Cliniques Universitaires St. Luc, Université Cathologique de Louvain, Brussels, Belgium

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1 FERTILITY AND STERILITY VOL. 81, NO. 2, FEBRUARY 2004 Copyright 2004 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A. Equivalence of the 3-month and 28-day formulations of triptorelin with regard to achievement and maintenance of medical castration in women with endometriosis Jacques Donnez, M.D., Ph.D., a Paul J. Dewart, M.D., b Bernard Hedon, M.D., c Antonio Perino, M.D., d Adolf E. Schindler, M.D., e Joëlle Blumberg, M.D., f and Denis Querleu, M.D. g Cliniques Universitaires St. Luc, Université Cathologique de Louvain, Brussels, Belgium Received February 14, 2003; revised and accepted July 3, Sponsored by Beaufour Ipsen Pharma/Ipsen Biotech, Paris, France. Reprint requests: Jacques Donnez, M.D., Ph.D., Université Catholique de Louvain, Service de Gynécologie, avenue Hippocrate 10, Brussels, Belgium (FAX: ; donnez@gyne.ucl.ac.be). a Head of the Department of Gynecology and Andrology, Université Catholique de Louvain, Service de Gynécologie. b Department of Obstetrics and Gynaecology, St John s Hospital at Howden, Livingstone, United Kingdom. c Hôpital Arnaud de Villeneuve, Service de Gynécologie-Obstétrique, Montpellier, France. d Clinica Ostetrica Ginecologica, Divisione di Ostetricia e Ginecologia, Istituto Materno Infantile, Palermo, Italy. e Zentrum für Frauenheilkunde, Universitätsklinikum Essen, Essen, Germany. f Beaufour-Ipsen Pharma, Paris, France. g Institut Claudius Regaud, Toulouse, France /04/$30.00 doi: /j.fertnstert Objective: The present study aims at demonstrating the equivalence of the 28-day and 3-month formulations of triptorelin SR (sustained release) in terms of percentage of patients achieving castration levels of estradiol ( 50 pg/ml) 84 days after treatment initiation. Design: A phase II, prospective, randomized, multicenter, open study was conducted in two parallel groups of women with endometriosis. Setting: Academic hospitals. Patient(s): Seventy-two women with endometriosis. were treated with a single intramuscular injection of 3-month triptorelin SR, and 74 patients were treated with one intramuscular injection of 28-day triptorelin SR every 28 days for 3 months. Intervention(s): As part of two parallel treatment groups, 72 women were given a single intramuscular injection of 3-month triptorelin SR, and 74 women were given one intramuscular injection of 28-day triptorelin SR every 28 days for 3 months. Main Outcome Measure(s): Percentage of patients achieving castration levels of estradiol at the end of the treatment period. Result(s): Patients participated in the study until resumption of menses. Ninety-seven percent of patients given the 3-month formulation and 94% of those given the 28-day formulation were in a state of medical castration on day 84. The mean time to achieve castration was shorter for the 3-month formulation, and the duration of castration was significantly longer. The FSH and LH parameters were comparable, though not always identical. Conclusion(s): The pharmacodynamic effects of the Decapeptyl SR 3-month formulation are equivalent to those of the 28-day formulation. The 3-month formulation provides the added advantage of a longer maintenance of medical castration in women who have endometriosis. (Fertil Steril 2004;81: by American Society for Reproductive Medicine.) Key Words: Medical castration, Decapeptyl, endometriosis, estrogen, triptorelin Endometriosis is a high-incidence, benign gynecologic disorder encountered in 7% to 10% of actively menstruating women, with a suspected prevalence as high as 22% in asymptomatic women, 60% in women with dysmenorrhea, and 30% in women with subfertility (1, 2). It is characterized by the presence of fragments of functional endometrial glands and stroma outside the uterine cavity, mainly in the pelvic area. Lesions may range from microscopic endometriotic implants to large ovarian cysts or endometriomas and deep retroperitoneal lesions (3). It is an estrogen-dependent disease and is relieved by the administration of antiestrogens, inhibitors of endogenous estrogen secretion, and by hormonal or surgical castration (4, 5). Two types of treatments are currently recommended for endometriosis, and may be complementary: surgery, usually by coelioscopic route (3, 6), and medical treatment aiming at suppressing the estrogen secretion that stimulates the growth of endometrial tissue 297

