Key words: controlled ovarian stimulation/ivf/local tolerance/pen device/recombinant FSH

Transcription

1 Human Reproduction Vol.18, No.6 pp. 1200±1204, 2003 DOI: /humrep/deg234 An open, randomized single-centre study to compare the ef cacy and convenience of follitropin b administered by a with follitropin a administered by a in women undergoing ovarian stimulation for IVF/ICSI Peter Platteau 1, Els Laurent, Carola Albano, Kaan Osmanagaoglu, ValeÂrie Vernaeve, Herman Tournaye, Michel Camus, Andre Van Steirteghem and Paul Devroey Centre for Reproductive Medicine, University Hospital and Medical school, Dutch-speaking Brussels Free University, Laarbeeklaan 101, 1090 Brussels, Belgium 1 To whom correspondence should be addressed. peter.platteau@az.vub.ac.be BACKGROUND: A, similar to an insulin pen, has been recently marketed for the administration of follitropin b in cartridges. A randomized controlled trial was performed to compare the ef cacy and convenience of this delivering follitropin b with a delivering follitropin a. METHODS: A total of 200 patients needing IVF/ICSI treatment and willing to self-inject were enrolled in the study. All subjects had ovarian stimulation according to a long protocol and were randomized to the pen or the group during down-regulation by means of a computer-generated randomization list using random numbers. Patients were asked to ll in a daily local tolerance book after each injection. On the day of hcg the patients scored a Visual Analogue Scale (VAS) for pain and convenience. RESULTS: The average duration, total dose of recombinant FSH and number of cumulus oocyte complexes retrieved were 10.8/12.0 days (P = 0.001), 1880/2226 IU (P < 0.001) and 15.2/13.1 respectively in the and groups; the presence of pain after the daily injection was signi cantly higher in the group (P = 0.027); the visual analogue scale score was similar for pain but signi cantly more convenient for the (P < 0.001). The live birth rate per embryo transfer was 32.9 and 34.4% respectively in the and groups. CONCLUSIONS: Self-injection with the is safe and easy, more convenient and less painful for the patient, requires less FSH and shortens the treatment duration. Key words: controlled ovarian stimulation/ivf/local tolerance//recombinant FSH Introduction Over the last decade, the convenience of fertility treatment has been improved with the introduction of puri ed gonadotrophin preparations suitable for s.c. injection (Howles et al., 1994; Wikland et al., 1994). Compared with the i.m. route, the s.c. route has as a main advantage the fact that self-administration is feasible. This is more convenient, and less time-consuming, as patients have to pay fewer visits to the clinic or hospital for injections. Since the mid 1990's, two gonadotrophin preparations (follitropin a and b), produced by recombinant DNAtechnology, have become commercially available (Howles et al., 1996; Olijve et al., 1996; Harlin et al., 2000). These recombinant FSH (rfsh) preparations have the advantage of absolute purity and high reproducibility over the gonadotrophin preparations derived from an urinary source. A metaanalysis showed an increased bioactivity of rfsh as proven by signi cantly more oocytes, embryos and pregnancies compared with urinary FSH (Daya et al., 1999). Until recently, the pharmaceutical presentation of these rfsh preparations was a freeze-dried lyosphere, which had to be dissolved in water for injection before administration. Lately, follitropin b has been made available as a ready-to-use solution. Two presentation forms have been developed: a vial presentation and a cartridge presentation containing 833 IU/ml of follitropin b for administration with a (approved brand name Puregon Pen TM ). This pen injector is an adapted insulin pen, which has been shown to be better accepted by diabetes patients in comparison with s, as it offers easier, safer, more accurate and discrete insulin injection (Kadiri et al., 1998; 1200 ã European Society of Human Reproduction and Embryology

2 Ef cacy and routes of administration of follitropin b and a Nancy et al., 1999). It is the rst multiple-use device available for s.c. self-administration of gonadotrophins, that facilitates precise and individualized dosing of follitropin b with dose increments of 25 IU and total dosages ranging from 50±450 IU. Additionally the injector's needle size and injection volume are smaller. A bioequivalence study was performed prior to use (Voortman et al., 1999), as absorption from the injection site could be in uenced by the pharmaceutical formulation, concentration of the drug and the administered volume. After correction of injection losses, follitropin b administered by a and syringe was shown to be bioequivalent in 22 healthy volunteers with respect to the rate and extent of absorption. In a second study with healthy volunteers (Craenmehr et al., 2001) follitropin b administered by the was far less painful than follitropin a administered by. The present study was designed to compare the local tolerance