# Treatment burden, adherence, and quality of life in children with daily GH treatment in France

Régis Coutant, Maithé Tauber, Béatrice Demaret, Robin Henocque, Yves

Brault, François Montestruc, Olivier Chassany, Michel Polak

► To cite this version:

Régis Coutant, Maithé Tauber, Béatrice Demaret, Robin Henocque, Yves Brault, et al. Treatment burden, adherence, and quality of life in children with daily GH treatment in France. Endocrine Connections, 2023, 12 (4), 10.1530/EC-22-0464. hal-04976783

HAL Id: hal-04976783

https://ut3-toulouseinp.hal.science/hal-04976783v1

Submitted on 4 Mar 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Treatment burden, adherence, and quality of life in children with daily GH treatment in France

Régis Coutant<sup>1</sup>, Maithé Tauber<sup>2,3,4</sup>, Béatrice Demaret<sup>5</sup>, Robin Henocque<sup>6</sup>, Yves Brault<sup>6</sup>, François Montestruc<sup>7</sup>, Olivier Chassany<sup>8,9</sup> and Michel Polak<sup>10</sup> on behalf of the QOLITHOR Study Group

**Correspondence should be addressed to R Coutant: ReCoutant@chu-angers.fr**

## Abstract

**Objective:** The objective of this study was to describe in a real-life setting the treatment burden and adherence and quality of life (QOL) of children treated with daily injections of growth hormone and their relationship with treatment duration.

**Design:** This non-interventional, multicenter, cross-sectional French study involved children aged 3–17 years treated with daily growth hormone injections.

**Methods:** Based on a recent validated dyad questionnaire, the mean overall life interference total score (100 = most interference) was described, with treatment adherence and QOL, using the Quality of Life of Short Stature Youth questionnaire (100 = best). All analyses were performed according to treatment duration prior to inclusion.

**Results:** Among the 275/277 analyzed children, 166 (60.4%) had only growth hormone deficiency (GHD). In the GHD group, the mean age was 11.7 ± 3.2 years; median treatment duration was 3.3 years (interquartile range 1.8–6.4). The mean overall life interference total score was 27.7 ± 20.7 (95% CI (24.2; 31.2)), with non-significant correlation with treatment duration (P = 0.1925). Treatment adherence was good (95.0% of children reported receiving >80% of planned injections over the last month); it slightly decreased with treatment duration (P = 0.0364). Children's overall QOL was good (81.5 ± 16.6 and 77.6 ± 18.7 according to children and parents, respectively), but subscores of the coping and treatment impact domains were <50. Similar results were observed in all patients independently of the condition requiring treatment.

**Conclusions:** This real-life French cohort confirms the treatment burden of daily growth hormone injections, as previously reported in an interventional study.

## Key Words

▶ growth hormone deficiency

▶ patient-reported outcomes

▶ quality of life

▶ recombinant growth hormone

▶ treatment burden

Endocrine Connections
(2023) **12**, e220464

<footnote n="1">¹Department of Pediatric Endocrinology and Diabetology, Reference Center for Rare Pituitary Diseases, University Hospital of Angers, Angers, France</footnote>

<footnote n="2">²Reference Center for the Prader-Willi syndrome and other rare obesities with feeding disorders (PRADORT), Children Hospital, CHU Toulouse, Toulouse, France</footnote>

<footnote n="3">³Pediatric team of the Clinical Investigation Center 9302/INSERM, Hospital of Children, Toulouse, France</footnote>

<footnote n="4">⁴Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), INSERM UMR1291 - CNRS UMR5051 - Université Toulouse III, Toulouse, France</footnote>

<footnote n="5">⁵GRANDIR - French Growth Disorders Association, Asnières-sur-Seine, France</footnote>

<footnote n="6">⁶Pfizer France, Paris France</footnote>

<footnote n="7">⁷eXYSTAT, Malakoff, France</footnote>

<footnote n="8">⁸Health Economics Clinical Trial Unit (URC-ECO), Hospital of Hotel-Dieu, AP-HP, Paris, France</footnote>

<footnote n="9">⁹Patient-Reported Outcomes Unit (PROQOL), UMR 1123, University Paris Cité, INSERM, Paris, France</footnote>

<footnote n="10">¹⁰Hôpital Universitaire Necker Enfants Malades, Pediatric Endocrinology, Gynecology and Diabetology, Imagine Institute, INSERM U1163, Cochin Institute, INSERM U1016, Centre de référence des pathologies endocriniennes rares de la croissance et du développement, Université de Paris Cité, Paris, France</footnote>
Introduction

Growth hormone deficiency (GHD) results in abnormal
linear growth in children (1, 2), associated with potential
early severe morbidity (psychosocial problems and
episodes of hypoglycemia). In addition, persistency of
GHD into adulthood is associated with increased risk of
cardiovascular morbidity and mortality.

Recombinant human GH (rhGH) replacement therapy has been proven to be safe and effective to enable children with short stature to achieve normal height, with early improvement of psychosocial problems (3, 4) and improvement in quality of life (QOL) (5, 6). In addition, rhGH injections are well tolerated (7, 8) even if adherence to treatment was shown as suboptimal (9). The majority of currently available rhGH products require daily subcutaneous injections. However, the burden of long-term daily administration can cause a reduction in adherence (10) and thus limit the therapeutic utility of existing formulations (11).

It was then hypothesized that switching to less
frequent injections could lead to more convenience
and treatment adherence, as previously shown in other
conditions (12). Based on positive efficacy and safety
outcomes from a phase III trial (13, 14), somatogron,
a long-acting rhGH for once-weekly subcutaneous
administration, was approved in the European Union
in February 2022 (15) for the treatment of children and
adolescents from 3 years of age with growth disturbance
due to insufficient secretion of GH. In addition, a 24-week
phase III study (NCT03831880) assessed the perception
of treatment burden in weekly GH (somatogron) vs daily
GH (genotropin) injections in children with GHD, with a
crossover at 12 weeks. Since treatment burden of the rhGH
injection is often a shared experience between patient and
caregiver, it was assessed using a Dyad Clinical Outcomes
Assessment (DCOA) questionnaire specifically developed
and validated prior to this trial to measure rhGH injection
treatment burden, with a simultaneous assessment using
a parent-child dyad (Life Interference Questionnaire for
Growth Hormone Deficiency (LIQ-GHD)) (16). First results
showed that treatment with somatogron administered
once-weekly improved the mean overall life interference
total score (primary outcome) after 12 weeks of treatment
compared to somatropin administered once-daily (mean
respective overall life interference total scores: 8.63 and
24.13; difference between mean scores: -15.49; 95% CI:
(-19.71, -11.27); P < 0.0001) (17).

