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Efficacy and tolerability of a new 7-day transdermal estradiol patch versus placebo in hysterectomized women with postmenopausal complaints
Maturitas 34 (2000) 143 – 153 www.elsevier.com/locate/maturitas
Efficacy and tolerability of a new 7-day transdermal estradiol patch versus placebo in hysterectomized women with postmenopausal complaints Thomas von Holst *, Birgitt Salbach Uni6ersity Gynaecological Clinic, Ruprecht-Karl Uni6ersity, Voßstrasse 9, D-69115 Heidelberg, Germany Received 4 May 1999; accepted 25 October 1999
Abstract Objecti6es: To investigate the efficacy and tolerability of a continuously applied 7-day-Estradiol patch (Fem7®, Merck KGaA, Germany) delivering 50 mg estradiol per day in the treatment of hysterectomized women with postmenopausal complaints compared with placebo. Design: A multicentre, randomized, double-blind study with an initial screening phase (phase I), a 3-month double-blind placebo-controlled phase (phase II) and a 3-month open follow-up phase (phase III). Methods: 186 patients were randomized for a 3-cycle placebo-controlled study followed by a 3-cycle open follow-up (total duration; 6 months). The changes in Kupperman Index (primary efficacy variable), hot flushes and urogenital symptom score were studied from baseline to the end of the study. In addition, skin tolerability was assessed and patients were also asked to grade the subjective acceptance of therapy. Results: A reduction in Kupperman Index was observed in both groups, and at each cycle of the placebo-controlled treatment phase the 7-day-Estradiol patch was superior compared with placebo (last value vs. baseline P= 0.0006). From the second treatment week onwards a distinct difference was noted in the reduction of hot flushes from baseline between the 7-day-Estradiol patch group and the placebo group. The difference between the groups was statistically significant for each cycle and at the end of the controlled treatment phase (mean weekly hot flush reduction at the end of the placebo-controlled treatment phase: − 32.5 for the 7-day-Estradiol patch vs. −22.0 for placebo, P =0.0025). The efficacy of the 7-day-Estradiol patch within the application period did not show any difference between days 1 – 3 and 4–7. Subjective acceptance of the 7-day-Estradiol patch was good and 72.4% of patients who took active medication throughout the study were willing to consider continuing its use. Conclusions: The 7-day-Estradiol patch is well tolerated and provides effective relief of moderate to severe vasomotor symptoms in hysterectomized women, with a rapid onset of action and 7-day duration of therapeutic effect. Although a placebo effect was observed, the 7-day-Estradiol patch significantly reduced hot flushes and other menopausal symptoms throughout the application period. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: 7-day-Estradiol patch; Transdermal once-weekly system; Estradiol; Kupperman index
* Corresponding author. Tel.: + 49-6221-567856; fax: + 49-6221-565713. 0378-5122/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 5 1 2 2 ( 9 9 ) 0 0 0 9 9 - 7
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1. Introduction Estrogen replacement therapy is effective in the treatment of climacteric symptoms and complaints from urogenital ageing. Vasomotor disorders (hot flushes) are the most frequent and particularly distressing climacteric complaint. They have been reported in about 85% of women at onset of menopause, and 30% of patients classified them as severe [1]. Furthermore, estrogens have been shown to be effective in the reduction of cardiovascular morbidity and mortality [2,3] and osteoporosis [4 – 10] in postmenopausal women. The beneficial effect on cardiovascular disease may in part be related to favourable alterations in the lipid profile produced by estrogens [11,12]. Unopposed prolonged application of estrogens is, however, known to induce endometrial hyperplasia. The additional administration of progestogens offers protection against this risk [13 – 19]. In this study, which included only hysterectomized patients, the additional administration of progestogens was not necessary. Estrogen replacement therapy can be administered either orally or parenterally, but the use of a transdermal therapeutic system offers several advantages. Much lower doses of estrogen are effective with transdermal delivery compared with oral therapy [20] since the former route avoids the portal system, resulting in no first-pass metabolism of estrogen and limiting disruption of the hepatic production of several proteins [21]. This may diminish the risk of increased smooth muscle tone, gall bladder disease and venous thrombosis. In addition, transdermal therapy has been reported to have a beneficial effect on glucose metabolism [22], and the increases in serum triglyceride levels observed with oral therapy [23,24] are not observed in patients with transdermal estrogen replacement therapy [25]. Fewer gastrointestinal adverse events (nausea, vomiting, abdominal pain) are associated with transdermal compared with oral therapy [26]. However, skin reactions (e.g. erythema and pruritus at the application site) are not uncommon with the transdermal route.
Treatment with transdermal estradiol replacement therapy alone or in combination with progestogens has been shown to be effective in many studies [20,27–34]. Estrogens are rapidly absorbed through the skin, with transdermal application providing controlled release and avoiding high initial peak concentrations of estradiol. The objective of this clinical study was to investigate the efficacy and tolerability of a newly developed 7-day-Estradiol patch (Fem7®, Merck KGaA, Germany) compared with placebo in the treatment of hysterectomized women with postmenopausal complaints. The 7-day-Estradiol patch contains estradiol in a new homogeneous adhesive matrix. This confers several advantages compared with the reservoir system, including a reduction in the thickness of the patch and fewer skin reactions. In addition, the prolongation of the application interval of this new patch — 7 days instead of 3–4 days — is thought to encourage greater patient compliance.
2. Subjects and methods
2.1. Study design This was a multicentre, randomized, doubleblind clinical study with an initial screening phase (phase I), a 3-month double-blind placebo-controlled phase (phase II) and a 3-month open follow-up phase (phase III), during which all patients were treated with active medication. The treatment phase was therefore a total of 6 months (six cycles of 28 days) and the medication was administered continuously during the entire cycle (without a hormone-free week). All patients included in the study received the following therapy for a total of 3 months (three cycles): 7-day-Estradiol patch (1.5 mg estradiol once a week with a delivery rate of approximately 50 mg estradiol/24 h) or once-weekly placebo. All patients received active drug therapy (7-dayEstradiol patch) for a further 3 months (three cycles). The patch used in this study comprised a thin flexible, transparent film of octagonal shape approximately 15 cm2 in size with a new patented
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SIS polymer matrix without any permeation enhancers. The non-acrylic matrix enables a very low estradiol loading of 1.5 mg per patch and a very high drug usage of 23% during the 7-day application period. Hysterectomized women with postmenopausal complaints were included in the study. All subjects were postmenopausal (aged between 40 and 65 years) or had a surgical postmenopausal status (bilateral oophorectomy more than 3 months prior to inclusion in the study). Inclusion criteria also required a normal gynaecological history and examination, serum estradiol (E2) levels less than 30 pg/ml and follicle stimulating hormone (FSH) levels greater than 30 IU/ml. All of the women had at least 20 hot flushes per week within the last month prior to screening and an overall Kupperman Index greater than 20. Patients were excluded from the study if they had received any of the following prior to its start: sex hormones taken orally within the last 28 days; locally-applied sex hormones within the last 21 days or injectable sex hormones within the last 6 months.
point for analysis was the individual endpoint (last observation) within the placebo-controlled study phase. Within the Kupperman Index, ‘hot flushes’ is the most important symptom and the frequency of hot flushes is generally considered the most relevant efficacy variable. In this study, the number of hot flushes was recorded daily in the patient’s diary. Apart from those symptoms included in the Kupperman Index, there are other frequent complaints reported by postmenopausal women. These include vaginal discomfort, loss of libido, and incontinence. Scores were given to each of these urogenital symptoms in accordance with the procedures used for the Kupperman Index and the sum of these scores was calculated. All patients were questioned at each visit as to the number of urogenital symptoms that occurred since the previous visit. The severity of these symptoms was assessed on a four-point scale (0; no symptoms, 1; mild symptoms; 2; moderate symptoms, 3; severe and heavy symptoms).
2.2. Efficacy assessments
All adverse events whether reported by the patient or observed by the investigator including data from haematology and serum biochemistry, were recorded, irrespective of any causal relationship with the study drugs. Systolic and diastolic blood pressure, heart rate, and body weight were determined at enrolment and at week 24. Skin tolerability was assessed by the patients with respect to the occurrence of skin reactions and pruritus. The following categories were used: no, slight, moderate, or severe skin reactions/pruritus. Results were recorded at the end of each application period in the patient’s diary. Skin tolerability was also assessed by the investigator for local signs of patch intolerability at each visit, separated for local erythema and oedema. They were classified as not visible, very slight, well defined, moderate to severe, or severe. Moderate to severe and severe erythema were taken together as clinically relevant erythema. Changes from earlier applications were also assessed. Again an ‘individual patient’ and ‘worse case’ basis was adopted.
The Kupperman Index — which considers a variety of common and important disorders in peri- and postmenopausal patients — is frequently used to classify the severity of climacteric disorders in clinical studies of hormone replacement therapy (HRT) [35]. It is based on the severity and intensity of various complaints including hot flushes, paresthesia, insomnia, nervousness, melancholia, vertigo, weakness, arthralgia/myalgia, headache, palpitation and formication. The maximum Kupperman Index is 51. A value of more than 20 points indicates moderate to severe postmenopausal complaints, whereas a value of about 10 points would be compatible with mild complaints. The present study enrolled patients with a Kupperman Index of greater than 20. The primary efficacy variable was the change in the Kupperman Index. The Kupperman index was measured after 4 (visit 3), 12 (visit 4), 16 (visit 5), and 24 weeks (visit 6) of therapy. The primary
2.3. Safety assessments
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All samples for haematology, biochemistry and serum lipid profile were assessed in fasting condition before enrolment, and after 16 (lipid profile only) and 24 weeks of therapy.
