Background
Recombinant human growth hormone (r-hGH) is used to treat growth hormone deficiency (GHD) in adults and short stature in children [
1‐
3]. Treatment improves growth in children whose short stature is caused by GHD, or in those for whom short stature is associated with conditions such as Turner syndrome (TS), chronic renal failure (CRF) or being born small for gestational age (SGA) [
1]. Early intervention with long-term r-hGH treatment improves adult stature, with some patients reaching target final height. However, lack of adherence hampers growth potential [
4,
5].
Maintaining commitment to r-hGH treatment is difficult, as the short-term burden of injection administration is often more apparent than the long-term benefits of therapy [
5]. Daily injections or needle-free administration is required, and treatment must be sustained over a prolonged period. Treatment fatigue may have a negative impact on adherence for patients taking r-hGH medication on a long-term basis, as suggested by the observation that chronicity of disease is a factor that influences adherence to therapy [
6]. Studies looking at adherence to r-hGH treatment have been constrained by the problem of recording adherence, but results have shown that non-adherence is a problem in some patients [
4‐
7]. One UK study highlighted how frequent poor adherence with r-hGH therapy can be: more than 1 injection/week was missed by 39% (29/75) of children, whilst 23% (17/75) missed >2 injections/week [
5].
The accurate monitoring of adherence rates is important as it enables poor adherence to be detected and acted upon [
8]. It can enable the physician to eliminate poor adherence as a reason for sub-optimal growth response and be more confident in their patient management decisions. Innovation in r-hGH delivery devices has sought to improve adherence by simplifying injection administration, making it less painful and more convenient, thereby improving patient acceptability of devices [
9‐
12]. The electronic auto-injector device, easypod™, has a number of features, such as preset dosing, an electronic skin sensor and adjustable injection settings, designed to make daily administration of r-hGH easier, more comfortable and convenient; it also allows accurate monitoring of treatment adherence [
13]. easypod™ has an injection log that automatically records injection history. This information can be accessed by patients or downloaded at their clinic to show which injections, if any, have been missed. Although patient opinion of the electronic auto-injector has been previously studied, albeit in a limited number of patients (n = 61) [
14,
15], adherence to treatment whilst using this device has not been explored at all.
We report here the results from the first study of adherence to treatment as recorded by the auto-injector. The primary objective of this study was to evaluate adherence to r-hGH therapy over 3 months of use. In addition, the survey explored perceptions of the electronic auto-injector device in a large multinational cohort. Study outcomes were also assessed separately for children who were either new to or had experience with r-hGH therapy, in order to identify any differences in adherence to therapy or opinions of the device.
Discussion
This multinational, observational survey of over 800 children using an electronic auto-injector device for up to 3 months found a good level of adherence to therapy. The dose history that had been automatically recorded by the device and reviewed by the physician showed that 87.5% of children were adherent to therapy (injecting at least 92% of doses over the 3-month period). Furthermore, 75.1% of all children did not miss any injections in month 1, 66.7% in both months 2 and 3.
Adherence to treatment has an important impact on overall treatment outcome. In a group of poorly compliant patients, growth rates were found to be significantly lower compared with patients who missed fewer doses [
4]: height velocity in patients missing >15 injections per month (equivalent to >3-4 per week) was 6.3 cm/year compared with 9.4 cm/year in those missing 11-15 doses per month (
p < 0.03). It has also been estimated that growth velocity suffers a significant decline if >2 injections per week are missed [
5]. In this survey, it was possible to monitor how many injections were missed during each month of the survey by looking at the dose-history data from the electronic auto-injector. By scaling up to find a comparable figure for the proportion of patients who missed >2 injections per week, only a relatively small percentage of children had a level of non-adherence that would have a serious impact on growth ( < 5% of children missed ≥7 injections in month 3).
Adherence was higher in treatment-naïve children compared with treatment-experienced children (89.7% vs 81.7%) over the course of the survey. This observation suggests that a drop in adherence may occur with increasing duration of treatment: longer-term users may be less enthusiastic or motivated about adhering to treatment compared with those users new to treatment, who may be more diligent. This agrees with previous studies with GH [
5] and other therapies taken on a long-term basis [
16,
17]. Even within the short duration of the survey, a moderate decline in adherence rates was observed. The very good levels of recorded adherence during the first month, when 75.1% of children missed no injections, fell in the second and third months, with 66.7% of children missing no injections at month 3. As this survey only followed children for 3 months, an evaluation of adherence over a longer time period is currently planned.
