European U rology
European Urology 45(2004)773–780
Evaluation of the Clinical Benefit of Permixon andT amsulosin in Severe BPHPatientsöPERMAL Study Subt Analysis $
Frans Debruyne a,*,Peter Boyle b ,Fernando Calais Da Silva c ,Jay G.Gillenwater d ,Freddie C.Hamdy e ,Paul Perrin f ,Pierre Teillac g ,Remigio Vela-Navarrete h ,Jean-Pierre Raynaud i ,Claude C.Schulman j
a
Department of Urology,Academic Hospital Nijmegen,Geert Grooteplein Zuid 16,426Afdeling Urologie,6500HB Nijmegen,The Netherlands b
Instituto Europeo di Oncologia,Milano,Italy c
Grupo Portugues Genito Urinario,Lisboa,Portugal d
University of Virginia Medical Center,Charlottesville,VA,USA e
Royal Hallamshire Hospital,Sheffield,UK f
Antiquaille Hospital,Lyon,France g
St.Louis Hospital,Paris,France h
Universidad Autonoma de Madrid,Madrid,Spain i
University Pierre &Marie Curie,Paris,France j
Ho
ˆpital Erasme,Brusls,Belgium Accepted 5January 2004Available online 19February 2004
Abstract
Objective:To compare the efficacy of the lipido-sterolic extract of Serenoa repens ,Permixon,to that of the a –blocker,tamsulosin,in the treatment of vere low urinary tract symptoms (LUTS)of benign prostatic hyperplasia (BPH).Methods:In a 12-month,double-blind,randomized study that showed equivalent efficacy of Permixon 320mg/day and tamsulosin 0.4mg/day (‘‘PERMAL study’’),685BPH p
atients with IPSS !10had been analyzed for efficacy.Of the,the 124patients with vere LUTS (IPSS >19)at randomization were retained for this subt analysis.After a 4-week run-in period,59and 65patients had been randomized to tamsulosin and Permixon groups,respectively.Both treatment groups were compared regarding the evolution from baline of total IPSS and its irritative and obstructive subscores,LUTS-related QoL,prostate volume,Q max and MSF-4(xual activity questionnaire)at different time points over 1year.An analysis of variance of changes from baline to end point was performed for all the parameters.The over-time evolutions of total,irritative and obstructive IPSS were further compared using a variance analysis for repeated measurements.
Results:At 12months,total IPSS decread by 7.8with Permixon and 5.8with tamsulosin (p ¼0:051);the irritative symptoms improved significantly more (p ¼0:049)with Permixon (À2.9versus À1.9with tamsulosin).The superiority of Permixon in reducing irritative symptoms appeared as soon as month 3and was maintained up to month 12(p ¼0:03).
Conclusion:Permixon 320mg/day was shown to be slightly superior to tamsulosin 0.4mg/day in reducing LUTS in vere BPH patients after 3months and up to 12months of treatment.#2004Elvier B.V .All rights rerved.
Keywords:Serenoa repens;Permixon;Phytotherapy;a -blockers;Tamsulosin;BPH
1.Intro ductio n
Low urinary tract symptoms (LUTS)are frequently associated with benign prostatic hyperplasia (BPH),a non-malignant enlargement of the prostate which
$
Supported by a grant from Pierre Fabre Me
´dicament,Castres,France,manufacturer of Permixon.*
Corresponding author.
E-mail address:
f.debruyne@uro.umcn.nl (F.Debruyne).
0302-2838/$–e front matter #2004Elvier B.V .All rights rerved.doi:10.1016/j.eururo.2004.01.015
occurs predominantly in men aged over60years. Medical therapies,5a-reducta inhibitors,a-blockers and phytotherapeutic agents,possibly to offer an alter-native to surgery,are assuming increasing importance in the treatment of LUTS[1–6].However,the safety profiles of the drugs vary.Indeed,a1-blockers can be associated with postural hypotension and retrograde ejaculation and5a-reducta inhibitors with impairment of erection[7].Thus,the u of phytotherapy(plant extracts)to alleviate LUTS is of growing interest. The lipido-sterolic extract of Serenoa repens,Per-mixon1,is the most extensively prescribed and studied phytotherapeutic agent approved as a medical treat-ment of symptomatic BPH.The clinical efficacy of Permixon in the medical managemen
t of BPH has been clinically demonstrated[8–11].A meta-analysis of Permixon trials has added evidence of its efficacy over placebo[12].In recent long-term comparative studies, Permixon320mg per day has been shown to have an equivalent efficacy tofinasteride5mg over6months [13],and to tamsulosin0.4mg over12months(‘‘PER-MAL study’’)[14]to relieve LUTS of BPH.
