COMPLIA: A 12-MONTH PROSPECTIVE, MULTICENTRE, NON-INTERVENTIONAL STUDY TO EVALUATE TREATMENT ADHERENCE AND TREATMENT SATISFACTION IN A GROWTH HORMONE DEFICIENT PAEDIATRIC POPULATION TREATED WITH NUTROPINAQ^® A SOMATROPIN ANALOGUE

Abstract

Background/Aims.

Growth hormone deficiency (GHD) in children and adolescents is managed with growth hormone (GH) therapy and aims to achieve optimal height development. However, treatment adherence can be poor, reducing the likelihood of a successful outcome. Adherence varies between geographic regions. This observational study assessed satisfaction and adherence to NutropinAq (somatropin, recombinant human GH) treatment in Romanian children with GHD.

Methods.

Patients ≥3 years of age with GHD for which GH replacement therapy with NutropinAq had been initiated were recruited from 13 centres in Romania (protocol number: A-38-58035-016). The primary variable was patient/caregiver-reported treatment adherence (assessed at 3, 6 and 12 months on a 5-item Likert scale), secondary variables included treatment satisfaction assessed by the treating physician and patient/caregiver on a 5-point scale.

Results.

Most patients did not miss any treatment injections in any 3-month period between assessments (≥79.8% of patients were 100% compliant). The incidence of missed injections was higher among patients <7 years of age than older children, but no differences between genders was observed. At study end, 94.3% of patients/caregivers and 94.3% of physicians reported complete satisfaction with treatment.

Conclusions.

Overall treatment adherence to NutropinAq was high in the Romanian GHD paediatric population, and a high level of treatment satisfaction was reported by patients/caregivers. This suggests reliable treatment outcomes can be anticipated in this population.

INTRODUCTION

Growth hormone deficiency (GHD) in children is characterised by low growth velocity after a period of normal growth, and short stature relative to the child’s chronological age, sex and pubertal stage (1). In children the most common aetiology is isolated idiopathic GHD, a general term that includes some individuals with an identifiable pathophysiology, but also others where the cause of the deficiency is not identifiable (1).

GHD is managed with growth hormone (GH) therapy (2), with the aim of achieving optimal height development and the hope of attaining normal adult height (3). Somatropin (molecular weight 22,125 Daltons) is a synthetic form of human GH produced by recombinant DNA technology with an identical sequence of 191 amino acids to endogenous human GH of pituitary origin (4). NutropinAq^® (Genentech, United States) is a solution containing 10 mg (30 International Units (IU)) of somatropin for subcutaneous use (5). In the paediatric population, NutropinAq^® is indicated for the long-term treatment of children with growth failure due to inadequate endogenous GH secretion, the long-term treatment of girls from 2 years old with growth failure associated with Turner syndrome, and the treatment of prepubertal children with growth failure associated with chronic renal insufficiency up to the time of renal transplantation (5). In Europe, NutropinAq^® is marketed by Ipsen Pharma.

Between 33.5% and 67% of children with GHD receiving human recombinant GH (rhGH) have poor adherence to therapy (6-9), and over 50% of patients fail to comply with some aspects of their treatment regimen (10). Growth outcomes have been positively linked with treatment adherence, which is a crucial component of treatment success (6, 8, 9). Poor adherence is classically attributed to poor physician-patient relationship, lack of patient training on device use, and a low educational level of the parents. Direct causes of poor adherence include misperceptions about the consequences of missed GH doses, injection discomfort, the patient’s age, the time course of the disease, and complex treatment regimens (8, 10). Patients receiving GH therapy need close monitoring and follow-up by paediatric endocrinologists in order to achieve the best outcome (6, 8, 11).

Adherence to GH treatment can vary between geographical locations and populations and may be influenced by insurance coverage, which highlights the importance of understanding local adherence patterns (6, 8, 9, 12). To date, no data have been available regarding adherence to NutropinAq^® treatment of Romanian children with GHD, and therefore, this prospective, non-interventional study was conducted in 13 Romanian sites to evaluate treatment adherence and treatment satisfaction in Romanian children presenting with GHD (protocol number: A-38-58035-016).

PATIENTS AND METHODS

Ethical considerations

All relevant Ethics Committees and Regulatory bodies gave necessary approval before commencement of the study and written informed consent was obtained from each patient or their parent/legal guardian (caregiver) before enrollment in the study and in accordance with the ethical principles stated in the Declaration of Helsinki and the International Ethical Guidelines for Epidemiological Studies, Council for International Organizations of Medical Sciences (CIOMS), Feb.2008.

