THE NATURAL HISTORY AND THE EFFECT OF PIVMECILLINAM IN LOWER URINARY TRACT INFECTION.

Transcription

1 MET9401 SE 10May 2000 Page 13 of SYNOPSS MET9401 SE THE NATURAL HSTORY AND THE EFFECT OF PVMECLLNAM N LOWER URNARY TRACT NFECTON. L A study of the natural hstory and the treatment effect wth pvmecllnam tablets (200 mg) one tablet three tmes a day for 7 days, pvmecllnam one tablet two tmes a day for 7 days, pvmecllnam two tablets two tmes a day for 3 days or placebo. Optmal lmts for sgnfcant bacterura n lower UT, ther natural hstory and the results of decentralsed dagnostc methods of lower UT. Objectves: To compare the clncal and bacterologcal effcacy of three dfferent pvmecllnam treatment regmens and placebo n females wth a lower urnary tract nfecton. Study Desgn: Ths was a prospectve, multcentre, randomsed, double-blnd, placebo controlled, parallel group comparson of a) pvmecllnam, 200 mg three tmes daly for 7 days b) pvmecllnam, 200 mg twce daly for 7 days c) pvmecllnam, 400 mg twce (two 200 mg tablets) daly for 3 days, and d) placebo, three tmes daly for 7 days. There were three study vsts, at day 0, (vst 1/baselne), after 8-10 days (vst 2) and after days (vst 3). Source of patents: Prmary healthcare centres n the county of Vasterbotten n the northern part of Sweden. l Ths document has been downloaded from WW\\'.leo-pharma.com subject to the terms of use state on the webs1te. t contans data and results regardng approved and non-approved uses, formulatons or treatment regmens, and t s provded for transparency and nformatonal purposes only. The content does not reflect the complete results from all studes related to a product. As a document of scentfc nature t s not to be seen as a recommendaton or advce regardng the use of any products and you must always consult the specfc prescrbng nformaton approved for the product pr1or to any prescrpton or use.

2 Page 14 of May2000 MET9401 SE Elgblty crtera: Females over 18 years of age wth symptoms of lower UT (frequency of urnaton, burnng on urnaton, low abdomnal pan, lon pan, each scored 0-3) and a total symptom score of at least 2. Excluded were pregnant women, patents plannng to become pregnant durng the study perod, patents who had receved antbotc treatment for UT n the prevous month, patents who were known or suspected of beng penclln allergc, had complcatng factors, such as known anatomcal abnormalty of the renal tract, dabetes, gental nfecton, or an upper UT (temperature of :?:38.5 C, kdney tenderness, CRP :?:25 mg/1 or urne sedment wth tubular kdney cells, granulated or wth abundant hyalne casts). ncontnent or cathetersed patents, uncooperatve patents and patents treated n the prevous 3 months wth an unapproved drug or who had partcpated prevously n the study were also excluded. Study medcaton: pvmecllnam hydrochlorde. Pvmecllnam (Selexd ) tablets contanng 200 mg Matchng placebo tablets. Crtera for effcacy and safety: The Prmary Response Crteron was the proporton of patents wth a postve bacterologcal culture at vst 1 assessed as both bacterologcal and clncal cures at vsts 2 and 3. Other response crtera ncluded:. Proporton of patents clncally cured at both vsts 2 and 3, and at vsts 2 and 3 ndvdually.. Proporton of patents bacterologcally cured at both vsts 2 and 3 and at vsts 2 and 3 ndvdually.. Symptomatc response. v. Bacterologcal effcacy n nfecton due to mecllnam senstve bactera. v. Bacterologcal effcacy aganst ndvdual urnary pathogens.

3 MET9401 SE 10May2000 Page 15 of 154 v. Adverse events. Study procedures: Vst Days Patents hstory * Clncal assessment * * * Urne sample * * * Randomsaton * Adverse events * * Dspense/ collect study medcaton * * Adverse events: At each vst patents were asked f they had experenced any problems. No specfc symptoms were asked for. Any adverse events reported (or observed by the nvestgator) were recorded n respect of nature, severty and relatonshp to therapy. Patent numbers: Calculaton of study populaton sze was based on the followng crtera: the prmary objectve of the study was to exclude a clncally sgnfcant dfference wth hgh probablty between the reference treatment 200 mg three tmes a day for 7 days (A) and the two treatment alternatves 200 mg twce daly for 7 days (B) and 400 mg twce daly for 3 days wth regard to the patents who were cleared from symptoms both after 8-10 days and at followup after days. A total of 250 patents per treatment group was requred n order to ensure wth 80% probablty that the upper 95% (one-alpha) confdence lmt for dfference between cure rate between alternatve A and the other two treatment