French available data on treatment burden of daily GH
injections are scare, in particular regarding long-term QOL

and life interference of treated children and caregivers.
In addition, such real-life data are becoming increasingly
important and now recommended by French, European,
and US Health Authorities to measure patient perceptions
and improve quality of care in routine clinical practice
(18, 19, 20, 21). In this context, the real-world French
QOLITHOR study aimed to describe the treatment burden
and adherence as well as the QOL of children treated with
rhGH (seven devices available in 2019 in France for once-
daily injections). In addition, this study was designed to
assess the extent to which these outcomes are associated
with the duration of rhGH treatment together with other
factors related to demographics and/or treatment.

Material and methods

Study design

QOLITHOR is a non-interventional, multicenter, cross-
sectional study conducted in 11 hospitals that belong to the
French network for rare disorders as well as endocrinologist
liberal practice centers throughout France. Eligible patients
were children aged between 3 and 17 years, who received
daily rhGH injections for at least 4 weeks to treat GHD only
or GH insufficiency as part of multiple pituitary hormone
deficiencies as well as other conditions (small for gestational
age (SGA), Prader-Willi syndrome (PWS), Turner syndrome,
or chronic renal failure). Pediatric patients on hormonal
replacement therapy for other hypothalamic pituitary axis
hormonal deficiencies and/or diabetes insipidus should
be on an optimized and stable treatment regimen for at
least 3 months prior to inclusion. Children with cancer
history, psychosocial dwarfism, diabetes mellitus, human
immunodeficiency virus infection, immunodeficiency
syndrome, tuberculosis, or other acute or chronic medical
or psychiatric condition were excluded from the study. In
order to ensure homogeneity according to rhGH treatment
duration, participant centers were asked to enroll eligible
children within three patient groups according to their
rhGH treatment duration prior to inclusion (<2, (2–5), and
≥5 years). In addition, inclusions were closely monitored to
achieve a limited number of patients receiving rhGH for a
condition other than GHD only and numbers of included
patients per age group sufficient for consistent analysis.

Written consent has been obtained from each patient
or subject after full explanation of the purpose and
nature of all procedures used. The study was conducted
in compliance with the ethical standards of the 1964
Helsinki declaration and its later amendments, the
deontology guidelines and Good Epidemiology Practices, and the French regulation on non-interventional studies. The study protocol was approved on March 5, 2021, by the independent Ethics Committee of 'Ile de France III' (reference number: 2020-A02952-37).

## Data collected

The following data were collected by physicians at the inclusion visit: patient and disease characteristics (demographics, disease history, and auxological data), current rhGH treatment, and concomitant medication.

Children and parents/caregivers completed six self-reported questionnaires (Fig. 1) on rhGH treatment burden (DCOA1) (16), QOL (Quality of Life of Short Stature Youth (QOLISSY) (22) and Pediatric Quality of Life Inventory (PedsQL) (23)), perceived impact on daily activities (Patient Global Impression Severity - Impact on Daily Activities, PGIS-IDA), and education level and occupation of parent/caregiver. DCOA1, QOLISSY, PedsQL, and PGIS-IDA are questionnaires validated in the French language.

The DCOA1 is a part of the LIQ-GHD which was previously used in the NCT03831880 trial to assess treatment burden in GHD children receiving rhGH treatment (16). It contains 22 questions covering the following domains: life interference due to regimen, missed injections, pen ease of use, regimen convenience, benefit/satisfaction/willingness to continue treatment, and injection-related signs/symptoms. The QOLISSY, aiming to measure QOL in short stature youth, assesses QOL in three core domains (physical, social, and emotional), three additional domains to measure predictors of QOL (coping, beliefs, and treatment), and two supplementary domains referring to the parent's worries about their child's future (future) and the impact of the child's condition on the

parents' well-being (effects on parents). The PedsQL, a generic tool aiming to measure children's QOL, can be completed by children, with versions available for children aged 5-7, 8-12, and 13-18. Parent-rated versions are available for children aged 2-4, 5-7, 8-12, and 13-18. The questionnaire includes four generic core scales (physical, emotional, social, and school). The PGIS-IDA assesses the severity of the impact of the disease on daily activities of parents/caregivers, children according to the point of view of parents/caregivers, and children themselves, using 7-point Likert scales.

## Statistical methods

Descriptive statistical analysis was performed in the population of all the eligible children (with GHD only and other or multiple deficiencies such as SGA, Turner syndrome, or PWS) and in the group of children with only GHD, overall and according to the treatment duration prior to inclusion (<2, (2-5), and ≥5 years). DCOA1, QOLISSY, PedsQL, and PGIS-IDA were analyzed according to the authors' instructions, and the total scores were converted on 0-100 scores for ease of interpretation. On this basis, a score of 100 corresponded to the most interference with patient daily life for the overall life interference total score, the best QOL for the QOLISSY and PedsQL scores, the strongest preference for weekly rhGH injections for the long-acting questionnaire, and the strongest severity of the disease impact on daily activities for the PGIS-IDA.

The primary criterion of interest was based on the life interference, a part of the DCOA1 completed by children and parents. The primary outcome of the study was the relationship between the overall life interference total score and the duration of treatment in children of the GHD group. A total of 255 eligible pediatric patients were expected in

<table><caption>**Figure 1**</caption><thead><tr><th rowspan="2">Questionnaire</th><th colspan="2">Respondent</th><th rowspan="2">Same or different questionnaire</th></tr><tr><th>Child</th><th>Parent/ caregiver</th></tr></thead><tbody><tr><td>DCOA1 of the LIQ-GHD</td><td>X</td><td>X</td><td>Only one apart from a subscale</td></tr><tr><td>Long-acting GH questionnaire</td><td colspan="2">By the child with the help of parent/ caregiver</td><td>Only one</td></tr><tr><td>QOLISSY</td><td>X</td><td>X</td><td>Different</td></tr><tr><td>PedsQL</td><td>X</td><td>X</td><td>Different</td></tr><tr><td>PGIS-IDA</td><td>X</td><td>X</td><td>Different</td></tr><tr><td>Education level and current occupation</td><td colspan="2">X</td><td>/</td></tr></tbody></table>

Self-reported questionnaires completed by children and parents/caregivers. DCOA, Dyad Clinical Outcomes Assessment; GH, growth hormone; LIQ-GHD, Life Interference Questionnaire for Growth Hormone Deficiency; PedsQL, Pediatric Quality of Life Inventory; PGIS-IDA, Patient Global Impression Severity - Impact on Daily Activities; QOLISSY, Quality of Life of Short Stature Youth. The DCOA1 of the LIQ-GHD covers life interference due to regimen, missed injections, pen ease of use, regimen convenience, benefit/satisfaction/willingness to continue treatment, and injection-related signs/symptoms.
this study: 164 children with only GHD (GHD group) and 91 children affected by another condition. Considering 164 patients in the GHD group, the correlation test (two-sided Fisher's z test) of $ρ = 0$ ($α = 0.05$ two-sided) for the level of the overall life interference total score according to the GH treatment duration (analyzed as a continuous variable) had 90% power to detect a correlation coefficient $ρ$ of at least 0.25.