Patient selection

Inclusion criteria

Patients ≥3 years of age diagnosed with GHD, for which GH replacement therapy with NutropinAq^® had been initiated by their paediatric endocrinologist, were eligible for participation in the study.

Exclusion criteria

Subjects with hypersensitivity to the active substance or any excipients, closed epiphyses, active neoplasm (therapy should be discontinued if evidence of tumour growth develops) and acute illnesses due to complications following open-heart or abdominal surgery, multiple accidental traumas or acute respiratory failure were excluded from this study.

Study design

COMPLIA was a prospective, multicentre, non-interventional, observational study to evaluate treatment adherence, performed at 13 investigational sites in Romania (protocol number: A-38-58035-016).

As this was a non-interventional study, the decision to prescribe NutropinAq^® was taken before, and independently from, the decision to enrol the patient in the study and the prescribing of NutropinAq^® was in accordance with routine clinical practice at the hospital concerned.

Data were collected by the treating physician at each visit. Study visits included an enrollment visit and four follow-up visits at 3 months interval. A schedule of assessments and data collection at each visit is provided in Table 1.

Table 1.

Study assessments

	Enrollment	Follow-up visits
	Baseline	3 months ±14 days	6 months ±14 days	9 months ±14 days	12 months ±14 days
Written informed consent	X
Visit date	X	X	X	X	X
Eligibility check	X
Demographic details	X
Relevant medical history	X
Date of diagnosis of GHD	X
Previous medications for GHD	X
Concomitant medications	X	X	X	X	X
Treatment adherence questiona		X	X	X	X
NutropinAq dose at baseline	X
Average NutropinAq dose used per week		X	X	X	X
Treatment satisfaction
Physician					X
Patient/caregiver					X
Visit status	X	X	X	X	X

GHD, growth hormone deficiency. ^aanswer provided by the patients/caregivers to the 5-items Likert-scale question: asked by the treating physician.

Treatment

Patients received NutropinAq^® administered as daily subcutaneous injections for 12 months. The recommended dosage of NutropinAq^® for growth failure in children due to GHD is 0.025–0.035 mg/kg bodyweight as a daily subcutaneous injection.

As the study was designed to document current clinical practice, treating physicians were permitted to alter or initiate concomitant medication, according to clinical need, at any time.

Primary objective

The primary objective was treatment adherence for the last 3 months (or since the last visit). Adherence was assessed qualitatively on a 5-item Likert scale based on answers given by the patient or their caregiver (if the child was not able to express an opinion on treatment adherence due to young age) in response to the following question asked by the physician: ‘During the last three months of therapy with NutropinAq, how often was a dose (i.e., injection) missed/skipped?’. Answers were recorded in the following categories: no missed injections; 1 to 3 missed injections; 4 to 6 missed injections; 7 to 10 missed injections; and more than 10 missed injections.

Secondary objectives

Treatment satisfaction reported by the treating physician and patient/caregiver was assessed at study end or study dropout with the following questions:

- Physician: ‘During the last year of treatment for GHD for this patient how would you describe your overall satisfaction with NutropinAq^® treatment?’

- Patient/caregiver: ‘During the last year of treatment for GHD how would you describe your overall satisfaction with the NutropinAq^® treatment?’

Both physicians and patients/caregivers rated their satisfaction on a 5-point scale as follows: completely satisfied; rather satisfied; neither satisfied nor dissatisfied; rather dissatisfied; or completely dissatisfied.

In addition, treatment adherence was analysed by sex and age ranges (3–6; 7-11; >11 years) as a secondary endpoint.

Safety

As this was a non-interventional study in which NutropinAq^® was administered and managed within routine medical care, adverse event (AE) reporting followed regulations related to spontaneous cases. Investigators were asked to report only treatment-related adverse events AEs (non-serious and serious) to the safety department of the manufacturer of NutropinAq^®, using the usual process for such reports.

Statistical analysis

A sample size of 190 was assumed. The enrolled population was defined as all patients who were fully informed about the study and who had given written consent to participate (or their caregiver had) before any study related procedure. The study population was defined as all enrolled patients with at least one follow-up visit.

The primary and secondary analyses were based on the study population. Only descriptive analyses were performed. Adherence was described in terms of number and percentage of patients with 95% confidence intervals (CI) on the five items at each visit.

Descriptive analyses were performed for treatment satisfaction reported by the treating physician and patient/caregiver at the study end or drop-out from the study. For agreement between treatment satisfaction reported by the physician and the treatment satisfaction of the caregiver, a shift table was produced and a Kappa coefficient was computed.

