Efficacy and tolerability of ®estraderm MX, a new estradiol matrix patch

JOURNAL OF THE CLIMACTERIC & POSTMENOPAUSE

ELSEVIER

Maturitas

Efficacy and tolerability

27 (1997)

285-292

of @Estraderm MX, a new estradiol matrix patch

Albert0 Bacchi-Modena a, Pierfrancesco Bolis b, Carlo Campagnoli ‘, Fiorenzo De Cicco d, Michele Meschia e, Francesco Pansini f, Roberto Pisati g,*, Gabriele Hills l.h a Clinica Ostetrico-Ginecologica, Universitci di Parrna, Parma, 1tal.v b Clinica Ostetrico-Ginecofogica, Ospedale Di Circolo, Varese, Italy Servizio di Ginecologia Endocrinologica, Ospedale S. Anna, Torino, Ital) ’ Clinica Ostetrico-Ginecologica, Universitri Cattolica Del Sacro Cuore. Roma, Ital) ’ Clinica Ostetrico-Ginecologica I, Ist. L. Mangiagalli, Universiti2 di Milano. Milano. Ital? ‘. Clinica Ostetrico-Ginecologica, Universith di Ferrara, Ferrara, Ital 8 Medical Department, Novartis, S.S. 233 Km 20.500, -71040, Origgio, Itao, ’ International Clinical Research, Novartis. Basle. Sxkerland Received

25 June

1996: received

in revised

form

25 March

1997: accepted

27 March

1997

Abstract Objectiues: To assess the efficacy and tolerability of a new matrix patch delivering 0.05 mg estradiol per day (Estraderm MX 50) in postmenopausalwomen with moderate to severepostmenopausalsymptoms.Methods: A multicenter, double-blind, randomized, between-patient,placebocontrolled trial in 109postmenopausalwomenwas carried out. Patcheswereappliedtwice weekly for 12 weeks,Patientswere assessed at 4. 8 and 12weeksof treatment. The primary efficacy variable was changefrom baselinein meannumber of moderateto severehot flushes(including night sweats)per 24 h during the last 2 weeksof treatment. Other variablesincluded Kupperman Index, local and systemictolerability. Plasmaconcentrationsof estradiol (E2), estrone(El) and estronesulfate (EIS) weredetermined before and after treatment. Results: EstradermMX wassignificantly superiorto placebo(P < 0.001)in reducingmean number of moderateto severehot flushes(including night sweats)per 24 h after 4, 8 and 12 weeksof treatment. The estimate of treatment group differences after 12 weeks was 4.2 hot flushes(95% confidence interval: 2.6-5.8). Estraderm MX also significantly reduced Kupperman Index at all time points comparedto placebo (P < 0.001). EstradermMX inducedincreasesin meanE2, El and ElS plasmalevelsasexpected(E2: baseline2.7 pgjml, 12weeks 38.9 pg/ml; El: baseline18.8 pg/ml, 12 weeks41.6 pg/ml; ElS: baseline235.6pg/ml, 12 weeks765.1pg/ml). Overall rates of adverseexperienceswere similar for EstradermMX and placebo. The number of patients reporting skin irritation waslow and similar in both groups. Conclusions: EstradermMX 50, a new matrix patch, offers an effective and well tolerated dosageform for transdermaldelivery of 0.05 mg E2 per day. 8 1997ElsevierScienceIreland Ltd.

* Corresponding author. Tel.: + 39 2 96542674; fax + 39 2 96701086. ’ For the “Estraderm MX Study Group (see Appendix A). 037%5122/971$17.00

0 1997 Elsevier

PI1 SO378-5122(97)00039-X

Science

Ireland

Ltd.