The relationship between the overall life interference total score and the rhGH treatment duration (continuous variable) was analyzed using a linear regression model. The associated correlation test (two-sided Fisher's z test) and the Pearson correlation coefficients were provided with associated 95% two-sided CI.

Linear regression models were also used to analyze the relationship between the other scores of the DCOA1 questionnaires, the QOLISSY score, the PedsQL score, and the treatment duration (in years). For the relationship between the treatment adherence as reported over the last month preceding the participation in the study by children and parents/caregivers (≤80% (6–28 missed injections) or >80% (0–5 missed injections) over the last 28-day period) and the treatment duration (<2, (2–5), and ≥5 years), a chi-square test for trend in proportions based on a binary logistic model was used.

To search for prognostic factors of treatment burden, adherence, and QOL, multivariate linear regression models were used. Univariate analyses were first performed using pertinent variables, after checking conditions of application of the model (the list of the tested variables is provided in Supplementary Data, see section on *supplementary materials* given at the end of this article). After selection of

variables associated with the dependent variable with a $P$ value ≤0.2, checks of multicollinearity between variables were performed; then a backward selection of variables with a significance level of 0.05 was applied.

## Results

### Patient and disease characteristics

Study populations are presented in Fig. 2. Among the 277 included children, 275 were retained in the overall population for analysis after the exclusion of two patients who did not meet the study selection criteria. Among these 275 patients, 166 (60.4%) were included in the GHD group, 87 (31.6%) were born SGA, 11 (4.0%) suffered from Turner syndrome, and 11 (4.0%) from PWS.

Patient and disease characteristics are detailed in Table 1. The 275 analyzed children of the overall population were aged 11.5 ± 3.3 years at inclusion and were more often male (60.7%). Compared to normal growth curves, children had a smaller height at inclusion (-1.2 ± 0.9 S.D.), but this difference tended to decrease when the duration of the rhGH treatment increased.

At inclusion, the median treatment duration of children was 3.5 years (interquartile range: 1.9–6.3) (mean duration: 4.3 ± 3.2 years; <2 years: 26.2%, 2–5 years: 40.7%, ≥5 years: 33.1%). At this time, Norditropin FlexPro® was the most frequent treatment used by children.

Concomitant aromatase inhibitors, gonadotropin-releasing hormone analogs, alternative hormone therapy, or other injection treatments (prescribed in 15.6% of

<figure><img src="image_2.png" /><figcaption>**Figure 2**

Study populations. GHD, growth hormone deficiency; rhGH, recombinant human growth hormone.</figcaption></figure>
<figure><img src="image_3.png" /></figure>