The average NutropinAq^® dose per week at each visit (3 months, 6 months, 9 months and 12 months) and change from baseline was calculated.

RESULTS

Patient demographics

A total of 187 patients were enrolled in the study. The first patient first visit was 2 June 2010 and the last patient last visit was 22 June 2014. The study population consisted of 181 patients (96.8% of the enrolled patients) and reasons for exclusion and the study flow are shown in Figure 1.

Figure 1.

Study flow.

The baseline characteristics of the enrolled patients are shown in Table 2. The mean patient age was 9.8 years, 63.1% of patients were male, and 21.4% had previously received rhGH treatment for GHD.

Table 2.

Baseline patient characteristics of the enrolled population

	Number of patients N (%)a
Patients enrolled in the study	187 (100)
Sex
Male	118 (63.1)
Female	69 (36.9)
Mean (SD) age, years	9.8 (3.6)
Age distribution
<7 years	46 (24.6)
7-11 years	84 (44.9)
>11 years	57 (30.5)
Mean (SD) height, cm	122.3 (18.8)
Height SDS	-2.5
Mean (SD) weight, kg	24.9 (10.2)
Weight SDS	-1.9
Mean (SD) time since diagnosis of GHD, monthsb	11.2 (18.57)
Mean (SD) duration of GH treatment at baseline, monthsc	1.83 (5.96)
Previous medication for GHD
Somatropin	40 (21.4)

^aUnless otherwise indicated. ^b8 patients had an estimated time since diagnosis of GHD at baseline, data missing for 4 patients. ^c9 patients had an estimated duration of treatment at baseline. BMI, Body Mass Index; GH, growth hormone; GHD, Growth Hormone Deficiency; N, number of patients.

Treatment adherence

The mean NutropinAq^® weekly dose was 0.220 mg/kg at baseline and 0.240 mg/kg after 12 months, corresponding to a mean change from baseline of 0.017 mg/kg.

Most patients in the study population had not missed any treatment injection during the follow-up period (≥79.8% of patients were 100% compliant; Table 3). The highest proportion of missed injections occurred in the first 3 months of treatment, and after this, those patients that missed injections generally missed three or fewer in any 3-month period.

Table 3.

Treatment adherence in the study population

	Follow up, n (%) [95% CI]
	3 months	6 months	9 months	12 months
N	181	181	181	181
Missing data, n	13	10	30	27
Missed injections
None	134 (79.8) [73.7–85.8]	141 (82.5) [76.8–88.2]	127 (84.1) [78.3–89.9]	131 (85.1) [79.4–90.7]
1 to 3	13 (7.7) [3.7–11.8]	21 (12.3) [7.4–17.2]	11 (7.3) [3.1–11.4]	13 (8.4) [4.1–12.8]
4 to 6	10 (6.0) [2.4–9.5]	3 (1.8) [0–3.7]	4 (2.6) [0.1–5.2]	3 (1.9) [0–4.1]
7 to 10	3 (1.8) [0–3.8]	2 (1.2) [0–2.8]	5 (3.3) [0.5–6.2]	0 -
>10	8 (4.8) [1.5–8]	4 (2.3) [0.1–4.6]	4 (2.6) [0.1–5.2]	7 (4.5) [1.3–7.8]

CI, confidence interval.

The incidence of missed injections was higher among patients <7 years of age than among older patients. At 12 months’ follow-up, for example, the proportions of patients reporting no missed injection were 78.0%, 88.9%, and 85.4% in patients <7 years, 7–11 years, and >11 years, respectively. Similar trends were seen at 3, 6 and 9 months. Overall, treatment adherence was similar between males and females: the proportions of male and female patients reporting no missed injections at 3, 6, 9, and 12 months were 82.9% and 74.6%, 85.2% and 77.8%, 80.6% and 89.7%, and 86.2% and 83.3%, respectively.

Treatment satisfaction

Data were missing for 40 pairs of patients/caregivers and physicians. Of those with data, 94.3% of patients/caregivers and physicians were completely satisfied with treatment (Table 4). No patient or physician reported complete dissatisfaction. The physician’s ratings of complete satisfaction concurred with those of the patients/caregivers in 92.2% (130/141) of cases (Table 5). For one patient, the physician was dissatisfied with the treatment but the patient rated the treatment as neither satisfying nor dissatisfying. The Kappa coefficient (0.477) indicated moderate agreement between the investigators’ and patients’ satisfaction assessments. Among the patients completely satisfied with the treatment, 89.5% (119/133) reported no missed injections at 12 months.

