nuevas alternativas en el manejo de los miomas uterinos

Francisco Vázquez,MD,PhDCEOGA LUGO

Ulipristal Acetate: A new medical treatment for medical treatment for uterine fibroids.Pearl I & II Clinical Studies

EDITORIAL

Uterine Fibroids and Evidence-Based Medicine — Not an Oxymoron

Elizabeth A. Stewart, M.DElizabeth A. Stewart, M.D

N Engl J Med 2012; 366:471-473

February 2, 2012

RANDOMISED, DOUBLE-BLIND PHASE III TRIAL

OF ULIPRISTAL ACETATE (UPA) VS PLACEBO

R

A

N

D

O

S

U

3 months

Once-daily oral UPA 5 mg+ concomitant iron

n=95

Patients with

6 months

PEARL I

O

M

I

S

A

T

I

O

N

U

R

G

E

R

Y

Once-daily oral UPA 10 mg+ concomitant iron

n=94

Once-daily oral Placebo+ concomitant iron

n=48

Patients withsymptomatic

uterinefibroids and

anaemia

Follow-up Period

ITT, intent-to-treat; UPA, ulipristal acetate

ITT Population

Donnez J ,Tatarchuk TF, Bouchard P et al. N Engl J Med 2012;366:409−20

BASELINE CHARACTERISTICS

Key Inclusion Criteria

● Excessive uterine bleeding

PBAC score >100 during Days 1–8 of menstruation

● Anaemia

Haemoglobin ≤10.2 g/dL

PEARL I

Baseline medical status

Placebo (N=48)

UPA 5 mg (N=95)

UPA 10 mg (N=94)

Mean PBAC 460 487 411

(range) (119–1284) (118–1645) (102–1570)

Mean haemoglobin 9.55 g/dL 9.32 g/dL 9.46 g/dL

Mean haematocrit 32.5% 32.1% 32.4%

ITT, intent-to-treat; PBAC, Pictorial Bleeding Assessment Chart; UPA, ulipristal acetate

ITT Population


PRIMARY AND SECONDARYSTUDY OBJECTIVES

Primary objectives• Demonstrate superior efficacy of UPA + iron versus placebo + iron for:

– Reducing excessive uterine bleeding prior to surgery

– Reducing total fibroid volume prior to surgery

Secondary objectives

PEARL I

Secondary objectives• Demonstrate improvements in fibroid-related symptoms, eg. QoL, pain

• Assess the capacity of UPA to decrease uterine volume

• Demonstrate superior efficacy of UPA + iron versus placebo + iron at correcting

anaemia caused by uterine fibroids

Assess overall safety of UPA in subjects with uterine fibroids

UPA, ulipristal acetate (ESMYA)Donnez J ,Tatarchuk TF, Bouchard P et al. N Engl J Med 2012;366:409−20

BLEEDING CONTROL IN MORE THAN 90%

OF WOMEN TREATED WITH UPA (PRIMARY ENDPOINT)

Patients withPBAC <75at the EOT

(Week 13; ITT)

WEEK 13*p<0.001 vs. placebo

*

PEARL I

*

Pa

tie

nts

Placebo UPA 5 mg UPA 10 mg

EOT, end of treatment; ITT, intent-to-treat; PBAC, Pictorial Bleeding Assessment Chart; UPA, ulipristal acetate

Pa

tie

nts


TIME TO CONTROL OF BLEEDING

60

80

100

Pa

tie

nts

(%

)

PBAC <75

PEARL I

UPA 10 mg

UPA 5 mg

Placebo

Bleeding was controlled 7 days from treatment initiation, in

● 75.9% of UPA 5 mg patients and

0

20

40

0 10 20 30 40 50 60 70 80 90 100

Time (days)

Pa

tie

nts

(%

)

7 days


● 75.9% of UPA 5 mg patients and

● 82.7% of patients in the UPA 10 mg group

PBAC, Pictorial Bleeding Assessment Chart; UPA, ulipristal acetate

HIGHER NUMBER OF PATIENTS WITH

CORRECTED ANAEMIA IN UPA GROUPS

Hb >12.0 g/dL

85.3%

89.4%

•(all patients had Hb ≤10.2 g/dL at screening)ANAEMIA CORRECTION AT WEEK 13

PEARL I

Pa

tie

nts

(%

)

77.1%

UPA, ulipristal acetate

Pa

tie

nts

(%

)

Placebo + iron

UPA 5 mg+ iron

UPA 10 mg+ iron


PEARL I. EFFECT ON FIBROID VOLUME(MEASURED WITH CENTRALISED BLINDED MRI READING)