2.4. Other assessments Compliance was measured by counting the unused medication returned by the patients and by questioning the patients on whether any applications had been missed. Patch adhesiveness was assessed by the investigators at weeks 4, 12, 16, and 24 and by the patient every week. The degree of detachment was reported as either no, slight, moderate, or total detachment. The amount of patch detachment was sorted by intervals of 20% of the total area detached (i.e. 0, \0 – 20%, \ 20 – 40% etc). In a second step, the results from all observations were grouped into two categories of sufficient ( B40% of detachment) and insufficient adhesiveness ( \ 40% detachment). In a third step, data were summarized on an ‘individual patient’ and ‘worst case’ basis. Handling, appearance and convenience of the patch were rated by the patients (as very good, good, moderate, or poor) after 12 and 24 weeks of therapy. In addition, patients were requested to indicate whether they would continue using the patch after the study.
treatment groups were compared using the Wilcoxon rank-sum test. As part of the descriptive analysis, the Wilcoxon rank-sum test was used to compare treatment groups in phase II considering the change in Kupperman Index at further time points, urogenital symptoms, and frequency of hot flushes. Differences between groups were quantified by calculating two-tailed 95% confidence intervals. Additionally, postmenopausal complaints were analysed based on changes in specified symptoms after three treatment cycles during the doubleblind, placebo-controlled phase II using the O’Brien method [36] (non-parametric set-up). The aim of this analysis was to combine various outcome measures from different sources. The efficacy measures of hot flush rate (recorded daily by the patient in diary cards), insomnia, nervousness/irritability and urogential symptoms were combined using this approach. The incidence of erythema, oedema, adverse events and patch detachment \ 40% were analysed descriptively. Patients were considered evaluable if they had been treated with the study medication at least once and had provided any follow-up data for one or more target variables. All statistical tests were performed two-sided with a significance level at 5%.
3. Results
2.5. Ethical appro6al and patient consent The study was carried out in accordance with the revised ‘Declaration of Helsinki’ (Tokyo 1975, Venice 1983 and Hong Kong 1989) as well as the ‘Rules of Guidance for Good Clinical Trials on Medicinal Products in the European Community’ (July 1990). All patients gave their written, informed consent to participate in the clinical study. Articles 40, 41, 64, 66, and 67 of the German Drug law (AMG) were a further basis for the declaration of patient informed consent.
2.6. Statistical methods For confirmatory proof of efficacy, the change in Kupperman Index from baseline at the end of the double-blind, placebo-controlled phase II for both
Of the 221 patients enrolled by 34 centres, 35 withdrew prior to randomization, as they did not meet the inclusion criteria (mainly regarding baseline hormone concentrations or number of hot flushes). A total of 186 women were randomized on a 1:1 basis to receive either the 7-day-Estradiol patch (n= 93) or placebo (n= 93). Of the 186 randomized patients, one patient did not receive any study medication. A further 12 patients (7-day-Estradiol patch group: n= 5; placebo group: n = 7) were excluded from the intention-to-treat analysis of the placebo-controlled phase because of lack of availability of efficacy data. Baseline values of estradiol and FSH were assessed before enrolment. The results during randomization were comparable between the treatment groups.
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Both groups were well matched in terms of patient characteristics such as demographic data, medical history, previous and concomitant medication as well as hormone status. The mean ages were 53.5 years and 53.4 years in the 7-day-Estradiol patch and placebo groups, respectively.
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patients were switched to active medication. The last values in the two groups of patients were similar at the end of phase III (8.1 for the 7-dayEstradiol patch group and 8.8 for the placebo/7day-Estradiol patch group).
3.2. Frequency of hot flushes 3.1. Kupperman index Mean baseline values were similar in the two treatment groups (mean values were 27.6 in the 7-day-Estradiol patch and 27.9 in the placebo group), but individual values were as high as 43 in the 7-day-Estradiol patch group and 44 in the placebo group. In both groups reductions in the Kupperman Index versus baseline were observed throughout the placebo-controlled phase (Fig. 1). The mean value of the Kupperman index in the 7-day-Estradiol patch group declined from 27.6 to 11.2 score points at the end of the placebo-controlled study (phase II). For the placebo group the results were 27.9 at baseline and 16.0 at the end of phase II (last value). The difference between groups in individual changes from endpoint to baseline was estimated at 4.46 score points (95% CI: 1.86–7.06), which yielded statistical significance (P=0.0006) in favour of the 7-dayEstradiol patch. The open follow-up phase showed a marked reduction in the Kupperman Index when placebo
The mean weekly number of hot flushes at baseline in the two groups was comparable (44.3 vs. 41.4) and indicated a moderate to severe intensity of climacteric complaints. However, a distinct difference in reduction of hot flushes from baseline between 7-day-Estradiol patch and placebo patients was noted from week 2 of treatment throughout the placebo-controlled phase (Fig. 2) Comparisons between the groups at the end of each cycle (Pweek4 = 0.0009, Pweek8 = 0.0016, Pweek12 = 0.0129) were statistically significant. At the end of the placebo-controlled study phase, the mean number of hot flushes decreased from 44.3 to 11.8 in the 7-day-Estradiol patch group, and from 41.4 to 19.4 in the placebo group, respectively. The difference between the groups in individual changes from baseline was estimated at 10.46 hot flushes per week (95% CI: 2.79–18.14), which yielded statistical significance (P= 0.0025) in favour of the 7-day-Estradiol patch. In the course of the open follow-up study (phase III), during which all patients received
Fig. 1. Mean values of Kupperman Index for the 7-day-Estradiol patch and placebo over 3 cycles.
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Fig. 2. Weekly frequency of hot flushes for the 7-day-Estradiol patch and placebo over 12 weeks. Between group comparisons: Pweek4 = 0.0009; Pweek8 = 0.0016; Pweek12 = 0.0129
active medication, the mean number of hot flushes was shown to be further reduced to 6.2 in the 7-day-Estradiol patch group and to 7.1 in the group of patients who switched from placebo to active medication during this phase (last value). In addition, throughout the double-blind, placebo-controlled phase, a statistically significant difference between the groups in the proportion of patients who experienced a clinically relevant reduction of at least 50% in the number of flushes versus baseline was reported (7-day-Estradiol patch versus placebo, P =0.0009). By separating the results for days 1 – 3 and 4 – 7, it was further shown that efficacy in terms of frequency of hot flushes on the active treatment (7-day-Estradiol patch) could be constantly maintained during the treatment period.
3.3. Urogenital symptoms The sums of scores for urogenital symptoms were identical in the two groups at baseline, although these baseline values were relatively low. Reductions were reported from the first cycle during the double-blind, placebo-controlled phase with additional improvements after 12 weeks (P B 0.05) (Table 1). These differences, although significant within both groups compared with baseline values, were not significant between treatment groups.
3.4. Further efficacy analysis The multiple efficacy outcome measures such as frequency of hot flushes, insomnia, nervousness/ irritability and urogenital symptoms were combined into a single measure to allow for an overall efficacy assessment of the double-blind, placebocontrolled phase II (O’Brien approach) [36]. With this analysis, the 7-day-Estradiol patch was found to be significantly more effective at improving these symptoms than placebo in the intention-totreat population (7-day-Estradiol patch group: n= 85; placebo group: n= 80; P= 0.0018). Table 1 Urogenital symptom scores during the double-blind, placebocontrolled phase II (Intention-to-treat population) 7-day-Estradiol patch (mean 9 SD) Baseline score 2.6 91.99 Change from base−0.891.60 line, Cycle 1, week 4 Change from base−1.491.97 line, Cycle 3, week 4 Change from base−1.391.99 line, Cycle 4, week 4 (last value)
Placebo patch (mean 9 SD) 2.6 91.98 −0.69 1.58
−1.09 1.50
−0.89 1.52
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3.5. Compliance, patch adhesi6eness and subjecti6e acceptance During the placebo-controlled phase, more than 80% of women completed every application period of 7 days in both groups. Throughout the study (phase II and III) the percentage of patients in whom it was positively stated that an application had been missed was never greater than 4.7% (visit 3, placebo group). Hence patient compliance was good. The patients assessed patch adhesiveness on a weekly basis. In total 2481 7-day-Estradiol patches were judged. Of these, 1959 patches (79%) showed either no or slight signs of detachment. Among 87 patients in the 7-day-Estradiol patch group during phase II, 90.8% had sufficient and 9.2% had insufficient adhesiveness, and among 136 patients of both original treatment groups during phase III, 93.4% had sufficient and 3.7% had insufficient adhesiveness (2.9% missing data). Generally, subjective acceptance of the patches by the patients (handling, appearance, and convenience of use) was good to very good and the majority of patients were willing to consider continuing treatment with the patches at the end of the study (72.4% of those receiving active medication throughout the study, and 66.3% of those who received placebo medication during the double-blind, placebo-controlled phase II before switching to active medication during phase III).