<table><caption>Table 1 Patient and disease characteristics.</caption><thead><tr><th rowspan="2">Parameters</th><th colspan="4">Overall population</th><th colspan="4">GHD group</th></tr><tr><th>rhGH &lt;2 years<br>(n = 72)</th><th>rhGH 2-5 years<br>(n = 112)</th><th>rhGH ≥5 years<br>(n = 91)</th><th>Total (n = 275)</th><th>rhGH &lt;2 years<br>(n = 44)</th><th>rhGH 2-5 years<br>(n = 69)</th><th>rhGH ≥5 years<br>(n = 53)</th><th>Total (n = 166)</th></tr></thead><tbody><tr><td>Indication of rhGH treatment, n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>GHD</td><td>44 (61.1%)</td><td>69 (61.6%)</td><td>53 (58.2%)</td><td>166 (60.4%)</td><td>44 (100.0%)</td><td>69 (100.0%)</td><td>53 (100.0%)</td><td>166 (100.0%)</td></tr><tr><td>Small for gestational age</td><td>25 (34.7%)</td><td>37 (33.0%)</td><td>25 (27.5%)</td><td>87 (31.6%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Turner syndrome</td><td>3 (4.2%)</td><td>1 (0.9%)</td><td>7 (7.7%)</td><td>11 (4.0%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Prader-Willi syndrome</td><td>0 (0.0%)</td><td>5 (4.5%)</td><td>6 (6.6%)</td><td>11 (4.0%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Etiology of deficiency, n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Congenital</td><td></td><td></td><td></td><td></td><td>43 (97.7%)</td><td>67 (97.1%)</td><td>48 (94.1%)</td><td>158 (96.3%)</td></tr><tr><td>Idiopathic</td><td></td><td></td><td></td><td></td><td>34 (79.1%)</td><td>56 (83.6%)</td><td>29 (60.4%)</td><td>119 (75.3%)</td></tr><tr><td>Other<sup>a</sup></td><td></td><td></td><td></td><td></td><td>9 (20.9%)</td><td>11 (16.4%)</td><td>19 (39.6%)</td><td>39 (24.7%)</td></tr><tr><td>Not applicable</td><td></td><td></td><td></td><td></td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td><td>0 (0.0%)</td></tr><tr><td>Acquired</td><td></td><td></td><td></td><td></td><td>1 (2.3%)</td><td>2 (2.9%)</td><td>3 (5.9%)</td><td>6 (3.7%)</td></tr><tr><td>GHD duration (years), median (IQR)</td><td>1.0 (0.5-1.6)</td><td>3.3 (2.6-4.0)</td><td>7.5 (6.3-9.9)</td><td>3.5 (1.9-6.3)</td><td>1.6 (0.9-2.0)</td><td>3.7 (2.9-4.7)</td><td>8.3 (7.0-10.9)</td><td>4.0 (2.2-7.1)</td></tr><tr><td>Duration of rhGH treatment (years), median (IQR)</td><td></td><td></td><td></td><td></td><td>1.1 (0.5-1.6)</td><td>3.1 (2.5-3.9)</td><td>7.8 (6.5-10.5)</td><td>3.3 (1.8-6.4)</td></tr><tr><td>rhGH dose (mg/kg/day), mean (s.D.)</td><td>0.041 (0.012)</td><td>0.043 (0.014)</td><td>0.039 (0.016)</td><td>0.041 (0.014)</td><td></td><td></td><td></td><td></td></tr><tr><td>Severity of deficiency, n (%)</td><td></td><td></td><td></td><td></td><td>0.037 (0.010)</td><td>0.041 (0.011)</td><td>0.036 (0.011)</td><td>0.038 (0.011)</td></tr><tr><td>Partial</td><td></td><td></td><td></td><td></td><td>37 (84.1%)</td><td>54 (78.3%)</td><td>34 (66.7%)</td><td>125 (76.2%)</td></tr><tr><td>Severe</td><td></td><td></td><td></td><td></td><td>6 (13.6%)</td><td>13 (18.8%)</td><td>17 (33.3%)</td><td>36 (22.0%)</td></tr><tr><td>Unknown</td><td></td><td></td><td></td><td></td><td>1 (2.3%)</td><td>1 (1.4%)</td><td>0 (0.0%)</td><td>2 (1.2%)</td></tr><tr><td>Not applicable</td><td></td><td></td><td></td><td></td><td>0 (0.0%)</td><td>1 (1.4%)</td><td>0 (0.0%)</td><td>1 (0.6%)</td></tr><tr><td>Male sex, n (%)</td><td>44 (61.1%)</td><td>65 (58.0%)</td><td>58 (63.7%)</td><td>167 (60.7%)</td><td>29 (65.9%)</td><td>48 (69.6%)</td><td>39 (73.6%)</td><td>116 (69.9%)</td></tr><tr><td>Age (years), mean (s.D.)</td><td>10.1 (3.4)</td><td>11.2 (3.4)</td><td>13.1 (2.3)</td><td>11.5 (3.3)</td><td>10.3 (3.4)</td><td>11.4 (3.3)</td><td>13.4 (2.3)</td><td>11.7 (3.2)</td></tr><tr><td>Height s.D. compared to general population (AFPA), mean (s.D.)</td><td>-1.8 (0.8)</td><td>-1.2 (0.7)</td><td>-0.7 (0.8)</td><td>-1.2 (0.9)</td><td>-1.7 (0.9)</td><td>-1.1 (0.7)</td><td>-0.4 (0.7)</td><td>-1.0 (0.9)</td></tr><tr><td>BMI compared to general population (AFPA), n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Leanness</td><td>18 (25%)</td><td>20 (18%)</td><td>14 (15%)</td><td>52 (19%)</td><td>13 (30%)</td><td>14 (20%)</td><td>7 (13%)</td><td>34 (20%)</td></tr><tr><td>Normal BMI</td><td>47 (65%)</td><td>84 (75%)</td><td>66 (73%)</td><td>197 (72%)</td><td>24 (55%)</td><td>50 (72%)</td><td>40 (75%)</td><td>114 (69%)</td></tr><tr><td>Overweight/obesity</td><td>7 (10%)</td><td>8 (7%)</td><td>11 (12%)</td><td>26 (9%)</td><td>7 (16%)</td><td>5 (7%)</td><td>6 (11%)</td><td>18 (11%)</td></tr><tr><td>Ongoing rhGH treatment, n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Norditropin FlexPro®</td><td>32 (44.4%)</td><td>41 (36.6%)</td><td>26 (28.6%)</td><td>99 (36.0%)</td><td>20 (45.5%)</td><td>26 (37.7%)</td><td>19 (35.8%)</td><td>65 (39.2%)</td></tr><tr><td>Saizen®</td><td>22 (30.6%)</td><td>19 (17.0%)</td><td>20 (22.0%)</td><td>61 (22.2%)</td><td>14 (31.8%)</td><td>15 (21.7%)</td><td>11 (20.8%)</td><td>40 (24.1%)</td></tr><tr><td>Omitrope®</td><td>6 (8.3%)</td><td>19 (17.0%)</td><td>7 (7.7%)</td><td>32 (11.6%)</td><td>3 (6.8%)</td><td>11 (15.9%)</td><td>4 (7.5%)</td><td>18 (10.8%)</td></tr><tr><td>Other</td><td>12 (16.7%)</td><td>33 (29.5%)</td><td>38 (41.8%)</td><td>83 (30.2%)</td><td>7 (15.9%)</td><td>17 (24.6%)</td><td>19 (35.8%)</td><td>43 (25.9%)</td></tr><tr><td>Time between GHD diagnosis and treatment onset (months), median (IQR)</td><td></td><td></td><td></td><td></td><td>3.2 (1.8-5.0)</td><td>3.6 (2.0-8.8)</td><td>3.5 (1.5-6.0)</td><td>3.4 (1.9-7.1)</td></tr><tr><td>Concomitant aromatase inhibitors, GnRH analog alternative hormone therapy or other injection treatments, n (%)</td><td>10 (13.9%)</td><td>10 (8.9%)</td><td>23 (25.3%)</td><td>43 (15.6%)</td><td>6 (13.6%)</td><td>8 (11.6%)</td><td>18 (34.0%)</td><td>32 (19.3%)</td></tr><tr><td>Current occupation of the answering parent/caregiver, n (%)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Professional activity</td><td>59 (96.7%)</td><td>79 (92.9%)</td><td>66 (88.0%)</td><td>204 (92.3%)</td><td>36 (97.3%)</td><td>53 (98.1%)</td><td>42 (91.3%)</td><td>131 (95.6%)</td></tr><tr><td>No professional activity</td><td>1 (1.6%)</td><td>3 (3.5%)</td><td>5 (6.7%)</td><td>9 (4.1%)</td><td>0 (0.0%)</td><td>1 (1.9%)</td><td>3 (6.5%)</td><td>4 (2.9%)</td></tr><tr><td>Did not wish to answer</td><td>1 (1.6%)</td><td>3 (3.5%)</td><td>4 (5.3%)</td><td>8 (3.6%)</td><td>1 (2.7%)</td><td>0 (0.0%)</td><td>1 (2.2%)</td><td>2 (1.6%)</td></tr></tbody></table>

Missing data (overall population with rhGH <2, (2-5), ≥5 years, total); GHD group with rhGH <2, (2-5), ≥5 years, total); etiology of GHD (0, 0, 2, and 2); severity of deficiency (0, 0, 2, and 2); time between GHD diagnosis and treatment onset (0, 0, 2, and 2); current occupation of the answering parent/caregiver (11, 27, 16, and 54; 7, 15, 7, and 29).

<figure><img src="image_4.png" /></figure>

<footnote>aRelated to the pituitary gland in 31 patients.</footnote>

<footnote>AFPA, Association Française de Pédiatrie Ambulatoire (French Association of Ambulatory Pediatrics); BMI, body mass index; GHD, growth hormone deficiency; GnRH, gonadotrophin-releasing hormone; IQR, interquartile range; rhGH, recombinant human growth hormone.</footnote>
<table><caption>**Table 2** Treatment burden of children, using the overall life interference total score.</caption><thead><tr><th></th><th>rhGH &lt;2 years (n = 44)</th><th>rhGH (2-5) years (n = 69)</th><th>rhGH ≥5 years (n = 53)</th><th>GHD-only group (n = 166)</th></tr></thead><tbody><tr><td>N</td><td>38</td><td>54</td><td>46</td><td>138</td></tr><tr><td>Overall life interference total score:</td><td></td><td></td><td></td><td></td></tr><tr><td>Mean (s.d.)</td><td>31.4 (20.5)</td><td>28.4 (20.1)</td><td>23.8 (21.2)</td><td>27.7 (20.7)</td></tr><tr><td>95% CI</td><td>(24.6; 38.1)</td><td>(22.9; 33.9)</td><td>(17.5; 30.1)</td><td>(24.2; 31.2)</td></tr><tr><td>Correlation with rhGH treatment duration</td><td></td><td></td><td></td><td></td></tr><tr><td>Pearson coefficient (95% CI)</td><td></td><td></td><td></td><td>-0.111 (-0.273; 0.057)</td></tr><tr><td>P-value</td><td></td><td></td><td></td><td>0.1925</td></tr></tbody></table>

GHD, growth hormone deficiency; rhGH, recombinant human growth hormone.

children of the overall population) included thyroxine in 23/275 patients (8.4% of the cases).

