Sponsor: GSK & Adolor Corporation Study Drug: SB-767905 Entereg® or Alvimopan Protocol: SB-767905/012 CRO = Parexel
Site #: Investigator #:
Lead CRA: Louise Wohlford 937-886-9492 Hotline: 877-216-0314
Central Lab: IRB: Copernicus
480 Subjects/ 200+ Sites: 6 Subjects per Site R 1:1:1 to: Alvimopan 0.5 mgm Once Daily: Alvimopan 0.5 mgm Twice Daily: or, Placebo
OBD: Opioid-induced Bowel Dysfunction: A decrease in BM frequency and symptoms of incomplete and/or difficult defecation following initiation of opioid therapy. Associated with: infrequent, difficult or incomplete defecation, abdominal bloating and discomfort, and GERD. Also, associated with: abdominal pain, abdominal distention, anorexia and nausea.
In contrast to other opioid induced side effects like nausea and sedation which tend to resolve with continued dosing, tolerance to OBD rarely develops
OBD SIS: OBD Symptoms Improvement Scale
PAC-QOL: Patient Assessment of Constipation- Quality Of Life Questionnaire
SBM’s: Spontaneous Bowel Movements SCBM: Spontaneous Complete Bowel Movement
Central Mu Opioid Receptors in the Brain when agonized cause pain relief.
Peripheral Mu Opioid Receptors in the GI tract when antagonized cause reversal of OBD
The Clinical Hypothesis: Competitive antagonism of Opioid Analgesics at the mu-opioid receptor in the gut wall will relieve symptoms of OBD without compromising analgesia
Daily Telephone Diary, IVRS (Interactive Voice Recognition System)
Opioid naïve subjects tolerated Alvimopan up to 120 mgm without AE’s whereas subjects on long-term opioids ad AE’s on 3 mgm’s of: severe GI complaints like: cramping, diarrhea, nausea and vomiting. Doses up to 1 mgm BID have AE’s similar to placebo.
RAMOS: Registration and Medication Ordering System
Rescue Laxative: Dulcolax (Bisacodyl) 5 mgms 2-6 tabs (10-30 mgm) Daily as needed
IC
Equal/greater than 18 And if on Metamucil, Stable Constant Dose
MS 30 mgm or more x 1 month stable prior to V1 (Except Codeine) for non-cancer pain
OBD: Decreased BM Frequency and at least one other BM symptom: Sense of Incomplete Evacuation after passing a stool; Hard Stools; or, Straining to pass a stool.
To be R on V2D1, need:
1. < 3 > 0 BM’s per wk;
2. One other BM Sx equal/greater than 25% of time, including: Sense of Incomplete Evacuation; Straining to Pass a Stool; Lumpy Hard Stools or Small Pellets
3. compliance with Standardized Rescue Laxative Use Guideline
EC
No BM x 7 D
Needs regular manual disimpaction
Diarrhea or use of anti-dirrheals
HIV, Hepatitis B or C
Cancer x 5 yrs

26 July 2005
VERSION: 1 2 3 4 5 6 7 8 9

GSK-012
Efficacy Study

V1 D -14 Lab, ICF, RTC 2 wks +/- 2D
V2 D 1 Lab, R, assign treatment number
V3 W 4 Lab +/- 3D
V4 W 8 Lab +/- 3D
V5 W 12 Lab, Treatment Withdrawal Visit +/- 3D
V6 W 14 Lab, Follow-Up Visit +/- 2D
Discuss 014 Extension, even if flunk out for noncompliance with:. … Telephonic Diary System or Ineligible Bowel Pattern

28 August 2005
VERSION: 1 2 3 4 5 6 7 8 9

GSK-012
Efficacy Study
Equianalgesic Dosing
Opioid Interchange MS 30

Morphine Sulfate (Avinza, Kadian) - 30
Tramadol (Ultram) - 300
Hydrocodone (Lortab, Vicodin) - 15
Propoxyphene (Darvocet) - 200
Codeine (Tylenol # 3) - 120
Levorphanol (Levodromoran) - 4
Hydromorphone (Dilaudid) - 7.5
Oxycodone (OxyIR, Oxycontin, Percocet) - 15
Methadone - 4
Fentanyl (Duragesic Patch) - 25

Investigator Meeting Lost Lake, Henderson, Nevada
Aug. 25-26 or 27-28