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Clarithromycin (CL) and omeprazole (OM) in the prevention of duodenal ulcer (DU) recurrence and eradication of H. pylori (Hp)
April 1995
Esophageal, Gastric, and Duodenal Disorders
CLARITHROMYCIN (CL) AND OMEPRAZOLE (OM) IN THE PREVENTION OF DUODENAL ULCER (DU) RECURRENCE AND ERADICATION OF H. PYLORI (Hp). KD Bardhan. RPH Logan, LR Celestin, A Theodossi, K Palmer, PI Reed, for the BHURG study, St. Mary's Hospital, London, UK
The results from the first dual therapy study of CL and OM with 12 month follow-up is reported. Patients with DU and Hp were enrolled in this randomized, double blind, multi-center study. Patients received either O M 40 mgQD for 4 weeks and either CL 500 mg TID or placebo (PL)for days 1-14. Repeat endoscopy was done at 2 and 4 weeks after the start of treatment (Rx) and 4-6 weeks, 6 months and 12 months after Rx. H. pylori status was assessed by antral and corpus histology, culture and by 13C.urea breath test at preRx and 4-6 weeks, 6 months and 12 months after treatment. E~acy_ HpEradicationat 4-6weekspostRx DURecurrenceat 12monthsPostRx Hp negative Hp positive
CL+OM
Pb-K:~
83% (57169) 4% 5% 0%
(2/48) (2/38) (0/10)
1%
(1/75)
77% (48/62) 0% (0/1) 79% (48/61)
* Includesall patientswithspecificvisits. CL and OM were well tolerated, only 4 of CL+OM and 1 of PL+OM patients withdrew from study due to adverse events. This dual therapy of clarithromycin and omeprazole shows promise as a treatment regimen for eradication of Hp and prevention of DU recurrence.
• GR122311X (RAN1TIDINE BISMUTH CITRATE) WITH CLARITHROMYCIN FOR THE TREATMENT OF DUODENAL ULCER. ~Bar~ 1, C Dalinire2, H Eisold3, AE Duggan4 IRotherham District Hospital, UK. 2St Francois d'Assisc Hospital, Quebec, Canada. 3M6ssingen, Germany. 4Glaxo Research and Development Limited, UK. Introduction: GRI22311X(GR) possesses anti-senrctory, anti-peptic, anti-Helicobacter pylori(I~.p) and mucosal protective properties. This doubleblind, randomised, multicentre study compared the efficacy and safety of OR 400mg bd monotherapy for 28 days (GR400) to trezmgnt with GR 400mg bd or 800rag bd in co-prescription with clarithromycin 250mg qds for 14 days, followed by 14 days of GR 400rag bd monotherapy (GR400+CLAR and GRS00+CLAR, respectively) in duodenal ulcer (DU) treatment. " • 232 patients with active DU (of whom 215 had confirmed H.p infection) entered the study. Patients with healed ulcers were followed for up to 6 months on no therapy with endoscopy at 1, 3 and 6 months. The primary efficacy assessment, overall success rate, was defined as the proportion of patients whose ulcers were healed and who remained ulcer-free dor~ing follow-up and was estimated by fife-table analysis. H.p was assessed by !3C-urea breath test (UBT) and CLOt•st® on 2 antra] and corpus biopsies at each endoscopy. In a prevalence analysis of patients with both CLOt•st and UBT results, H.p eradication was assumed if all tests were negative (e.g 4 biopsies and excess B13C02 ~5 per rail) >4 weeks after the end of trentnu=zt. Trough plasma bismuth levels were also assayed. Re.cult~ (Intent-to-Treat Analvsis~
• •
GR400
GR400 +
GRS00 +
CLAR 75 89%*
CLAR 75 87%*
Numbers of patients with DU 82 Overall success rates after 6m 51% follow-up (life-table estimates) • Healing rates at 4wk (LOCF)t 83% 89% 93% • Relapse rates atter 6m (LOCF)t 40% 6%* 9%* • ~ pyiort eradication (prevalence) 2% 94%* 84%* • Patients with any adverse event 29% 28% 25% '0 Median 4wk bismuth (ng/mL) 2.0 5.3 6.5 *p<0.001 for comparisonof monotherapywith each co-precdption regimen. tLOCF = last observationcaxded forward Conclusion GR in co-prescription with clarithromy¢in was well tolerated and was effective in healing of DU, eradication o f H. pylori and prevention of DU recurrence. Compared with monotherapy a higher proportion of patients treated with GR and clarithromycin remained ulcer free for up to 6 months. Funded by Glaxo Research and Development Ltd.