The anti-androgenic,anti-proliferative and anti-inflammatory complementary activities of Serenoa repens extracts[15,16]could constitute an advantage over a-blockers to treat vere symptomatic BPH where both‘‘obstruction’’and‘‘irritation’’are involved.Thus, the prent analysis is aimed at comparing,using the data of the PERMAL study,the efficacy of Permixon and that of tamsulosin in the most verely sympto-matic patients(International Prostate Symptom Score, IPSS>19).
2.Patients and methods
2.1.PERMAL study description
The PERMAL study was a12-month,double-blind,rando-mized,2-arm comparison of Permixon320mg/day and tamsulosin 0.4mg/day.
Inclusion criteria included an IPSS!10,a maximal urinary flow rate(Q max)of5–15ml/s with a voided v
olume!150ml,a prostate volume!25cc,and a rum prostate-specific antigen (PSA)<4ng/ml or,if it ranges from4–10ng/ml,with a free/total PSA ratio!15%.
A total of685men with symptomatic BPH(IPSS!10)made up the intention-to-treat(ITT)Efficacy were randomized and treated after a4-week placebo run-in period(340by Permixon and345by tamsulosin)and had a valid IPSS measurement at baline and at least once during treatment.
Asssment visits were scheduled at lection(DayÀ28),ran-domization(Day0),week6and months3,6,9and12.The IPSS and LUTS-related quality of life score(QoL)[17],Q max[18]and Male Sexual Function score(MSF-4)[19]were assd at each visit. Additionally,patients underwent a transrectal ultrasound to measure prostate volume[20]at lection and months6and12.
Adver events(AEs),rious(SAE)and non-rious,were reported over the entire the study period.
2.2.Analyzed patient subt
For the prent subt analysis,124patients from the PERMAL ITT-Efficacy datat who had vere LUTS(IPSS>19)at rando-mization were retained:65had been treated by Permixon and59by tamsulosin according to the initial randomization schedule.
2.3.Statistical analysis
An endpoint between-group comparison of mean changes from he start of the double-blind period)was carried out using a variance analysis with baline value as covariate (ANCOV A).All comparisons were two-sided,with p-values of <0.05being considered significant.
Total IPSS and its3-item(incread frequency/urgency/nocturia) irritative and4-item(incomplete emptying/intermittency/weak stream/hesitancy)obstructive subscores were also analyzed in two baline IPSS verity subgroups:21(n¼63)and>21(n¼61). Their evolution from month3to month12was further compared using a variance analysis(ANOV A)for repeated measurements.
‘At visit’results are graphically displayed using meanÆstandard error of the mean(SEM)and t test for p-values.
Adver events recorded in this population were classified by system-organ class and preferred term as defined by the WHO-ART dictionary.Frequency and percentage of patients with at least one reported treatment-emergent adver event(TEAE)were prented for:any AEs,any SAEs,any AEs for which relationship with study drug could not be excluded by the investigator and any AEs suggestive of a-adrenoreceptor antagonism.
半剖视图画法3.Results超级航母
3.1.Baline patient characteristics
There were no clinically meaningful differences between treatment groups(n¼65/Permixon,59/tam-sulosin)with respect to any demographic or clinical baline characteristics(Table1):Overall,the mean (S.D.)patient age was65.2(7.5)years and the mean baline IPSS was22.7(3.35),corresponding to9.4 (2.3)and13.3(2.7)for irritative and obstructive parts, respectively.