Self-reported adherence, collected via the survey, showed slightly higher rates of adherence than the dose-history data (90.2% vs 87.5%). Although asking the user about their injection habits may be the most straightforward approach to evaluating adherence, these results show that it may not always be a reliable and accurate method. Missed doses may be forgotten and adherence overestimated. Electronic recording of the dosing history using a device with an integrated dose log offers an improved, objective method of accurately monitoring adherence.
The rates of compliance reported here compare well with previous studies [
4,
5]. Data from an American GH registry based on physician-reported adherence, indicate that 76-85% missed 0-3 doses per month, over a 24-month period [
4]. In the current survey, a child was considered adherent to treatment if they missed a maximum of two injections per month. Therefore, a proportion of the children considered adherent in the American GH registry (those who missed three injections per month) will not have been considered adherent in our study. In a study of 75 children attending a UK clinic, an assessment of adherence was based on prescriptions over 12 months [
5]. The frequency of missed injections was estimated to be 0 in 36% of children, up to 1 per week in 25% of children, >1-2 per week in 16% of children and >2 per week in 23% of children.
Although the factors influencing adherence and persistence in GH treatment were not explored here, misperceptions about the consequences of missed GH doses, discomfort with injections, dissatisfaction with treatment results and inadequate contact with healthcare providers are among the key reasons reported in other studies [
6,
7]. Coaching by healthcare professionals and ongoing discussions about the benefits of treatment are important to achieve good adherence [
18]. Better patient autonomy in managing their own condition is also predictive of treatment adherence, as is involving the patient in treatment decisions [
19]. Patients may be more likely to be adherent to treatment if they are allowed to choose the delivery device [
5,
20]. Potential barriers to better adherence include the use of complicated delivery devices [
18], suggesting that having a good perception of the delivery device is a factor that may also influence adherence.
The current survey also showed that children and their parents had a very good perception of the electronic auto-injector after 3 months of use, rating specific features of the device highly. The majority considered the device to be quick, easy and comfortable to use. There was little difference between treatment-naïve and treatment-experienced children in their responses to questions.
These results support the findings of previous, smaller (up to 61 patients), shorter-term (up to 60 days) studies, which together indicate a high level of patient acceptance of the electronic auto-injector for daily administration of r-hGH [
14,
15]. Results from an open-label multicentre survey that included 61 patients showed that the majority of patients had a good overall impression of the device after 60 days of use [
14]. In addition, the nurses/physicians who trained them how to use the device also rated the device favourably with respect to participants' ease in learning to use the device [
14]. Unlike previous user trials of the electronic auto-injector [
14,
15], the current study is the first to include data on adherence as captured using the device.
In a survey conducted at a UK hospital, patients commencing GH therapy were given the freedom to choose their delivery device [
20]. Of those switching devices, 74% changed to the electronic auto-injector. None of the patients who started on this novel device later switched to using another device. Although the present survey did not provide children or their parents with a free choice of injection device, at the end of the survey, 92% of children/parents stated that they would like to continue using it. Interestingly, adherence in children who did not want to continue using the device was slightly lower than that in the overall population (when considering all children in the evaluable population, 74.6% vs 84.1%, respectively).
Acknowledgements