2 (5, 7). Other treatments still under assessment include aromatase inhibitors, antiprogestatins, antiangiogenesis factors, metalloproteinase inhibitors, or retinoic acid (6, 8 10). Hormonal treatment with GnRH analogues is most frequently combined with surgery, especially in cases of extensive endometriosis (5). This combination is either used preoperatively (11 15) or postoperatively (5, 16 18) with notable effects, especially as concerns pain relief. It was also noted that up to 48% of patients suffering from superficial endometriosis experienced pain improvement following diagnostic celioscopy (19). Our phase II, prospective, randomized, comparative, multicenter study was designed to demonstrate the pharmacodynamic equivalence of the 28-day and the 3-month formulations of triptorelin D-Trp6-GnRH (Decapeptide SR, Beaufour-Ipsen Pharma, Paris, France) in women with endometriosis. MATERIALS AND METHODS Objectives The primary objective of the study was to assess the relative pharmacodynamic equivalence of the 3-month sustained-release (SR) triptorelin formulation as compared with the 28-day, based on the percentage of patients achieving castration-level estradiol of 50 pg/ml (184 pmol/l) at day 84, the end of the 12-week treatment period. Secondary objectives included the comparison of the two formulations as concerns the following: time to achieve the castration level of estradiol (T lag, interval in days between injection and first time to reach estradiol castration), duration of medical castration (T cast, interval in days between first time castration observed and first time estradiol above castration levels), pharmacokinetic and pharmacodynamic profile of triptorelin 3-month formulation, changes in plasma levels of estradiol (C max, peak estradiol concentration in pg/ml, and T max time to peak estradiol concentration in days), plasma levels of FSH and LH, evolution of clinical symptoms (20), time to return to menses and to ovarian activity after the end of treatment, and clinical and biological tolerability of the two formulations. Study Design This was a phase II, prospective, randomized, open, multicenter, comparative study in two parallel groups: group A received a single intramuscular (IM) injection of 3-month triptorelin SR and group B received one intramuscular injection of 28-day triptorelin SR every 28 days during 3 months. The duration of the treatment period was 3 months (12 weeks), plus the follow-up period from day 84 (the end of the 12 weeks of treatment) until menses recovery (maximum time expected at 12 more weeks). The study took place in 25 study sites in France, Belgium, the United Kingdom, Germany, Spain, and Italy, between September 1998 and May It was conducted in compliance with European and FDA Good Clinical Practice guidelines, ICH guidelines, and with the ethical principles of the Declaration of Helsinki. Ethics committee approval was obtained for each clinical site prior to study initiation, and written consent was duly obtained from all patients. The study enrolled 152 patients, 75 in the 3-month group and 77 in the 28-day group. The pharmacokinetic profile of triptorelin 3-month was assessed by three sites in 11 patients of the 3-month group, and additional samples were collected at 10 sites from 68 patients (35 in the 3-month group and 33 in the 28-day group) for the determination of estradiol, FSH, and LH pharmacodynamic profiles. Estradiol, FSH, and LH measurements were performed for the global population on days 0, 2, 3, 7, 14, 21, 28, 56, 84, 91, 112, 140 and on resumption of menses, and were performed for the 68 pharmacodynamic subgroup patients on day 0 (at hours 0, 2, 4, 8, 12, 24, 48, and 72) and on days 7, 14, 21, 28, 56, 70, 77, 84, 91, and 98. Patients To be included into the study, women with laparoscopyconfirmed recurrent or newly diagnosed endometriosis had to be aged between 18 to 40 years (inclusive), give a written informed consent, have had regular cycles between 25 and 35 days during the previous 6 months, and use an effective barrier method of contraception for 1 month after the first injection. Patients were excluded from the study for any of the following reasons: menopause, pregnancy, or lactation; treatment with GnRH analogues in the previous 3 months or concomitant treatment with coumarin or indanedione derivatives; history of hypersensitivity to GnRH analogues; having received any other hormonal treatment during the previous 1 month (estrogens, progestogens, danazol, gestrinone, or cyproterone acetate); having received an unlicensed drug within the prior 30 days; presence of any associated malignancy except curatively treated basocellular skin cancer; or inability