A53
EROSIVE ESOPHAGITIS(EE): OUTCOME OF REPEATED LONGTERM TREATMENTWITH LOW DOSEOMEPRAZOLE(OM) 10mg OR PLACEBO(PLA). KD Bardhan, P Cherian, A Vaishnavi, RB Jones, M Thompson, P Morris, A Brooks, J D'Silva, KRW Gillon*, C Wason*, J Patterson*. Rotherham General Hospital, UK. We investigated the efficacy of daily low dose OM lOmg in reducing the relapse rate of EE, and i f repeated therapy gave similar results. METHOD300 consecutive patients with EE grades 2, 3(isolated & confluent erosion) and 4(ulceration) were treated with OM 20mg daily for up to 12 weeks. After healing they were randomly allocated to double-blind daily therapy with OM 10mgor PLA for up to 18 months. Endoscopywas done at 6,12 & 18 months i f asymptomatic or whenever symptoms recurred. Upon relapse (recurrence of erosive changes or of typical symptoms) the cycle was repeated. Analysis involved all
patients treated.
RESULTS Cuwlative healino on Oil 20mg
~ 8wk 12wk ist course 300 77% 86% 90% The grade of disease did 2nd course 134 74% 81% 90% not affect healing rates Maintenance treatment(HTl DemoqraphvBoth groups were similar. Cumulative relapse n ~ 12~o l~mo Ist course PLA 133 72% 81% 84% <0.0001 OM IOmg 130 29% 37% 44% 2nd course PLA 88 84% 91% 91% 0.016 OM IOmg 28 64% 75% 75% Subarouo of patients who had 2 courses of MT: Cumulative relapse rate Course No. 6mo 12mo 18mo PLA n=8B Ist 67% 78% 79% 2nd 84% 91% 91% OM IOmg n=2B Ist 71% 93% 96% 2nd 64% 75% 76% ]. Half the recurrences were symptomatic only; one-quarter had erosive, silent disease and the remainder symptomatic EE. 2. Grade of disease, healing rates, smoking and drinking did no__tt affect outcome. DISCUSSIONThe high spontaneous relapse rate is halved byOM 10mgdaily: The natural history of the disease repeats i t s e l f : relapse on PLA or on OM 10mg is generally followed by the same outcome i f treatment is repeated. Therefore, the few relapsing on OM 10mg may need OM 20mg (preliminary results: relapse <10%). CONCLUSIONDaily MT with OM IOmg markedly reduces the relapse rate of EE. Supported by *Astra Clinical Research Unit, Edinburgh, UK.