3.2.IPSS
After12months,a higher mean decrea in the total IPSS was obrved in the Permixon group,À7.8(6.4) than in the tamsulosin group,À5.8(6.3).This2-point difference approached statistical significance(p¼0:051;adjusted95%confidence interval for difference between mean changes(CI):[À4.53,0.008]).The cor-responding mean percentage decrea in total IPSS was 35.2%for Permixon and25.0%for tamsulosin.
This between-group difference in the mean total IPSS decrea was equally obrved in the IPSS irritative part,À2.9(3.3)andÀ1.9(2.8)and the obstructive part,À4.9(4.3)andÀ3.9(4.5),for Permixon and tamsu-losin,respectively.Statistically,it reached significance
774F.Debruyne et al./European Urology45(2004)773–780
for the former subscore,p¼0:049(adjusted95%CI: [À2.23,0.005])and was borderline significant for the latter,p¼0:079(adjusted95%CI:[À3.32,À0.18]) (Table2).
The respon rates(IPSS decrea!3)were80.0% and71.2%in the Permixon and tamsulosin groups,
respectively.The difference in favor of Permixon mainly concerned the highest IPSS improvements: 41.5%of Permixon-treated versus25.4%of tamsulo-sin-treated patients benefitted from a decrea by at least9points in total IPSS.A clinically significant IPSS worning(increa!4)affected one(1.5%) Permixon-treated patient and four(6.8%)tamsulo-sin-treated patients(Fig.1).
Similar over-time profiles were obrved for all symptom score and subscores.
At6weeks,the mean IPSS score had decread similarly in both treatment groups(p¼0:33).The between-group difference was maximal as soon as month3and was maintained up to month12for the irritative symptoms(p¼0:03,ANOV A for repeated measurements)while it incread regularly over time from month3to reach its maximum at12months for the obstructive symptoms(Fig.2).
The further analys according to baline IPSS verity subclass show that the above-described
between-group differences in favor of Permixon mainly concerned the most verely symptomatic patients (IPSS>21;n¼61).In this subgroup,the between-group difference was maximal as soon as month3 and was maintained up to month12for both irritative and obstructive IPSS(Fig.3).Although the patient number was halved smaller,the between group differ-ence was still statistically significant over this period for the irritative symptoms(p¼0:045,ANOV A for repeated measurements).
T able1
Demographic and other baline a patient characteristics
Tamsulosin (N¼59)Permixon
(N¼65)
Total
(N¼124)
Age(years)
Mean(S.D.)64.9(7.62)65.5(7.45)65.2(7.51)
Body Mass Index(kg/m2)
Mean(S.D.)26.6(4.71)26.3(3.14)26.4(3.95) Total IPSS
Mean(S.D.)23.2(3.62)22.3(3.06)22.7(3.35) QoL
Missing101
Mean(S.D.) 3.9(1.09) 4.1(1.18) 4.0(1.14) Q max(ml/s)
Missing437
Mean(S.D.)10.3(3.87)10.7(4.27)10.5(4.07) MSF-4
Missing303
Mean(S.D.)8.0(5.55)8.9(5.70)8.5(5.63) Prostate volume(cc)
Missing101
Mean(S.D.)47.7(19.53)48.5(16.89)48.1(18.1)
a DayÀ28for age,BMI and prostate volume;Day0for the other parameters.T able2
Mean(S.D.)changes in efficacy parameters from day0to month12 endpoint
Tamsulosin
用豆腐自制豆腐干(N¼59)
Permixon
(N¼65) Total IPSS-EndpointÀBaline a
Mean(S.D.)À5.8(6.29)À7.8(6.44) Irritative IPSS-EndpointÀBaline b
Missing10
Mean(S.D.)À1.9(2.82)À2.9(3.29) Obstructive IPSS-EndpointÀBaline c
Missing10
请款申请
Mean(S.D.)À3.9(4.49)À4.9(4.28) QoL-EndpointÀBaline d
蔡伦改进造纸术
Missing10
Mean(S.D.)À0.9(1.40)À1.2(1.21) Q max-EndpointÀBaline(ml/s)e
Missing53
Mean(S.D.) 1.7(4.61) 1.2(4.98) MSF-4-EndpointÀBaline f
Missing33
Mean(S.D.) 1.0(4.03)0.2(3.68) Prostate V olume-EndpointÀBaline(cc)g
Missing38
Mean(S.D.)À0.9(11.48)À2.2(12.48)
a ANCOV A:Treatment effect:p¼0:0508.台风最新消息2016年
b ANCOV A:Treatment effect:p¼0:0489.