3.6. Ad6erse e6ents Treatment with the 7-day-Estradiol patch was well tolerated. Only three serious adverse events were reported: cholecystectomy and extensor tendolysis after a motorcycle accident (7-day-Estradiol patch group) and urinary retention (placebo group). None of these events were regarded as being causally related to study medication. A total of 18 patients experienced adverse events that led to their premature withdrawal from the study. During the double-blind phase, there was no relevant difference between the numbers of 7-day-Estradiol patch (n = 9) and
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placebo patients (n= 7) who discontinued as a result of adverse events, and during the open follow-up phase there were just two further cases on the 7-day-Estradiol patch. There were also no relevant differences between the treatment groups with respect to adverse events considered by the investigators as being possibly or probably related to study medication. The most frequent adverse events were application site reactions: during the placebocontrolled phase there were four cases reported with the 7-day-Estradiol patch and three in the placebo group. Four additional cases occurred during the follow-up phase. Throughout the trial, breast tenderness was reported in four patients on the 7-day-Estradiol patch (no cases were reported with placebo). It appears likely that these were due to estradiol replacement. The most frequent of all events — viral infection — occurred 18 times, when both groups and phases were taken together. There was no difference between the groups during the placebo-controlled phase, and other types of adverse events were too infrequent to be clinically relevant.
3.7. Skin tolerability Patients assessed skin tolerability and pruritus of the patches on a weekly basis. In total 2485 7-day-Estradiol patches were judged on skin tolerability and 2488 on pruritus, respectively. Of these, 2283 of 2485 patches (92%) showed either no or slight reactions and 2294 of 2488 patches (92%) showed either no or slight pruritus. Severe skin reactions and pruritus were reported by only 1% of patients, based on all applications of the 7-day-Estradiol patch. Most patients in both groups did not experience moderate or severe reactions. According to the investigators’ judgement, there were no severe cases of erythema and oedema throughout the entire study in either patient group. In the controlled phase of the study the incidence of moderate or severe erythema was estimated at 0% in the 7-day-Estradiol patch group and approximately 4% in the
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Table 2 Serum lipid concentrations – phases II and III 7-day-Estradiol patch (phases II and III) (mean9 SD)
Placebo patch (phase II)/7-day-Estradiol patch (phase III) (mean 9SD)
Triglyerides (mg/dl) Baseline 131.39 77.18 Cycle 3, week 4a 123.79 78.71 Cycle 6, week 4b 118.1 9 75.18
125.5 990.99 120.4 969.89 108.3 961.97
Total cholesterol (mg/dl) Baseline 258.4 9 51.38 Cycle 3, week 4a 247.6 9 50.43 Cycle 6, week 4b 241.1 9 48.91
245.4 956.84 242.5 946.10 237.0 947.39
LDL (mg/dl) Baseline Cycle 3, week 4a Cycle 6, week 4b
170.4 951.93 167.2 947.61 162.1 946.51
a b
184.9 9 49.87 171.2 9 46.28 168.4 9 46.85
Last cycle of double-blind, placebo-controlled phase (phase II) Last cycle of open, follow-up phase (phase III)
placebo group, with the difference between groups not reaching significance (P =0.110). The incidence of moderate to severe oedema was estimated at 0% in the 7-day-Estradiol patch group and 1% in the placebo group. One case (1%) of moderate erythema on the 7-day-Estradiol patch and moderate oedema on placebo were reported in the follow-up phase.
3.8. Blood pressure, heart rate and body weight No relevant changes for systolic or diastolic blood pressure or heart rate were noted throughout the study in either group. A slight and clinically irrelevant mean increase in body weight of 0.7 kg at the end of the study was found in both groups.
3.9. Haematology, biochemistry data and lipid profile Apart from the lipid profile, no trends or meaningful changes on an individual basis were identified for biochemistry and haematology. There was a trend towards a reduction in serum triglycerides, and total and LDL-cholesterol in both treatment groups, with reductions being most apparent during treatment with active medication (Table 2).
4. Discussion The results from our study clearly show that the 7-day-Estradiol patch — a continuously applied drug-in-adhesive-matrix patch — was superior to placebo in reducing postmenopausal symptoms in hysterectomized women and was well tolerated. Moreover, the open follow-up phase showed that early treatment effects were maintained with prolonged therapy. The significant reduction in Kupperman Index is consistent with results found in other studies: one comparing the 7-day-Estradiol patch with another transdermal therapeutic system (Estradiol TTS, Ciba Geigy) for 24 weeks [37] and another comparing a matrix system and a reservoir system in patients treated for 6 months [38]. In the latter trial, however, patients had somewhat lower Kupperman Index scores (approximately 23 at baseline). In addition, the significant reductions in hot flushes are similar to the findings with other transdermal systems with comparable patient groups and treatment durations [37–41]. Although the reductions in Kupperman Index and number of hot flushes were significant for patients receiving active therapy compared with placebo during the double-blind phase of this study, significant placebo effects compared with
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baseline was also seen during this period. Some placebo effects may have been expected since these results are based on subjective scoring of symptom severity and, indeed, similar placebo effects have been reported in other studies assessing the benefits of hormone replacement therapy in postmenopausal women [42 – 44]. It is of note that during the double-blind, placebo-controlled phase II, the Kupperman Index in patients receiving placebo stabilized at a higher level than that of patients on active therapy. However, when patients receiving placebo switched to active therapy during the open follow-up phase, the scores for the Kupperman Index fell towards those seen in patients receiving active therapy during both phases of the study. Placebo effects must be borne in mind when designing studies of hormone replacement therapy in postmenopausal women and particularly when interpreting their results. Therapeutic effectiveness did not change over the 7-day application period. One patch per week was found to be sufficient, which, in terms of patient compliance, may be an important advantage with respect to other twice-weekly patches. Maintenance of the therapeutic effects with prolonged therapy was again shown during the follow-up phase similar to the findings in another 7-day-Estradiol patch trial [45]. As in the case of Kupperman Index, there was a marked improvement in patients in the placebo group during the first cycle with active medication during the follow-up phase. Improvements in urogenital symptoms were more pronounced in the 7-day-Estradiol patch group than with placebo, although it should be noted that baseline values were relatively low, and a placebo effect was again seen. It was therefore difficult to demonstrate the clinical relevance of these findings. Improvements in urogenital complaints have generally been reported previously for the 7-day-Estradiol patch and other transdermal systems [38,39,41,45]. The slight changes in the lipid profile agree well with reports in the literature on the use of nonoral estrogens [12,25,41] and are reported to have a favourable influence on cardiovascular morbidity.
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Many women fear an increase in body weight with estrogen replacement therapy. A slight and clinically irrelevant mean increase of 0.7 kg at the end of the study was found in both groups. Only one patient was withdrawn from the study in connection with increased body weight, and this may have been due to fluid retention. The positive results for subjective acceptability and patch adhesiveness (the latter comparable with other studies with the 7-day-Estradiol patch [38,45]) have important implications for compliance. It should be noted that the rate of sufficient patch adherence might be underestimated since a very strict definition had been applied (worst case approach). Local skin tolerability of the patches was good. Although methods to assess local skin reactions are not standardized across different studies, the results reported here appear more or less comparable to those reported from studies using drug-in-adhesive matrix systems [38,39,41] Treatment with the 7-day-Estradiol patch was well tolerated overall. There were just three serious adverse events, none of which was regarded as being related to study medication. The frequency of local adverse events was no higher in this study than in others investigating other transdermal systems as far as incidences have been reported [40]. Throughout the trial, breast tenderness was reported in four patients on the 7-day-Estradiol patch (no cases with placebo). It appears likely that this was caused by the replacement of estradiol. However, breast pain or sensitivity during hormone replacement has been reported from other studies as one of the more common adverse events [38,40,41]. In conclusion, the 7-day-Estradiol patch was shown to be well tolerated and effective in the relief of moderate to severe vasomotor symptoms in hysterectomized women with postmenopausal complaints, with the patch showing a rapid onset of action and 7-day duration of therapeutic effect.
Acknowledgements Principal in6estigator: Th von Holst, Heidelberg, Germany; Clinical monitor: S Hackel,
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Darmstadt, Germany; Clinical research associate: B Gu¨nther, Darmstadt, Germany; Biometric processing: M Schlichting, Darmstadt, Germany; Reporting: R van der Does, Mannheim, Germany.Clinical centres (Germany) : Th von Holst, Heidelberg; L Hoppe, Schriesheim; H-J Paulski, Bammental; H-D Scheffzek, Heidelberg; L Kiesel, Tu¨bingen; H Rohde-Werner, Eggenstein; R Hussong, Villingen-Schwenningen; M R van Santen, Karlsruhe; S Scho¨nian, Rheinstetten; R Schenkl, Ettlingen; J-M Klug, Rain/Lech; L Ritter, Donauwo¨rth; U Kohoutek, Karlsruhe; P Zimber, Gau-Algesheim; R Landthaler, Krumbach; E Seibicke, Bonn-Bad Godesberg; J Repas, Schleiden; J Herold, Mu¨nchen; D Tschu¨rtz, Mu¨nchen; W Schmid, Ellwangen; B Evers, Wo¨rrstadt; M Luckhardt, Hamburg; H Hoppe, U8 bach-Palenberg; N Scha¨fer, Wu¨rselen; R Leblanc, Grevenbroich; G Crass, Krefeld; Ch Werner, Duisburg; Th. Minack, Hamburg; C Gru¨newald, Bingen; Ch. Zindikus, Bonn; J Klinghammer, Ko¨ln; W Kasper, Mainz; B Schu¨ssler, Neuss; K Urbaniak-Fischer, Ko¨ln.