"HIGH-RISK" DUODENAL ULCER(DU): LONGTERM MAINTENANCE TREATMENT(MT) WITH LOW(1Omg) & FULL(2Omg) DOSEOMEPRAZOLE(OM) VS RANITIDINE(RAN). KD Bardhan, P Cherian, A Vaishnavi, RB Jones, P Morris, M Thompson, A Brooks, J D'Silva, KRWGillon*, SA Parkin*, J Patterson*. RotherhamGeneral Hospital, UK. AIM We compared the efficacy of MT with OM 10mg and 20mg daily against RAN 160mg nightly, a standard regime, in preventing relapse in high-risk(HR) DU patients. PATIENTSThose particularly likely to (I) relapse:~>3 recurrences in past 24 months, or refractory ulcer or (2) have complications (previous bleed or perforation); (3) those in whom complications carry higher mortality (age >60 and/or with associated disease). NETIN)O 120 consecutive HR DU patients (of 400 DU patients screened) were preallocated to double-blind MT (for up to 24 months) but f i r s t given healing therapy with OM 20mg daily or RAN i50mg bd. Patients were endoscoped6-monthly during MT or earlier i f symptoms developed. The cycle was repeated upon relapse. Analysis involved a l l patients treated. RESULTS OemoaraDhv The 3 groups were similar. Cumuiative healinq n 2wk 4wk 8Wlk Previous frequent • OM 20mg* 40 65% 78% 80% relapses or • OM 20mg 40 65% 88% 88% refractoriness had • RAN 150mg x 2 40 68% 96% 85% no significant effect * Subsequently had MT OH 10mg Cumulative relapse on MT Q 6m___Q 12~o ]8mo 24mo OH 10mg 32 16% 19% 22% 25% OM 20mg 39 15% 21% 21% 21% RAN I50mg 39 46% 54% 54% 56% ON vs RAN: p=O.O006 Factors affectina relaose Patients aged <60 years (p=0.0059) and smokers (p=0.0057) had significantly higher relapse rate. Outcome of reDeated treatment IO and 16 patients were retreated with OM20 or RAN 150mg bd respectively; only 2, 4 and 12 then had repeat MT with OM lOmg, OH 20mg and RAN 150nKJ: I, 2, and g respectively relapsed by 24 months. DISCUSSION The high relapse rate on RAN reflects the aggressive nature of the disease in the patients selected (and contrasts to our observed recurrence of 26% at 5 years in unselected patients). This relapse rate is halved by OM. CONCLUSIONMT with OM 10mg and 20mg daily markedly reduces the relapse rate in high-risk DU patients and is significantly superior to RAN 150mg nightly.
SupPorted by *Astra Clinical Research Unit, Edinburoh. UK.
Esophageal, Gastric, and Duodenal Disorders
CLARITHROMYCIN (CL) AND OMEPRAZOLE (OM) IN THE PREVENTION OF DUODENAL ULCER (DU) RECURRENCE AND ERADICATION OF H. PYLORI (Hp). KD Bardhan. RPH Logan, LR Celestin, A Theodossi, K Palmer, PI Reed, for the BHURG study, St. Mary's Hospital, London, UK
The results from the first dual therapy study of CL and OM with 12 month follow-up is reported. Patients with DU and Hp were enrolled in this randomized, double blind, multi-center study. Patients received either O M 40 mgQD for 4 weeks and either CL 500 mg TID or placebo (PL)for days 1-14. Repeat endoscopy was done at 2 and 4 weeks after the start of treatment (Rx) and 4-6 weeks, 6 months and 12 months after Rx. H. pylori status was assessed by antral and corpus histology, culture and by 13C.urea breath test at preRx and 4-6 weeks, 6 months and 12 months after treatment. E~acy_ HpEradicationat 4-6weekspostRx DURecurrenceat 12monthsPostRx Hp negative Hp positive
CL+OM
Pb-K:~
83% (57169) 4% 5% 0%
(2/48) (2/38) (0/10)
1%
(1/75)
77% (48/62) 0% (0/1) 79% (48/61)
* Includesall patientswithspecificvisits. CL and OM were well tolerated, only 4 of CL+OM and 1 of PL+OM patients withdrew from study due to adverse events. This dual therapy of clarithromycin and omeprazole shows promise as a treatment regimen for eradication of Hp and prevention of DU recurrence.