Difference in Median Total FibroidVolume Reduction vs Placebo

Median Reduction

Placebo 3.0%

WEEK 13

UPA 5 mg -21.22% ∆ -22.61%

UPA 10 mg -12.31% ∆ -18.19%

● The results include reduction of all fibroids captured with the MRI scan

Placebo UPA 5 mg UPA 10 mg

UPA, ulipristal acetate (ESMYA) Donnez J ,Tatarchuk TF, Bouchard P et al. N Engl J Med 2012;366:409−20

The effect of medical therapy onmyoma size (MRI scan)

Before therapy After therapy

PEARL I. QUALITY OF LIFE(DISCOMFORT DUE TO UTERINE FIBROIDS)

• Discomfort due to uterine

fibroids (median):

• 7 questions (0–4)*

• Bleeding

18

16

14

12

16.0

14.7

14.014.1

BL, BaselineW13, Week 13

UPA SIGNIFICANTLY IMPROVED DISCOMFORT DUE TO UTERINE FIBROIDS

• Bleeding• Abdominal pressure• Urination frequency• Daily activity• Fatigue• Mood• Sexual activity

* lower = better

Placebo

0

10

8

6

4

2

UPA 5 mg UPA 10 mg

BL W13 BL W13BL W13

14.7

2.9

4.0

UPA, ulipristal acetate (ESMYA) Donnez J ,Tatarchuk TF, Bouchard P et al. N Engl J Med 2012;366:409−20

PEARL I. EFFECT ON PAIN(SF-MCGILL SHORT FORM PAIN QUESTIONNAIRE*)

● UPA resulted in a clinically meaningful reduction of pain

● This reduction (7 points) is comparable to the reduction of post operative pain obtained

with narcotic or non-narcotic analgesics

*Melzack R. The short-form McGill pain questionnaire. Pain 1987;30:191–197 Donnez J, et al. N Engl J Med 2012;366:409−420 (PEARL I)UPA, ulipristal acetate (ESMYA)

RANDOMISED, DOUBLE-BLIND PHASE III TRIAL OF ULIPRISTAL ACETATE (UPA) VS GnRHa

R

A

N

D

O

S

U

3 months

Once-daily oral UPA 5 mgn=97

6 months

PEARL II

Patients withO

M

I

S

A

T

I

O

N

U

R

G

E

R

Y

Once-daily oral UPA 10 mgn=103

Intramuscular leuprorelin3.75 mg once every 4 weeks

n=101

Follow-up Period

Donnez J, Tomaszewski J, Vázquez F et al.N Engl J Med 2012;366:421−32

GnRHa, gonadotrophin-releasing hormone agonist UPA, ulipristal acetate

ITT Population

Patients withsymptomatic

uterinefibroids

PEARL II Study - Spanish Participants

20

25

30

35

40

Treatment completed

Early termination

24

19

14

85

2

63

8

0

5

10

15

BASELINE CHARACTERISTICS*

Key Inclusion Criteria

● Excessive uterine bleeding

PBAC score >100 during Days 1–8 of menstruation

● Anaemia not required

● Eligible for surgical procedureHysterectomy, myomectomy, uterine artery embolisation or endometrial

PEARL II

Hysterectomy, myomectomy, uterine artery embolisation or endometrial

ablation

Baseline medical status

UPA 5 mg (N=93)

UPA 10 mg (N=95)

Lupron 3.75 mg (N=93)

Mean PBAC 379 328 404

(range) (109–1984) (120–1809) (102–2104)

PBAC, Pictorial Bleeding Assessment Chart; PP, per protocol; UPA, ulipristal acetate

*PP Population


PRIMARY AND SECONDARYSTUDY OBJECTIVES

Primary objectives• Demonstrate non-inferior efficacy of UPA versus GnRHa for reducing excessive

uterine bleeding due to uterine fibroids prior to surgery

• Demonstrate superior safety and tolerability of UPA versus GnRHa for hot flushes and estradiol levels

PEARL II

Secondary objectives• Demonstrate improvements in fibroid-related symptoms, eg. QoL, pain

• Assess the capacity of UPA to:

– Decrease the volume of the 3 largest fibroids

– Decrease uterine volume

Assess overall safety of UPA in subjects with uterine fibroids

GnRHa, gonadotrophin-releasing hormone agonist QOL, quality of life; UPA, ulipristal acetate (ESMYA)


UPA IS AS EFFECTIVE AS GnRHa IN CONTROLLING BLEEDING AT THE END OF THERAPY

Primaryefficacy endpoint(non-inferiority)

