IC
21-75
OA Hip or Knee
Taken an Analgesic for Arthritis Pain for the majority of days in the previous 3 months and for at least 4 days/wk during the previous 4 wks
Must Meet at Least 1 of the Following:
1. Is unable to consistently control index joint pain with Non-Opioid Analgesics or Ultram (Tramadol)
2. Is unable to treat index joint pain with non-opioid analgesics because treatment is medically contraindicated due to side effects or physician judgment
3. Currently requiring an Opioid (single or combination product) for treatment of index joint pain with the equivalent of ? 60 MS inclusive of breakthrough pain medication
Meets the following Flare Criteria at Baseline Visit:
1. Subjects Assessment of Arthritis Pain Intensity by VAS of equal/greater than 40 mm
2. An increase of ? 10 mm from the Subject’s Assessment of Arthritis Pain Intensity by VAS obtained at the Screening Visit
3. Subject’s Global Assessment of Arthritis Status at Baseline Visit if Fair, Poor or Very Poor

EC
Has incurred an injury to the index joint within 3 months prior to Screening Visit
Major Surgery to the index joint within the last year
Joint replacement/reconstruction to the index joint
Arthroscopic or open surgery to the index joint within the last year
Any surgery within 3 months prior to the Screening Visit
h/o Inflammatory Arthritides such as: RA; Seronegative Spondyloarthropathy; Gout, or Pseudogout
Other Chronic Painful Syndromes such as Paget’s disease or FM
Infectious Arthritis involving the index joint
Any steroids x 1 month
Index joint steroids within 2 months
Viscosupplementation therapy (Synvisc or Hylagan) to the index joint within 4 months
More than 4 ETOH Alcoholic Drinks per Day
Cancer within 5 years
Hepatitis A, B or C
AST/ALT equal/greater than 1.5x ULN
Creatinine > 1.5
Major Depression or any Psych disorder x 2 yrs
Unable to discontinue all formulations of prior analgesics (opioid and/or non-opioid) during the Washout Period of the study
Workman’s Comp or Litigation
Any new adjunctive OA therapy such as PT within 1 month Screening Visit

27 March 2006
VERSION: 1 2 3 4 5 6 7 8 9

Abbott Vicodin CR
M04-697 OA Hip & Knee

V1 W Scr. Lab, ICF, Screening, EKG, Washout, RM OK, Hold RM 48H prior to V2
V2 W Baseline Lab, Baseline, If meet Flare Criteria, R to: Vicodin CR vs. Placebo. Begin Titration-Up Period: take 1 Tab Vicodin® CR 15/500 HS vs. Placebo x 4days, then ? 1 Tab BID x 3 days (Baseline-Titration)
. V3 W 1 BT One Tab BID x 1 week (Baseline-Titration)
V4 W 2 BT AM: One Tab + PM: 2 Tabs(Baseline-Titration)
V5 W 3 BT 2 Tabs BID (Baseline-Titration)
V6 W 1M Lab Maintenance Period
V7 W 2M Maintenance Period
V8 W 4M Lab, Maintenance Period
V9 W 6M Lab, Maintenance Period
V10 W 8M Lab
V11 W 12M Lab, EKG
V12 W 13Taper One Tab BID x 4 D: One Tab Daily x 3 D V13 W 14 F/U

23 March 2006
VERSION: 1 2 3 4 5 6 7 8 9

Abbott Vicodin CR
M04-697 OA Hip & Knee
Equianalgesic Dosing
Opioid Interchange of MS 60 mgm Equivalent

Morphine Sulfate (Avinza, Kadian) — 60
Tramadol (Ultram) — 600
Hydrocodone (Lortab, Vicodin) — 30
Propoxyphene (Darvocet) — 400
Codeine (Tylenol # 3) — 240
Levorphanol (Levodromoran) — 7.5
Hydromorphone (Dilaudid) — 15
Oxycodone (OxyIR, Oxycontin, Percocet) — 30
Methadone — 7.5
Fentanyl (Duragesic Patch) — 25

23 March 2006
VERSION: 1 2 3 4 5 6 7 8 9

Questions

1. Will there be a grading system to judge the severity of the OA like we used on the BUP trials? Yes: Pi to assign grade
2. Will they need an x-ray to prove the have OA of the HIP or KNEE? Yes
3. We can all do a study like this, but the drop out rate is bound to be high. I hope Abbott appreciates this and is appropriately factored into the budget as it is obvious that there will be many subjects that will withdraw consent due to their pain not being adequately controlled. That is, by definition a potential subject entering this trial would not be adequately controlled with the RM provided. At the investigator meeting in Chicago 23-25 Sept. we should encourage sites to tell subjects that we understand that a third of them will receive placebo with inadequate RM back up and that we expect them to drop out for uncontrolled pain.
4. Since we are devising a study where up front we are grossly under treating subjects who are in chronic pain, we are to expect compliant subjects to markedly reduce their activity as the only way to diminish the OA pain. Are we planning on compensating subjects higher than usual for requesting them in the name of science to place themselves in harms way in such a fashion? And, this will be needed to be spelled out in the ICF regarding how the study plans to restrict pain medication to a group of patients that are accustomed to taking them more often and in stronger forms than they will be provided in the study and that we expect them to withdraw consent if the pain becomes too severe or their disability worsens.
5. Will there be a disability questioner like the BUP to capture how the OA is impacting their QOL and what they can or can not due with their pain? No