reappraisal of published randomized luts/bph clinical trials –what have we learned and where do we...

男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02

Reappraisal of Published Randomized LUTS/BPH Clinical Trials –What Have

We Learned and Where Do We Stand?

王炯珵醫師恩主公醫院泌尿科

Chung Cheng Wang, M.D. Ph.DDepartment of Urology, En Chu Kong Hospital, Taipei


Dr. Charles Sydney Burwell, Dean, Harvard Medical School 1935-49

Half of what we are going to teach you is wrong, and half of it is right

Our problem is that we don't know which half is which

在十年內 , 你們現在學習的知識有一半會被證明是錯誤的 , 更糟糕的是我們不知道那一半是錯誤的


請問蒲永孝教授講話比較有公信力還是王炯珵醫師 ?


Guidelines Include Algorithms to Illustrate Medical Treatment Choices According to Evidence-based Medicine and Patients’ Profiles

AUA1 EAU2

http://www.theodora.com/maps/united_states_map.html


Recommendations for Treatment of Men with BPH Have Evolved in Line With Available Clinical Evidence

VA Co-op6

(finasteride + terazosin)

ALFIN7

(finasteride + alfuzosin)

PREDICT9

(finasteride + doxazosin)

MTOPS8

(finasteride + doxazosin)

CombAT 2-year data10

(dutasteride + tamsulosin)

CombAT 4-year data11

(dutasteride + tamsulosin)

AUA and NICE 2010 guidelines3,5

EAU 2011 guidelines4

AUA 2003 guidelines3


AUA 1994 guidelines1


2005 20102000 2014



VACOOP study

Terazosin + Finasteride

N Engl J Med 1996;335:533–9

• Prospective, randomized, double-blind

• 1229 patients enrolled

• Primary endpoint: AUA-SI & Qmax

• Follow up for 52 weeks

Finasteride 和 Placebo 差不多

Terazosin 和 Combination 差不多


ALFIN Study

Alfuzosin + Finasteride

Eur Urol 1998; 34:169–75



• Primary endpoint: I-PSS & Qmax

• Follow up for 6 months

有沒有加Finasteride 沒差

F

A and A +F


What does the guidelines recommend?

Eur Urol 2001; 40:256-263

Based on the ALFIN and VACOOP Trial


PREDICT studyFinasteride + Doxazosin

Urology 2003;61:119–26



• Primary endpoint: I-PSS & Qmax

• Follow up for 52 weeks D F D+F P


MTOPS Study

Finasteride + Doxazosin

N Engl J Med 2003;349:2387–98



• Primary endpoint: clinical progression

• Follow up for 4.5 years(mean)

愛久見人心


Guideline Update

EAU BPH Guidelines 2004

Eur Urol 46; 2004: 547-554


事後諸葛亮很重要

Learning From Clinical Trial Experience


Prostate volume: Higher Baseline PV Associated With an Increase in BPH Progression Events in MTOPS

Adapted from Crawford ED et al. J Urol 2006;175:1422–1427.

3.43.0

0.3 0.6

5.6

4.3

1.02.0

0.0

2.0

4.0

6.0

8.0

Overall BPHprogression

≥4-pointAUA SS

progression

AUR Invasivetherapy

<31 ml

p<0.0001 p=0.001 p=0.034 p=0.0005

Inci

denc

e ra

te (e

vent

s pe

r 100

Pyr

)

≥31 mlTotal prostate volume


PSA: Higher Baseline PSA Associated With an Increase in BPH Progression Events in MTOPS

Adapted from Crawford ED et al. J Urol 2006;175:1422–1427.

3.1 2.8

0.30.8

5.9

4.5

1.01.8

0.0

2.0

4.0

6.0

8.0p=0.0002 p=0.0281 p=0.029 p=0.018

Inci

denc

e ra

te (e

vent

s pe

r 100

Pyr

)

Overall BPHprogression

≥4-pointAUA SS

progression

AUR Invasivetherapy

<1.6 ng/ml ≥1.6 ng/mlPSA level


CombAT study is Designed to Investigate the Efficacy and Safety of Combination Therapy in Men with m-s Symptoms of BPH and at Risk of Clinical Progression

Contemporary Clinical Trial 28; 2007:770-779


CombAT Study

Dutasteride + Tamsulosin

Eur Urol 2009;55:461–71.