to comply fully with the study protocol. Patients were withdrawn from the study if pregnancy was detected, or if estrogen, progestogen, danazol, or other GnRH-agonist treatment was initiated. Patients were randomized into a study group according to a central four-block list of treatment allocation codes produced by Beaufour-Ipsen Pharma s Biometrics Department. On patient inclusion, each investigator called an Interactive Voice Response System (IVRS) company to obtain the patient number and treatment code (4C-SONS, Asnières, France). Study Treatments and Assessments The study treatment was manufactured and supplied for the study by Ipsen Pharma Biotech (Toulon, France). The study product was the triptorelin SR (sustained-release) formulation over 3 months (triptorelin SR 3-month), which 298 Donnez et al. Decapeptyl pharmacodynamics in endometriosis Vol. 81, No. 2, February 2004

3 delivers a minimum dose of mg of triptorelin. The study dose was one IM injection. In the control group, triptorelin SR formulation over 28 days (triptorelin SR 28-day) was administered, which delivers a minimum dose of 3 mg of triptorelin. The study dose was one IM injection every 28 days during 3 months. Treatment was to start during the beginning of the follicular phase (first five days of cycle). During the study, hormonal therapy other than that of the protocol was not allowed. Visits were scheduled at study inclusion (day 0) for the first treatment injection, at day 28 for the second treatment injection of the 28-day group, at day 56 for the third treatment injection of the 28-day group, at the end of the treatment period (day 84), for follow-up visits once every month until the recovery of menses (week 16, week 20), and for a final visit coinciding with the first visit after menses recovery (potentially the same as week 16 or week 20, or later). Clinical tolerability was assessed by collecting adverseevent and concomitant treatment data during each visit, and biological tolerability was assessed through general hematology and biochemistry assessments performed on day 0, day 84, and on menses recovery. The hormonal assessments were performed by a central laboratory (BARC, Ghent, Belgium). Triptorelin plasma levels were evaluated by IP- SEN Pharma SA (Barcelona, Spain) using a radioimmunoassay (RIA) method. The limit of quantitation (loq) of the method was 20 pg/ml, and the accepted coefficient of variability (CV) for sample duplicates was 15%. Statistical Methods Sample size determination was based on the percentage of patients with estradiol plasma levels 50 pg/ml at day 84. Based on normal approximations (21), 58 patients per group would have allowed an 80% power to reject the null hypothesis that the two treatment groups were not equivalent (difference 0.1 or farther from zero in the same direction). The alternative hypothesis was that the two groups were equivalent using a one-sided 0.05 statistical significance level and assuming the expected difference was zero and the proportion in the standard group was Assuming a maximum dropout of 10%, a minimum of 130 patients needed to be included. An intent-to-treat (ITT) analysis was conducted on the main efficacy parameters tested in all randomized patients who had received treatment. A per-protocol analysis (PP) was conducted on patients who followed the protocol without major violations. An analysis of tolerability was conducted on all randomized patients. For continuous parameters, the mean, standard deviation (SD), median, upper and lower quartiles were determined. For qualitative and discrete parameters frequencies and percentages were determined. Descriptive statistics were performed for all variables: T lag was calculated by interpolation from the curves, Student s t-test for continuous variables assuming variance homogeneity was used to compare treatment groups at baseline, a one-sided 95% confidence interval (CI) method was used for the equivalence test on the primary criterion, and a two-sided 90% confidence interval method was used for the equivalence test on C max, area under the curve (AUC) of estradiol, LH, FSH, and triptorelin. A two-sided 95% confidence interval was calculated when the confidence interval of the mean was given (as for C max or AUC of the pharmacokinetic subpopulation) without any test performed. RESULTS Study Population One hundred and fifty-two patients were included into the study, of which 146 patients received treatment (ITT and safety population), 72 in the 3-month and 74 in the 28-day triptorelin SR groups. The per-protocol (PP) population comprised 