All

rights

reserved

X6

A. Bacchi-Modmu

Estrogen

Kqworcis:

trolled

replacement

therapy:

et ul. , Maturitrrs

Transdermal:

Estradiol;

17 (1997)

285

292

Hot flushes: Menopausal

symptoms:

Placebo-con-

trial

-

1. Introduction

2. Materials

Estrogen replacement therapy (ERT) has been effectively used for decades to treat menopausal symptoms (e.g. vasomotor disturbances, urogenital atrophy) [I]. It also provides protection against osteoporosis [2]. In addition, epidemiological studies have consistently shown that estrogen use in postmenopausal women is associated with lower all-cause mortality, primarily through a reduction in coronary heart disease [3]. ERT is generally administered by the oral or transdermal route. The transdermal route of administration provides relatively constant blood levels of estradiol and avoids first-pass metabolism, thus closely mirroring ovarian release during the pre-follicular phase of the menstrual cycle [4]. Estraderm TTS, delivering 0.025 mg, 0.05 mg or 0.100 mg estradiol (E2) per day via the transdermal route, has been used in clinical practice for over a decade and is well established to be effective and well tolerated both in the treatment of postmenopausal symptoms and in the prevention of osteoporosis [5,6]. Although the majority of women experience no problems during short and long-term use of Estraderm TTS, a small number may experience local tolerability problems. In approximately 6’% of women skin irritation with Estraderm TTS is sufficiently severe to lead to discontinuation of therapy [5,6]. The skin irritation appears to be due to the ethanol component and/or to the adhesive rather than to E2 [7-91. Matrix patches, devoid of alcohol, have recently been developed [lo-141. In these systems, E2 is contained within the adhesive component itself and, for women with sensitivity to alcohol, they may represent an advance. The new matrix patch described in this study was developed to deliver E2 at bioequivalent doses to existing Estraderm TTS. The current study examines the efficacy and tolerability of this new matrix patch delivering 0.05 mg E2 per day (Estraderm MX 50) in the treatment of moderate to severe hot flushes and other postmenopausal symptoms.

2.1. Patients

and methods

Healthy female outpatients, requiring treatment for climacteric symptoms, were eligible to participate in the study. Patients had to be aged between 35 and 65 years and were required to be at least 8 months after their last natural menstrual cycle or at least 6 weeks post-oophorectomy. To ensure that climacteric symptoms were of at least moderate severity, a minimum mean number of 7 moderate to severe hot flushes per 24 h during the last two weeks of a 4 week run-in period was required as an inclusion criterion. Moderate hot flushes were defined as ‘warm sensation with sweating, able to continue activity’ and severe as ‘hot sensation with sweating, must stop activity’. Patients were also required to have baseline serum follicle-stimulating hormone (FSH) concentrations > 50 IUjl and serum E2 concentrations < 20 pg/ml. Patients who had received oral hormone replacement therapy (HRT) within 8 weeks, transdermal HRT within 4 weeks or vaginal estrogen within 6 weeks before the start of trial treatment were not eligible to participate. These long washout periods are required by some registration authorities to ensure that there is no possibility of carry-over effects from previous HRT. The differences for different routes of administration reflect the variations in pharmacokinetics associated with these forms. All patients gave written consent to participate in the study which was approved by the relevant local Ethics Committee. 2.2. Study design This was a multicenter, double-blind, randomized, 12 week, between-patient trial. Following an open drug-free run-in period, to confirm the presence of moderate to severe climacteric symptoms, patients were randomized in equal numbers to receive either Estraderm MX 50 (nominal delivery 0.05 mg E2 per day) or placebo. Patches were