• GR122311X (RAN1TIDINE BISMUTH CITRATE) WITH CLARITHROMYCIN FOR THE TREATMENT OF DUODENAL ULCER. ~Bar~ 1, C Dalinire2, H Eisold3, AE Duggan4 IRotherham District Hospital, UK. 2St Francois d'Assisc Hospital, Quebec, Canada. 3M6ssingen, Germany. 4Glaxo Research and Development Limited, UK. Introduction: GRI22311X(GR) possesses anti-senrctory, anti-peptic, anti-Helicobacter pylori(I~.p) and mucosal protective properties. This doubleblind, randomised, multicentre study compared the efficacy and safety of OR 400mg bd monotherapy for 28 days (GR400) to trezmgnt with GR 400mg bd or 800rag bd in co-prescription with clarithromycin 250mg qds for 14 days, followed by 14 days of GR 400rag bd monotherapy (GR400+CLAR and GRS00+CLAR, respectively) in duodenal ulcer (DU) treatment. " • 232 patients with active DU (of whom 215 had confirmed H.p infection) entered the study. Patients with healed ulcers were followed for up to 6 months on no therapy with endoscopy at 1, 3 and 6 months. The primary efficacy assessment, overall success rate, was defined as the proportion of patients whose ulcers were healed and who remained ulcer-free dor~ing follow-up and was estimated by fife-table analysis. H.p was assessed by !3C-urea breath test (UBT) and CLOt•st® on 2 antra] and corpus biopsies at each endoscopy. In a prevalence analysis of patients with both CLOt•st and UBT results, H.p eradication was assumed if all tests were negative (e.g 4 biopsies and excess B13C02 ~5 per rail) >4 weeks after the end of trentnu=zt. Trough plasma bismuth levels were also assayed. Re.cult~ (Intent-to-Treat Analvsis~
• •
GR400
GR400 +
GRS00 +
CLAR 75 89%*
CLAR 75 87%*
Numbers of patients with DU 82 Overall success rates after 6m 51% follow-up (life-table estimates) • Healing rates at 4wk (LOCF)t 83% 89% 93% • Relapse rates atter 6m (LOCF)t 40% 6%* 9%* • ~ pyiort eradication (prevalence) 2% 94%* 84%* • Patients with any adverse event 29% 28% 25% '0 Median 4wk bismuth (ng/mL) 2.0 5.3 6.5 *p<0.001 for comparisonof monotherapywith each co-precdption regimen. tLOCF = last observationcaxded forward Conclusion GR in co-prescription with clarithromy¢in was well tolerated and was effective in healing of DU, eradication o f H. pylori and prevention of DU recurrence. Compared with monotherapy a higher proportion of patients treated with GR and clarithromycin remained ulcer free for up to 6 months. Funded by Glaxo Research and Development Ltd.
A53
EROSIVE ESOPHAGITIS(EE): OUTCOME OF REPEATED LONGTERM TREATMENTWITH LOW DOSEOMEPRAZOLE(OM) 10mg OR PLACEBO(PLA). KD Bardhan, P Cherian, A Vaishnavi, RB Jones, M Thompson, P Morris, A Brooks, J D'Silva, KRW Gillon*, C Wason*, J Patterson*. Rotherham General Hospital, UK. We investigated the efficacy of daily low dose OM lOmg in reducing the relapse rate of EE, and i f repeated therapy gave similar results. METHOD300 consecutive patients with EE grades 2, 3(isolated & confluent erosion) and 4(ulceration) were treated with OM 20mg daily for up to 12 weeks. After healing they were randomly allocated to double-blind daily therapy with OM 10mgor PLA for up to 18 months. Endoscopywas done at 6,12 & 18 months i f asymptomatic or whenever symptoms recurred. Upon relapse (recurrence of erosive changes or of typical symptoms) the cycle was repeated. Analysis involved all
patients treated.