Week 13

WEEK 13

Patients

with P

BA

C <

75

PEARL II

UPA 5 mg UPA 10 mg Lupron 3.75 mg

Patients

with P

BA

C <

75

GnRHa, gonadotrophin-releasing hormone agonist;

PBAC, Pictorial Bleeding Assessment Chart; PP, per protocol;

UPA, ulipristal acetate

● >90% of patients

have normalised

bleeding (PP)


TIME TO CONTROL OF BLEEDING

PBAC<75

60

80

100

Pa

tie

nts

(%

)

UPA 5 mgUPA 10 mgLupron 3.75 mg

PEARL II

0

20

40

0 10 20 30 40 50 60 70 80 90 100

Time (days)

Pa

tie

nts

(%

)

7 days

GnRHa, gonadotrophin-releasing hormone agonist; PBAC, Pictorial Bleeding Assessment Chart; UPA, ulipristal acetate

30 days

● UPA normalised bleeding faster than

GnRHa (7 days vs 30 days)


UPA 5 mg

UPA STOPS HEAVY BLEEDING FASTER AND MORECONSISTENTLY THAN GnRHa (INDIVIDUAL PATIENT DATA)

Da

ily P

BA

C s

co

re

Da

ily P

BA

C s

co

re

PEARL II

GnRHa

UPA 10 mg

GnRHa, gonadotrophin-releasing hormone agonist; PBAC, Pictorial Bleeding Assessment Chart; UPA, ulipristal acetate

Da

ily P

BA

C s

co

re

Planned timepoint (days)7 days

7 daysPlanned timepoint (days)

28 days

● After first menstruation, most UPA

patients are in amenorrhoea, while

many GnRHa patients have further

bleeds during the next 3 weeks due

to flare-up effect


PEARL II. EFFECT ON FIBROID VOLUME REDUCTION

Media

n %

volu

me r

eduction in

th

e la

rgest fibro

ids

0

-10

-20

LupronUPA 5 mg UPA 10 mg Change from

baseline at Week 13 (%)

(PP population)

WEEK 13

Media

n %

volu

me r

eduction in

th

e la

rgest fibro

ids

-30

-40

-50

-60

-53.45

-42.05

-35.55

● No significant

difference between

GnRHa and UPA

GnRHa, gonadotrophin-releasing hormone agonist; UPA, ulipristal acetate (ESMYA)


EOT

Follow-upEOT

Follow-up

-30

-20

-10

0EOT

Follow-up

-16.5

3 mo 6 mo 3 mo 6 mo 3 mo 6 mo

PEARL II. MEDIAN % VOLUME REDUCTION IN3 LARGEST FIBROIDS AT WEEK 13, 26 & 38

EOT (Week 13)mo (months)

Subpopulation

● Change from EOT (Wk 13) to 6 mo follow up for UPA 5 mg and UPA 10 mg vs Lupron: p< 0.05 -70

-60

-50

-40

-30

-45.5

-50.0

-44.8

-55.7

-43.3

-62.5

-56.7-54.8

LupronUPA 5 mg UPA 10 mg

Subpopulation of subjects where no

surgery/UAE was performed

UAE, uterine artery embolisation; UPA, ulipristal acetate (ESMYA)


Patients

with m

odera

te a

nd s

evere

hot flushes (

%)

45

40

35

30

25

Oestradiol Hot flushes70

60

50

40

Media

n s

eru

m o

estr

adio

l (pg/m

L) Coprimary

Safetyendpoints

(superiority)

PEARL II. UPA HAS A SUPERIOR SAFETY PROFILE TO GnRHa AS IT DOES NOT INDUCE MENOPAUSAL SYMPTOMS

SAFETY, WEEK 13

● UPA shows a superior safety profile to GnRHa

● UPA does not induce menopausal symptomsP

atients

with m

odera

te a

nd s

evere

hot flushes (

%)

Lupron0

20

15

10

5

UPA 5 mg

UPA 10 mg

0

30

20

10

Media

n s

eru

m o

estr

adio

l (pg/m

L)

LupronUPA 5 mg

UPA 10 mg

GnRHa, gonadotrophin-releasing hormone agonist; UPA, ulipristal acetate (ESMYA)

77.172.2

55.4

80.5

Six Domains1- Concern2- Activities3- Energy / mood4- Control5- Self consciousness