and convenience of follitropin b (presented as readyto-use cartridges) administered with the new, with follitropin a (presented as a freeze-dried cake in ampoules) administered with a in patients needing IVF/ICSI. The secondary objective was to assess the clinical ef cacy of the pen injector in comparison with the conventional syringe. The outcome will provide important information for doctors, clinical staff and patients on the new pen device and cartridges in comparison with the currently used syringes and ampoules. Materials and methods Study population The protocol for this prospective, randomized, single centre, groupcomparative study proposed the enrolment of 200 infertile women (100 in each group) for whom IVF or ICSI was indicated. With 100 evaluable subjects in each treatment group and assuming a standard deviation of 6.4 oocytes for the total number of oocytes retrieved, then with a power of 80%, using a two-sided t-test with a signi cance level of 5%, a difference of ~3.6 oocytes can be detected between the two treatment groups. The precision (SE) of the mean in each group is approximately 0.91 oocytes. In a similar way a difference in total dose of ~565 IU can be detected (assuming a SD of 1000 IU). The study was performed according to the principles of the declaration of Helsinki and good clinical practice; our local ethics committee gave its approval, and all patients provided written informed consent. Patients understood that they could withdraw from the study at any stage of their treatment. If they felt they could no longer carry on with self-injection, patients were allowed to drop-out of the study and continue their treatment with FSH injections given by paramedical staff. The main inclusion criteria were: between 18±39 years of age at the time of screening, normal ovulatory cycles with a mean length of 24±35 days, a body mass index (BMI) between 18 and 29 kg/m 2 and a willingness to self-inject rfsh medication. The main exclusion criteria were: previous treatment in which less than three oocytes were retrieved, any ovarian abnormality that would interfere with adequate stimulation, previous hospitalization due to severe OHSS, history of (within 12 months) or current abuse of alcohol or drugs and previous enrolment in this same study. Study design Patients were pre-treated with buserelin nasal spray (Suprefact â ; Aventis Pharma Deutschland, Frankfurt A/M, Germany) 0.1 mg six times daily from the mid-luteal phase onward to achieve downregulation. Patients were randomized by one of the study nurses (by means of a computer-generated randomization list using random numbers) during down-regulation to self-inject either with follitropin b (Puregon â ; Organon, Oss, The Netherlands), with a equipped with a needle sized 29G 3 13 mm (Puregon PenÔ) or follitropin a (Gonal-F â ; Serono, Geneva, Switzerland) with a equipped with a needle sized 25G 3 16 mm. Follitropin b was supplied in cartridges containing IU in ml aqueous solution (833 IU/ml) with a maximum deliverable dose of 600 IU. Follitropin a was supplied as a freeze-dried cake in ampoules, each containing 75 IU, to be dissolved in 1 ml uid for reconstitution. Up to four ampoules were dissolved in 1 ml of solvent. A study nurse instructed the patients how to self-inject s.c. in the abdominal wall around the umbilicus with the or with a during this randomization visit. When estradiol serum levels were <66 ng/l and a transvaginal ultrasound con rmed the absence of ovarian activity, FSH stimulation was started. The starting dose for the rst 5 days was 150/225 IU follitropin a or 150/200 IU follitropin b decided by the clinician looking after the patient before randomization (two or three ampoules), depending on the patient's age, previous response and basal serum FSH levels. Thereafter the dose was adjusted according to the individual ovarian response monitored by transvaginal ultrasound examinations and serum estradiol levels. Ovulation was triggered with IU of hcg (Pregnyl â ; Organon) administered as a single i.m. injection, when at least three follicles >17 mm had developed. Transvaginal ultrasound-directed oocyte retrieval was performed 36 h after hcg administration. Oocyte retrieval, IVF and ICSI procedures have been described in detail previously (Devroey et al., 1995; Joris et al., 1998; Van Steirteghem et al., 1998). Two or three (if the patient was >37 years) embryos were transferred on day 3 or day 5 following oocyte retrieval. Micronized progesterone pessaries (Utrogestan â ; Laboratoires Piette International, Brussels, Belgium), 200 mg three times daily, were given as luteal support, starting from the day after oocyte retrieval until 16 days thereafter. This was continued for another 5 weeks if a pregnancy occurred. Local tolerance assessment The severity of local tolerance symptoms was assessed by the patients themselves and lled in a `local tolerance diary book', within 5 min, at 1 and 3 h after injection. Local tolerance items scored were pain, redness, itching, bruising and swelling. The