RESULTS Cuwlative healino on Oil 20mg
~ 8wk 12wk ist course 300 77% 86% 90% The grade of disease did 2nd course 134 74% 81% 90% not affect healing rates Maintenance treatment(HTl DemoqraphvBoth groups were similar. Cumulative relapse n ~ 12~o l~mo Ist course PLA 133 72% 81% 84% <0.0001 OM IOmg 130 29% 37% 44% 2nd course PLA 88 84% 91% 91% 0.016 OM IOmg 28 64% 75% 75% Subarouo of patients who had 2 courses of MT: Cumulative relapse rate Course No. 6mo 12mo 18mo PLA n=8B Ist 67% 78% 79% 2nd 84% 91% 91% OM IOmg n=2B Ist 71% 93% 96% 2nd 64% 75% 76% ]. Half the recurrences were symptomatic only; one-quarter had erosive, silent disease and the remainder symptomatic EE. 2. Grade of disease, healing rates, smoking and drinking did no__tt affect outcome. DISCUSSIONThe high spontaneous relapse rate is halved byOM 10mgdaily: The natural history of the disease repeats i t s e l f : relapse on PLA or on OM 10mg is generally followed by the same outcome i f treatment is repeated. Therefore, the few relapsing on OM 10mg may need OM 20mg (preliminary results: relapse <10%). CONCLUSIONDaily MT with OM IOmg markedly reduces the relapse rate of EE. Supported by *Astra Clinical Research Unit, Edinburgh, UK.
"HIGH-RISK" DUODENAL ULCER(DU): LONGTERM MAINTENANCE TREATMENT(MT) WITH LOW(1Omg) & FULL(2Omg) DOSEOMEPRAZOLE(OM) VS RANITIDINE(RAN). KD Bardhan, P Cherian, A Vaishnavi, RB Jones, P Morris, M Thompson, A Brooks, J D'Silva, KRWGillon*, SA Parkin*, J Patterson*. RotherhamGeneral Hospital, UK. AIM We compared the efficacy of MT with OM 10mg and 20mg daily against RAN 160mg nightly, a standard regime, in preventing relapse in high-risk(HR) DU patients. PATIENTSThose particularly likely to (I) relapse:~>3 recurrences in past 24 months, or refractory ulcer or (2) have complications (previous bleed or perforation); (3) those in whom complications carry higher mortality (age >60 and/or with associated disease). NETIN)O 120 consecutive HR DU patients (of 400 DU patients screened) were preallocated to double-blind MT (for up to 24 months) but f i r s t given healing therapy with OM 20mg daily or RAN i50mg bd. Patients were endoscoped6-monthly during MT or earlier i f symptoms developed. The cycle was repeated upon relapse. Analysis involved a l l patients treated. RESULTS OemoaraDhv The 3 groups were similar. Cumuiative healinq n 2wk 4wk 8Wlk Previous frequent • OM 20mg* 40 65% 78% 80% relapses or • OM 20mg 40 65% 88% 88% refractoriness had • RAN 150mg x 2 40 68% 96% 85% no significant effect * Subsequently had MT OH 10mg Cumulative relapse on MT Q 6m___Q 12~o ]8mo 24mo OH 10mg 32 16% 19% 22% 25% OM 20mg 39 15% 21% 21% 21% RAN I50mg 39 46% 54% 54% 56% ON vs RAN: p=O.O006 Factors affectina relaose Patients aged <60 years (p=0.0059) and smokers (p=0.0057) had significantly higher relapse rate. Outcome of reDeated treatment IO and 16 patients were retreated with OM20 or RAN 150mg bd respectively; only 2, 4 and 12 then had repeat MT with OM lOmg, OH 20mg and RAN 150nKJ: I, 2, and g respectively relapsed by 24 months. DISCUSSION The high relapse rate on RAN reflects the aggressive nature of the disease in the patients selected (and contrasts to our observed recurrence of 26% at 5 years in unselected patients). This relapse rate is halved by OM. CONCLUSIONMT with OM 10mg and 20mg daily markedly reduces the relapse rate in high-risk DU patients and is significantly superior to RAN 150mg nightly.
SupPorted by *Astra Clinical Research Unit, Edinburoh. UK.