• 450 centers in 34 countries worldwide

• p< 0.001

• Primary end point at 2 and 4 years

• Pivotal trial

Tamsulosin 0.4 mg+ dutasteride-matched placeboDutasteride 0.5 mg+ tamsulosin-matched placeboCombination(dutasteride 0.5 mg + tamsulosin 0.4 mg)

Placeborun-in

Scre

enin

g

Double-blindSingle-blind

Safetyfollow up

Pre-screen

\Screen Baseline M48 Follow-up(End of

treatment +16 weeks)

M24Visits every 3 months, QD dosing

IPSS Time to AUR or surgery


Combination Therapy Significantly Reduces the Relative Risk of AUR and/or BPH-related Surgery at 4 years

Eur Urol. 2010;57:123–131

For combination versus tamsulosin at Year 4:Relative risk reduction = 65.8%, Absolute risk reduction = 7.7%NNT: 13 patients

5ARI >> Alpha blocker


Combination Therapy Reduces Risk of AUR, BPH-related Surgery and BPH Clinical Progression

Eur Urol. 2010;57:123–131


Dutasteride Plus Tamsulosin Provided Significantly Greater Symptom Benefit Than Either Monotherapy

Eur Urol 2010;57:123–131

Alpha blocker 越吃越沒效


Drug Adherence

Nichol MB et al. J Urol. 2009;181:2214-21.

Time to non-adherence with medication

Combination

5ARI

Alpha blocker


找對人很重要 !

Choose the Right Population for Study


Entry Criteria for CombAT Included a BPH Population at Higher Risk of Progression Than MTOPS

Plo, placebo; Dox, doxazosin; Fin, finasteride; Comb, combination; Tam, tamsulosin; Dut, dutasteride

1. McConnell J et al. N Engl J Med. 2003;349:2387–2398; 2. Roehrborn C et al. Eur Urol. 2010;57:123–131..

MTOPS1

PloDox. 4–8 mgFin. 5 mgComb.Age ≥50 years IPSS 8–30 PSA ≤10 ng/ml

Median:serum PSA 1.6 ng/ml

PV 31 cc3047 patients

4.5 years mean follow up

CombAT2

Tam. 0.4 mgDut. 0.5 mgComb.

Entry criteria:serum PSA ≥1.5 ng/mlPV ≥30 cc

Median:PV 48.9 cc

71% of moderate BPH symptoms

Age ≥50 years IPSS ≥12 PSA 1.5–10 ng/mlPV ≥30 cc 4844 patients

4 years LOCF


Differences between MTOPS and CombAT in the population under study

Mean ± S.D. CombAT(n=4844)

MTOPS(n=3047)

Age (years) 66.1 ± 7.01 62.6 ± 7.3

Caucasian 4259 (88%) 2509 (82%)

Total IPSS 16.4 ± 6.16 16.9 ± 5.9

Total prostate volume (cc)

55.0 ± 23.58 36.3 ± 20.1

Serum PSA (ng/ml) 4.0 ± 2.08 2.4 ± 2.1

Qmax (mL/sec) 10.7 ± 3.62 10.5 ± 2.6

Post-void residual volume (ml)

67.7 ± 64.87 68.1 ± 82.9

CombAT and MTOPS: different patient populations


Long-term Benefit of 5-ARI and α1-Blocker Combination Therapy1,2,3

1. Füllhase C et al. Eur Urol. (2013), doi: 10.1016/j.eururo.2013.01.018; 2. Roehrborn C et al. Eur Urol. 2010;57:123–131. 3. Roehrborn CG et al. BJU Int 2015 doi:10.1111/bju.13033

The only [5ARI + α1-blocker] combinations assessed for efficacy and safety in long-term RCTs