A. Bacchi-Modena

et al. / Maturitas

applied twice weekly (i.e. every 3-4 days) for the 12 week treatment period. A double-blind treatment phase of 12 weeks was considered appropriate for the assessment of efficacy in this population, anticipating the fact that placebo treated patients would show an initial treatment response and some regression towards the mean. Patients were assessed prior to randomization and at 4, 8 and 12 weeks of treatment. Patients were asked to record each day the number of moderate to severe hot flushes (daytime hot flushes and night sweats separately) for the entire study period, including the run-in phase. Occurrence of any bleeding during the treatment phase was also recorded daily in the patient diary. At each visit, patients’ diaries were carefully checked and the presence and severity of menopausal symptoms was assessed by means of the Kupperman scale [15]. Weight and blood pressure were also measured. In addition, local tolerability at the site of the previous patch application and the occurrence of any adverse experiences were assessed by direct questioning. Compliance with dosing regimen was checked by counting used and unused patches. Blood samples for routine hematological and biochemical parameters and plasma E2, estrone (El) and estrone sulfate (ElS) levels were taken at baseline and at the end of treatment. El, E2 and ElS assays were carried out by the Bioanalytics and Pharmacokinetics Department, Ciba-Geigy, Basle, Switzerland. Both El and E2 were assayed using competitive radioimmunoassay (RIA) and specific rabbit antiserum. For E2 and El the sensitivity of the assays was 1 pg/ml and 2.5 pg/ml respectively. with interassay coefficients of variation for a pool of control samples from postmenopausal women of 16.4% (E2) and 16.8% (El). ElS was assayed using a radioimmunoassay for El before and after enzymatic hydrolysis-the difference indicating the amount of El derived from the sulfate as previously described [ 16,171. Hormone replacement therapy other than trial medication or any other drugs used for the treatment of climacteric symptoms, including alphaand beta-blockers, antidepressants, ergots or ergot derivatives were not allowed throughout the study period.

27 (1997)

285-292

281

As the duration of exposure to unopposed estrogen in the study was relatively short, it was not felt to be necessary to administer post trial progestogen to induce withdrawal bleeding. 2.3. Stutistical

methodolog?

A sample size of at least 35 evaluable patients per group was calculated to be required to detect a difference between treatments of three hot flushes per 24 h with 90% power, assuming the standard deviation of the primary efficacy criterion to be 3.8 hot flushes per day. As it was expected that 20% of randomized patients would not be evaluable, at least 44 patients per group were to be randomized. The primary efficacy criterion was the change from baseline (i.e. the last two weeks of the run-in period) in mean number of moderate to severe hot flushes (including night sweats) per 24 h in the last 2 weeks of treatment. Secondary efficacy criteria included change from baseline in mean number of moderate to severe hot flushes (including night sweats) per 24 h in the 2 weeks prior to assessments at 4 and 8 weeks of treatment, and Kupperman Index at 4, 8 and 12 weeks of treatment. Data were analyzed according to an intent-totreat approach for all primary and secondary efficacy criteria. For the ‘intent-to-treat’ analyses all randomized patients with data on the number of moderate to severe hot flushes for at least 10 days during the last 2 weeks prior to assessment were included. For the primary criterion an additional ‘acceptable-for-efficacy’ analysis was performed, comprising those patients who completed the whole treatment period of 12 weeks. Analysis of covariance (ANCOVA) with baseline value as covariate and treatment and center as further effects in the model was used for the primary efficacy variable as well as for all secondary variables. For tests on treatment differences a significance level of 5% (two-sided) was applied. Secondary variables were analyzed in an exploratory way and no adjustment of significance levels was performed.

Table 1 Patient demographics

and baseline

data --.

All randomized

patients

Estraderm

matrix

(N = 53)

.4gc (years) Mean (S.D.) 52.5 (3.8) Range 46-61 Body weight (kg) Mran (S.D.) 62.1 (8.6) Range 42-88 Duration of menopause (months) Median 38.4 Range 2-222 Duration of symptoms (months) Median 36.0 Range 2-228 Kupperman index Mean (SD.) 28.9 (8.1) Range 13-47 Mean number of hot flushes per 24 hours Mean (SD.) 10.7 (4.2) Range 6.9-23.4

