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. e-mail: peter.platteau{at}az.vub.ac.be
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Abstract |
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Key words: controlled ovarian stimulation/IVF/local tolerance/pen device/recombinant FSH
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Introduction |
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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 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
for administration with a pen device (approved brand name Puregon PenTM).
This pen injector is an adapted insulin pen, which has been shown to be better accepted by diabetes patients in comparison with conventional syringes, as it offers easier, safer, more accurate and discrete insulin injection (Kadiri et al., 1998; Nancy et al., 1999
). It is the first multiple-use device available for s.c. self-administration of gonadotrophins, that facilitates precise and individualized dosing of follitropin
with dose increments of 25 IU and total dosages ranging from 50450 IU. Additionally the injectors 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 influenced by the pharmaceutical formulation, concentration of the drug and the administered volume. After correction of injection losses, follitropin
administered by a pen device 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
administered by the pen device was far less painful than follitropin
administered by conventional syringe.
The present study was designed to compare the local tolerance and convenience of follitropin (presented as ready-to-use cartridges) administered with the new pen device, with follitropin
(presented as a freeze-dried cake in ampoules) administered with a conventional syringe in patients needing IVF/ICSI. The secondary objective was to assess the clinical efficacy 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.
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Materials and methods |
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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 1839 years of age at the time of screening, normal ovulatory cycles with a mean length of 2435 days, a body mass index (BMI) between 18 and 29 kg/m2 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®; Aventis Pharma Deutschland, Frankfurt A/M, Germany) 0.1 mg six times daily from the mid-luteal phase onward to achieve down-regulation. 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 (Puregon®; Organon, Oss, The Netherlands), with a pen device equipped with a needle sized 29G x 13 mm (Puregon PenTM) or follitropin
(Gonal-F®; Serono, Geneva, Switzerland) with a conventional syringe equipped with a needle sized 25G x 16 mm. Follitropin
was supplied in cartridges containing 737.5 IU in 0.885 ml aqueous solution (833 IU/ml) with a maximum deliverable dose of 600 IU. Follitropin
was supplied as a freeze-dried cake in ampoules, each containing 75 IU, to be dissolved in 1 ml fluid 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 pen device or with a conventional syringe during this randomization visit.
When estradiol serum levels were <66 ng/l and a transvaginal ultrasound confirmed the absence of ovarian activity, FSH stimulation was started. The starting dose for the first 5 days was 150/225 IU follitropin or 150/200 IU follitropin
decided by the clinician looking after the patient before randomization (two or three ampoules), depending on the patients 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 10 000 IU of hCG (Pregnyl®; 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®; 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 filled 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).
Efficacy endpoints
Patient characteristics such as age, BMI, number of previous IVF attempts, duration and cause of infertility were recorded. The main efficacy 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).
Implantation rate was defined 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 significance, 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 MannWhitney test. The Fisher Exact test was used for the regrouped maximal symptom score (none/mild versus moderate/severe).
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Results |
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Clinical efficacy
The various clinical efficacy 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 conventional syringe group. Overall, patients injecting follitropin with the pen device needed significantly less rFSH (P < 0.001) (a difference of 15.6%), had a significantly shorter stimulation (P = 0.001) and had significantly more frozen embryos (P = 0.034).
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The overall pregnancy rate was 44.4% (positive hCG per embryo transfer). In the conventional syringe group, there was one biochemical pregnancy and three spontaneous abortions, whereas in the pen device group there was one ectopic pregnancy, seven biochemical pregnancies and two spontaneous abortions. Sixty-five patients had an ongoing pregnancy at 7 weeks gestation. There was one triplet pregnancy in the follitropin group (with monozygotic twins) and one (tri-amniotic, tri-chorionic) triplet pregnancy (after a two-embryo transfer) in the follitropin
group, which spontaneously reduced to twins. There were no differences in the ongoing pregnancy and implantation rate between the two groups of patients. One pregnancy was terminated at 23 weeks gestation because of multiple fetal malformations (follitropin
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 pen device and the conventional syringe 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 significant differences in the incidences of most individual local tolerance symptoms as well as of overall local tolerance symptoms. However, the prevalence of pain was significantly higher in the conventional syringe group (P = 0.027).
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Safety
In the conventional syringe group, there were four cases (4%) of OHSS, whereas in the pen device group there were seven cases of OHSS (7.5%). In six (two in the conventional syringe group and four in the pen device group) cases the OHSS was severe, as defined by hospitalization.
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Discussion |
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This present study is the first randomized study in patients to compare the efficacy of follitropin administrated with a pen device and follitropin
injected with a conventional syringe. It reflects the day to day reality when a clinician decides to prescribe a recombinant FSH preparation to the patient in front of him.
An earlier study with volunteers (Craenmehr et al., 2001) showed that injection pain is experienced less frequently when follitropin
is administered by a pen device than when follitropin
is administered with a conventional syringe. 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 difficulties in self-injecting or side effects. The convenience score on the visual analogue scale was significantly better in the pen group, which reflects the user friendliness of the device and confirms 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 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 pen device will also increase convenience for patients in ovulation induction treatment: it permits the accurate titration of the rFSH dose from 50450 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 specific adverse reactions due to the pen were reported, neither was there any significant 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 modification to reduce the number of technically incorrect injections (Lavery et al., 2002).
In conclusion, self-injection with the pen device 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.
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Acknowledgements |
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References |
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Daya, S. and Gunby, J. (1999) Recombinant versus urinary FSH for ovarian stimulation in assisted reproduction. Hum. Reprod., 14, 22072215.
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 efficacy study to compare the effects of Normegon and Metrodin in infertile female patients undergoing in-vitro fertilization. Hum. Reprod., 10, 332337.[Abstract]
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, 239244.
Howles, C.M. (1996) Genetic engineering of human FSH (Gonal-F). Hum. Reprod. Update, 2, 172191.
Howles, C.M., Loumaye, E., Giroud, D. and Luyet, G. (1994) Multiple follicular development and ovarian steridogenesis following subcutaneous administration of a highly purified urinary FSH preparation in pituitary desensitized women undergoing IVF: a multicentre European phase III study. Hum. Reprod., 9, 424430.[Abstract]
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), 7686.
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, 1523.[CrossRef]
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 pen devices-simple to use tools may help young and old alike. Postgraduate Medicine, 106, 5768.
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®). Mol. Hum. Reprod., 2, 371382.[Abstract]
Robertson, K.E., Glazer, N.B. and Campbell, R.K. (2000) The latest development in insulin injection devices. Diabetes Educator, 26, 135138.
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), 134142.[ISI][Medline]
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®) by Pen-injector and syringe. Hum. Reprod., 7, 16981702.[CrossRef]
Wikland, M., Borg, J., Hamberg, L. and Svalander, P. (1994) Simplification of IVF: minimal monitoring and the use of s.c. highly purified FSH administration for ovulation induction. Hum. Reprod., 9, 14301436.[Abstract]
Submitted on November 26, 2002; accepted on February 11, 2003.