References [1] Oldenhave A, Jaszman LJB, Haspels AA, Everaerd W, Th AM. Impact of climacteric on well-being. Am J Obstet Gynecol 1993;168:772–80. [2] Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses health study. N Engl J Med 1991;325:756 –62. [3] Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016–37. [4] Balfour JA, McTavish D. Transdermal estradiol: a review of its pharmacological profile and therapeutic potential in the prevention of postmenopausal osteoporosis. Drug Aging 1992;2:487 – 507. [5] Corson SL. A decade of experience with transdermal estrogen replacement therapy: Overview of key pharmacologic and clinical findings. Int J Fertil 1993;38:79–91. [6] Farrish E, Hart DM, Gray CE, Beastall G, Fletcher CD, Lindsay R. Effects of treatment with oestradiol/ levonorgestrel on bone, lipoproteins and hormone status in postmenopausal women. Clin Endocrinol 1989;31:607– 15. [7] Jacobs HS, Loeffler FE. Regular Review. Postmenopausal hormone replacement therapy. Br Med J 1992;305:1403– 8.
[8] Lufkin EG, Wahner HW, O’Fallon WM, et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Int Med 1992;117:1 – 9. [9] Session DR, Kelly AC, Jewelewicz R. Current concepts in estrogen replacement therapy in the menopause. Fertil Steril 1993;59:277 – 84. [10] Smith R, Studd JWW. Drug development report (7). Hormone replacement therapy: a review. J Drug Dev 1992;4:235 – 44. [11] Cheang A, Sitruk-Ware R, Samsioe G. Transdermal oestradiol and cardiovascular risk factors. Br J Obstet Gynaecol 1994;101:571 – 81. [12] Sitruk-Ware R, Ibarra de Palacios P. Oestrogen replacement therapy and cardiovascular disease in postmenopausal women. A review. Maturitas 1989;11:259 – 74. [13] Brinton LA, Hoover RN. Estrogen replacement therapy and endometrial cancer risk: unresolved issues. Obstet Gynecol 1993;81:265 – 71. [14] Chetkowski RJ, Meldrum DR, Steingold KA, et al. Biologic effects of transdermal estradiol. N EngI J Med 1986;314:1615– 20. [15] Clisham PR, Cedars MI, Greendale G, Fu YS, Gambone J, Judd HL. Long-term transdermal estradiol therapy: effects on endometrial histology and bleeding patterns. Obstet Gynecol 1992;79:196 – 201. [16] Deligdisch L. Effects of hormone therapy on the endometrium. Mod Pathol 1993;6:91 – 106. [17] Persson I, Adami HO, Bergkvist L, et al. Risk of endometrial cancer after treatment with oestrogens alone or in conjunction with progestogens: results of a prospective study. Br Med J 1989;298:147 – 51. [18] Voigt LF, Weiss NS, Chu J, Daling JR, McKnight B, Van Belle G. Progestogen supplementation of exogenous oestrogens and risk of endometrial cancer. Lancet 1991;338:274 – 7. [19] Whitehead MI, Hillard TC, Crook D. The role and use of progestogens. Obstet Gynecol 1990;75:59S – 76S. [20] Padwick ML, Endacott J, Whitehead MI. Efficacy, acceptability and metabolic effects of transdermal estradiol in the management of postmenopausal women. Am J Obstet Gynecol 1985;152:1085 – 91. [21] Steingold KA, Matt DW, DeZiegler D, Sealey JE, Fratkin M, Reznikow S. Comparison of transdermal to oral estradiol administration on hormonal and hepatic parameters in women with premature ovarian failure. J Clin Endocrinol Metab 1991;73:275 – 80. [22] Cagnacci A, Soldani R, Carriero PL, Paoletti AM, Fioretti P, Melis GB. Effects of low doses of transdermal 17 beta-estradiol on carbohydrate metabolism in postmenopausal women. J Clin Endocrinol Metab 1992;74:1396 – 400. [23] Huppert LC. Hormonal replacement therapy: benefits, risks, doses. Med Clin North Am 1987;71:23 – 39. [24] Walsh BW, Schiff I, Rosner B, Greenberg L, Ravnikar V, Sacks FM. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 1991;325:1196– 204.
T. 6on Holst, B. Salbach / Maturitas 34 (2000) 143–153 [25] Mu¨ck AO, Salbach B, Rabe T, von Holst T, Runnebaum B. Serum lipids in treatment with transdermal estradiol and oral norethisterone acetate. Geburtshilfe Frauenheilkunde 1995;55:393–9. [26] Cedars MI, Judd HL. Nonoral routes of estrogen administration. Obstet Gynecol Clin North Am 1987;14:269–98. [27] Murad F, Kuret JA. Estrogens and progestins. In: Gilman A, Goodman LS, editors. The Pharmacological Basis of Therapeutics. New York: Macmillan, 1990:1384–412. [28] Cortellaro M, Nencioni T, Boschetti C, et al. Cyclic hormonal replacement therapy after the menopause: transdermal versus oral treatment. Eur J Clin Pharmacol 1991;41:555 – 9. [29] Jensen PJ, Jensen J, Riis BJ, Rodbro P, Strom V, Christiansen C. Climacteric symptoms after oral and percutaneous hormone replacement therapy. Maturitas 1987;9:207 – 15. [30] Judd H. Efficacy of transdermal estradiol. Am J Obstet Gynecol 1987;156:1326–31. [31] Nachtigall LE, Utian WH. Comparative efficacy and tolerability of transdermal estradiol and conjugated estrogens-a double-blind multicentre study. In: Lauritzen C, editor. Transdermal Estrogen Substitution. Bern: Hans Huber, 1987:3749. [32] Place VA, Powers M, Darley PE, Schenkel L, Good WR. A double-blind comparative study of Estraderm and Premarin in the amelioration of postmenopausal symptoms. Am J Obstet Gynecol 1985;153:1092–9. [33] Steingold KA, Laufer L, Chetkowski RJ, et al. Treatment of hot flushes with transdermal estradiol administration. J Clin Endocrinol Metab 1986;61:627–32. [34] Stevenson JC, Cust MP, Gangar KF, Hillard TC, Lees B, Whitehead MI. Effects of transdermal versus oral hormone replacement therapy on bone density in spine and proximal femur in postmenopausal women. Lancet 1990;335:265 – 9. [35] Kupperman HS, Blatt MHG, Wiesbader H, Filler W. Comparative clinical evaluation of estrogen preparation by the postmenopausal and amenorrheal indices. J Clin Endocrinol 1953;13:688–703.
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[36] O’Brien PC. Procedures for comparing samples with multiple endpoints. Biometrics 1984;40:1079 – 87. [37] Lutkie AWHM, Hackel S. Efficacy, tolerability, and compliance of FemSeven*, a once-weekly transdermal system, compared with Estraderm*TTS 50. Eur J Clin Res 1997;9:111 – 22. [38] The Transdermal HRT Investigators Group. A randomized study to compare the effectiveness, tolerability and acceptability of two different transdermal estradiol replacement therapies. Int J Fertil 1993;38:5 – 11. [39] Van Leusden HAIM, Albertyn G, Verlaine C, Van Ruymbeke J. A comparative multicenter study of two transdermal estradiol replacement therapies in the treatment of postmenopausal symptoms. Int J Fertil 1993;38:210 – 8. [40] Sefaty D, Caulin F. Efficacy and tolerability of transdermal 17 beta-estradiol in patients with climacteric symptoms: dose titration according to individual choice. Curr Ther Res 1996;57:506 – 15. [41] Studd JWW, McCarthy K, Zamblera D, et al. Efficacy and tolerance of Menorest® compared to Premarin® in the treatment of postmenopausal women. A randomised, multicentre, double-blind, double-dummy study. Maturitas 1995;22:105 – 14. [42] Good WR, John VA, Ramirex M, et al. Double-masked, multicenter study of an estradiol matrix transdermal delivery system (Alora) versus placebo in postmenopausal women experiencing menopausal symptoms. Clin Ther 1996;18(6):1093– 105. [43] Baachi-Modena A, Bolis P, Campagnoli C, et al. Efficacy and tolerability of Estraderm MX, a new estradiol matrix patch. Maturitas 1997;27:285 – 92. [44] Studd J, Pornel B, Marton I, et al. Efficacy and acceptability of intranasal 17b-oestradiol for menopausal symptoms: randomised dose-response study. Lancet 1999;353:1574– 8. [45] Lutkie AWHM, Hackel S, van de Ven LLM. Long-term tolerability and efficacy of Fem7®, a once-weekly transdermal system, in women with post-menopausal complaints. J Clin Res 1998;1:161 – 71.