70 and 71 patients in the respective groups. Patients not included in the PP population had missed an estradiol dosage at day 84. Nine patients (five in the 3-month group and four in the 28-day group) prematurely withdrew during the follow-up phase after completion of the treatment phase, but were still included in the PP population analyses. Eleven patients were included in the pharmacokinetic subgroup, and 68 patients (35 for the 3-month and 33 for the 28-day forms) in the hormone pharmacodynamics subgroup. Ninety five patients with at least one estradiol concentration above castration level in the first 28 days after day 0 were tested for T lag and T cast, 46 from the 3-month and 49 from the 28-day formulations. Treatment group characteristics were not found to represent any significant bias to analysis. Table 1 shows patient baseline characteristics in each treatment group. FSH and LH Serum Levels Following an initial flare-up of FSH and LH values, both levels decreased in circulating serum, confirming pituitary desensitization. Equivalence of the two formulations as to AUC of FSH (in the ITT and PP populations and in the hormone pharmacodynamics subgroup) could be demonstrated, but not C max equivalence on day 2 to day 3. The shift of T max for FSH concentration between the two formulations was estimated to be 0 days (90% CI [ ; ]). Equivalence of the two formulations as to the area under the curve (AUC) of LH (in ITT, PP and hormone pharmacodynamics groups) could be demonstrated, but not the equivalence in C max on day 2 to day 3. The shift of T max for LH was estimated at 0.5 hours (90% CI [ 0.33; 1.99]). Table 2 shows the main FSH and LH pharmacodynamic parameters in the hormone pharmacodynamics subpopula- FERTILITY & STERILITY 299

4 TABLE 1 Patient characteristics on study inclusion. Parameter Triptorelin SR 3-month Triptorelin SR 28-day FIGURE 1 (A) FSH, (B) LH, and (C) estradiol log linear scale plasma profiles in the two treatment groups (} SR 3-month; SR 28-day). Disposition of patients (ITT population) Patients randomized (n 152) Patients treated (n 146) Age SD years years Estradiol concentrations at baseline (pharmacodynamics sub population) E 2 (pg/ml) n mean SD median Endometriosis (ITT population) First diagnosis 50 (63%) 54 (65%) Recurrence 22 (28%) 20 (24%) Stage I (minimal) a 9 (13%) 7 (9%) Stage II (mild) a 9 (13%) 12 (16%) Stage III (moderate) a 26 (36%) 19 (26%) Stage IV (severe) a 28 (39%) 34 (46%) a At first laparoscopy. tion, and the evolution of FSH and LH mean plasma concentrations ( SEM) in time is shown in Figure 1. Estradiol Serum Levels The triptorelin 3-month SR formulation was not found to be less effective than the 28-day formulation as concerns the TABLE 2 Evolution of the FSH and LH levels with time, and pharmacokinetics of estradiol in the hormone pharmacodynamics subgroups. Parameter (mean SD range) Triptorelin 3-month SR (n 35) Triptorelin 28-day SR (n 33) 90% confidence interval LH C max (U/L) ; a LH T max (days) ; b FSH C max (U/L) ; a FSH T max (days) ; b Estradiol C max (pg/ml) (pmol/l) ; a ; 1.25 Estradiol ; b T max (days) c a Equivalence cannot be concluded. b Equivalence can be concluded. c Median. percentage of patients remaining medically castrated at day 84. In the 3-month group, 68 patients (97%) and 67 patients (94%) in the 28-day group were still castrated on day 84 with estradiol concentration 50 pg/ml (184 pmol/l). This result was confirmed both in the ITT and in the PP populations. Changes in estradiol levels with time were measured in the 68-patient hormone pharmacodynamics population. Baseline (day 0) median levels were comparable (28.01 pg/ml in the 3-month group and pg/ml in the 28-day 300 Donnez et al. Decapeptyl pharmacodynamics in endometriosis Vol. 81, No. 2, February 2004

5 group), and mean levels showed a variability comparable to that observed in any given population, with few aberrant data on a scatterplot. On day 2, mean and median estradiol levels increased in both the 3-month and 28-day groups (flare-up effect, median levels and pg/ml, respectively). On day 3, median levels decreased in both groups, the decrease persisting on day 7, with median values then remaining stable until day 91. On day 112, however, a marked difference was noted in mean and median values of both groups, with the 3-month group showing a lower estradiol level than the 28-day group (median levels pg/ml and pg/ml, respectively). On day 140, median values were and pg/ml, respectively. After return to menses, the respective levels were again comparable (median values and