## Treatment burden

### Overall life interference

Among the analyzed children, 225/275 (81.8%) of the overall population completed the life interference questionnaire, including 138/166 (83.1%) of the GHD group (primary criterion), 68/87 patients (78.2%) with SGA, 10/11 (90.9%) with Turner syndrome, and 9/11 (81.8%) with PWS.

The total mean overall life interference score in the GHD group (primary analysis) was 27.7 ± 20.7 (n = 138) (Table 2). It was 27.1 ± 18.3 in patients with SGA, and as follows for the smaller groups: 20.7 ± 16.6 in patients with Turner syndrome and 50.0 ± 20.7 in patients with PWS (Table 3).

In the GHD group, this mean score tended to decrease (less interference) when the treatment duration increased (31.4 ± 20.5 (<2 years), 28.4 ± 20.1 ((2-5) years), 23.8 ± 21.2 (≥5 years)), and no significant correlation with the rhGH treatment duration was observed (Pearson coefficient:

r = -0.11, 95% CI (-0.27; 0.06); P = 0.1925 - univariate regression analysis). Nevertheless, using multivariate analysis, treatment duration was shown as a prognostic factor of less interference with the daily life of children (interference decrease: -1.13, 95% CI; (-2.21; -0.06) per year of treatment, P = 0.0383), as well as seven rhGH injections per week (least square means (95% CI): 36.01 (30.65; 41.37) for 6 days a week vs 28.53 (22.60; 34.46) for seven injections a week; P = 0.0365). In contrast, deficiency severity seemed to be a prognostic factor (27.03 (22.76; 31.30) for partial vs 37.52 (29.70; 45.33) for severe, P = 0.0217). The device used for rhGH treatment was also a prognostic factor of interference on patient daily life (Supplementary Table 1).

According to the different items of the life interference questionnaire, rhGH injections interfered the most with 'spending the night away from home' and 'travel' (often or always in 20.7% and 27.1% of the cases, respectively) (Fig. 3).

No correlation was also observed between the mean overall life interference total score and the rhGH treatment duration in the overall population (r = 0.01, 95% CI (-0.12; 0.14), P = 0.8747). Using multivariate analysis, two independent factors were significantly associated to this

<table><caption>**Table 3** Treatment burden, treatment adherence, and quality of life of children born small for gestational age (SGA), with Turner syndrome (TS), and with Prader-Willi syndrome (PWS).</caption><thead><tr><th></th><th>SGA (n = 87)</th><th>TS (n = 11)</th><th>PWS (n = 11)</th></tr></thead><tbody><tr><td>Overall life interference total score</td><td>N = 68</td><td>N = 10</td><td>N = 9</td></tr><tr><td>Mean (s.d.)</td><td>27.1 (18.3)</td><td>20.7 (16.6)</td><td>50.0 (20.7)</td></tr><tr><td>95% CI</td><td>(22.7; 31.5)</td><td>(8.9; 32.6)</td><td>(34.1; 65.9)</td></tr><tr><td>Number of missed rhGH injections over the last 28 days</td><td>N = 71</td><td>N = 10</td><td>N = 9</td></tr><tr><td>Mean (s.d.)</td><td>2.5 (4.7)</td><td>1.9 (4.6)</td><td>4.4 (9.2)</td></tr><tr><td>>80% of planned injections done (according to respondents), n (%)</td><td>64 (90.1%)</td><td>9 (90.0%)</td><td>7 (77.8%)</td></tr><tr><td>QoLISSY score</td><td></td><td></td><td></td></tr><tr><td>Children, mean (s.d.)</td><td>N = 69</td><td>N = 9</td><td>N = 9</td></tr><tr><td></td><td>73.1 (17.8)</td><td>65.7 (19.2)</td><td>84.1 (15.0)</td></tr><tr><td>Caregivers, mean (s.d.)</td><td>N = 66</td><td>N = 9</td><td>N = 9</td></tr><tr><td></td><td>72.3 (19.5)</td><td>65.9 (20.6)</td><td>87.7 (9.1)</td></tr></tbody></table>

QoLISSY, Quality of Life of Short Stature Youth; rhGH, recombinant human growth hormone.
<figure><img src="image_5.png" /><figcaption>**Figure 3**</figcaption></figure>

Detailed results from the life interference questionnaire according to the rhGH treatment duration (GHD-only group). GHD, growth hormone deficiency; rhGH, recombinant human growth hormone.

score: seven injections (compared to six injections) per week of rhGH were less likely to interfere, and the device used for rhGH treatment was also a prognostic factor of interference on patient daily life (Supplementary Table 2). In univariate analysis, the indication of rhGH treatment (GHD only vs other or multiple deficiencies) was not associated with the total overall life interference score (P=0.7143).

## Impact of the disease severity on daily activities

Using the PGIS-IDA in the GHD group, the concordance of assessments by children and caregivers was strong between caregivers for themselves and for their children (kappa coefficient: 0.61, 95% CI (0.51; 0.71)), moderate between caregivers for children and children for themselves (0.47 (0.37; 0.58)), and slight between caregivers for themselves and children for themselves (0.371 (0.27; 0.47)).

## Quality of life

Using the QoLISSY, a good QOL of children of the GHD group was observed according to children and parents/caregivers (respective mean scores: 81.5 ± 16.6 and 77.6 ± 18.7 on a 0–100 scale where 100 = best QOL) (Fig. 4). For patients with SGA, Turner syndrome, and PWS, similar mean scores between children and caregivers were found: 73.1 ± 17.8 and 72.3 ± 19.5, 65.7 ± 19.2 and 65.9 ± 20.6, and 84.1 ± 15.0 and 87.7 ± 9.1 (Table 3).