3. Results 3.1. Putients A total of 177 patients were screened in 11 centers in Italy. One hundred and nine (109) were randomized to receive treatment with Estraderm MX (n = 53) or placebo (n = 56). Sixty six of the 68 patients who were enrolled but not randomized, were excluded either because their FSH/E2 levels were outside the limits defined in the protocol (i.e. < 50 IUjl, and > 20 pg/ml, respectively), or because they had a mean number of moderate to severe hot flushes < 7 in the last 2 weeks of the run-in period. One other patient had abnormal laboratory values at screening and one withdrew consent prior to randomization. Ninety-eight (90.0%) of the 109 patients completed the trial (50 patients (94.3%) on Estraderm MX, 48 patients (85.7%) on placebo). Eight of 11 patients who withdrew prematurely were from the placebo group. The most frequent reason for discontinuation was lack of therapeutic effect, which led to the withdrawal of five patients, all on placebo. Two patients (one on Estraderm MX and one on placebo) withdrew because of adverse experiences, three withdrew for administrative

Placebo

(N = 56)

Total

(A’=

51.3 (4.1) 39-58

51.9 (4.0) 39 61

64.4 (8.5) 47-86

63.3 (8.6) 42-88

21.6 l-161

34.2 1L222

33.0 2-168

36.0 2-228

27.8 (7.2) 10-41

28.3 (7.6) 10-47

11.1 (6.7) 6.4-52.7

10.9 (5.6) 6.4-52.7

109)

reasons (one on Estraderm MX and two on placebo) and a further patient on Estraderm MX was withdrawn because of poor compliance. Table 1 shows that baseline data and demographics were comparable between the groups apart from a slightly longer duration of menopause in the Estraderm MX group (median 38.4 months) compared to placebo (27.6 months). As the allocation of patients to trial medication was randomized, it is likely that this difference arose by chance. However, as baseline symptoms and other demographic data were comparable, it is unlikely that this difference alone would influence the efficacy and safety parameters studied. 3.2. Efficacy Results for the ‘intent-to-treat’ dataset were comparable to those for the ‘acceptable-for-efficacy’ dataset. The data for the intent-to-treat population are presented. Estraderm MX was statistically significantly superior to placebo in reducing the number of hot flushes at all time points post treatment (P < 0.001). Reductions observed with Estraderm MX were approximately twice as high as those seen with placebo.

A. Bacchi-Modem Table Mean

2 change

from

baseline

in number

of moderate Weeks

Change from E2 Matrix Placebo

baseline:

(adjusted

Treatment group contrast Mean estimated value 95%, Confidence Interval P-value

rt al. / Maturitas

to severe

3+4

27 (1997)

hot flushes Weeks

7+8

-785.-292

289

per 24 h (intent-to-treat Last

dataset)

IO- 14 days

of treatment

values) -6.9 - 3.9

(E2 Matrix

--Placebo) -3.0 -4.5. -1.6
The estimated differences between treatments with the associated 95% confidence intervals and the P-values are summarized in Table 2. Improvements are expressed as negative values (i.e. reduction from baseline), with a positive value reflecting worsening of symptoms. The estimated treatment group difference after 12 weeks was - 4.2, showing that treatment with Estraderm MX reduced the mean number of moderate to severe hot flushes per 24 h from baseline by 4.2 after subtraction of the effect of placebo. A significant treatment difference in favor of Estraderm MX was already present at 4 weeks ( - 3.0) with a slight increase in treatment difference observed over time ( - 3.7 at 8 weeks. -4.2 at 12 weeks). Estraderm MX was also statistically significantly more effective than placebo in reducing the Kupperman Index at 4, 8 and 12 weeks (P < 0.001) (Table 3). Mean plasma E2, El and ElS concentrations at baseline and after 12 weeks of treatment are presented in Table 4. In the Estraderm MX group, mean E2 concentrations were increased at 12 weeks (38.9 pg/ml) by a factor of 14 compared to baseline (2.7 pg/ml). El was increased by a factor of 2.2 (from 18.8 pg/ml at baseline to 41.6 pg/ml at 12 weeks) and ElS increased by a factor of 3.2 (from 235.6 pg/ml at baseline to 765.1 pg/ml at 12 weeks). Although the calculation of EZ/El ratios on the basis of low steroid concentrations at baseline may give little information, mean E2/El ratio increased from 0.14 at baseline to 0.96 at 12 weeks, a value similar to the ratio observed in pre-menopausal women. As expected, in the placebo group mean E2, El and ElS values at 12 weeks were essentially unchanged from baseline.