c ANCOV A:Treatment effect:p¼0:0792.
d ANCOV A:Treatment effect:p¼0:32.
e ANCOV A:Treatment effect:p¼0:7096.
f ANCOV A:Treatment effect:p¼0:4610.
g ANCOV A:Treatment effect:p¼0:
6393.
-25-20-15-10-50510
Fig.1.Cumulative%of patients by total IPSS level of change from baline.
F.Debruyne et al./European Urology45(2004)773–780775
3.3.Other ef ficacy parameters After 12months (Table 2):
The improvement in LUTS-related quality of life was non-signi ficantly higher in the Permixon group with a mean decrea in QoL by 1.2(1.2)versus 0.9(1.4)in the tamsulosin group,p ¼0:32.
The mean Q max increa was non-signi ficantly higher in the tamsulosin group:1.7(4.6)ml/s versus 1.2(4.98)ml/s in the Permixon group (p ¼0:71)for a baline value of 10.3and 10.7,respectively. The prostate volume had decread on average by 2.2(12.5)cc in the Permixon group and 0.9(11.5)cc in the tamsulosin group.Becau of the high inter-individual variability,this difference was not statis-tically signi ficant,p ¼0:64.
The xual function was almost unchanged in both groups with a mean increa of MSF-4by 1.0(4.0)
with tamsulosin and 0.2(3.7)with Permixon,p ¼0:46.
With respect to the qualitative by-item analysis,the item ‘‘achieving ejaculation ’’rather worned in the tamsulosin group (from month 6)and remained unchanged in the Permixon group all over the stu
dy cour.At 12months,a borderline statistically significant between-group difference was obrved for this item,p ¼0:087.
3.4.Safety
During the 12-month treatment period,12(20.0%)tamsulosin-and 16(24.6%)Permixon-treated patients experienced potentially drug-related AEs.In the patients with vere LUTS,the incidence of AEs generally related to a -blockade was similar (headache,hypertension,urinary infection)between groups or lower (gastro-intestinal disorders,rhinitis,and asthe-nia)in the tamsulosin group.Ejaculation disorders occurred only in one tamsulosin-treated patient.
SAEs were reported in six (10.0%)tamsulosin-and four (6.2%)Permixon-treated patients.In one Per-mixon-treated patient,the relationship between the SAE (atrial fibrillation)and the study drug was not excluded by the investigator.An acute urinary retention occurred in two (3.3%)tamsulosin-and one (1.5%)Permixon-treated patients (Table 3).4.Discussion
This analysis aimed at comparing the ef ficacy of Permixon 320mg/day and tamsulosin 0.4mg/day
in
T able 3
510152025D0D42D91D182D273D364
T o t a l I -P S
S
24681012D0D42D91D182D273D364
I r r i t a t i v e I -P S S
51015D0
D42
D91
D182
D273D364
O b s t r u c t i v e I -P S S
Fig.2.Mean total,irritative and obstructive IPSS pro files over time.
776F .Debruyne et al./European Urology 45(2004)773–780
the treatment of verely symptomatic BPH (IPSS >19)over 12months.
The analyzed patient subt was reprentative of the global population from the PERMAL study [14]
for either demographic characteristics (mean age of 65.2years for 64.9years in the parent population)or ef ficacy variables other than IPSS and LUTS-related QoL (respectively impaired by about 50%and 20%).This datat was homogeneous and well balanced between treatment groups.It was constituted by more than 50patients per group,which allowed a reliable statistical analysis.