This study was funded by Merck Serono S.A. - Geneva, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany. The authors take full responsibility for the content of the paper but thank MaiLee Wong, PhD, and Polly Field, DPhil, of Caudex Medical (supported by Merck Serono S.A. - Geneva, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany) for their assistance in the preparation of this manuscript. The authors thank the investigators of the easypod™ survey study group who provided the data for this study: Brazil: Carlos Alberto Longui, São Paulo; Czech Republic: Lidka Lisá, Praha; Božena Kalvachová, Praha; Marta Šnajderová, Praha; Jiřina Zapletalová, Olomouc; Jana Černá, Ostrava; Vlasta Janštová, Ostrava; Jaroslav Škvor, Ústí nad Labem; Renata Pomahačová, Plzeň; Olga Magnová, Brno; Finland: Päivi Miettinen, Helsinki; Marja-Terrtu Saha, Tampere; Hanna Huopio, Kuopio; France: Paola Adiceam, Aix en Provence; Pascal Barat, Bordeaux; Anne-Marie Bertrand, Besancon; Yves Brusquet, Puyricard; Maryse Cartigny, Lille; Pierre Chatelain, Bron; Michel Colle, Bordeaux; Régis Coutant, Angers; François Despert, Tours; Clémentine Dupuis, La Tronche; Marcel Guillot, Lisieux; Bernard Le Luyer, Le Havre; Béatrice Lebon Labich, Vandoeuvre Les Nancy; Eric Mallet, Rouen; Jean-Christophe Mas, Nice; Chantal Metz, Brest; Marc Nicolino, Bron; Catherine Payen, Toulouse; Marc Petrus, Tarbes; Graziella Pinto, Paris; Michel Polak, Paris; Olivier Puel, Bordeaux; Catherine Raynaud, St Priest en Jarez; Berthe Razafimahefa, La Seyne sur Mer; Sabine Remond Baron, Nantes; Dinane Samara, Paris; Sylvie Soskin, Strasbourg; Pierre-François Souchon, Reims; Anne Spiteri Vasseur, La Tronche; Véronique Sulmont, Reims; Maïthé Tauber, Toulouse; Cécile Teinturier, Paris; Cathy Wagner, Nice; Germany: Peter Beyer, Oberhausen; Jürgen Brämswig, Münster; Ullrich Brand, Ludwigsburg; Helmut-Günter Dörr, Erlangen; Jutte Gellermann, Berlin; Berthold Hauffa, Essen; Annerose Hempel, Berlin; Gerd Horneff, Sankt Augustin; Angela Hübner, Dresden; Jochen Ittner, Augsburg; Detief Kunze, Munich; Monika Mix, Rostock; Klaus Mohnike, Magdeburg; Reinhard Mühlenberg, Krefeld; Hermann Müller, Oldenburg; Christian Ockert, Munich; Johannes Otte, Bielefeld; Roland Pfäffle, Leipzig; Anette Richter-Unruh, Bochum; Eckhard Schönau, Cologne; Hans-Peter Schwarz, Munich; Bettina Weiblich, Dresden; Klaus-Peter Ullrich, Bad Langensalza; Claudia Vilser, Jena; Christian Vogel, Chemnitz; Stefan Wüller, Aachen; Greece: Dionisios Chrysis, Patras; Alexandra-Maria Mayakou, Athens; Italy: Lodovico Benso, Turin; Mauro Bozzola, Pavia; Marco Coppa, Rome; Giuliana Marcella Cardinale, Casarano; Giuseppe Citro, Potenza; Piernicola Garofalo, Palermo; Francesco Saveiro Indovina, Palermo; Maria Rosario Licenziati, Napoli; Sandro Loche, Cagliari; Mariacarolina Salerno, Naples; Maria Antonia Satta, Rome; Michele De Simone, L'Aquila; Norway: Halvor Bævre, Gjøvik; Seksjonsoverlege Hilde Bjørndalen, Oslo; Ole Christian Danielsen, Arendal; Ingjerd Linnebo-Eriksen, Lørenskog; Eirik Vangsøy-Hansen, Bergen; Rønnaug Ødegård, Trondheim; Dag Veimo, Bodø; Portugal: Hospital Curry Cabral, Hospital Santa Maria, Centro Hospitalar de Lisboa Central - Hospital Dona Estefânia, Centro Hospitalarde Lisboa Ocidental - Hospital Egas Moniz, Hospital Amadora Sintra, Centro Hospitalar Ponta Delgada, Centro Hospitalar do Porto, Hospital Especializado de Crianças Maria Pia, Hospital São Marcos, Unidade Local de Saúde de Matosinhos - Pedro Hispano, Centro Hospitalar Do Alto Minho - Viana, Centro Hospitalar de Coimbra, Hospitais da Universidade de Coimbra, Centro Hospitalar Vila Nova Gaia; Sweden: Carl-Göran Arvidsson, Västerås; Jovanna Dahlgren, Gothenberg; Karel Duchen, Linköping; Maria Elfving, Lund; Hans Fors, Trollhättan; Maria Halldin-Stenlid, Uppsala; Ulf Jansson, Jönköping; Bo Klintberg, Visby; Svante Norgen, Stockholm; Björn Rathsman, Stockholm; Kalle Snellman, Eskilstuna; Switzerland: Piero Balice, Bellinzona; Urs Eiholzer, Zurich; Alexandre Maret, Fribourg; Valérie Schwitzgebel, Geneva; Taiwan: Fu-Sang Lo, Taoyuan; San-Ren Tsai, Taichung; San-Ging Shu, Taichung; Yu-Mei Wang, Changhua. Note that investigators are not provided for all countries; in some countries (Argentina, Mexico, Portugal and Spain) the survey was administered by nurses.
Competing interests
MB, MC and MH-S declare that they have no competing interests. SL and MZ are employees of Merck Serono S.A. - Geneva, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany.
Authors' contributions
MB: Critically reviewed and revised the manuscript. MC: Critically reviewed the manuscript. MH-S: Critically reviewed the manuscript and has been a principal investigator in Sweden. SL: Was involved in the statistical design and analysis of the study and critically reviewed the manuscript. MZ: Was involved with the design and analysis of the study and critically reviewed the manuscript. All authors have read and approved the final version of the manuscript.