severity of symptoms was scored as none, mild, moderate or severe. In addition, on the day of hcg administration, patients were asked to rate on a visual analogue scale (VAS), their overall pain and convenience experienced with this self-injection method. The VAS scale ranged from 0 (severe pain, not convenient) to 10 (no pain, very convenient). Ef cacy endpoints Patient characteristics such as age, BMI, number of previous IVF attempts, duration and cause of infertility were recorded. The main ef cacy endpoints were the number of oocyte complexes (COC) retrieved, the total rfsh dose, the number of treatment days, the number of follicles on the day of hcg, the estradiol level on the day of hcg, the number of embryos replaced and frozen, the biochemical, miscarriage, ectopic and vital pregnancy rate and incidence of ovarian hyperstimulation syndrome (OHSS). 1201

3 P.Platteau et al. Implantation rate was de ned as the number of viable fetuses, as assessed by ultrasound at 7 weeks gestation, divided by the number of embryos transferred for each subject. Statistical analysis Statistical testing was performed with two-tailed test, at the 5% level of signi cance, using SAS (version 8.2). The comparison of the quantitative variables was performed by means of two-way ANOVA. The model considers FSH dose (two or three ampoules), FSH type (Puregon Pen or Gonal-F) and their interaction as factors. For the VAS for convenience and the VAS for pain, a three-way ANOVA without interactions was also performed, with the factors as FSH dose, FSH type and previous use of gonadotrophin. The comparison of the maximal symptom score in the two treatment groups was performed using the Mann±Whitney test. The Fisher Exact test was used for the regrouped maximal symptom score (none/mild versus moderate/severe). Table I. Main demographic and infertility baseline characteristics (Values are means 6 SD) (n = 96) (n = 104) Age (years) Body mass index (kg/m 2 ) Duration of infertility (years) Subjects with primary infertility (%) Main cause of infertility (%) Male Tubal Unexplained Other Results Study population A total of 200 patients were randomized between September 2000 and December A total of 104 were allocated to the group and 96 to the group. The two groups of patients were comparable with respect to their demographic and infertility baseline characteristics (Table I). Male factor infertility was the most frequent cause of infertility reported in both groups and ~60 % had primary infertility. The mean duration of infertility was ~4 years in each group. Nine patients (4.5 %) never started ovarian stimulation: three patients had an inadvertent spontaneous pregnancy during down-regulation, two patients stopped treatment because of an interfering operation, one patient emigrated, one couple stopped because of personal problems and two patients (1%) never started self-injection because of needle phobia (one patient in each group). So, 191 patients injected themselves at least once with rfsh (see Figure 1). Six patients stopped ovarian stimulation because of poor ovarian response (three in each group). Seven patients had no embryo transfer because of failed fertilization or abnormal embryo development (two in the group and ve in the group). In total 185 patients had oocyte retrieval and 178 had embryo transfer. Clinical ef cacy The various clinical ef cacy parameters with the two administration devices are presented in Tables II and III. In the pen device group, 34.4% of the patients started their ovarian stimulation with the higher FSH dose (200 IU) compared with 26.5% in the group. Overall, patients injecting follitropin b with the needed signi cantly less rfsh (P < 0.001) (a difference of 15.6%), had a signi cantly shorter stimulation (P = 0.001) and had signi cantly more frozen embryos (P = 0.034). Seventy patients (75%) injecting with the did not use the whole cartridge they started as only cartridges of 600 IU of follitropin b were used in the study. There was therefore a 1202 Figure 1. Flowchart for randomized study of 200 IVF/ICSI patients. mean `non-use' of follitropin b of 261 IU per patient using the. The overall pregnancy rate was 44.4% (positive hcg per embryo transfer). In the group, there was one biochemical pregnancy and three spontaneous abortions, whereas in the group there was one ectopic pregnancy, seven biochemical pregnancies and two spontaneous abortions. Sixty- ve patients had an ongoing pregnancy at 7 weeks gestation. There was one triplet pregnancy in the follitropin a group (with monozygotic twins) and one (triamniotic, tri-chorionic) triplet pregnancy (after a two-embryo transfer) in the follitropin b group, which spontaneously reduced to twins. There were no differences in the ongoing pregnancy and implantation rate between the two groups of

