An open, randomized single-centre study to compare the efficacy and convenience of follitropin {beta} administered by a pen device with follitropin {alpha} administered by a conventional syringe in women undergoing ovarian stimulation for IVF/ICSI

Peter Platteau1, Els Laurent, Carola Albano, Kaan Osmanagaoglu, Valérie Vernaeve, Herman Tournaye, Michel Camus, André 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. e-mail: peter.platteau{at}az.vub.ac.be


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: A pen device, similar to an insulin pen, has been recently marketed for the administration of follitropin {beta} in cartridges. A randomized controlled trial was performed to compare the efficacy and convenience of this pen device delivering follitropin {beta} with a conventional syringe delivering follitropin {alpha}. 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 conventional syringe group during down-regulation by means of a computer-generated randomization list using random numbers. Patients were asked to fill 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 pen device and conventional syringe groups; the presence of pain after the daily injection was significantly higher in the conventional syringe group (P = 0.027); the visual analogue scale score was similar for pain but significantly more convenient for the pen device (P < 0.001). The live birth rate per embryo transfer was 32.9 and 34.4% respectively in the pen device and conventional syringe groups. CONCLUSIONS: 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.

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


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Over the last decade, the convenience of fertility treatment has been improved with the introduction of purified gonadotrophin preparations suitable for s.c. injection (Howles et al., 1994Go; Wikland et al., 1994Go). 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 {alpha} and {beta}), produced by recombinant DNA-technology, have become commercially available (Howles et al., 1996Go; Olijve et al., 1996Go; Harlin et al., 2000Go). These recombinant FSH (rFSH) preparations have the advantage of absolute purity and high reproducibility over the gonadotrophin preparations derived from an urinary source. A meta-analysis showed an increased bioactivity of rFSH as proven by significantly more oocytes, embryos and pregnancies compared with urinary FSH (Daya et al., 1999Go).

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 {beta} 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 {beta} 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., 1998Go; Nancy et al., 1999Go). It is the first multiple-use device available for s.c. self-administration of gonadotrophins, that facilitates precise and individualized dosing of follitropin {beta} 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., 1999Go), 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 {beta} 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., 2001Go) follitropin {beta} administered by the pen device was far less painful than follitropin {alpha} administered by conventional syringe.

The present study was designed to compare the local tolerance and convenience of follitropin {beta} (presented as ready-to-use cartridges) administered with the new pen device, with follitropin {alpha} (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.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study population
The protocol for this prospective, randomized, single centre, group-comparative 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 significance 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/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 {beta} (Puregon®; Organon, Oss, The Netherlands), with a pen device equipped with a needle sized 29G x 13 mm (Puregon PenTM) or follitropin {alpha} (Gonal-F®; Serono, Geneva, Switzerland) with a conventional syringe equipped with a needle sized 25G x 16 mm. Follitropin {beta} 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 {alpha} 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 {alpha} or 150/200 IU follitropin {beta} 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 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., 1995Go; Joris et al., 1998Go; Van Steirteghem et al., 1998Go). 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 Mann–Whitney test. The Fisher Exact test was used for the regrouped maximal symptom score (none/mild versus moderate/severe).


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study population
A total of 200 patients were randomized between September 2000 and December 2001. A total of 104 were allocated to the conventional syringe group and 96 to the pen device 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.


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Table I. Main demographic and infertility baseline characteristics (Values are means ± SD)
 
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).



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Figure 1. Flowchart for randomized study of 200 IVF/ICSI patients.

 
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 conventional syringe group and five in the pen device group). In total 185 patients had oocyte retrieval and 178 had embryo transfer.

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 {beta} 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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Table II. Efficacy parameters (Values are means ± SD)
 

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Table III. Clinical outcome (Values are means ± SD)
 
Seventy patients (75%) injecting with the pen device did not use the whole cartridge they started as only cartridges of 600 IU of follitropin {beta} were used in the study. There was therefore a mean ‘non-use’ of follitropin {beta} of 261 IU ± 206 per patient using the pen device.

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 {alpha} group (with monozygotic twins) and one (tri-amniotic, tri-chorionic) triplet pregnancy (after a two-embryo transfer) in the follitropin {beta} 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 {alpha} 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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Figure 2. Percentage of subjects with moderate or severe local tolerance symptoms.

 
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. 8.8 ± 1.5 and 9.1 ± 0.9 after administration of follitropin {alpha} by syringe and follitropin {beta} by pen device respectively. The overall convenience score on the contrary was significantly better in the group injecting with the pen device, i.e. 9.2 ± 0.8 compared with 7.4 ± 2.6 in the syringe group (P < 0.001).

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.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Gonadotrophins have been used successfully in ovarian stimulation for >30 years. Over this time period they have become totally purified, 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 pen device 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., 2000Go). The introduction of a similar pen device for the administration of follitropin {beta} was therefore a logical step to make infertility treatment easier, more flexible and less stressful. A first study (Voortman et al., 1999Go) demonstrated that the injection of similar amounts of follitropin {beta} using either a dissolved cake with a conventional syringe or a ready-for-use solution with a pen device were bio-equivalent. However due to the void volume of the syringe and losses while filling the syringe and/or removing excess air there was a loss of 18% of rFSH. This 18% loss due to the use of a conventional syringe explains the differences found in our study in efficacy 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 significantly fewer frozen embryos. A starting dose of 177/236 IU of follitropin {alpha} in the syringe group would most probably give us equal efficacy parameters. This is also the reason why we used 200 IU instead of 225 IU as a starting dose in the three ampoule pen device group, as we anticipated, on the basis of the study of Voortman, that in fact we would be injecting the same dose as 265.5 IU in a conventional syringe with possible risks of OHSS.

This present study is the first randomized study in patients to compare the efficacy of follitropin {beta} administrated with a pen device and follitropin {alpha} 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., 2001Go) showed that injection pain is experienced less frequently when follitropin {beta} is administered by a pen device than when follitropin {alpha} 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., 1999Go).

In 75% of the patients using the pen there was some ‘wastage’ of follitropin {beta} 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 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 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., 2002Go).

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.


    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
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Craenmehr, E., Bontje, P. M., Hoomans, E., Voortman, G. and Mannaerts, B.M.J.L. (2001) Follitropin-{beta} administered by pen device has superior local tolerance compared with follitropin-{alpha} 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.[Abstract/Free Full Text]

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, 332–337.[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, 239–244.[Abstract/Free Full Text]

Howles, C.M. (1996) Genetic engineering of human FSH (Gonal-F). Hum. Reprod. Update, 2, 172–191.[Free Full Text]

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, 424–430.[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), 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.[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, 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®). Mol. Hum. Reprod., 2, 371–382.[Abstract]

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.[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, 1698–1702.[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, 1430–1436.[Abstract]

Submitted on November 26, 2002; accepted on February 11, 2003.