Efficacy and tolerability of a new 7-day transdermal estradiol patch versus placebo in hysterectomized women with postmenopausal complaints Thomas von Holst *, Birgitt Salbach Uni6ersity Gynaecological Clinic, Ruprecht-Karl Uni6ersity, Voßstrasse 9, D-69115 Heidelberg, Germany Received 4 May 1999; accepted 25 October 1999
Abstract Objecti6es: To investigate the efficacy and tolerability of a continuously applied 7-day-Estradiol patch (Fem7®, Merck KGaA, Germany) delivering 50 mg estradiol per day in the treatment of hysterectomized women with postmenopausal complaints compared with placebo. Design: A multicentre, randomized, double-blind study with an initial screening phase (phase I), a 3-month double-blind placebo-controlled phase (phase II) and a 3-month open follow-up phase (phase III). Methods: 186 patients were randomized for a 3-cycle placebo-controlled study followed by a 3-cycle open follow-up (total duration; 6 months). The changes in Kupperman Index (primary efficacy variable), hot flushes and urogenital symptom score were studied from baseline to the end of the study. In addition, skin tolerability was assessed and patients were also asked to grade the subjective acceptance of therapy. Results: A reduction in Kupperman Index was observed in both groups, and at each cycle of the placebo-controlled treatment phase the 7-day-Estradiol patch was superior compared with placebo (last value vs. baseline P= 0.0006). From the second treatment week onwards a distinct difference was noted in the reduction of hot flushes from baseline between the 7-day-Estradiol patch group and the placebo group. The difference between the groups was statistically significant for each cycle and at the end of the controlled treatment phase (mean weekly hot flush reduction at the end of the placebo-controlled treatment phase: − 32.5 for the 7-day-Estradiol patch vs. −22.0 for placebo, P =0.0025). The efficacy of the 7-day-Estradiol patch within the application period did not show any difference between days 1 – 3 and 4–7. Subjective acceptance of the 7-day-Estradiol patch was good and 72.4% of patients who took active medication throughout the study were willing to consider continuing its use. Conclusions: The 7-day-Estradiol patch is well tolerated and provides effective relief of moderate to severe vasomotor symptoms in hysterectomized women, with a rapid onset of action and 7-day duration of therapeutic effect. Although a placebo effect was observed, the 7-day-Estradiol patch significantly reduced hot flushes and other menopausal symptoms throughout the application period. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: 7-day-Estradiol patch; Transdermal once-weekly system; Estradiol; Kupperman index
* Corresponding author. Tel.: + 49-6221-567856; fax: + 49-6221-565713. 0378-5122/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 5 1 2 2 ( 9 9 ) 0 0 0 9 9 - 7
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1. Introduction Estrogen replacement therapy is effective in the treatment of climacteric symptoms and complaints from urogenital ageing. Vasomotor disorders (hot flushes) are the most frequent and particularly distressing climacteric complaint. They have been reported in about 85% of women at onset of menopause, and 30% of patients classified them as severe [1]. Furthermore, estrogens have been shown to be effective in the reduction of cardiovascular morbidity and mortality [2,3] and osteoporosis [4 – 10] in postmenopausal women. The beneficial effect on cardiovascular disease may in part be related to favourable alterations in the lipid profile produced by estrogens [11,12]. Unopposed prolonged application of estrogens is, however, known to induce endometrial hyperplasia. The additional administration of progestogens offers protection against this risk [13 – 19]. In this study, which included only hysterectomized patients, the additional administration of progestogens was not necessary. Estrogen replacement therapy can be administered either orally or parenterally, but the use of a transdermal therapeutic system offers several advantages. Much lower doses of estrogen are effective with transdermal delivery compared with oral therapy [20] since the former route avoids the portal system, resulting in no first-pass metabolism of estrogen and limiting disruption of the hepatic production of several proteins [21]. This may diminish the risk of increased smooth muscle tone, gall bladder disease and venous thrombosis. In addition, transdermal therapy has been reported to have a beneficial effect on glucose metabolism [22], and the increases in serum triglyceride levels observed with oral therapy [23,24] are not observed in patients with transdermal estrogen replacement therapy [25]. Fewer gastrointestinal adverse events (nausea, vomiting, abdominal pain) are associated with transdermal compared with oral therapy [26]. However, skin reactions (e.g. erythema and pruritus at the application site) are not uncommon with the transdermal route.
Treatment with transdermal estradiol replacement therapy alone or in combination with progestogens has been shown to be effective in many studies [20,27–34]. Estrogens are rapidly absorbed through the skin, with transdermal application providing controlled release and avoiding high initial peak concentrations of estradiol. The objective of this clinical study was to investigate the efficacy and tolerability of a newly developed 7-day-Estradiol patch (Fem7®, Merck KGaA, Germany) compared with placebo in the treatment of hysterectomized women with postmenopausal complaints. The 7-day-Estradiol patch contains estradiol in a new homogeneous adhesive matrix. This confers several advantages compared with the reservoir system, including a reduction in the thickness of the patch and fewer skin reactions. In addition, the prolongation of the application interval of this new patch — 7 days instead of 3–4 days — is thought to encourage greater patient compliance.
2. Subjects and methods
2.1. Study design This was a multicentre, randomized, doubleblind clinical study with an initial screening phase (phase I), a 3-month double-blind placebo-controlled phase (phase II) and a 3-month open follow-up phase (phase III), during which all patients were treated with active medication. The treatment phase was therefore a total of 6 months (six cycles of 28 days) and the medication was administered continuously during the entire cycle (without a hormone-free week). All patients included in the study received the following therapy for a total of 3 months (three cycles): 7-day-Estradiol patch (1.5 mg estradiol once a week with a delivery rate of approximately 50 mg estradiol/24 h) or once-weekly placebo. All patients received active drug therapy (7-dayEstradiol patch) for a further 3 months (three cycles). The patch used in this study comprised a thin flexible, transparent film of octagonal shape approximately 15 cm2 in size with a new patented
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SIS polymer matrix without any permeation enhancers. The non-acrylic matrix enables a very low estradiol loading of 1.5 mg per patch and a very high drug usage of 23% during the 7-day application period. Hysterectomized women with postmenopausal complaints were included in the study. All subjects were postmenopausal (aged between 40 and 65 years) or had a surgical postmenopausal status (bilateral oophorectomy more than 3 months prior to inclusion in the study). Inclusion criteria also required a normal gynaecological history and examination, serum estradiol (E2) levels less than 30 pg/ml and follicle stimulating hormone (FSH) levels greater than 30 IU/ml. All of the women had at least 20 hot flushes per week within the last month prior to screening and an overall Kupperman Index greater than 20. Patients were excluded from the study if they had received any of the following prior to its start: sex hormones taken orally within the last 28 days; locally-applied sex hormones within the last 21 days or injectable sex hormones within the last 6 months.
point for analysis was the individual endpoint (last observation) within the placebo-controlled study phase. Within the Kupperman Index, ‘hot flushes’ is the most important symptom and the frequency of hot flushes is generally considered the most relevant efficacy variable. In this study, the number of hot flushes was recorded daily in the patient’s diary. Apart from those symptoms included in the Kupperman Index, there are other frequent complaints reported by postmenopausal women. These include vaginal discomfort, loss of libido, and incontinence. Scores were given to each of these urogenital symptoms in accordance with the procedures used for the Kupperman Index and the sum of these scores was calculated. All patients were questioned at each visit as to the number of urogenital symptoms that occurred since the previous visit. The severity of these symptoms was assessed on a four-point scale (0; no symptoms, 1; mild symptoms; 2; moderate symptoms, 3; severe and heavy symptoms).
2.2. Efficacy assessments
All adverse events whether reported by the patient or observed by the investigator including data from haematology and serum biochemistry, were recorded, irrespective of any causal relationship with the study drugs. Systolic and diastolic blood pressure, heart rate, and body weight were determined at enrolment and at week 24. Skin tolerability was assessed by the patients with respect to the occurrence of skin reactions and pruritus. The following categories were used: no, slight, moderate, or severe skin reactions/pruritus. Results were recorded at the end of each application period in the patient’s diary. Skin tolerability was also assessed by the investigator for local signs of patch intolerability at each visit, separated for local erythema and oedema. They were classified as not visible, very slight, well defined, moderate to severe, or severe. Moderate to severe and severe erythema were taken together as clinically relevant erythema. Changes from earlier applications were also assessed. Again an ‘individual patient’ and ‘worse case’ basis was adopted.
The Kupperman Index — which considers a variety of common and important disorders in peri- and postmenopausal patients — is frequently used to classify the severity of climacteric disorders in clinical studies of hormone replacement therapy (HRT) [35]. It is based on the severity and intensity of various complaints including hot flushes, paresthesia, insomnia, nervousness, melancholia, vertigo, weakness, arthralgia/myalgia, headache, palpitation and formication. The maximum Kupperman Index is 51. A value of more than 20 points indicates moderate to severe postmenopausal complaints, whereas a value of about 10 points would be compatible with mild complaints. The present study enrolled patients with a Kupperman Index of greater than 20. The primary efficacy variable was the change in the Kupperman Index. The Kupperman index was measured after 4 (visit 3), 12 (visit 4), 16 (visit 5), and 24 weeks (visit 6) of therapy. The primary
2.3. Safety assessments
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All samples for haematology, biochemistry and serum lipid profile were assessed in fasting condition before enrolment, and after 16 (lipid profile only) and 24 weeks of therapy.