4 Page 16 of May2000 MET9401 SE alternatves B and C was less than 10%, provded that treatment A, B and C have the same cure rates. Ths assumed that the frequency of patents remanng cleared from symptoms after one month's follow-up n treatment group A was 80%. As there were two equal comparsons A versus Band A versus C, the 95% lmt (one-alpha) was replaced wth the 97.5% lmt (one-alpha') (alpha'=alpha/2=2.5%), whch corresponds to a Bonferron correcton of the type 1 errors. n order to compensate for an expected drop out of max 20%, 300 patents were to be enrolled per treatment group, correspondng to a total of 1,200 patents.

5 MET9401 SE 10May2000 Page 17 of154 Effcacy results: Prmarv Response Crteron r Results n respect of the Prmary Response Crteron, namely proportons of patents cured both clncally and bacterologcally at both vsts 2 and 3 are shown n the table. Clncal & bacterolocal response at vst 2 & 3 (prmary response crteron). Clncal & P vmecllnam P vmecllnam Pvmecllnam bacterologcal 200 mg, t..d 200 mg, b..d 400 mg, b..d r esponse for 7 days for 7 days for 3 days Placebo ln 204 ) (n 193J (na202) (n=197) Number of Number of Numbe r of Number of Ch -square patents % patents % patem:s patents % test L 1 l t l F Falure S p < Cure Total There was a statstcally sgnfcant dfference among the treatments n respect of the response accordng to the Prmary Response Crteron (p<0.001). The dfference and the confdence nterval of the dfference between the three pvmecllnam treatments and placebo, and between the two 7 day regmens and the 3 day regmen n respect of the rates accordng to the Prmary Response Crteron at both vsts 2 and 3 are shown n the followng table. j f- rr ' t L,._ F L. b '

6 Page 18 of154 10May2000 MET9401 SE Dfference n and confdence nteroals for clncal & bacterologcal response at vst 2 & 3 (prmary effcacy crteron). Treatment comparson 11 Dfference Confdence lmt(s)" P-value" A - D 38.2 % B - D 46.0 % c - D 32.6 % c -A -5.6 % c - B % 27.8 % to 48.5 % < % to 56.5 % < % to 43.0 % < % % ) A: Pvmecllnam 200 mg, t..d for 7 days B: Pvmecllnam 200 mg, b..d for 7 days C: Pvmecllnam 400 mg, b..d for 3 days D: Placebo 2) The comparsons A-D, B- D and C-D are performed on sgnfcance level (98.3% C), and the comparsons C- A and C- Bare performed on sgnfcance level (97.5% C). The dfference between each of the three pvmecllnam treatments and placebo was statstcally sgnfcant and n favour of pvmecllnam treatment (pvmecllnam 200 mg three tmes daly for 7 days versus placebo p<o.ool, pvmecllnam 200 mg twce daly for 7 days versus placebo p<o.ool, pvmecllnam 400 mg twce daly for 3 days versus placebo p<o.ool). The dfference between the pvmecllnam 200 mg three tmes daly 7 day and the 3 day pvmecllnam regmen was not statstcally sgnfcant. The dfference between the pvmecllnam 200 mg twce daly 7 day regmen and the 3 day pvmecllnam regmen was statstcally sgnfcant (p=0.004). Clncal response Clncal effcacy n respect of patents cured clncally at both vsts 2 and 3 are shown n the table.