76.4

81.5

56.5

73.2s

co

re

PEARL II. EFFECT OF TREATMENT ON HRQOL

USING VALIDATED UFS-QOL QUESTIONNAIRE*

BL, BaselineW13, Week 13PP population

HRQoL

LupronUPA 5 mg UPA 10 mg

49.455.454.2

5- Self consciousness6- Sexual function

The higher the score the better; score is specific to uterine fibroids and is not a measure of overall QoL

53.356.5

50.1

Me

an

HR

Qo

Ls

BL W13 BL W13BL W13

*Spies et al. Obstet.Gynecol 2002;99:290–300Donnez J,Tomaszewski J, Vázquez F, et al. N Engl J Med 2012;366:421−432 (PEARL II)

HRQoL, health-related quality of life; UPA, ulipristal acetate (ESMYA)

Symptom severity score

1- Bleeding

2- Abdominal pressure

3- Urination frequency

4- FatigueM

ed

ian

sym

pto

m s

eve

rity

sc

ore

PEARL II. EFFECT OF TREATMENT ON SYMPTOM

SEVERITY USING UFS-QOL QUESTIONNAIRE*

SYMPTOM SEVERITY SCORE

4- Fatigue

The lower the score the better; score is specific to uterine fibroids and is not a measure of overall QoL M

ed

ian

sym

pto

m s

eve

rity

sc

ore

● UPA significantly improved QOL

● The level of symptom severity score at end of treatment corresponds to typical

healthy subject scores

QoL, quality of life; UPA, ulipristal acetate (ESMYA)


PEARL II. EFFECT ON PAIN(SF-MCGILL SHORT FORM PAIN QUESTIONNAIRE*)

● UPA resulted in a clinically meaningful reduction of pain

● This reduction (7 points) is comparable to the reduction of post-operative pain obtained

with narcotic or non-narcotic analgesics

UPA, ulipristal acetate (ESMYA)


PEARL I & II SAFETY

SPRMS EFFECT ON ENDOMETRIUM

Novel and benign endometrial changes represent a

new morphological category which has been referred

to as PRM Associated Endometrial Change (PAEC)

Distinguished features of PAEC are

1) low mitotic activity in both glands and stroma

Key Features of PAEC

1) low mitotic activity in both glands and stroma

2) abortive subnuclear vacuoles

3) apoptosis

4) absence of stromal breakdown and glandular crowding

5) the cystically dilated glands are lined by flattened epithelium without nuclear pseudostratification

PAEC disappeared 2 months after the end of therapy

Images courtesy of Professor A. Williams. Edinburgh University Medical School

SPRM, selective progesterone receptor modulator

PEARL II. UPA EFFECT ON BONE

• Serum Markers

● P1NP (epiotope of type 1 N terminal propeptide)

● Reflects bone forming activity

● Elevated levels indicate an increase in bone formation

● BSAP (bone specific alkaline phosphatase)

● Elevated levels indicate increased rate of turnover & bone modeling

•Urine Markers

● DpD (deoxypyridinoline)

● Released into the circulation during bone resorption

● CTX (C-Terminal telopeptide of type I collagen)

● Elevated levels may indicate bone resorption

Me

dia

n C

TX

(u

g/m

mo

l C

r)

PEARL I & PEARL II

● UPA rapidly stops excessive bleeding (within a week), normalises

menstrual bleeding in 90−98% of patients (PBAC <75) and induces

amenorrhea in 75% of patients (Pearl II)

● UPA reduces significantly the volume of the three largest fibroids (by

35% and 42% for UPA 5 mg and 10 mg, respectively) and the effect on fibroid

volume reduction seems to be maintained for up to 6 months after

CONCLUSIONS (1)

volume reduction seems to be maintained for up to 6 months after

treatment cessation (Pearl II)

● UPA restores patients’ QoL scores to the level of healthy women (Pearl I & II)

● Majority of patients resume menstruation and ovulation within one month after

treatment cessation (Pearl I & II)

PEARL I & PEARL II

● Pearl II shows that, compared to GnRHa, UPA 5 mg and 10 mg:

● Appear to control bleeding faster and more consistently (7 days vs 30 days)

● Maintain fibroid volume reduction for up to 6 months (-44.8% and -54.8% for UPA 5

mg and 10 mg respectively vs -16.5% for GnRHa)

● Have a superior safety profile as oestradiol levels are maintained in mid-follicular

range

CONCLUSIONS (2)

range

nuevas alternativas en el manejo de los miomas uterinos

Health & Medicine

capacity of upa

haematocritplacebo n

d n engl j med

placebo iron

upa primary endpointweek

uterine volume

uterine fibroidsupa

ulipristal acetatedonnez