2.4. Other assessments Compliance was measured by counting the unused medication returned by the patients and by questioning the patients on whether any applications had been missed. Patch adhesiveness was assessed by the investigators at weeks 4, 12, 16, and 24 and by the patient every week. The degree of detachment was reported as either no, slight, moderate, or total detachment. The amount of patch detachment was sorted by intervals of 20% of the total area detached (i.e. 0, \0 – 20%, \ 20 – 40% etc). In a second step, the results from all observations were grouped into two categories of sufficient ( B40% of detachment) and insufficient adhesiveness ( \ 40% detachment). In a third step, data were summarized on an ‘individual patient’ and ‘worst case’ basis. Handling, appearance and convenience of the patch were rated by the patients (as very good, good, moderate, or poor) after 12 and 24 weeks of therapy. In addition, patients were requested to indicate whether they would continue using the patch after the study.
treatment groups were compared using the Wilcoxon rank-sum test. As part of the descriptive analysis, the Wilcoxon rank-sum test was used to compare treatment groups in phase II considering the change in Kupperman Index at further time points, urogenital symptoms, and frequency of hot flushes. Differences between groups were quantified by calculating two-tailed 95% confidence intervals. Additionally, postmenopausal complaints were analysed based on changes in specified symptoms after three treatment cycles during the doubleblind, placebo-controlled phase II using the O’Brien method [36] (non-parametric set-up). The aim of this analysis was to combine various outcome measures from different sources. The efficacy measures of hot flush rate (recorded daily by the patient in diary cards), insomnia, nervousness/irritability and urogential symptoms were combined using this approach. The incidence of erythema, oedema, adverse events and patch detachment \ 40% were analysed descriptively. Patients were considered evaluable if they had been treated with the study medication at least once and had provided any follow-up data for one or more target variables. All statistical tests were performed two-sided with a significance level at 5%.
3. Results
2.5. Ethical appro6al and patient consent The study was carried out in accordance with the revised ‘Declaration of Helsinki’ (Tokyo 1975, Venice 1983 and Hong Kong 1989) as well as the ‘Rules of Guidance for Good Clinical Trials on Medicinal Products in the European Community’ (July 1990). All patients gave their written, informed consent to participate in the clinical study. Articles 40, 41, 64, 66, and 67 of the German Drug law (AMG) were a further basis for the declaration of patient informed consent.
2.6. Statistical methods For confirmatory proof of efficacy, the change in Kupperman Index from baseline at the end of the double-blind, placebo-controlled phase II for both
Of the 221 patients enrolled by 34 centres, 35 withdrew prior to randomization, as they did not meet the inclusion criteria (mainly regarding baseline hormone concentrations or number of hot flushes). A total of 186 women were randomized on a 1:1 basis to receive either the 7-day-Estradiol patch (n= 93) or placebo (n= 93). Of the 186 randomized patients, one patient did not receive any study medication. A further 12 patients (7-day-Estradiol patch group: n= 5; placebo group: n = 7) were excluded from the intention-to-treat analysis of the placebo-controlled phase because of lack of availability of efficacy data. Baseline values of estradiol and FSH were assessed before enrolment. The results during randomization were comparable between the treatment groups.
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Both groups were well matched in terms of patient characteristics such as demographic data, medical history, previous and concomitant medication as well as hormone status. The mean ages were 53.5 years and 53.4 years in the 7-day-Estradiol patch and placebo groups, respectively.
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patients were switched to active medication. The last values in the two groups of patients were similar at the end of phase III (8.1 for the 7-dayEstradiol patch group and 8.8 for the placebo/7day-Estradiol patch group).
3.2. Frequency of hot flushes 3.1. Kupperman index Mean baseline values were similar in the two treatment groups (mean values were 27.6 in the 7-day-Estradiol patch and 27.9 in the placebo group), but individual values were as high as 43 in the 7-day-Estradiol patch group and 44 in the placebo group. In both groups reductions in the Kupperman Index versus baseline were observed throughout the placebo-controlled phase (Fig. 1). The mean value of the Kupperman index in the 7-day-Estradiol patch group declined from 27.6 to 11.2 score points at the end of the placebo-controlled study (phase II). For the placebo group the results were 27.9 at baseline and 16.0 at the end of phase II (last value). The difference between groups in individual changes from endpoint to baseline was estimated at 4.46 score points (95% CI: 1.86–7.06), which yielded statistical significance (P=0.0006) in favour of the 7-dayEstradiol patch. The open follow-up phase showed a marked reduction in the Kupperman Index when placebo
The mean weekly number of hot flushes at baseline in the two groups was comparable (44.3 vs. 41.4) and indicated a moderate to severe intensity of climacteric complaints. However, a distinct difference in reduction of hot flushes from baseline between 7-day-Estradiol patch and placebo patients was noted from week 2 of treatment throughout the placebo-controlled phase (Fig. 2) Comparisons between the groups at the end of each cycle (Pweek4 = 0.0009, Pweek8 = 0.0016, Pweek12 = 0.0129) were statistically significant. At the end of the placebo-controlled study phase, the mean number of hot flushes decreased from 44.3 to 11.8 in the 7-day-Estradiol patch group, and from 41.4 to 19.4 in the placebo group, respectively. The difference between the groups in individual changes from baseline was estimated at 10.46 hot flushes per week (95% CI: 2.79–18.14), which yielded statistical significance (P= 0.0025) in favour of the 7-day-Estradiol patch. In the course of the open follow-up study (phase III), during which all patients received
Fig. 1. Mean values of Kupperman Index for the 7-day-Estradiol patch and placebo over 3 cycles.
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Fig. 2. Weekly frequency of hot flushes for the 7-day-Estradiol patch and placebo over 12 weeks. Between group comparisons: Pweek4 = 0.0009; Pweek8 = 0.0016; Pweek12 = 0.0129
active medication, the mean number of hot flushes was shown to be further reduced to 6.2 in the 7-day-Estradiol patch group and to 7.1 in the group of patients who switched from placebo to active medication during this phase (last value). In addition, throughout the double-blind, placebo-controlled phase, a statistically significant difference between the groups in the proportion of patients who experienced a clinically relevant reduction of at least 50% in the number of flushes versus baseline was reported (7-day-Estradiol patch versus placebo, P =0.0009). By separating the results for days 1 – 3 and 4 – 7, it was further shown that efficacy in terms of frequency of hot flushes on the active treatment (7-day-Estradiol patch) could be constantly maintained during the treatment period.
3.3. Urogenital symptoms The sums of scores for urogenital symptoms were identical in the two groups at baseline, although these baseline values were relatively low. Reductions were reported from the first cycle during the double-blind, placebo-controlled phase with additional improvements after 12 weeks (P B 0.05) (Table 1). These differences, although significant within both groups compared with baseline values, were not significant between treatment groups.
3.4. Further efficacy analysis The multiple efficacy outcome measures such as frequency of hot flushes, insomnia, nervousness/ irritability and urogenital symptoms were combined into a single measure to allow for an overall efficacy assessment of the double-blind, placebocontrolled phase II (O’Brien approach) [36]. With this analysis, the 7-day-Estradiol patch was found to be significantly more effective at improving these symptoms than placebo in the intention-totreat population (7-day-Estradiol patch group: n= 85; placebo group: n= 80; P= 0.0018). Table 1 Urogenital symptom scores during the double-blind, placebocontrolled phase II (Intention-to-treat population) 7-day-Estradiol patch (mean 9 SD) Baseline score 2.6 91.99 Change from base−0.891.60 line, Cycle 1, week 4 Change from base−1.491.97 line, Cycle 3, week 4 Change from base−1.391.99 line, Cycle 4, week 4 (last value)
Placebo patch (mean 9 SD) 2.6 91.98 −0.69 1.58
−1.09 1.50
−0.89 1.52
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3.5. Compliance, patch adhesi6eness and subjecti6e acceptance During the placebo-controlled phase, more than 80% of women completed every application period of 7 days in both groups. Throughout the study (phase II and III) the percentage of patients in whom it was positively stated that an application had been missed was never greater than 4.7% (visit 3, placebo group). Hence patient compliance was good. The patients assessed patch adhesiveness on a weekly basis. In total 2481 7-day-Estradiol patches were judged. Of these, 1959 patches (79%) showed either no or slight signs of detachment. Among 87 patients in the 7-day-Estradiol patch group during phase II, 90.8% had sufficient and 9.2% had insufficient adhesiveness, and among 136 patients of both original treatment groups during phase III, 93.4% had sufficient and 3.7% had insufficient adhesiveness (2.9% missing data). Generally, subjective acceptance of the patches by the patients (handling, appearance, and convenience of use) was good to very good and the majority of patients were willing to consider continuing treatment with the patches at the end of the study (72.4% of those receiving active medication throughout the study, and 66.3% of those who received placebo medication during the double-blind, placebo-controlled phase II before switching to active medication during phase III).