pg/ml). The mean estradiol plasma concentration in pg/ml versus days for both groups in the ITT population is shown in Figure 1. The evolution of estradiol levels in the PP population was identical. A shift in T max of estradiol was observed in the hormone pharmacodynamics population between the 28-day and 3-month formulations estimated to be 1.99 hours (90% CI [ 1.75; 18.33]). The tests for equivalence on estradiol C max (ITT and PP populations) and AUC in the hormone pharmacodynamics group were inconclusive. Table 2 shows the pharmacodynamic parameters of estradiol in the hormone pharmacodynamics subgroup for both treatments. No statistically significant differences were detected in the time to achieve medical castration (T lag ). The duration of castration (T cast ) was significantly lower for the 28-day than for the 3-month triptorelin formulations, both at the 184 and the 110 pmol/l thresholds. A statistically significant difference (90% confidence interval [3.328; 6.569]) was detected as concerns time to return to menses, the latter being longer in the 3-month (5.0 months) than in the 28-day group (4.3 months), both in the ITT and in the PP populations. Table 3 shows the mean time and duration of medical castration, as well as the mean time to exit castration (T exit ) and time to return to menses in patients tested for these parameters in each treatment group. No difference was detected between the two treatment groups as concerns the evolution of clinical symptoms, although all targeted symptoms of moderate to severe intensity showed a clear decrease in incidence following treatment: in the 3-month group and 28-days group, respectively, dysmenorrhea dropped from 50% and 56% to 0 and 1%, pelvic pain dropped from 34% to 1% and 5%, pelvic tenderness from 22% to 0 and 6%, dyspareunia from 21% and 30% to 1% and 2%, and induration from 17% and 14% to 0 and 6%, respectively. TABLE 3 Mean time to achieve medical castration (T lag ), mean duration of castration (T cast ), mean time to exit castration (T exit ), and time to return to menses in both treatment groups. Parameter (mean SD) Triptorelin 3-month SR Triptorelin 28-day SR 90% confidence interval T lag (days) a T cast (days) 50 pg/ml P.0007 a T cast (days) 30 pg/ml P.0008 a T exit (days) 50 pg/ml T exit (days) 30 pg/ml Time to return to menses (months) a a Equivalence cannot be concluded. Pharmacokinetics of the 3-Month Formulation In patients receiving a single injection of triptorelin 3-month SR, the plasma concentration peak of triptorelin was achieved rapidly after administration (2 hours), followed by a rapid decline to a pseudo-plateau. In most patients, the mean concentration of the plateau exceeded 0.1 ng/ml, approximately up to day 21. Although some fluctuation was observed from this time onward, a decline was observed to a new plateau of about ng/ml. Triptorelin could be detected in the plasma up to 84 to 140 days after injection. The number of patients with longer periods of detected plasma levels was higher following the 3-month than the 28-day treatment. Triptorelin concentration curves were identical in the ITT and PP populations. Table 4 shows the pharmacokinetic parameters of triptorelin 3-month SR in the pharmacokinetic subgroup, and Figure 2 shows mean SD triptorelin concentrations over time for triptorelin 3-month and 28-day formulations. Tolerability One hundred and five patients experienced at least one adverse event during the study period (treatment and fol- TABLE 4 Mean SD concentrations of triptorelin following a single IM injection of SR 3-month formulation in the pharmacokinetic subpopulation. Parameter (mean SD) Triptorelin 3-month SR (n 11) C max (ng/ml) T max (days) AUC 91 (ng/ml/day) FERTILITY & STERILITY 301

6 FIGURE 2 Mean triptorelin SD concentration over time following a single IM injection of triptorelin 3-month SR ( Group A) and following three monthly IM injections of triptorelin 28-day SR (E Group B). TABLE 5 Incidence of the prevalent adverse events in the two treatment groups during the study period. Number of patients (%) Prevalent adverse events 3-month group (n 72) 28-day group (n 74) low-up periods): 50 (69% of patients in this treatment group) in the triptorelin 3-month group and 55 (74% of patients in this treatment group) in the triptorelin 28-day group. No statistically significant difference was found between groups in the occurrence of adverse events (P.58). No deaths or life-threatening events were reported. Ninety-eight patients experienced at least one adverse event during the treatment period (day 0 to day 91): 