4 Ef cacy and routes of administration of follitropin b and a Table II. Ef cacy parameters (Values are means 6 SD) (n = 93) (n = 98) Total dose of rfsh (IU) * Duration of treatment (days) ** Estradiol level day of hcg (ng/l) No. of follicles >15 mm (n) No. of oocytes retrieved (n) No of embryos frozen (n) *** *P < **P = ***P = Table III. Clinical outcome (Values are means 6 SD) Embryos replaced (n) Positive hcg perattempt (%) Positive hcg pertransfer (%) Clinical pregnancy rate (%) Implantation rate (%) Live birth rate (%) patients. One pregnancy was terminated at 23 weeks gestation because of multiple fetal malformations (follitropin a group). Two twin pregnancies (one in each group) resulted in a live birth and a stillborn baby. There were 36 singleton, 23 twin and one triplet pregnancies resulting in 83 healthy children. The live birth rate per embryo transfer was 32.9 and 34.4% respectively in the and the groups. Local tolerance Of the 191 FSH-treated subjects, 171 (89.5%) had one or more local tolerance symptoms (bruising, pain, redness, swelling or itching). Considering only the moderate and severe scores (Figure 2), there were no statistically signi cant differences in the incidences of most individual local tolerance symptoms as well as of overall local tolerance symptoms. However, the prevalence of pain was signi cantly higher in the conventional syringe group (P = 0.027). A total of 150 (78.5%) and 152 (79.6%) patients scored their overall pain and convenience respectively on a visual analogue scale on the day of hcg. The mean overall pain score was low and not different (score 0 is very painful, score 10 is no pain at all), i.e and after administration of follitropin a by syringe and follitropin b by respectively. The overall convenience score on the contrary was signi cantly better in the group injecting with the pen device, i.e compared with in the syringe group (P < 0.001). Safety In the group, there were four cases (4%) of OHSS, whereas in the group there were seven Figure 2. Percentage of subjects with moderate or severe local tolerance symptoms. cases of OHSS (7.5%). In six (two in the group and four in the group) cases the OHSS was severe, as de ned by hospitalization. Discussion Gonadotrophins have been used successfully in ovarian stimulation for >30 years. Over this time period they have become totally puri ed, available in a ready-to-use solution and easy to self-administer by s.c. injection. All these developments made their use more patient-friendly. The introduction of a in order to deliver recombinant insulin showed a reduction in pain at the injection site, improved the convenience for the patients and proved to be an accurate method of drug delivery (Robertson et al., 2000). The introduction of a similar for the administration of follitropin b was therefore a logical step to make infertility treatment easier, more exible and less stressful. A rst study (Voortman et al., 1999) demonstrated that the injection of similar amounts of follitropin b using either a dissolved cake with a or a ready-for-use solution with a were bio-equivalent. However due to the void volume of the syringe and losses while lling the syringe and/or removing excess air there was a loss of 18% of rfsh. This 18% loss due to the use of a explains the differences found in our study in ef cacy parameters: a higher total amount of rfsh needed (difference of 15.6% in our study) which means in practice at least 1 more day of rfsh treatment, probably a lower follicle recruitment due to the lower starting dose and therefore a trend towards the recovery of fewer oocytes resulting in signi cantly fewer frozen embryos. A starting dose of 177/236 IU of follitropin a in the syringe group would most probably give us equal ef cacy parameters. This is also the reason why we used 200 IU instead of 225 IU as a starting dose in the three ampoule group, as we anticipated, on the basis of the study of Voortman, that in fact we would be injecting the same dose as IU in a with possible risks of OHSS. This present study is the rst randomized study in patients to compare the ef cacy of follitropin b administrated with a pen device and follitropin a injected with a. It re ects the day to day reality when a clinician decides to prescribe a recombinant FSH preparation to the patient in front of him. 1203

5 P.Platteau et al. An earlier study with volunteers (Craenmehr et al., 2001) showed that injection pain is experienced less frequently when follitropin b is administered by a than when follitropin a is administered with a. This is most probably due to the micro-needle and micro-volume of rfsh injected by the pen, which largely reduce local tolerance problems such as pain at the injection site. In our study, the overall score for pain on a visual analogue scale at the end of the treatment was very low and similar in both groups. It is interesting to note that none of the patients withdrew from the study because of dif culties in self-injecting or side effects. The convenience score on the visual analogue scale was signi cantly better in the pen group, which re ects the user friendliness of the device and con rms the previous experiences with similar devices in diabetic patients (Nancy et al., 1999). In 75% of the patients using the