Date post: | 07-Jul-2015 |
Category: |
Health & Medicine |
Upload: | ginecologos-privados-ginep |
View: | 539 times |
Download: | 0 times |
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
Donnez J ,Tatarchuk TF, Bouchard P et al. N Engl J Med 2012;366:409−20
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
Donnez J ,Tatarchuk TF, Bouchard P et al. N Engl J Med 2012;366:409−20
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
Donnez J ,Tatarchuk TF, Bouchard P et al. N Engl J Med 2012;366:409−20
● 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
Donnez J ,Tatarchuk TF, Bouchard P et al. N Engl J Med 2012;366:409−20
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
Donnez J, Tomaszewski J, Vázquez F et al.N Engl J Med 2012;366:421−32
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)
Donnez J, Tomaszewski J, Vázquez F et al.N Engl J Med 2012;366:421−32
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)
Donnez J, Tomaszewski J, Vázquez F et al.N Engl J Med 2012;366:421−32
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)
Donnez J, Tomaszewski J, Vázquez F et al.N Engl J Med 2012;366:421−32
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
Donnez J, Tomaszewski J, Vázquez F et al.N Engl J Med 2012;366:421−32
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)
Donnez J, Tomaszewski J, Vázquez F et al.N Engl J Med 2012;366:421−32
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)
Donnez J, Tomaszewski J, Vázquez F et al.N Engl J Med 2012;366:421−32
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)
*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)
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)
*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)
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