Compared to the results in the whole PERMAL population,the higher magnitude of mean total IPSS decline obrved in this subt of patients with vere dia (À7.8with Permixon and À5.8with tamsulosin versus À4.4and À4.2,respectively in the PERMAL study)is related to the baline score:the higher the initial score,the greater the decrea [21].However,the 2-point difference in favor of Permixon,clo to signi ficance (p ¼0:051,adjusted 95%CI:[À4.53,0.008])cannot be attributed to this fact as the baline mean value was higher in the tamsulosin group (23.2)than in the Permixon group (22.3).Compared to the literature,the IPSS improvement with tamsulosin in the patients with vere LUTS appears limited:the subt analysis of the results from a 53-week study [22]has shown a mean decrea from baline in IPSS by 11.98points in 63patients with vere dia (IPSS >19)receiving tamsulosin 0.4mg once daily [23].Tho results are not comparable to the prent analysis,since the study designs were different,as for example the fact that the decrea during the run-in period was not taken in consideration in the PERMAL study.At 6w
eeks the IPSS decrea was not statistically different in both tamsulosin and Permixon groups (p ¼0:33).
The between-group difference in IPSS improvement,which appeared as soon as month 3(time point of Permixon full activity while that of tamsulosin was week 6)and was maintained up to month 12,became signi ficant when considering the irritative part of IPSS:at 12months,the adjusted 95%CI between irritative IPSS changes was:[À2.23,0.005],p ¼0:049.Also,this difference further incread between the most verely symptomatic patient subgroups (IPSS >21):at 12months,the adjusted 95%CI between total IPSS changes was [À6.75,0.35].
21 > Baline total IPSS >19
Baline total IPSS >21
tamsulosin (n=26)tamsulosin (n=33) Permixon
(n=37)
-5
-4-3-2-10D0
D42D91
D182
D273
D364
I r r i t a t i v e I -P S S c h a n g
e
-5
-4-3-2-10D0
D42D91D182D273D364
-6
-5-4-3-2-10D0
D42
D91看起来毫不费力
D182
孽藤缘
D273
D364
O b s t r u c t i v e I -P S S c h a n g
e
-7
-6-5-4-3-2-10D0D42D91D182D273D364
Permixon (n=28)
Fig.3.Mean irritative and obstrutive IPSS change pro files over time according to baline IPSS Class.21!Baline total IPSS >19:(---)tamsulosin
(n ¼26),(—)Permixon (n ¼37).Baline total IPSS >21:(---)tamsulosin (n ¼33),(—)Permixon (n ¼28).
F .Debruyne et al./European Urology 45(2004)773–780777
Similar between-group outcomes were obrved for the other analyzed efficacy parameters except for the ejaculation quality(MSF-4item)which rather wor-ned with tamsulosin and remained unchanged with Permixon.The higher incidence of abnormal ejacula-tion(retrograde ejaculation or diminished volume or abnce of ejaculate)with tamsulosin than with non-a-antagonist controls has been related to the relaxation effect of the a1blockade on the prostatic smooth muscle and the vas deferens[24].However,only one ejaculation disorder was reported as an adver event in the tamsulosin group(1.7%)while such dis-orders have been reported to occur in4–11%of patients treated with tamsulosin0.4mg daily including the PERMAL study[14,21,22,25].
The prentfindings on tamsulosin efficacy and safety suggest that,once the high baline IPSS-induced bias is eliminated,the effects of the a1-antag-onism on prostatic tissue are reduced in ver
ely symptomatic BPH.This would be explained by a higher contribution of the static mechanism of obstruc-tion(mechanical compression of the urethra)to the detriment of the a-adrenoreceptor-mediated dynamic mechanism.
Converly,the accepted triple mechanism of action of Permixon appears to be enhanced with the verity of LUTS,due to its anti-androgenic(by inhibition of5a-reducta type1and2),anti-prolif-erative(by contraction of prostate epithelial cells and suppression of tissue dihydrotestosterone levels through a possible effect on DNA structure[26])and anti-inflammatory properties(through inhibition of arachidonic acid metabolites[16]),which allows the drug to reduce both obstructive and irritative symptoms.
Acknowledgements
The authors have received rearch grants from or have rved as consultants or members or speakers for Pierre Fabre Me´dicament and/or for other com-panies that make products ud in the treatment of BPH.
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