7 MET9401 SE 10May2000 Page 19 of 154 Clncal res onse at vst 2 & 3. Clncal P vmecllnam Pvmecllnam Pvmecllnam response 200 mg, t..d 200 mg, b..d 400 mg, b..d for 7 days for 7 days for 3 days Placebo {n=280) {n=289) {n=283) {n=280) Number of Number of Number of Number of Ch-square patents % patents % patents patents % test Falure p < Cure Total There was a statstcally sgnfcant dfference among the treatments n respect of the clncal cure rates at both vsts 2 and 3 (p<o.ool). The dfference and the confdence nterval of the dfference between the three pvmecllnam treatments and placebo, and between the two 7-day regmens and the 3 day regmen n respect of the clncal cure rates at both vsts 2 and 3 are shown n the Table below. D erence n and con dence ntervals or clncal res onse at vst 2 & 3. Treatment comparson 1 ) Dfference Confdence lmt{s)" P-value 2 ) A - B - C - C - C - D D D A B 29.8 % 30.9 % 25.7 % -4.1 % -5.2 % 20.0 % to 39.5 % 21.2 % to 40.5 % 15.9 % to 35.5 % 4.1 % 2.9 % < < < ) A: Pvmecllnam 200 mg, t..d for 7 days B: Pvmecllnam 200 mg, b..d for 7 days C: Pvmecllnam 400 mg, b..d for 3 days D: Placebo 2) The comparsons A-D, B- D and C-D are performed on sgnfcance level {98.3% C), and the comparsons C- A and C- Bare performed on sgnfcance level {97.5% C). The dfference between each of the three pvmecllnam treatments and placebo was statstcally sgnfcant and n favour of pvmecllnam treatment (pvmecllnam 200 mg three tmes daly for 7 days versus placebo p<0.001, pvmecllnam 200 mg twce daly for 7 days versus placebo p<o.ool, pvmecllnam 400 mg twce daly for 3 days versus placebo p< 0.001). The dfference between each of 7 day pvmecllnam regmens and the 3 days pvmecllnam regmen was not statstcally sgnfcant.

8 Page 20 of May2000 MET9401 SE Bacterologcal effcacy a) Bacterologcal cure rate at both vsts 2 and 3 The bacterologcal cure rate at both vsts 2 and 3 are shown n the followng table. Bacterologcal response at vst 2 & 3. Bacterologcal response Pvmecllnam 200 mg, t..d for 7 days (n=204) Pvmecllnam 200 mg, b..d for 7 days (n=193) Pvmecllnam 400 mg, b..d for 3 days (n=202) Placebo (n=197) Number of patents Number of patents Number of patents % Number of Ch-square patents % test Falure Cure Total p < There was a statstcally sgnfcant dfference among the treatments n respect of the bacterologcal cure rate at both vst 2 and at vst 3 (p<o.ool). The dfference and the confdence nterval of the dfference between the three pvmecllnam treatments and placebo, and between the two 7 day regmens and the 3 day regmen n respect of the bacterologcal cure rates at vst 2 and 3 are shown n the followng table.

9 MET9401 SE 10May2000 Page 21 of 154 Dfference n and confdence ntervals for bacterologcal response at vst 2 & 3. Tr eatment compa r son 11 Dfference Confdence lm t(s)" P- value" A - D B - D C - D C- A C - B 51.9 % 53.5 % % -11.3% % % to % t t o 64.1 % % to 51.8 % % % < < < ) A: vmecllnam 200 mg, t..d for 7 days B: vme c llnam 200 mg, b..d for 7 days C: vmecllnam 400 mg, b..d for 3 days 0: Pl acebo 2 > The comparsons A - 0, B - D and C - Dare performed on sgnfcance l evel (98. 3 % C ), and t he comparsons c - A and C - 8 are performed on sgnfcance level (97. 5 % C}. r- The dfference between each of the three pvmecllnam treatments and placebo was statstcally sgnfcant and n favour of pvmecllnam treatment (pvmecllnam 200 mg three tmes daly for 7 days versus placebo p<o.ool, pvmecllnam 200 mg twce daly for 7 days versus placebo p<0.001, pvmecllnam 400 mg twce daly for 3 days versus placebo p<o.ool). The dfference between each of the 7 day pvmecllnam regmens and the 3 day pvmecllnam regmen was statstcally sgnfcant and n favour of the 7 day treatment regmen (pvmecllnam 200 mg three tmes daly for 7 days versus pvmecllnam 400 mg twce daly for 3 days p=o.olo, pvmecllnam 200 mg twce daly for 7 days versus pvmecllnam 400 mg twce daly for 3 days p=0.004). b) Bacterologcal cure rate at vsts 2 and 3 n patents wth nfectons due to mecllnam senstve bactera. The bacterologcal response at vst 2 (day 8-10) and at vst 3 (day 35-49) ndvdually n patents wth nfectons due to mecllnam senstve bactera s shown n the table. ' c t 1 j L t 1 : ' l