-8.3 -4.6

-8.2 -4.0

-3.7 -5.0, -2.3
-4.2 -5.8, -2.6
3.3. Safety and tolerability

Both systemic and local tolerability was good in both groups. The overall rate of patients with adverse experiences was similar in the two patient groups (58.5% on Estraderm MX and 66.1% on placebo). Most adverse experiences were considered by the investigator to be possibly or probably related to study medication. The two most frequently reported adverse experiences were breast tenderness and application site reaction. Breast tenderness was reported by 15 patients in each treatment group (28.3% and 26.8% for Estraderm MX and placebo respectively). Application site reaction (mostly erythema and itching) was reported by 16 patients receiving Estraderm MX (30.2%) and 11 patients receiving placebo (19.6%). The percentage of patients reporting skin irritation increased with time in both treatment groups. After 4 weeks of treatment the frequency of skin irritation was 13.2% (seven patients) for Estraderm MX and 7.1% (four patients) for placebo, while after 12 weeks the corresponding values were 19.6% (ten patients) and 21.6% (11 patients). However, no patients discontinued the study prematurely due to poor local tolerability. Other adverse experiences reported by more than two patients (5%) in either treatment group were vaginal spotting/bleeding (15.1 and 12.5% for Estraderm MX and placebo respectively), headache (7.5 and 5.4% for Estraderm MX and placebo respectively) and abdominal pain (7.5 and 5.4% for Estraderm MX and placebo respectively). No clinically important changes in blood pressure, body weight, or routine laboratory variables were observed during the study in either group.

Table Mean

i change

from

baseline

in Kupperman

index

(intent-to-treat

dataset) _ -~__---.

Weeks Change from E2 Matrix Placebo

baseline

Adjusted treatment Estimated mean 95’:i, Confidence P-value

(mean

3+4

7+ 8

Last

.~-

IIS 14 days of treatment

values) - 13.8 -7.1

group value Interval

Weeks

contrast*

(E2 Matrix -Placebo) -6.4 (-9.3, -3.5)
4. Discussion This study demonstrates that a new matrix patch, delivering 0.05 mg E2 per day (Estraderm MX), is effective at treating moderate to severe climacteric symptoms in postmenopausal women. A significant reduction in hot flushes and Kupperman Index compared to placebo was present by the first visit after randomization (i.e. after 4 weeks of treatment) and at 8 and 12 weeks of treatment. The magnitude of the decrease in symptom severity was so pronounced at the 4 week time point that it is likely some effect was present as early as weeks 1 and 2 of treatment. Although caution is required when comparing data across different studies, both the extent and the time-course of the efficacy of Estraderm MX seen in the current study are in keeping with those previously reported with Estraderm TTS [4,5]. This would be anticipated from a matrix patch delivering bioequivalent amounts of E2 to Estraderm TTS. The tolerability profile of Estraderm MX was good. The overall rate of systemic adverse experiences was similar for Estraderm MX and placebo and the observed adverse experiences (i.e. breast tenderness, vaginal bleeding, headache and abdominal pain) are typical symptoms seen in postmenopausal women. Breast tenderness, the most frequent systemic adverse experience reported in this study, occurred in the same number of women in both treatment groups. In the absence of a placebo group this finding might have been

- 17.4 -9.7 -7.5 ( - 10.3.
- 18.0 -9.0

-4.7)