ALFIN1

0.5 year1051 patientsAlfuzosin 2x5 mg/Finasteride 5 mg

MTOPS1

6 year3047 patientsDoxazosin 4-8 mg/Finasteride 5 mg

VA-COOP1

1 year1229 patientsTerazosin 10 mg/Finasteride 5 mg

PREDICT1

1 year1095 patientsDoxazosin 4–8 mg/Finasteride 5 mg

CombAT2

2–4 year4844 patientsTamsulosin 0.4 mg/Dutasteride 0.5 mg

1995 1996 2001 2003 2010

2yrs change in IPSS from baseline 4yrs Time to first AUR or BPH related surgery

CONDUCT3

2 year742 patients*Fixed-dose DUT+TAM combination vs. WW with initiation of tamsulosin if symptoms did not improve

2015

Primary endpoint

Primary endpointAUA-SS/IPSS and Qmax

2yrs change in IPSS from baseline

Clinical progression

Evidence from CombAT resulted in changes to the

guidelines

[DUT + TAM] CombAT, CONDUCT [FIN + DOX] MTOPS study

*Fixed-dose combination therapy (dutasteride + tamsulosin) vs.Watchful Waiting with initiation of tamsulosin if symptoms did not improveBoth treatment arms included lifestyle advice administered


Lifestyle advice ?真的有嗎 ?

40mL


Create More Benefits by Designing Following Study to Fill the Data Gap


Understanding the Study Patient PopulationsMTOPS vs. CombAT vs. CONDUCT

MTOPS IPSS range (8‒30)

MTOPS1 (4.5 years mean follow up)Combination therapy vs. Placebo and Doxazocin 4–8 mg and Finasteride 5 mg

3047 pts

Entry criteria:Age ≥ 50,PSA ≤10 ng/mL

Baseline:Mean PSA: 2.4 ng/mL, Median PV: 31.0 mL

International Prostate Symptom

Score (IPSS)

Mean IPSS 16.9

812

19

35

30Mean IPSS 16.6

Moderate

Severe

CONDUCT* IPSS range (8‒19)

CONDUCT4,5 (2y)Fixed-dose combination therapy (dutasteride + tamsulosin) vs.Watchful Waiting with initiation of tamsulosin if symptoms did not improve

742 pts

100% treatment naive,PSA 1.5-10.0 ng/mLPV ≥30 mL

Baseline,:Mean PSA: 3.9 ng/mL Mean PV: 51.0 mL

Mean IPSS 13.2

71% patients with moderate symptoms2 CombAT IPSS range (12‒35)

CombAT2,3 (4y LOCF)Combination therapy (dutasteride + tamsulosin) vs. dutasteride 0.5 mg and tamsulosin 0.4 monotherapy

4844pts

Entry criteria: Age ≥50,PSA 1.5‒10 ng/mL, PV ≥30 mL

Baseline:Mean PSA: 4.0 ng/mL Median PV: 48.9 mL, 38% treatment naïve

*Both treatment arms included lifestyle advice administered


Rationale for the CONDUCT StudyAdds to existing evidence

CONDUCT1,2 investigated several areas which would benefit from further investigation:

Less symptomatic (moderate) patients

All Treatment-naive patients

Earlier (4 weeks) fixed-dose combination of dutasteride and tamsulosin efficacy measurement

Comparison to a recognised clinical approach for some patients at risk of progression – Watchful Waiting with initiation of tamsulosin if symptoms did not improve


Randomisation 1:1

V1(screenin

g)

V2(baselin

e)

V3(W4)

V4(W13)

V9(W78)

V10(W91

)

V11(W10

4)

IPSS, BII score, Patient Perception of Study Treatment measured at each visit

If initiated, escalation to tamsulosin 0.4 mg once daily at any visit after Visit 2 would be continued for the remainder of the study unless the subject elected to withdraw prematurely

Fixed-dose combination of dutasteride and tamsulosin

+ lifestyle advice

Watchful Waiting with initiation of tamsulosin if symptoms did not improve from baseline

(V2)+ lifestyle advice

CONDUCT: Study Design

1. Protocol Summary : http://clinicaltrials.gov/ct2/show/NCT01294592?term=NCT01294592&rank=1 (Accessed 5 April 2015)

2. Roehrborn CG et al. BJU Int 2015 doi:10.1111/bju.13033


CONDUCT 最偉大的地方 : 30min 衛教


**Both treatment arms included lifestyle advice administered

Efficacy: Mean IPSS at Each Visit

Mean IPSS at visit (LOCF*) demonstrates the effect of study treatment arms** on the symptom category (moderate vs mild) throughout the study course1,2