In the GHD group, the lowest mean scores were observed for the coping domain (children: 42.6 ± 22.2; parents: 42.7 ± 21.8) and the domain associated with the rhGH treatment (46.0 ± 17.2 and 49.8 ± 18.5, respectively). Both total scores increased with the rhGH treatment duration in the GHD group (r=0.26, 95% CI (0.10; 0.41), P=0.0017 and r=0.28 (0.11; 0.42), P=0.0009, respectively) and in the overall population (P=0.0005 and 0.0023, respectively). Using multivariate analysis, a high daily dose of rhGH was more likely to lead to a poor children QOL according to children themselves and their parents/caregivers in the GHD group (QOL decrease: -276.51, 95% CI (-510.45; -42.57), P=0.0209 and -300.82 (-586.03; -15.61), P=0.0389, respectively), while a higher height s.d. compared to general population was more likely to lead to a good QOL (QOL increase: 6.72 (3.77; 9.67), P < 0.0001 and 5.40 (1.91; 8.89), P=0.0027, respectively) (Supplementary Tables 3 and 4). The same two independent prognostic factors of the children QOL were observed in the overall population (Supplementary Tables 5 and 6). The indication of rhGH treatment (GHD only vs other or multiple deficiencies) was not found as an independent factor associated to the QoLISSY score.

Using the PedsQL, a good QOL was also observed for children of the GHD-only group (mean scores around 80 according to children for themselves and parents for their children, whatever the patient group age was), but no significant correlations with the treatment duration were shown in both populations (P=0.5177 and P=0.3784, respectively).
<figure><img src="image_6.png" /><figcaption>**Figure 4**</figcaption></figure>

Mean QoLISSY total scores based on children's and parent's assessments (GHD only group). GHD, growth hormone deficiency; QoLISSY, Quality of Life of Short Stature Youth.

## Missed rhGH injections

The number of missed injections reported by children and parents/caregivers over the last 28 days of treatment led to a mean score of 1.7 ± 2.2 (0: no missed injections; 28: all injections missed) in patients of the GHD group. On this basis, a high treatment adherence was estimated in 95% of them (>80% of planned injections were done according to respondents). The score for missed injections significantly increased with the duration of rhGH treatment in the GHD group ($r=0.24$, 95% CI: (0.08; 0.39), $P=0.0033$) and in the overall population (0.14 (0.01; 0.26), $P=0.0364$).

In other groups of patients, the mean numbers of missed injections over the last 28 days were 2.5 ± 4.7 for SGA, 1.9 ± 4.6 for Turner syndrome, and 4.4 ± 9.2 for PWS (Table 3), with a high treatment adherence whatever their condition was (in 90%, 90%, and 78% of patients, respectively).

## Factors related to daily rhGH injections impacting patient daily life

Ranking nine factors that may impact children's daily life of the GHD group (from 1, the most important to 9,

the less important), daily injections were reported as the most impacting factor (mean quotation out of 9: 3.0 ± 2.6) compared to others (subcutaneous injections, pain during injections, going away for the weekend or on holidays, visiting or sleeping at friends' house in the evening, medication storage in refrigerator or not, medical visits, reconstitution steps, and dose adjustment).

## Discussion

Treatment with daily rhGH injections has been shown to promote linear growth in children with GHD until their adult height target has been achieved, lead to few adverse events, and improve their QOL (3, 4, 5, 6, 7, 8). However, treatment adherence to daily injection regimens remains suboptimal, and non-compliance could compromise height velocity in children (9, 10, 11, 24).

After first results from a crossover phase III trial which showed that treatment burden of weekly injections of somatropin was lower than that of somatropin administered once daily in children with GHD (NCT03831880 trial) (17), the real-world cross-sectional French QOLITHOR study,
conducted in 275 pediatric patients including 166 children with GHD, provides complementary information on patient experience as recommended by French, European, and US Health Authorities (18,19, 20, 21).

Using the recently developed, validated dyad LIQ-GHD questionnaire (16) to assess rhGH treatment burden, the interference of daily injections with the daily life of children with GHD was similar in both studies (mean overall life interference total scores: 27.7 in QOLITHOR vs 24.13 after a 12-week treatment period in the NCT03831880 trial). These results are in favor of the relevance and the consistency of the questionnaire on life interference due to regimen to assess treatment burden in children with GHD.

No correlation between the mean overall life interference total score and the duration of rhGH treatment was observed. Nevertheless, using multivariate analysis, treatment duration was shown as a prognostic factor of less interference with the daily life of children. The interpretation of these results remains difficult as the lack of current therapeutic alternative may probably lead to an adaptation process, despite the fact that the ongoing treatment of children was not optimal. In addition, the efficacy of current rhGH treatments over time may tend to minimize the treatment burden.

Our real-life data showed a good adherence to daily injections of rhGH (according to 95.0% of children and parents, more than 80% of planned injections over the last 28-day period were done) which was consistent with findings from an Italian cross-sectional study conducted in 1007 children (24.4% missed at least one injection during a typical week) (25). However, these self-reported rates were based on respondents' own declarations, which may lead to an overestimation of treatment adherence. That being said, our study confirmed in a real-life setting that adherence to rhGH injections significantly decreased according to the treatment duration, even if the increase in missed injections was limited. This result was consistent with previous findings (26, 27, 28). Since a significant correlation was reported between the treatment adherence and the growth velocity of children (27, 28), our results tend to highlight the need for a better treatment adherence over time to achieve a better therapeutic efficacy.

The QOLITHOR study showed a high level of QOL in children under daily rhGH injections, using the QoLISSY questionnaire specifically developed for pediatric patients with short stature. QOL was better when assessment was performed by children compared to parents' evaluation (81.5 vs 77.6), as previously observed (29). For children and parents, child height compared to the general population was found as an independent prognostic factor of a good

QOL, which suggests that the possible constraints related to daily injections may be outweighed by the efficacy of their rhGH treatment over time. This result was consistent with previous 1-year findings having showed that height s.d. score gains were positively correlated with QoLISSY self-report score gains (P=0.001) and QoLISSY parent-report gains (P=0.00001) (30). In addition, it should be noted that the QoLISSY domain related to rhGH treatment showed a stronger impact on the QOL of children, with a mean score below 50/100 which is still in line with the impact of daily injections on children life. Coping difficulties were also observed in treated children.

In addition, once-daily injections were assessed by children as the most important treatment-related parameter that may impact their daily life, compared to eight other factors (mean rank out of 9: 3.0). This result is consistent with data from a previous discrete choice experiment study having showed that patients prefer a less frequent injection regimen for treating GHD (31). Our mean overall life interference total score related to daily injections of somatropin was consistent with the one found in the NCT03831880 trial (27.7 and 24.13), and three times higher than the mean score related to weekly injections of somatogron (8.63, *P* < 0.0001 between groups) (17). As reported in other conditions, a reduced treatment burden may result in improvement treatment adherence (12).

Our study has several limitations. Considering the real-life design of QOLITHOR study, medical assessments were not always available in patients' medical files. In addition, self-reported questionnaires were not always completed and returned by children and parents. However, the number of missed questionnaires was limited. For analysis, the overall life interference total score (primary criterion of interest) could be calculated in 138 patients of the 166 children with GHD (83.1%). This high completion rate for a non-interventional study highlights the high engagement from caregivers and children.

