BUP 3019
Randomized, Double-blind, Multicenter, Active Comparator Study to Determine the Efficacy and Safety of BTDS 20 or OxyIR versus BTDS 5 in Subjects with Moderate to Severe Osteoarthritis (OA) Pain

Sponsor: Purdue Pharma L.P. (PPLP)
Study Drug: Buprenorphine Transdermal System BTDS = Buprenorphine Transdermal System: 5, 10 & 20
Subutex = Temgesic = Buprenex marketed as an injectable since 1982, BTDS & SL now available in England; Schedule III
Over 3100 subjects enrolled
Medical Monitor: Lucille Russell, MD 203-588-8281/203-588-6205(Fax)/203-912-8423(Cell) Lucille.Russell@Pharma.com
CRA: Pat Williams, RN PatWilms@aol.com 910-367-2198 Fax: 775-640-7490
Partial mu-opioid agonist and kappa-opioid antagonist
40 BTDS prolongs QTc interval
Mu-opioid agonist-related AE’s: nausea, vomiting, dizziness, dry mouth, somnolence and constipation
Rescue Drug: ibuprofen 200 or Tylenol if intolerant to ibuprofen
Central IRB: Coast
Central Lab: LabCorp
Site #: 114A
Investigator #: 2384
Site Specific Subject #: 16101; 16102, etc…
Alliance Call Center
Phase 3
696 Subjects/80 Sites = 9 Subjects per Site (232 Subjects R in each of the three groups: BTDS 5, BTDS 20 or OxyIR® 10 q 6h)
Triple-Dummy Technique: BTDS 5: BTDS 20: OxyIR 10 mgm QID Randomized in a 1:1:1 ratio

IC
Age: 40 years & older
Clinical Dx LBP, OA Hip (supine) or Knee (standing) x 1 yr confirmed by grade ii-iv X-Ray evidence within past 2 yrs
Currently on MS 30-80 mgm per day at least 4 days a week for the last month

EC
Other chronic painful conditions frequently requiring analgesic therapy
Unstable Steroids less than 6 weeks
Intra-articular steroid x 6 wks or Hylagan or Synvisc
Workman’s compensation or other litigation
QTc or QT > 500 msec, QTcF > 480 msec
Duragesic (fentanyl) or Palladone
Any prior participation in a BTDS Study
High Potassium Level
FH Congenital Long QT Interval