5

6

7

8

9

10

11

12

13

14

7.9

9.4

Months from randomisation

Me

an

IP

SS

24211815129631 Combination therapy resulted in shifting of BPH symptom score from moderate to mild category from month 9 onwards

9.4

7.6

Moderate

Mild

*Last observation carried forward

Fixed dose combination of dutasteride and tamsulosin (n=369)Watchful Waiting with initiation of tamsulosin if symptoms did not improve (n=373)

9.4

7.9


*Improvement thresholds were selected for the lower IPSS baseline score (8-19)**Both treatment arms included lifestyle advice administered

Study Results: IPSS Change

-6

-5

-4

-3

-2

-1

0


Fixed dose combination of dutasteride and tamsulosin (n=369)**Watchful Waiting with initiation of tamsulosin if symptoms did not improve (n=373)**

p<0.001

Patient assessment of

improvement thresholds*,3

Ad

juste

d m

ean

ch

an

ge

from

baselin

e in

IP

SS

Slight-1.9

Moderate-4.0

Marked-7.4

-0.9

-2.4

-3.6 -3.6

-5.2

-4.5

-3.2

24211815129631

Rapid symptom improvement with combination therapy (measured at month 1)

Superior symptom improvement with combination therapy at each post-baseline visit (p<0.001) vs. Watchful Waiting with initiation of tamsulosin if symptoms did not improve

Sustained superiority of fixed dose combination in symptom improvement over 2 years of treatment vs. Watchful Waiting with initiation of tamsulosin if symptoms did not improve

-5.4


Efficacy: BPH Clinical Progression1

*Overall clinical progression events defined by a rise in IPSS of ≥3 points at any visit when compared to Visit 2 (baseline), AUR related to BPH, UTI related to BPH, Incontinence related to BPH, Renal insufficiency related to BPH.

0.0 6.0 12.0 18.0 24.00

10

20

30


Su

bje

cts

wit

h p

rog

res

sio

n, %

Fixed dose combination of dutasteride and tamsulosin**Watchful Waiting with initiation of tamsulosin if symptoms did not improve**

29%

18%

Cumulative number of events/Subjects at risk Year 1 Year 2

Fixed dose combination of dutasteride and tamsulosin 48/369 17/276

Watchful Waiting with initiation of tamsulosin if symptoms did not improve 94/373 14/251

43.1% relative risk reduction at year 2; (p<0.001)

11.3% absolute risk reduction (risk difference)

Number needed to treat: 9


CONDUCT Results: Summary1,2

1. Study Results Summary at http://clinicaltrials.gov/ct2/show/results/NCT01294592?term=NCT01294592&rank=1 accessed on 13 January 2015, 2. Roehrborn CG et al. BJUInt 2015 doi:10.1111/bju.13033

CONDUCT Study

Supports first line

use

Consistent safety profile

Rapid symptom

improvement

Compliments CombAT

data

http://onlinelibrary.wiley.com/doi/10.1111/bju.13033/abstract


Dig Out Useful Evidence Beyond Studies by Post-hoc Analysis


5ARI Prostate Cancer Risk Reduction Studies

1. Thompson I et al. Prostate 1997;33:217–221; 2. Thompson I et al. N Engl J Med 2003;349:215–224; 3. Andriole G et al. J Urol 2004;172:1314–1317; 4. Andriole GL et al. N Engl J Med 2010;362:1192–1202.

2010 20141994 2003

PCPT: results published(finasteride versus placebo)

• Increased incidence of high-grade tumors with finasteride2

PCPT initiated(finasteride versus placebo) 1

REDUCE initiated(dutasteride versus placebo)3

REDUCE: results published(dutasteride versus placebo)

•Increased incidence of high-grade tumors with dutasteride4


Prostate Cancer Prevention Trial


Reduction of Dutasteride of Prostate Cancer Event

(REDUCE)


Figure out the purposeImprove the study design by lessons Choose the right population Fill the data gapPost-hoc analysis

Take Home Messages

reappraisal of published randomized luts/bph clinical trials –what have we learned and where do we...

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