10 Page 22 of May2000 MET9401 SE Bacterologcal response at vst 2 and at vst 3 for patents wth nfectons senstve to mecllnam at vst 1. Bacterologcal Pvmecllnam Pvmecllnam P vmecllnam response 200 mg, t..d 200 mg, b..d 400 mg, b..d for 7 days for 7 days for 3 days Placebo (n=204) (n=193) (n=202) ln=197) Number of Number of Number of Number of Ch-square patents patents % patents % patents % test Vst 2 Falure p < Cure Total Vst 3 Falure p = Cure Total There was a statstcally sgnfcant dfference among treatments n respect of the bacterologcal response n patents nfected wth mecllnam senstve bactera at both vst 2 (p<o.ool) and vst 3 (p=o.oos). The dfference and the confdence nterval of the dfference between the three pvmecllnam treatments and placebo, and between the two 7 day regmens and the 3 day regmen n respect of the clncal cure rates at vst 2 and at vst 3 are shown n the followng table.

11 MET9401 SE 10May2000 Page 23 of154 Dfference n and confdence ntervals for bacterologcal response at vst 2 and at vst 3 for patents senstve to mecllnam at vst 1. Treatment comparson 1 ) Dfference Confdence lmt (s)" P-value" Vst 2 Vst 3 A - D 57.7 % 46.8 % to 68.5 % < B - D 61.9 % 51.4 % to 72.4 % < c - D 53.3 % % to 64.7 % < C -A -4.4 % 3.6 % 0.14 c - B -8.6 % -1.0 % A - D 19.4 % 4.8 % to 34.0 % B - D 15.3 % 0.2 % to 30.3 % c - D 11.6 % -3.9 % to 27.0 % c - A -7.8 % 1.5 % c - B -3.7 % 6.1 % ) A: Pvmecllnam 200 mg, t..d for 7 days B: Pvmecllnam 200 mg, b..d for 7 days C: Pvmecllnam 400 mg, b..d for 3 days D: Placebo 21 The comparsons A - D, B - D and C - D are performed on sgnfcance level (98.3 % C), and the comparsons c - A and C - B are performed on sgnfcance level (97.5 % C). At vst 2 the dfference between each of the three pvmecllnam treatments and placebo was statstcally sgnfcant and n favour of the pvmecllnam treatment regmen (all p<0.001). At vst 2 there was no statstcally sgnfcant dfference between the pvmecllnam 200 mg three tmes daly 7 day regmen and the 3 day pvmecllnam regmen. However, there was a statstcally sgnfcant dfference between the pvmecllnam 200 mg twce daly 7 day regmen and the 3 day pvmecllnam regmen (p=0.013). At vst 3, the dfference between the two 7 day pvmecllnam regmen and placebo was statstcally sgnfcant and n favour of the 7 day treatment regmen (p=0.002 three tmes daly and p=0.015 twce daly). The dfference between the 3 day pvmecllnam regmen and placebo was not statstcally sgnfcant. However, the great loss of patents at vst 3 n the placebo arm probably nfluenced ths result.

12 Page 24 of May2000 MET9401 SE ' r. At vst 3, there were no statstcally sgnfcant dfferences between the two 7 day pvmecllnam regmens and the 3 day pvmecllnam regmen. Adverse events Overall, adverse events were reported by 12.1% patents gven placebo, by 17.4% of patents gven pvmecllnam 200 mg three tmes daly for 7 days, by 11.6% patents gven pvmecllnam 200 mg twce daly for 7 days and by 13.6% patents gven pvmecllnam 400 mg twce daly for 3 days. There s no statstcally sgnfcant dfference n the ncdence of patents wth adverse events among treatments (p=0.17). The most common adverse event n all four treatment groups was "gastrontestnal system dsorders". Adverse events caused/ contrbuted to treatment wthdrawal n 3 patents gven pvmecllnam 200 mg three tmes daly for 7 days, n 1 patent gven pvmecllnam 200 mg twce daly for 7 days and n 3 patents gven pvmecllnam 400 mg twce daly for 3 days. No patent gven placebo ceased treatment due to adverse events. Concluson: Pvmecllnam treatment s sgnfcantly more effectve than placebo, both clncally and bacterologcally, n lower UT n women. Clncally there was no dfference between the 3 day and 7 day regmens n contrast to the bacterologcal and the combned bacterologcal and clncal effcacy where sgnfcant dfferences exsted between one of the 7 day regmens and the 3 day regmen. Thus, treatment wth pvmecllnam for 7 days showed advantage over treatment for 3 days. l j r.. - f ' j r- r 1 f l E