pen there was some `wastage' of follitropin b due to the fact that we only used cartridges of 600 IU in the study. This wastage would have been lower if cartridges of 300 IU were also used and will be further minimized in the future, if smaller cartridges are marketed. The will also increase convenience for patients in ovulation induction treatment: it permits the accurate titration of the rfsh dose from 50±450 IU in 25 increments. This means that drug doses can be individualized for each patient and ovarian stimulation achieved at the minimum effective dose. No accidental overdose or other speci c adverse reactions due to the pen were reported, neither was there any signi cant difference in OHSS between both groups. We can therefore say that the pen injector is a safe delivery device for rfsh. The clinician should be aware, however, that by using the pen 18% more rfsh is injected and that the starting rfsh dose might have to be adapted accordingly. The next step to further improve patient convenience is the development of a needle-free device for the administration of gonadotrophins. The device already exists, but needs further modi cation to reduce the number of technically incorrect injections (Lavery et al., 2002). In conclusion, self-injection with the is safe and easy, more convenient and less painful for the patient, requires less FSH and shortens the treatment duration. The Puregon Pen is a welcome addition to our treatment armamentarium. Acknowledgements The authors thank Dr Marie-Paule Derde for statistical help and the study nurses of the centre for Reproductive Medicine. This work was supported by a grant from NV Organon International, Oss, The Netherlands. References Craenmehr, E., Bontje, P. M., Hoomans, E., Voortman, G. and Mannaerts, B.M.J.L. (2001) Follitropin-b administered by has superior local tolerance compared with follitropin-a administered by conventional syringe. RBM Online, 3, 185±189. Daya, S. and Gunby, J. (1999) Recombinant versus urinary FSH for ovarian stimulation in assisted reproduction. Hum. Reprod., 14, 2207±2215. Devroey, P., Tjandraprawira, K., Mannaerts, B., Coelingh Bennink, H., Smitz, J., Bonduelle, M., De Brabanter, A. and Van Steirteghem, A.C. (1995) A randomized, assessor-blind, group-comparative ef cacy study to compare the effects of Normegon and Metrodin in infertile female patients undergoing in-vitro fertilization. Hum. Reprod., 10, 332±337. Harlin, J., Czemiczky, G., Wramsby, H. and Fried, G. (2000) Recombinant follicle-stimulating hormone in in-vitro fertilization treatment ± clinical experience with follitropin alpha and follitropin beta. Hum. Reprod., 15, 239±244. Howles, C.M. (1996) Genetic engineering of human FSH (Gonal-F). Hum. Reprod. Update, 2, 172±191. Howles, C.M., Loumaye, E., Giroud, D. and Luyet, G. (1994) Multiple follicular development and ovarian steridogenesis following subcutaneous administration of a highly puri ed urinary FSH preparation in pituitary desensitized women undergoing IVF: a multicentre European phase III study. Hum. Reprod., 9, 424±430. Joris, H., Nagy, Z., Van de Velde, H., De Vos, A., Van Steiteghem, A. (1998) Intracytoplasmic sperm injection: laboratory set-up and injection procedure. Hum. Reprod., 13, (Suppl. 1), 76±86. Kadiri, A., Chraibi, A., Marouan, F., Ababou, M.R., el Guermai, N., Wadjinny, A., Kerfati, A., Douiri, M., Bensouda, J.D., Belkhadir, J. et al. (1998) Comparison of NovoPen 3 and syringes/vials in the acceptance of insulin therapy in NIDDM patients with secondary failure to oral hypoglycaemic agents. Diabetes Res. Clin. Pract., 41, 15±23. Lavery, S.A., Paul, K., Turner, C., Margara, R. and Trew, G. (2002) Evaluation of a needle-free vehicle for administration of gonadotrophins. Hum. Reprod., 17, O-20. Nancy, J. and Bohannon, M. D. (1999) Insulin delivery using ssimple to use tools may help young and old alike. Postgraduate Medicine, 106, 57±68. Olijve, W., De Boer, W., Mulders, J.W.M. and Van Wezenbeek, P.M.G.F. (1996) Molecular biology and biochemistry of human recombinant follicle stimulating hormone (Puregon â ). Mol. Hum. Reprod., 2, 371±382. Robertson, K.E., Glazer, N.B. and Campbell, R.K. (2000) The latest development in insulin injection devices. Diabetes Educator, 26, 135±138. Van Steirteghem, A., Nagy, P., Joris, H., Janssenswillen, C., Staessen, C., Verheyen, G., Camus, M., Tournaye, H., Devroey, P. (1998) Results of intracytoplasmic sperm injection with ejaculated, fresh and frozen-thawed epididymal and testicular spermatozoa. Hum. Reprod., 13, (Suppl. 1), 134±142. Voortman, G., van de Post, J., Schoemaker, R.C. and van Gerven, J.M.A. (1999) Bioequivalence of subcutaneous injections of recombinant human follicle stimulating hormone (Puregon â ) by Pen-injector and syringe. Hum. Reprod., 7, 1698±1702. Wikland, M., Borg, J., Hamberg, L. and Svalander, P. (1994) Simpli cation of IVF: minimal monitoring and the use of s.c. highly puri ed FSH administration for ovulation induction. Hum. Reprod., 9, 1430±1436. Submitted on November 26, 2002; accepted on February 11,