45 patients (63% of group) in the 3-month group and 53 patients (72% of group) in the 28-day group. The prevalent adverse events (AEs) were not significantly different in either treatment group, during treatment or the follow-up period. Only reproductive and psychiatric disorders were considered to bear some relation to treatment. The comparison of the two treatment groups as to the percentage of patients showing at least one expected side effect (flush, vaginal dryness, headache, asthenia, local reaction) was not statistically significant (P.44); the same was true for each individual side effect. Hematological and biochemical parameters were similar in both treatment groups, except for an increase in abnormal alanine aminotansferase (ALT) values (total of six patients during the whole study) and fasting glucose levels (total of five patients during whole study) between baseline and day 84 in the 3-month group. Hemoglobin and red blood cell values did not show a significant evolution over time, which included patients who suffered withdrawal bleeding, and the number of patients with low hemoglobin or red blood cell values decreased at day 84 as compared with their number on Prevalent adverse events per body system Reproductive disorders 24 (33%) 27 (36%) Gastrointestinal disorders 9 (13%) 10 (14%) Psychiatric disorders 14 (19%) 9 (12%) Respiratory system disorders 8 (11%) 8 (11%) General disorders 7 (10%) 6 (8%) Expected side effects a Hot flushes 63 (90%) 67 (93%) Headaches 43 (63%) 38 (57%) Asthenia 33 (50%) 37 (51%) Vaginal dryness 30 (42%) 34 (46%) Local reaction 1 (1%) 3 (4%) Other adverse events b Withdrawal bleeding 18 (25%) 20 (27%) Insomnia 6 (8%) 4 (5%) Depression 4 (6%) 3 (4%) Nausea 4 (6%) 2 (3%) Back pain 4 (6%) 1 (1%) Dizziness 4 (6%) 1 (1%) Pharyngitis 2 (3%) 4 (5%) Menstrual disorder 2 (3%) 4 (5%) Vertigo 0 (0%) 4 (5%) Dysuria 0 (0%) 4 (5%) a Appearing after study treatment initiation. b Occurring in 5% of patients in any of the study groups. day 0. Changes in vital signs and weight showed no tendency over time and no clinical differences between groups. Six patients four patients in the 3-month group and two patients in the 28-day group experienced a total of seven serious adverse events during the whole study. The events were as follows: serious gastrointestinal disorders in three patients, serious reproductive disorders in two patients, Vasquez disease diagnosed during the study in one patient, and right inguinal fossa pain in one patient. Of these seven events, two were considered as possibly and probably related to treatment, namely a worsening of Crohn disease and a heavy withdrawal bleeding, both in patients in the 3-month triptorelin group. Both events resolved with treatment. Table 5 shows the incidence of the prevalent adverse events in both treatment groups. DISCUSSION Triptorelin (D-Trp6-GnRH) is a synthetic GnRH agonist. Triptorelin was first registered in France in Therapeutic indications are hormonal-dependent pathologies, including prostate cancer, breast cancer, endometriosis, fibromy- 302 Donnez et al. Decapeptyl pharmacodynamics in endometriosis Vol. 81, No. 2, February 2004

7 oma, precocious puberty, and assisted reproduction, in combination with gonadotropins. Medical castration is achieved with triptorelin at a dosage of 0.1 mg/day (Devissaguet, unpublished report). A sustained-release formulation for long-term treatment is available as an injection every 28 days. This SR formulation combines the active ingredient with biocompatible and biodegradable microparticles of copolymers (lactide-glycolide). The novel formulation of triptorelin with a longer release over a 3-month duration aims at reducing injection frequency, thus improving compliance and improving the patient s quality of life in a treatment that needs to be administered over several months. This compound was obtained by salification of triptorelin acetic acid, and contains the same active ingredient as triptorelin 28-day. The dosage of mg was calculated to induce a kinetic release over 3 months. The first positive aspect that needs to be mentioned concerning the present study resides in an adequate compliance to protocol. This allowed a full assessment of the pharmacokinetic and pharmacodynamic properties of triptorelin and its target hormones with a minimal loss due to dropouts or protocol violations. In prior studies, dropout rates were as large as 40 out of 48 patients (83.3%) during a 6-month treatment and 12-month follow-up study (22), or 7 out of 50 patients (14%) during a 6- to 12-month follow-up study (23). For