3.6. Ad6erse e6ents Treatment with the 7-day-Estradiol patch was well tolerated. Only three serious adverse events were reported: cholecystectomy and extensor tendolysis after a motorcycle accident (7-day-Estradiol patch group) and urinary retention (placebo group). None of these events were regarded as being causally related to study medication. A total of 18 patients experienced adverse events that led to their premature withdrawal from the study. During the double-blind phase, there was no relevant difference between the numbers of 7-day-Estradiol patch (n = 9) and
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placebo patients (n= 7) who discontinued as a result of adverse events, and during the open follow-up phase there were just two further cases on the 7-day-Estradiol patch. There were also no relevant differences between the treatment groups with respect to adverse events considered by the investigators as being possibly or probably related to study medication. The most frequent adverse events were application site reactions: during the placebocontrolled phase there were four cases reported with the 7-day-Estradiol patch and three in the placebo group. Four additional cases occurred during the follow-up phase. Throughout the trial, breast tenderness was reported in four patients on the 7-day-Estradiol patch (no cases were reported with placebo). It appears likely that these were due to estradiol replacement. The most frequent of all events — viral infection — occurred 18 times, when both groups and phases were taken together. There was no difference between the groups during the placebo-controlled phase, and other types of adverse events were too infrequent to be clinically relevant.
3.7. Skin tolerability Patients assessed skin tolerability and pruritus of the patches on a weekly basis. In total 2485 7-day-Estradiol patches were judged on skin tolerability and 2488 on pruritus, respectively. Of these, 2283 of 2485 patches (92%) showed either no or slight reactions and 2294 of 2488 patches (92%) showed either no or slight pruritus. Severe skin reactions and pruritus were reported by only 1% of patients, based on all applications of the 7-day-Estradiol patch. Most patients in both groups did not experience moderate or severe reactions. According to the investigators’ judgement, there were no severe cases of erythema and oedema throughout the entire study in either patient group. In the controlled phase of the study the incidence of moderate or severe erythema was estimated at 0% in the 7-day-Estradiol patch group and approximately 4% in the
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Table 2 Serum lipid concentrations – phases II and III 7-day-Estradiol patch (phases II and III) (mean9 SD)
Placebo patch (phase II)/7-day-Estradiol patch (phase III) (mean 9SD)
Triglyerides (mg/dl) Baseline 131.39 77.18 Cycle 3, week 4a 123.79 78.71 Cycle 6, week 4b 118.1 9 75.18
125.5 990.99 120.4 969.89 108.3 961.97
Total cholesterol (mg/dl) Baseline 258.4 9 51.38 Cycle 3, week 4a 247.6 9 50.43 Cycle 6, week 4b 241.1 9 48.91
245.4 956.84 242.5 946.10 237.0 947.39
LDL (mg/dl) Baseline Cycle 3, week 4a Cycle 6, week 4b
170.4 951.93 167.2 947.61 162.1 946.51
a b
184.9 9 49.87 171.2 9 46.28 168.4 9 46.85
Last cycle of double-blind, placebo-controlled phase (phase II) Last cycle of open, follow-up phase (phase III)
placebo group, with the difference between groups not reaching significance (P =0.110). The incidence of moderate to severe oedema was estimated at 0% in the 7-day-Estradiol patch group and 1% in the placebo group. One case (1%) of moderate erythema on the 7-day-Estradiol patch and moderate oedema on placebo were reported in the follow-up phase.
3.8. Blood pressure, heart rate and body weight No relevant changes for systolic or diastolic blood pressure or heart rate were noted throughout the study in either group. A slight and clinically irrelevant mean increase in body weight of 0.7 kg at the end of the study was found in both groups.
3.9. Haematology, biochemistry data and lipid profile Apart from the lipid profile, no trends or meaningful changes on an individual basis were identified for biochemistry and haematology. There was a trend towards a reduction in serum triglycerides, and total and LDL-cholesterol in both treatment groups, with reductions being most apparent during treatment with active medication (Table 2).
4. Discussion The results from our study clearly show that the 7-day-Estradiol patch — a continuously applied drug-in-adhesive-matrix patch — was superior to placebo in reducing postmenopausal symptoms in hysterectomized women and was well tolerated. Moreover, the open follow-up phase showed that early treatment effects were maintained with prolonged therapy. The significant reduction in Kupperman Index is consistent with results found in other studies: one comparing the 7-day-Estradiol patch with another transdermal therapeutic system (Estradiol TTS, Ciba Geigy) for 24 weeks [37] and another comparing a matrix system and a reservoir system in patients treated for 6 months [38]. In the latter trial, however, patients had somewhat lower Kupperman Index scores (approximately 23 at baseline). In addition, the significant reductions in hot flushes are similar to the findings with other transdermal systems with comparable patient groups and treatment durations [37–41]. Although the reductions in Kupperman Index and number of hot flushes were significant for patients receiving active therapy compared with placebo during the double-blind phase of this study, significant placebo effects compared with
T. 6on Holst, B. Salbach / Maturitas 34 (2000) 143–153
baseline was also seen during this period. Some placebo effects may have been expected since these results are based on subjective scoring of symptom severity and, indeed, similar placebo effects have been reported in other studies assessing the benefits of hormone replacement therapy in postmenopausal women [42 – 44]. It is of note that during the double-blind, placebo-controlled phase II, the Kupperman Index in patients receiving placebo stabilized at a higher level than that of patients on active therapy. However, when patients receiving placebo switched to active therapy during the open follow-up phase, the scores for the Kupperman Index fell towards those seen in patients receiving active therapy during both phases of the study. Placebo effects must be borne in mind when designing studies of hormone replacement therapy in postmenopausal women and particularly when interpreting their results. Therapeutic effectiveness did not change over the 7-day application period. One patch per week was found to be sufficient, which, in terms of patient compliance, may be an important advantage with respect to other twice-weekly patches. Maintenance of the therapeutic effects with prolonged therapy was again shown during the follow-up phase similar to the findings in another 7-day-Estradiol patch trial [45]. As in the case of Kupperman Index, there was a marked improvement in patients in the placebo group during the first cycle with active medication during the follow-up phase. Improvements in urogenital symptoms were more pronounced in the 7-day-Estradiol patch group than with placebo, although it should be noted that baseline values were relatively low, and a placebo effect was again seen. It was therefore difficult to demonstrate the clinical relevance of these findings. Improvements in urogenital complaints have generally been reported previously for the 7-day-Estradiol patch and other transdermal systems [38,39,41,45]. The slight changes in the lipid profile agree well with reports in the literature on the use of nonoral estrogens [12,25,41] and are reported to have a favourable influence on cardiovascular morbidity.
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Many women fear an increase in body weight with estrogen replacement therapy. A slight and clinically irrelevant mean increase of 0.7 kg at the end of the study was found in both groups. Only one patient was withdrawn from the study in connection with increased body weight, and this may have been due to fluid retention. The positive results for subjective acceptability and patch adhesiveness (the latter comparable with other studies with the 7-day-Estradiol patch [38,45]) have important implications for compliance. It should be noted that the rate of sufficient patch adherence might be underestimated since a very strict definition had been applied (worst case approach). Local skin tolerability of the patches was good. Although methods to assess local skin reactions are not standardized across different studies, the results reported here appear more or less comparable to those reported from studies using drug-in-adhesive matrix systems [38,39,41] Treatment with the 7-day-Estradiol patch was well tolerated overall. There were just three serious adverse events, none of which was regarded as being related to study medication. The frequency of local adverse events was no higher in this study than in others investigating other transdermal systems as far as incidences have been reported [40]. Throughout the trial, breast tenderness was reported in four patients on the 7-day-Estradiol patch (no cases with placebo). It appears likely that this was caused by the replacement of estradiol. However, breast pain or sensitivity during hormone replacement has been reported from other studies as one of the more common adverse events [38,40,41]. In conclusion, the 7-day-Estradiol patch was shown to be well tolerated and effective in the relief of moderate to severe vasomotor symptoms in hysterectomized women with postmenopausal complaints, with the patch showing a rapid onset of action and 7-day duration of therapeutic effect.
Acknowledgements Principal in6estigator: Th von Holst, Heidelberg, Germany; Clinical monitor: S Hackel,
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Darmstadt, Germany; Clinical research associate: B Gu¨nther, Darmstadt, Germany; Biometric processing: M Schlichting, Darmstadt, Germany; Reporting: R van der Does, Mannheim, Germany.Clinical centres (Germany) : Th von Holst, Heidelberg; L Hoppe, Schriesheim; H-J Paulski, Bammental; H-D Scheffzek, Heidelberg; L Kiesel, Tu¨bingen; H Rohde-Werner, Eggenstein; R Hussong, Villingen-Schwenningen; M R van Santen, Karlsruhe; S Scho¨nian, Rheinstetten; R Schenkl, Ettlingen; J-M Klug, Rain/Lech; L Ritter, Donauwo¨rth; U Kohoutek, Karlsruhe; P Zimber, Gau-Algesheim; R Landthaler, Krumbach; E Seibicke, Bonn-Bad Godesberg; J Repas, Schleiden; J Herold, Mu¨nchen; D Tschu¨rtz, Mu¨nchen; W Schmid, Ellwangen; B Evers, Wo¨rrstadt; M Luckhardt, Hamburg; H Hoppe, U8 bach-Palenberg; N Scha¨fer, Wu¨rselen; R Leblanc, Grevenbroich; G Crass, Krefeld; Ch Werner, Duisburg; Th. Minack, Hamburg; C Gru¨newald, Bingen; Ch. Zindikus, Bonn; J Klinghammer, Ko¨ln; W Kasper, Mainz; B Schu¨ssler, Neuss; K Urbaniak-Fischer, Ko¨ln.
