 0.021) but not a 30 days (p = 0.375).
We also found lack of agreement between the WOMAC and the SF-36 assessments, these are not uncommon and have been previously reported , still the WOMAC is the most common and appropriate tool for evaluation of hip and knee osteoarthritis .
The fact that there were positive fecal occult blood tests (FOBT) in all the groups to include placebo makes it difficult to use this as a safety marker. Since the total number of positive test results in the placebo group, was equal to or greater than the two UP446 treatment groups (Table 10), the occurrence of positive FOBT test results is not UP446 treatment related. The guaiac test utilizes a colorimetric indicator that produces a detectable color change upon oxidation . The presence of occult blood is based on oxidation of the indicator by the heme moiety of hemoglobin, which possesses peroxidase activity. There are however, a large number of other redox substances and peroxidases or peroxidase-like enzymes that will test positive or otherwise interfere with this assay . Many of these interferants are present in normal dietary foods. While patients may be warned not to eat red meat or certain fruits and vegetables, to avoid use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), and to avoid ingesting vitamin C, e.g., orange juice, all for the 72 hour period before testing, strict compliance with these instructions is likely poor.
The baseline average systolic blood pressures for the study groups range from a mean of 134 to 159; thus all groups are pre-hypertensive or overtly hypertensive as defined by the American Heart Association. The high baseline systolic blood pressures combined with the reported increased physical activity and the observed weight loss for all three of the treatment groups is likely to account for the beneficial reduction in systolic blood pressure with the result that participants in the treatment groups are closer to desirable blood pressure values as per the American Heart Association Guidelines, less 120 mm Hg Systolic and less than 80 mm Hg Diastolic. Notably maximal reduction in systolic blood pressure was achieved after 30 days dosing with no further reduction observed after dosing for 90 days. Diastolic blood pressure and resting pulse did not change during the course of the study.
All active treatment groups experienced weight loss, with BMI changes of between 1.6-2.4 kg/m2. The study participants reported no other adverse events and the clinical laboratory evaluations showed no abnormal results that would be indicative of abnormal nutritional status or metabolism. Per protocol the study participants had no dietary or exercise restrictions. These changes can be attributed to increased physical activity reported by study participants as a result of improved mobility and reduced discomfort associated with treatment regimens.