our study, during the treatment phase, the dropout rate was 5 out of 146 patients (3.4%); during the post-treatment follow-up period, 9 out of 141 patients (6.3%) dropped out. In our study, the administration of triptorelin SR in its 3-month formulation successfully induced medical castration in patients suffering from endometriosis, an estrogendependent disorder. This castration was similar to that observed with triptorelin 28-day SR. Ninety-seven percent of patients treated with a single injection of the 3-month form achieved medical castration (estradiol levels 50 pg/ml) within a mean time of 9.8 days and remained castrated 12 weeks later; 94% of those treated with three successive injections of the 28-day form achieved medical castration within 11.3 days and were castrated at week 12. The mean castration duration was significantly longer with the 3-month form than with the 28-day form: days and 93.6 days, respectively. As a consequence, women returned to menses later with the 3-month form than with the 28-day form (5.1 months versus 4.4 months). The amplitude of the initial flare-up after the first injection of both forms was comparable and similar to that observed in the late follicular phase of the physiological menstrual cycle. Equivalence was also shown between the two formulations in terms of AUC 0 91, FSH, and LH. No shift of T max was observed for FSH, while for LH levels T max occurred 0.5 hours later with the 3-month formulation, which could be explained by the differences in triptorelin plasma concentrations which are higher in the first hours after treatment administration for the 28-day than for the 3-month formulation. Thus, pituitary desensitization was concurrent to castration, as had been previously reported for triptorelin (24 26). As concerns safety, GnRH-agonist treatment has been reported to cause hypertension, arthralgia (joint pain), allergy or rash, hot flushes, amenorrhea, menorrhagia, headache, and decreased bone density. In the present study, safety results were found to be particularly satisfactory for both expected and unexpected events. The adverse events observed were globally similar to those previously reported with triptorelin use, be it with the triptorelin 28-day SR or 3-month SR. Hot flushes were the predominant expected events, followed by headache, asthenia, and vaginal dryness, whereas arthralgia, rash, menorrhagia, local reaction, and heart rate and rhythm disorders were rare. The intensity of adverse events was mostly mild to moderate in the present study, with only 10 of the 94 events rated in the 3-month group and 7 of 103 in the 28-day group rated as severe. Within the events considered to be possibly or probably related to treatment, only five severe events were recorded in the 3-month group of a total of 51 related events, and three severe events were recorded within the 48 related events in the 28-day group. CONCLUSION An optimal treatment of endometriosis aims at alleviating the disease without inducing in itself novel symptoms or occasioning a worsening of the patient s quality of life through multiple injections, unexpected bleeds, or androgenic effects. Triptorelin treatment in this sense, and especially so the longer-term SR formulations, adequately responds to that existing need, even as it ensures an adequate control of the estrogenic etiology of endometriosis. The present study results demonstrate the similar effectiveness of the 3-month formulation as compared with the 28-day formulation of triptorelin in terms of pharmacodynamic equivalence and achievement of medical castration, with no enhancement of the flare-up mechanism. The 3-month formulation of triptorelin SR combines the advantages of an adequate treatment with those of a longer duration of action, hence a minimal discomfort to the patient. References 1. Farquhar CM. Endometriosis. BMJ 2000;320: Nisolle M, Donnez J. Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril 1997;68: Donnez J, Nisolle M, Squifflet J. Ureteral endometriosis: a complication of rectovaginal endometriotic (adenomyotic) nodules. Fertil Steril 2002;77: Donnez J, Nisolle M, Grandjean P, Gillerot S, Clerckx F. The place of GnRH agonists in the treatment of endometriosis and fibroids by advanced endoscopic techniques. Br J Obstet Gynaecol 1992;99(suppl 7): Donnez J, Chantraine F, Nisolle M. The efficacy of medical and surgical treatment of endometriosis-associated infertility: arguments in favour of a medico-surgical approach. Hum Reprod Update 2002;8: FERTILITY & STERILITY 303

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