功能性消化不良英文课件

TEGASEROD PROGRAM FUNCTIONAL DYSPEPSIA Sam O. Sue, MD VP/Clinic Research Development Global Medical Advisor East Hanover, NJ USA NOVARTIS PHARMACEUTICALS CORPORATION 1 Functional Dyspepsia w Recurrent upper Abnominal Discomfort without identifiable cause w Often meal related epigastric discomfortBloating, Early Satiety, Fullness w 20 to 30% Gastro Consults 2 Tegaserod Mechanistic Properties w Tegaserod accelerates Gastric Emptying - Volunteers w Tegaserod normalizes delayed Gastric Emptying - FD w Tegaserod improves post meal Gastric accommodation Merz, M. et al Clinical Pharmacology Report, Novartis oct 99 Earnest, D. et al submitted Gastro - DDW 2003 Jack, J. et al UEGW 2002 (references?) 3 Functional Dyspepsia Phase II Studies w 4 DBPC dose finding studies (D2201-2204) Patient Population: FD 3 months duration Treatment : 8 weeks Gastric emptying status NGEBID (D2202) TID (D2204) DGE (+NGE)BID (D2201) 12 mg x TID (D2203) 0.5 mg x x x 2 mg x x x x 6 mg x x x x 4 Study Design Placebo Tegaserod bid/tid Tegaserod bid/tid Tegaserod bid/tid Screening 1 week2 weeks Baseline 8 weeks EndoscopyEndoscopy ScintigraphyScintigraphy Random-Random- izationization Daily (first week) and WeeklyDaily Touch-Tone Dyspepsia Assessment (IVRS) 5 FD: Efficacy Assessments w Primary: Satisfactory relief of meal related stomach problems (IVRS): Yes/No Daily (last week baseline, first week treatment) Weekly (remainder of treatment) w Secondary: Daily severity of (4-pt scale, IVRS): early satiety, postprandial fullness, postprandial bloating in the stomach region, stomach pain, nausea, vomiting Quality of Life Generic (MOS SF-36) Disease specific (Nepean) 6 Secondary Efficacy Assessments Weekly:most bothersome symptom Daily: early satiety postprandial fullness postprandial bloating in the stomach region nausea epigastric/stomach pain vomiting (yes/no) Daily discomfort scale 0 = none (not present) 1 = mild (awareness of the symptom but easily tolerated) 2 = moderate (discomfort sufficient to interfere with normal activities such as work and sleep) 3 = severe (incapacitating with inability to perform normal activities such as work and sleep) 7 Disease characteristics at Baseline Most bothersome symptoms (Pooled ITT) 37% 21% 19% 10% 10% 2% 0% 5% 10% 15% 20% 25% 30% 35% 40% Percent of patients Postprandial bloating Epigastric/Stomach Pain Postprandial fullness Nausea Early Satiety Vomiting 8 Responder Rates for Satisfactory Relief Responder: Satisfactory relief at least 50% or 75% of the weeks during treatment period Placebo BID (n=125) T 0.5 mg bid (n=69) T 2 mg bid (n=120) T 6 mg bid (n=119) T 12 mg bid (n=55) Placebo TID (n=95) T 0.5 mg tid (n=94) T 2 mg tid (n=94) T 6 mg tid (n=89) 50% 75% Responders (pooled ITT) BIDTIDBIDTID 11.8% 5.6% 37.6% 24.8% 40.6% 24.6% 37.5% 21.7% 35.3% 22.7% 36.4% 10.9% 26.3% 12.6% 24.5% 13.8% 31.9% 24.5% 14.6% 29.2% 0% 10% 20% 30% 40% * 9 T24T18T12T6Placebo Gastric Retention (%) of Meal at 4 hours post meal (DGE-ITT) * “normal” gastric retention rate at 4 hours is 6.3% 10 Summary of Tolerability (D2201-2204) w Most frequent adverse event is diarrhea Dose dependent increase in frequency irrespective of gastric emptying status Leading rarely to discontinuation, highest in 6 mg TID with 9% More frequent in males Diarrhea not well defined and frequency possibly overestimated 11 Conclusions w Baseline severity and gastric emptying status were significant covariates for all symptoms. Other “less important” covariates include age and hp status. w For fullness, satiety, and bloating, the medium doses, i.e. 2 tid, 6 bid and 6 tid showed positive treatment effects at most weeks. The best treatment effects were around 0.1 (improvement over placebo). 12 Conclusions (cont.) w Better treatment responses were observed in some patient subgroups, e.g. Female patients tended to be more responsive with me