In conclusion, the real-world French QOLITHOR study confirms the burden associated with daily injections of rhGH treatment in children with GHD, as previously shown in an interventional study.

**Supplementary materials**

This is linked to the online version of the paper at https://doi.org/10.1530/EC-22-0464.

**Declaration of interest**

RC has received honoraria as scientific advisor or for lectures from Pfizer, Novo-Nordisk, Merck-Serono, Lilly, and Sandoz; MT has received reimbursement of participation fees for scientific meetings, and continuing
medical education events as well as lecture honoraria and funding for research projects from Millendo, Pfizer, Novo Nordisk, and Merck Serono; BD has received honoraria for lectures from Ipsen, Merck-Serono, Novo Nordisk, Pfizer, and Sandoz; RH and YB are employees of Pfizer; FM is an employee of eXYSTAT (statistical analysis of the study data); OC has received honoraria from Pfizer; MP has received research support form Pfizer, Novo Nordisk, Ipsen, Sandoz, Merck-Serono, Lilly, and Sanofi, National French grants (public funding, PHRC and ANR), and participated in advisory boards for Increxel (Ipsen), GNAP (Novo Nordisk), and KIGS France (Pfizer).

## Funding

This work was supported by Pfizer France, Paris, France.

## Author contribution statement

RC, MT, and MP: conceptualization, methodology, investigation, validation, and writing - review and editing; BD and OC: conceptualization, methodology, validation, and writing - review and editing; RH: conceptualization, methodology, validation, writing - review and editing, supervision, and funding acquisition; YB and FM: conceptualization, methodology, formal analysis, validation, and writing - review and editing.

## Acknowledgements

The authors would like to thank all the physicians and patients for their participation in the QOLITHOR study. Assistance funded by Pfizer France was provided by Constant Josse from eXYSTAT (statistical analysis) and Dr Marie-Odile Barbaza from Auxesia (manuscript preparation under the direction of the authors). QOLITHOR Study Group: Prof. Pascal BARAT, Hôpital Pédiatrique, Bordeaux, France; Prof. Régis COUTANT, Dr Natacha BOUHOURS-NOUET, Dr Aurélie DONZEAU, Dr Jessica AMSELLEM JAGER, Dr Stéphanie ROULEAU, and Dr LEVAILLANT, CHU d'Angers, Angers, France; Dr Isabelle FLETCHNER, Centre Médical Spécialisé de l'Enfant et de l'Adolescent, Paris, France; Dr Maxime GERARD, Paris, France; Dr Christine LEFEVRE, CHU de Lille, Hôpital Jeanne de Flandre, Lille, France; Prof. Agnès LINGLART, and Dr Cécile THOMAS-TEINTURIER, Hôpital du Kremlin-Bicêtre, Le Kremlin-Bicêtre, France; Prof. Marc NICOLINO, Hôpital Femme-Mère-Enfant, Bron, France; Prof. Michel POLAK, Dr Isabelle FLETCHNER, Dr Graziella PINTO, Dr Dinane SAMARA-BOUSTANI, Dr Athanasia STOUPA, and Dr Caroline THALASSINOS, AP-HP, Hôpital Necker Enfants Malades, Paris, France; Prof. Rachel REYNAUD, Dr Delphine BERNOUX, Dr Emeline MARQUANT, and Dr Sarah CASTETS, Hôpitaux Publics, Marseille, France; Prof. Sylvie ROSSIGNOL, Dr Marie MANSILA, and Dr François BREZIN, Hôpital de Haute-pierre, Strasbourg, France; Prof. Maithé TAUBER and Dr Béatrice JOURET, CHU de Toulouse, Hôpitaux Mère et Enfant, Toulouse, France.

## References

1. Krysiak R, Gdula-Dymek A, Bednarska-Czerwińska A & Okopień B. Growth hormone therapy in children and adults. *Pharmacological Reports* 2007 **59** 500–516.

2. Thomas JD & Monson JP. Adult GH deficiency throughout lifetime. *European Journal of Endocrinology* 2009 **161** (Supplement 1) S97–S106. (https://doi.org/10.1530/EJE-09-0258)

3. Ho KK & GH Deficiency Consensus Workshop Participants. Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia. *European Journal of Endocrinology* 2007 **157** 695–700. (https://doi.org/10.1530/EJE-07-0631)

4. Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, Ross JL, Chernausek SD, Savage MO, Wit JM & ISS Consensus Workshop Participants. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. *Journal of Clinical Endocrinology and Metabolism* 2008 **93** 4210–4217. (https://doi.org/10.1210/jc.2008-0509)

5. González Briceño LG, Viaud M, Beltrand J, Flechtner I, Dassa Y, Samara-Boustani D, Thalassinos C, Pauwels C, Busiah K, Pinto G, et al. Improved general and height-specific quality of life in children with short stature after 1 year on growth hormone. *Journal of Clinical Endocrinology and Metabolism* 2019 **104** 2103–2111. (https://doi.org/10.1210/jc.2018-02523)

6. Quitann J, Bloemeke J, Silva N, Bullinger M, Witt S, Akkurt I, Dunstheimer D, Vogel C, Böttcher V, Kuhnle Krahl U, et al. Quality of life of short-statured children born small for gestational age or idiopathic growth hormone deficiency within 1 year of growth hormone treatment. *Frontiers in Pediatrics* 2019 **164**. (https://doi.org/10.3389/fped.2019.00164)

7. Reh CS & Geffner ME. Somatotropin in the treatment of growth hormone deficiency and Turner syndrome in pediatric patients: a review. *Clinical Pharmacology: Advances and Applications* 2010 **2** 111–122. (https://doi.org/10.2147/CPAA.S6525)

8. Sävendahl L, Polak M, Backeljauw P, Blair JC, Miller BS, Rohrer TR, Hokken-Koelega A, Pietropoli A, Kelepouris N & Ross J. Long-term safety of growth hormone treatment in childhood: two large observational studies: NordiNet IOS and ANSWER. *Journal of Clinical Endocrinology and Metabolism* 2021 **106** 1728–1741. (https://doi.org/10.1210/clinim/dgab080)

9. Fisher BG & Acerini CL. Understanding the growth hormone therapy adherence paradigm: a systematic review. *Hormone Research in Paediatrics* 2013 **79** 189–196. (https://doi.org/10.1159/000350251)

10. Koledova E, Stoyanov G, Ovbul E & Davies PSW. Adherence and long-term growth outcomes: results from the easypod™ connect observational study (ECOS) in paediatric patients with growth disorders. *Endocrine Connections* 2018 **7** 914–923. (https://doi.org/10.1530/EC-18-0172)