(-

-8.7 11.6, -5.8)
incorrectly attributed to an estrogen related side effect. This finding demonstrates the value of placebo-controlled, double-blind studies when defining the ‘true’ characteristics of a new drug. It is interesting to speculate on the reason for the high frequency of estrogen-related side effects reported in the placebo group. The finding may suggest that such ‘side effects’ are relatively common in this population even in the absence of exogenous estrogens or may simply reflect both the patients and investigators being primed to the possibility of these adverse experiences occurring with study medication. Estraderm MX increased mean E2, El and ElS plasma levels as expected. The observed E2 and El values were comparable to the mean O-96 h concentrations observed at steady state in a previous pharmacokinetic study [18]. The three-fold increase in ElS over baseline is in keeping with that observed with Estraderm TTS 100 after 6 weeks, but is less than that reported after oral administration of 2 mg micronized estradiol per day for 6 weeks [19]. In conclusion, Estraderm MX 50 is significantly superior to placebo in reducing moderate to severe hot flushes and other postmenopausal symptoms within 4 weeks of starting treatment. Estraderm MX is well tolerated with an observed systemic tolerability profile similar to placebo, and good local tolerability. Estraderm MX 50 therefore offers a new, effective, and well tolerated dosage form for transdermal delivery of 0.05 mg estradiol per day.

A. Bacchi-Modena et al. / Maturitas 27 (1997) 285-292

291

Table 4 Mean (SD) E2. El and EIS plasma concentrations E2 Matrix

Wpdmll Wz/mll E 1Sk-M4 E2/E I ratio

Placebo

Baseline

Final Visit

2.7 (2.5) 18.8 (7.3) 235.6 (132.7) 0.14 (0.11)

38.9 (25.4) 41.6 (20.7) 765.1 (646.2) 0.96 (0.41)

Acknowledgements

We would like to acknowledge the collaboration and commitment of all the local investigators and their staff without whom the present study would not have been possible (see appendix). We would also like to thank Giancarlo Monza, MD and Friedhelm Hornig, MSc for their review of the manuscript.

Appendix A. The @Estraderm MX Study Group

Universita di Milano: Prof. P Crosignani, Dr. F Bruschi, Dr. D Perotti; Universita di Parma: Dr. C Sacchini, Dr. P Bertoli; Ospedale Di Circolo, Varese: Dr. M Franchi, Dr. E Castoldi, Dr. M Grazia Terreni; Ospedale S. Anna, Torino: Dr. L Lesca, Dr. C Cantamessa, Dr. A Sandri; Universita Cattolica Del Sacro Cuore, Roma: Prof. S Dell’ Acqua, Dr. F Rossiello, Dr. AM Valenzano; Universita di Bologna: Prof. D de Aloysio, Dr. A Roncuzzi; Ospedale S. Chiara, Pisa: Prof. V Facchini, Dr. B Cappagli, Dr. M Gambacciani, Dr. A Spinetti; Ospedale S. Raffaele, Milano: Prof. A Ferrari, Dr. R Chionna, Dr. R Marabini; Istituto Artemisia, Roma: Prof. C Giorlandino, Dr. G Gambuzza; Universita di Ferrara: Prof. G Mollica, Dr. G Bonaccorsi; Universita di Milano: Prof. T Nencioni, Dr. M Durini; Ciba-Geigy, Basel: Dr L Botta

Baseline 2.6 (1.3) 18.4

(8.2) 249.6 (144.0) 0.16 (0.07)

Final Visit 3.7 (4.0) 19.4 (9.4) 253. I (204.4) 0.19 (0.14)

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[I91 Selby LP, McGarrigle HHG, Peacock M. Comparison of the effects of oral and transdermal oestradiol administration on estrogen metabolism, protein synthesis. gonadotrophin release, bone turnover and climacteric symptoms in postmenopausal women. Clin Endocrinol 1989:30:241-9.