Table 4.

Treatment satisfaction of the treating physician or the patient/caregiver at end of study in the study population

	Treatment satisfaction assessment, n (%)
	Physician	Patient/caregiver
N	181	181
Missing data, n	40	40
Completely satisfied	133 (94.3)	133 (94.3)
Rather satisfied	5 (3.5)	6 (4.3)
Neither satisfied nor dissatisfied	2 (1.4)	2 (1.4)
Rather dissatisfied	1 (0.7)	0
Completely dissatisfied	0	0

Table 5.

Agreement between treatment satisfaction of the treating physician and treatment satisfaction of the patient/caregiver in the study population*

		Treatment satisfaction of the patient/caregiver
		Completely satisfied	Rather satisfied	Neither satisfied nor dissatisfied	Rather dissatisfied	Completely dissatisfied
Treatment satisfaction of the physician	Completely satisfied	130 (92.2)	3 (2.1)	0	0	0
	Rather satisfied	3 (2.1)	2 (1.4)	0	0	0
	Neither satisfied nor dissatisfied	0	1 (0.7)	1 (0.7)	0	0
	Rather dissatisfied	0	0	1 (0.7)	0	0
	Completely dissatisfied	0	0	0	0	0

* missing data n=40.

Safety

No treatment-related AEs were reported.

DISCUSSION

Adherence to NutropinAq^® treatment was good among children with GHD in Romania. Most patients (≥79.8%) from the study population had no missed treatment injection. Patients reporting missed injections generally missed no more than three injections in any 3-month period.

The high adherence rate observed in our study differs from non-adherence rates reported elsewhere of 33.5% to 67% in children and adolescents receiving GH for GHD (6-9). While one study using a fully automated injection device reported an 87.5% adherence rate over 3 months, a 12-month study with the same device reported an adherence rate of 56.7 % (6, 8, 13). The discrepancy between the current study and most others may be ascribed to differing definitions of non-adherence employed in these studies. For example, in one study adherence was calculated based on device refill rate (8, 9), while in our study it was assessed as a patient reported outcome.

In this study, adherence was not affected by the patient’s sex but better adherence in boys than in girls has been reported elsewhere (14). Aydin et al. used a slightly different definition of adherence with categorization of patients in four different categories (excellent, good, fair, and poor) based on the percentage of omitted doses, which may account for the differences between studies. The current study included fewer girls than boys, which may also have been an obstacle to the detection of different adherence rates between the sexes.

Our study suggested there may be a trend towards lower adherence among younger patients. There is disagreement in the literature on the effect of age on treatment adherence, with studies reporting no effect of age on adherence (6, 8, 9) or better adherence in younger children than in adolescents (8, 9). Interestingly, self-administration of GH in adolescents seemed to have a negative impact on treatment adherence (8, 9).

Treatment satisfaction was high. At the end of the study, complete satisfaction with treatment was reported for most patients regardless of whether the patient’s satisfaction was rated by the treating physician, or by the patients or their caregiver. Many previous studies of satisfaction with GH therapy among children have focussed on the injection/delivery device (6, 8, 15, 16), and therefore, comparisons with previous data are limited (17). However, treatment satisfaction does not appear to be a major driver of non-adherence.

The limitations of the study were those associated with any non-interventional study, including the effects of differing procedures at the treatment centres, as well as the absence of a control population. In addition, further work would be needed to assess how treatment adherence changes once children reach adulthood. The transition, in this case, should be based on close cooperation between the paediatrician and the adult endocrinologist. Discussion between patients receiving GH and those who refuse treatment should be encouraged to ensure medication adherence according to the prescribed regimen (18).

A treatment for GHD that is well adhered to and generally viewed with satisfaction by physicians and patients (and their caregivers) should help achieve optimum outcomes (6, 8, 9).

Treatment adherence to NutropinAq^® was high in the Romanian GHD paediatric population, and a high level of treatment satisfaction was reported by patients/caregivers. This suggests reliable treatment outcomes can be anticipated in this population.

Acknowledgements

The authors take full responsibility for the content of this paper and thank Tim Latham and Martin Gilmour of ESP Bioscience Ltd., Crowthorne, UK (supported by Ipsen) for editorial assistance in the preparation of the manuscript.

Disclosures statements

C.D. and M.A have received honoraria/grants from Ipsen for presentations, advisory boards or research. C.P, N.D., and I.M. do not have any disclosures to make. A.M. was an Ipsen employee at the time this study was conducted.