References [1] Oldenhave A, Jaszman LJB, Haspels AA, Everaerd W, Th AM. Impact of climacteric on well-being. Am J Obstet Gynecol 1993;168:772–80. [2] Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses health study. N Engl J Med 1991;325:756 –62. [3] Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016–37. [4] Balfour JA, McTavish D. Transdermal estradiol: a review of its pharmacological profile and therapeutic potential in the prevention of postmenopausal osteoporosis. Drug Aging 1992;2:487 – 507. [5] Corson SL. A decade of experience with transdermal estrogen replacement therapy: Overview of key pharmacologic and clinical findings. Int J Fertil 1993;38:79–91. [6] Farrish E, Hart DM, Gray CE, Beastall G, Fletcher CD, Lindsay R. Effects of treatment with oestradiol/ levonorgestrel on bone, lipoproteins and hormone status in postmenopausal women. Clin Endocrinol 1989;31:607– 15. [7] Jacobs HS, Loeffler FE. Regular Review. Postmenopausal hormone replacement therapy. Br Med J 1992;305:1403– 8.
[8] Lufkin EG, Wahner HW, O’Fallon WM, et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Int Med 1992;117:1 – 9. [9] Session DR, Kelly AC, Jewelewicz R. Current concepts in estrogen replacement therapy in the menopause. Fertil Steril 1993;59:277 – 84. [10] Smith R, Studd JWW. Drug development report (7). Hormone replacement therapy: a review. J Drug Dev 1992;4:235 – 44. [11] Cheang A, Sitruk-Ware R, Samsioe G. Transdermal oestradiol and cardiovascular risk factors. Br J Obstet Gynaecol 1994;101:571 – 81. [12] Sitruk-Ware R, Ibarra de Palacios P. Oestrogen replacement therapy and cardiovascular disease in postmenopausal women. A review. Maturitas 1989;11:259 – 74. [13] Brinton LA, Hoover RN. Estrogen replacement therapy and endometrial cancer risk: unresolved issues. Obstet Gynecol 1993;81:265 – 71. [14] Chetkowski RJ, Meldrum DR, Steingold KA, et al. Biologic effects of transdermal estradiol. N EngI J Med 1986;314:1615– 20. [15] Clisham PR, Cedars MI, Greendale G, Fu YS, Gambone J, Judd HL. Long-term transdermal estradiol therapy: effects on endometrial histology and bleeding patterns. Obstet Gynecol 1992;79:196 – 201. [16] Deligdisch L. Effects of hormone therapy on the endometrium. Mod Pathol 1993;6:91 – 106. [17] Persson I, Adami HO, Bergkvist L, et al. Risk of endometrial cancer after treatment with oestrogens alone or in conjunction with progestogens: results of a prospective study. Br Med J 1989;298:147 – 51. [18] Voigt LF, Weiss NS, Chu J, Daling JR, McKnight B, Van Belle G. Progestogen supplementation of exogenous oestrogens and risk of endometrial cancer. Lancet 1991;338:274 – 7. [19] Whitehead MI, Hillard TC, Crook D. The role and use of progestogens. Obstet Gynecol 1990;75:59S – 76S. [20] Padwick ML, Endacott J, Whitehead MI. Efficacy, acceptability and metabolic effects of transdermal estradiol in the management of postmenopausal women. Am J Obstet Gynecol 1985;152:1085 – 91. [21] Steingold KA, Matt DW, DeZiegler D, Sealey JE, Fratkin M, Reznikow S. Comparison of transdermal to oral estradiol administration on hormonal and hepatic parameters in women with premature ovarian failure. J Clin Endocrinol Metab 1991;73:275 – 80. [22] Cagnacci A, Soldani R, Carriero PL, Paoletti AM, Fioretti P, Melis GB. Effects of low doses of transdermal 17 beta-estradiol on carbohydrate metabolism in postmenopausal women. J Clin Endocrinol Metab 1992;74:1396 – 400. [23] Huppert LC. Hormonal replacement therapy: benefits, risks, doses. Med Clin North Am 1987;71:23 – 39. [24] Walsh BW, Schiff I, Rosner B, Greenberg L, Ravnikar V, Sacks FM. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 1991;325:1196– 204.
T. 6on Holst, B. Salbach / Maturitas 34 (2000) 143–153 [25] Mu¨ck AO, Salbach B, Rabe T, von Holst T, Runnebaum B. Serum lipids in treatment with transdermal estradiol and oral norethisterone acetate. Geburtshilfe Frauenheilkunde 1995;55:393–9. [26] Cedars MI, Judd HL. Nonoral routes of estrogen administration. Obstet Gynecol Clin North Am 1987;14:269–98. [27] Murad F, Kuret JA. Estrogens and progestins. In: Gilman A, Goodman LS, editors. The Pharmacological Basis of Therapeutics. New York: Macmillan, 1990:1384–412. [28] Cortellaro M, Nencioni T, Boschetti C, et al. Cyclic hormonal replacement therapy after the menopause: transdermal versus oral treatment. Eur J Clin Pharmacol 1991;41:555 – 9. [29] Jensen PJ, Jensen J, Riis BJ, Rodbro P, Strom V, Christiansen C. Climacteric symptoms after oral and percutaneous hormone replacement therapy. Maturitas 1987;9:207 – 15. [30] Judd H. Efficacy of transdermal estradiol. Am J Obstet Gynecol 1987;156:1326–31. [31] Nachtigall LE, Utian WH. Comparative efficacy and tolerability of transdermal estradiol and conjugated estrogens-a double-blind multicentre study. In: Lauritzen C, editor. Transdermal Estrogen Substitution. Bern: Hans Huber, 1987:3749. [32] Place VA, Powers M, Darley PE, Schenkel L, Good WR. A double-blind comparative study of Estraderm and Premarin in the amelioration of postmenopausal symptoms. Am J Obstet Gynecol 1985;153:1092–9. [33] Steingold KA, Laufer L, Chetkowski RJ, et al. Treatment of hot flushes with transdermal estradiol administration. J Clin Endocrinol Metab 1986;61:627–32. [34] Stevenson JC, Cust MP, Gangar KF, Hillard TC, Lees B, Whitehead MI. Effects of transdermal versus oral hormone replacement therapy on bone density in spine and proximal femur in postmenopausal women. Lancet 1990;335:265 – 9. [35] Kupperman HS, Blatt MHG, Wiesbader H, Filler W. Comparative clinical evaluation of estrogen preparation by the postmenopausal and amenorrheal indices. J Clin Endocrinol 1953;13:688–703.
.
153
[36] O’Brien PC. Procedures for comparing samples with multiple endpoints. Biometrics 1984;40:1079 – 87. [37] Lutkie AWHM, Hackel S. Efficacy, tolerability, and compliance of FemSeven*, a once-weekly transdermal system, compared with Estraderm*TTS 50. Eur J Clin Res 1997;9:111 – 22. [38] The Transdermal HRT Investigators Group. A randomized study to compare the effectiveness, tolerability and acceptability of two different transdermal estradiol replacement therapies. Int J Fertil 1993;38:5 – 11. [39] Van Leusden HAIM, Albertyn G, Verlaine C, Van Ruymbeke J. A comparative multicenter study of two transdermal estradiol replacement therapies in the treatment of postmenopausal symptoms. Int J Fertil 1993;38:210 – 8. [40] Sefaty D, Caulin F. Efficacy and tolerability of transdermal 17 beta-estradiol in patients with climacteric symptoms: dose titration according to individual choice. Curr Ther Res 1996;57:506 – 15. [41] Studd JWW, McCarthy K, Zamblera D, et al. Efficacy and tolerance of Menorest® compared to Premarin® in the treatment of postmenopausal women. A randomised, multicentre, double-blind, double-dummy study. Maturitas 1995;22:105 – 14. [42] Good WR, John VA, Ramirex M, et al. Double-masked, multicenter study of an estradiol matrix transdermal delivery system (Alora) versus placebo in postmenopausal women experiencing menopausal symptoms. Clin Ther 1996;18(6):1093– 105. [43] Baachi-Modena A, Bolis P, Campagnoli C, et al. Efficacy and tolerability of Estraderm MX, a new estradiol matrix patch. Maturitas 1997;27:285 – 92. [44] Studd J, Pornel B, Marton I, et al. Efficacy and acceptability of intranasal 17b-oestradiol for menopausal symptoms: randomised dose-response study. Lancet 1999;353:1574– 8. [45] Lutkie AWHM, Hackel S, van de Ven LLM. Long-term tolerability and efficacy of Fem7®, a once-weekly transdermal system, in women with post-menopausal complaints. J Clin Res 1998;1:161 – 71.