Effects of an Herbal Topical Cream on Osteoarthritis Symptoms, Biomarkers, and Disease Progression in the Knee

General Procedure: Subjects will be screened for: a history of knee pain and surgery by
questionnaire; kidney disease as determined by blood creatinine levels; knee diameter less
than 17cm and body diameter less than 60 cm due to the physical constraints of the MRI. Any
prior X-rays or MRIs will be examined to evaluate the subject's level of OA. If they qualify
and wish to enroll, they will be matched on age, sex and degree of OA and assigned by a 3rd
party investigator to either a placebo group or active treatment group. Subjects will be
asked to complete baseline questionnaires, functional tests, and have blood draws and MRI
screenings before starting their treatment. Enrolled subjects will apply 2.5 grams of active
or placebo cream 3 times per day to the skin over the affected knee for 12 weeks. Further
measurements will be taken periodically throughout the course of the study, as detailed
below.

MRI: Subjects will receive MRI scans of the affected knee 3 times: at enrollment, 12 weeks,
and 15 months. The MRI scan sessions will take place at the Lucas Center for MRI at Stanford
University. In preparation for the MRI scan, subjects will be required to fill out a
standard MRI screening form to ensure that there are no conditions that could interfere with
the MRI imaging or that could make scanning in any way hazardous. During the sessions,
subjects will lie on the scanner table on their backs with their legs straight. We will scan
one knee. The time for this scan will be approximately 1 hour. This entire session will take
approximately 1 and 1/2 hours, including setup time.

Subjects may be asked to receive a small dose of intravenous gadolinium contrast agent,
administered by Dr. Gold. This is to improve the evaluation of the articular cartilage.

Questionnaires: Subjects will receive physical activity, pain and function questionnaires at
enrollment, 4 weeks, 8 weeks, 12 weeks, 14 weeks, 16 weeks, 20 weeks, 6 months, 9 months, 12
months, and 15 months. They will also keep a log of use of other pain medicine, such as
aspirin.

Blood/Urine Samples: A small amount of blood (2 tablespoons or 30 ml) will be drawn and
urine collected up to 11 times throughout the investigation to study blood markers of
cartilage breakdown (COMP, CTX2, Glc-Gal-PYD) and synthesis (PIIANP) as well as inflammation
(HA, CRP) and joint vascularity (TNF-alpha, IL-6, osteocalcin). Blood creatinine levels will
be tested at baseline only.

Functional Testing: Subjects will also participate in functional testing that will include
walking tests, rising from a chair, and climbing stairs up to 11 times throughout the
15-month study. The "6-minute Walk" test is a good indicator of cardiovascular capacity. We
will ask subjects to cover as much ground as possible in 6 minutes at a maintainable pace,
and will record the distance traveled. The "Get up and Go" test will measure the time it
takes a subject to rise from a standard chair, walk three meters, turn around, return, and
sit down again. Subjects will perform 3 trials, and their fastest time will be recorded. The
"Timed Stair Climb" test will measure the time it takes subjects to climb up and down five
standardized steps. Subjects will be instructed to ascend and descent as fast as possible
using the handrails provided. They will perform 3 trials and the fastest time will be
selected. Walking speed tests offers an indirect way to measure the functional impact of
pain. We will ask subjects to walk 10 meters at a maximal or a self-selected pace and will
calculate their walking speeds. They will perform between 3 to 6 trials of each test.

All tests will be performed in accordance with ACSM guidelines for exercise testing.

Inclusion Criteria:-Men and women between 40-70 years old

- Have a history of knee pain

- Exhibit mild osteoarthritis on the knee, as determined by Dr. Gold through MRIs and
radiographs (if available). Exclusion Criteria:-Outside of age range

- Prior knee surgery

- History of knee or knee ligament instability

- History of intermittent or persistent knee joint swelling

- History of trauma to the knee or lower extremities resulting in fracture, tears of
menisci, ligaments or joint capsule, or cartilage damage

- Unable to have MRI scan due to the presence of metallic internal devices that would
represent a risk factor for MRI and known or suspected pregnancy.

History of corticosteroid use

- Kidney Disease

- Knee diameter greater than 17cm and body diameter greater than 60 cm due to the
physical constraints of the MRI