11. Rosenfeld RG & Bakker B. Compliance and persistence in pediatric and adult patients receiving growth hormone therapy. *Endocrine Practice* 2008 **14** 143–154. (https://doi.org/10.4158/EP.14.2.143)

12. Loftus J, Yaworsky A, Roland CL, Turner-Bowker D, McLafferty M, Su S & Lamoureux RE. Experience of switching from a daily to a less frequent administration of injection treatments. *PLoS One* 2022 **17** e0278293. (https://doi.org/10.1371/journal.pone.0278293)

13. Deal CL, Pastrack A, Silverman LA, Valluri SR, Wajnrajch MP & Cara JE. OR10-06 Somatogron growth in the treatment of pediatric growth hormone deficiency: results of the pivotal pediatric phase 3 clinical trial. *Journal of the Endocrine Society* 2020 **4** (Supplement 1) OR10-OR06. (https://doi.org/10.1210/jendso/bvaa046.1279)

14. Pampanini V, Deodati A, Inzaghi E & Cianfarani S. Long-acting growth hormone preparations and their use in children with growth hormone deficiency. *Hormone Research in Paediatrics* 2022. (https://doi.org/10.1159/000523791)

15. European Medicines Agency. Ngenla: Summary of product characteristics. (available at: https://www.ema.europa.eu/en/documents/product-information/ngenla-epar-product-information_en.pdf).

16. Turner-Bowker DM, Yaworsky A, Palladino A, Lamoureux RE, Kelly M, Love E, Pleil AM, Shields A & Loftus J. Development and psychometric evaluation of the Life Interference Questionnaire for growth hormone deficiency (LIQGHD) to assess growth hormone injection burden in children and adults. *Patient* 2020 **13** 289–306. (https://doi.org/10.1007/s40271-019-00405-7)

17. Maniatis AK, Carakushansky M, Galcheva S, Prakasam G, Fox LA, Dankovcikova A, Loftus J, Palladino AA, de Los Angeles Resa M, Turich Taylor C, et al. Treatment burden of weekly somatogron vs
daily somatropin in children with growth hormone deficiency: a
randomized study. *Journal of the Endocrine Society* 2022 **6** bvac117.
(https://doi.org/10.1210/jendso/bvac117)

18 Haute Autorité de Santé. Guide Aide à l'Utilisation de Questionnaires Patients de Mesure des Résultats de Soins (Proms) pour Améliorer la Pratique Clinique Courante - Approche Théorique et Critères Opérationnels. (available at: https://www.has-sante.fr/upload/docs/ application/pdf/2021-07/iqss_guide_proms_general_2021.pdf)

19 Haute Autorité de Santé. Rapport Qualité des Soins Perçue par le Patient - Indicateurs Proms et PREMs Panorama d'Expériences Étrangères et Principaux Enseignements. (available at: https:// www.has-sante.fr/upload/docs/application/pdf/2021-07/rapport_ panorama_proms_prems_2021.pdf)

20 European Medicines Agency. Regulatory guidance for the use of health-related quality of life (HRQL) measures in the evaluation of medicinal products - Scientific guideline. (available at: https://www. ema.europa.eu/en/regulatory-guidance-use-health-related-quality- life-hrql-measures-evaluation-medicinal-products)

21 Food and Drug Administration. Guidance document. Patient-Reported Outcome Measures: use in medical product development to support labeling claims. (available at: https://www.fda.gov/ regulatory-information/search-fda-guidance-documents/patient- reported-outcome-measures-use-medical-product-development- support-labeling-claims)

22 Bullinger M, Quitmann J, Power M, Herdman M, Mimoun E, DeBusk K, Feigerlova E, Lunde C, Dellenmark-Blom M, Sanz D, et al. Assessing the quality of life of health-referred children and adolescents with short stature: development and psychometric testing of the QoLISSY instrument. *Health and Quality of Life Outcomes* 2013 **11** 76. (https://doi.org/10.1186/1477-7525-11-76)

23 Varni JW, Seid M & Rode CA. The PedsQL: measurement model for the pediatric quality of life inventory. *Medical Care* 1999 **37** 126–139. (https://doi.org/10.1097/00005650-199902000-00003)

24 Cutfield WS, Derraik JG, Gunn AJ, Reid K, Delany T, Robinson E & Hofman PL. Non-compliance with growth hormone treatment in

children is common and impairs linear growth. *PLoS One* 2011 **6** e16223. (https://doi.org/10.1371/journal.pone.0016223)

25 Bagnasco F, Di Iorgi N, Roveda A, Gallizia A, Haupt R, Maghnie M & Adherence Investigators Group. Prevalence and correlates of adherence in children and adolescents treated with growth hormone: a multicenter Italian study. *Endocrine Practice* 2017 **23** 929–941. (https://doi.org/10.4158/EP171786.OR)

26 Farfel A, Shalitin S, Morag N & Meyerovitch J. Long-term adherence to growth hormone therapy in a large health maintenance organization cohort. *Growth Hormone and IGF Research* 2019 **44** 1–5. (https://doi.org/10.1016/j.ghir.2018.10.004)

27 Haverkamp F, Johansson L, Dumas H, Langham S, Tauber M, Veimo D & Chiarelli F. Observations of nonadherence to recombinant human growth hormone therapy in clinical practice. *Clinical Therapeutics* 2008 **30** 307–316. (https://doi.org/10.1016/j.clinthera.2008.02.017)

28 Maggio MC, Vergara B, Porcelli P & Corsello G. Improvement of treatment adherence with growth hormone by easypod™ device: experience of an Italian centre. *Italian Journal of Pediatrics* 2018 **44** 113. (https://doi.org/10.1186/s13052-018-0548-z)

29 Quitmann J, Rohenkohl A, Sommer R, Bullinger M & Silva N. Explaining parent-child (dis)agreement in generic and short stature-specific health-related quality of life reports: do family and social relationships matter? *Health and Quality of Life Outcomes* 2016 **14** 150. (https://doi.org/10.1186/s12955-016-0553-0)

30 González Briceño LG, Viaud M, Beltrand J, Flechtner I, Dassa Y, Samara-Boustani D, Thalassinos C, Pauwels C, Busiah K, Pinto G, et al. Improved general and height-specific quality of life in children with short stature after 1 year on growth hormone. *Journal of Clinical Endocrinology and Metabolism* 2019 **104** 2103–2111. (https://doi.org/10.1210/jc.2018-02523)

31 McNamara M, Turner-Bowker DM, Westhead H, Yaworsky A, Palladino A, Gross H, Pleil A & Loftus J. Factors driving patient preferences for growth hormone deficiency (GHD) injection regimen and injection device features: A discrete choice experiment. *Patient Prefer Adherence* 2020 **14** 781–793. (https://doi.org/10.2147/PPA.S239196)

Received 2 March 2023

Accepted 3 March 2023

Available online 3 March 2023

Version of Record published 28 March 2023