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BUP 3019

V1 W -4 Lab, ICF Pre-Randomization /Screen/Prospective Assessment, EKG x 4 10 min. apart, x-ray within 2 yrs, RTC 7d
V2 W -3 Reduce pain-meds/opioid taper, RTC 7d or sooner if pain (Not longer than 7 d), SOWS
Phone call - - - 3 days later, if pain score equal/greater than 5 on two consecutive days, may stop taper
V3 W -2 Poor pain control x 2 d (pain score equal/greater than 5 & SOWS equal/less than 23), begin open-label run-in with BTDS 10, opioid taper completed, - EKG x 4 10 min. apart, RTC 7d, reduced non-opioid analgesic to ½
Phone call - - - 3 days later and increase to 20 if well tolerated. May wait 7 days to increase or flunk out
V4 W -1 Flunk out if not tolerating BTDS 20 & complete V5 early term., RTC 7d, must use supplemental analgesic medication QID . . or less! Apply new BTDS 20 Patch, tell subjects not to take supplemental pain Meds for 48 H prior to V5
V4.1W-1 EKG x 4
V5 D 0 Lab, R if: achieved stable analgesia equal/less than 4 wearing BTDS 20 x 7 days, early term run-in period (send home with a bottle OxyIR 5 mgm for BID prn use if ibuprofen & Tylenol not adequate pain relief)
V6 W 1 Call subject 72h prior & tell don’t take supplemental analgesic for 48 hrs prior to V
V7 W 2 Call subject 72h prior & tell don’t take supplemental analgesic for 48 hrs prior to V
V8 W 4 Call, EKG x 4 ten min. apart from each other, Dispense Only 2 wks
V8.1W 6 Dispense 2 weeks (No need to see Doctor)
V9 W 8 Call subject 72h prior & tell don’t take supplemental analgesic for 48 hrs prior to V
V9.1W 10 Dispense 2 weeks (No need to see Doctor)
V10 W 12 (Ext wk 0) Lab EKG x 4 ten min. apart., Call, Extension Phase BTDS 5 Patch
The Extension Phase
52 wk (12 month) open-label extension using BTDS 5, 10 and 20 to evaluate the long-term safety and tolerability of BTDS.
Begin with BTDS 5 and 72 h later may increase BTDS 10 Patch; 72 h after that increase BTDS 20 Patch
OK to titrate Patch up or down during Extension Phase
OK to use short acting opioids like OxyIR 5 mgm prn as needed for breakthrough pain during Extension Phase
V11 W 13 (Ext wk 1) 1st Extension Visit, Begin BTDS 5 and may titrate BTDS up q 72h to 10 and 20.
V12 W 16 (Ext wk 4) OK to titrate BTDS up or down prn as needed during extension phase
V13 W 20 (Ext wk 8) OK to add short acting narcotics like OxyIR 5 prn during extension phase
V14 W 24 (Ext wk 12) Subjects need to pay for short acting narcotics they use prn during extension phase
V15 W 28 (Ext wk 16)
V16 W 32 (Ext wk 20)
V17 W 36 (Ext wk 24) Lab
V18 W 40 (Ext wk 28)
V19 W 44 (Ext wk 32)
V20 W 48 (Ext wk 36)
V21 W 52 (Ext wk 40)
V22 W 56 (Ext wk 44)
V23 W 60 (Ext wk 48)
V24 W 64 (Ext wk 52) Lab

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BUP 3019
Equianalgesic Dosing
Opioid Interchange MS 30 – 80 mgm

Morphine Sulfate (Avinza, Kadian) — 30-80
Hydrocodone (Lortab, Vicodin) — 15-40
Propoxyphene (Darvocet) — 225-600
Levorphanol (Levodromoran) — 2-5
Hydromorphone (Dilaudid) — 4-10
Codeine (Tylenol # 3) — 90-250
Oxycodone (OxyIR, Oxycontin, Percocet) — 15-40
Merperidine (Demerol) — 150-400
Methadone — 10-27
Tramadol (Ultram) — 300-800
Fentanyl (Duragesic Patch) — 25-50
Palladone (Hydromorphone XL) 12mgm =Duragesic 50mcg = Oxycontin 40
(Available as: 12, 16, 24, 32)
(Duragesic Patch & Palladone are not allowed)

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BUP 3019 X-Ray Grading System
Osteoarthritis Severity Grades for Knee, His and Spine Joints

Subjects are required to have radiographic evidence of Grade 2-4 osteoarthritis of the hip, knee or spine. The scale used for assessing OA, described below, must be applied to a radiograph of the joint (Standing position required for knee. Supine for Hip.)
Knee and Spine Joints (Standing Knee)
0 Normal
1 Doubtful narrowing of joint space and possible osteophyte lipping
2 Definite osteophytes and possible narrowing of joint space
3 Moderate multiple osteophytes, definite narrowing of joint space and some sclerosis and some sclerosis and possible deformity of bone ends
4 Large osteophytes, marked narrowing of joint space, severe sclerosis and definite deformity of bone ends
Hip Joint (Supine Hip)
0 Normal
1 Possible narrowing
2 Definite narrowing of joint space inferiorly, definite osteophytes and slight sclerosis
3 Marked narrowing of joint space, slight osteophytes, some sclerosis and cyst formation and deformity of femoral head and acetabulum
4 Gross loss of joint space with sclerosis and cysts, marked deformity of femoral head and acetabulum and large osteophytes
Adapted from the Council for International Organizations of Medical Sciences 1963