Challenges with managing growth hormone deficiency

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The current paradigm in GHD

Even though growth hormone therapy is safe and effective, patients who are not compliant with daily injections may not fully benefit from treatment.1-3 Read on to understand why.

Patients and caregivers have reported noncompliance with rhGH therapy

Rosenfeld and Bakker conducted a survey study as part of an effort to identify key factors influencing compliance and persistence in patients receiving growth hormone treatment and to promote the development of interventions to support continuous GH use. The study involved 158 adult patients, 326 adolescents, and 398 parents of children currently receiving or previously treated with rhGH.

Survey questions explored a number of topics, which included disruptions affecting compliance. Compliance was defined by a categorical assessment of frequency of missed rhGH doses for specific reasons.

In Rosenfeld and Bakker’s study, approximately two-thirds of patients with GHD or caregivers of children receiving rhGH were found to be not fully compliant with their prescribed rhGH.

Patient segmentation based on compliance with GH therapy, shown by age group

Chart
Chart
Chart
Highly compliant patients
Occasionally noncompliant patients
Noncompliant or skeptical patients

Noncompliance in survey participants was defined as “occasionally noncompliant” or “noncompliant and skeptical.” Participants (N=882) included adults and adolescents diagnosed with GHD, as well as caregivers of children who were receiving growth hormone therapy at the start of the study or at any time during the 2 years preceding the study. Of 9 potential reasons for missing a dose, “highly compliant” patients responded “never” to 8 or 9 reasons, “occasionally noncompliant” patients responded “never” to 6 or 7 reasons, and “noncompliant and skeptical” patients responded “never” to 5 or fewer reasons.

  • Reported rates of nonadherence to pediatric GH therapy are highly variable and may be as high as 36% to 49% depending on assessment method and definition used2,5,6

Growth may be compromised when doses of rhGH are missed

Cutfield et al conducted a survey study to understand the relationship between growth and compliance with rhGH using a complete national cohort of 175 New Zealand children and adolescents over a 4-month period.

Compared with previous studies using self-reporting or prescription data, this study collected used vials of growth hormone treatment from caregivers as an objective measurement of compliance. A total of 25 patients failed to return a single vial during the study period and were excluded from the analysis.3

In Cutfield et al’s study, noncompliance with rhGH resulted in reduced height velocity standard deviation score during the study period.

HVSDS over 6 to 8 months according to the level of compliance with rhGH

Chart

Compliance was evaluated by the number of GH vials required each month and the number of empty vials returned to the administrator each month, expressed as a percentage of the number of vials prescribed. Growth data were routinely obtained every 6 months for all patients. Growth rates were calculated for the 6- to 8- month period that encompassed the interval of this audit. Changes in height were recorded and converted to HVSDS to control for sex and age differences.

  • 66% (73/110) of patients missed more than one injection per week
  • One or more missed doses per week resulted in significantly reduced linear growth during the study period
  • Authors claimed this study was the first to provide evidence that noncompliance is a common cause of suboptimal response to GH treatment in children and adolescents with GHD

Separately, De Pedro et al examined the variability in patient adherence to GH treatment and treatment outcomes by conducting an observational longitudinal study carried out in the Endocrinology Pediatrics area of the Germans Trias i Pujol University Hospital in Badalona, Spain. 158 children 4 to 16 years of age receiving daily rhGH were included in the study. To evaluate adherence, the prescribed annual dose was compared to the number of doses annually picked up by the patient from the hospital pharmacy. Serum insulin-like growth factor I (IGF-I) measurements were used as a biomarker for adherence.5

In De Pedro et al’s study, patients with moderate to poor adherence had significantly lower IGF-I SDS and HVSDS.5

Comparison of patients with varying levels of adherence to daily rhGH5

Good adherence Moderate to poor adherence P-value
IGF-I SDS 1.3 ± 1.03 0.48 ± 1.09 <.0001
HVSDS 1.57 ± 1.90 0.61 ± 1.50 .002

“Good adherence” was defined as missing ≤92% of prescribed doses and “poor adherence” was defined as missing <85% of prescribed doses, corresponding to at least 1 dose missed per week. IGF-I values were expressed as SDS from an age-related reference population. Changes in height were recorded for a year and converted to HVSDS based on gender and age, following the standards of the Spanish Studies for Growth 2010.

  • HVSDS and IGF-I SDS were significantly higher in children with good adherence when compared with children with moderate adherence (P=.019 and P=.026, respectively)
  • In this study, treatment duration was identified as a risk factor for nonadherence—every year of treatment increased the risk of nonadherence by 30%

Pinpointing the reasons behind nonpersistency with rhGH therapy

Miller et al analyzed the American Norditropin Studies: Web-Enabled Research (ANSWER) program registry, a noninterventional observational study that collected long-term GH effectiveness and safety information from more than 13,000 patients treated at 175 clinical sites to determine persistence rates and height outcomes of children who discontinued GH treatment. The International Society for Pharmacoeconomics and Outcomes Research has defined medication persistence as “the duration of time from initiation to discontinuation of therapy” and medication adherence as “the extent to which a patient acts in accordance with the prescribed interval and dose of a dosing regimen.” Reasons for GH therapy discontinuation were evaluated and recorded by physicians during each patient’s last clinic visit.7

In Miller et al’s study, the most common reasons for GH discontinuation were final height achieved, insurance issues, and patient and caregiver decision.7

Identified reasons for GH discontinuation7

Reasons Patients (%)
Final height achieved 34.9
Insurance issues 28.0
Patient and caregiver decision 16.2
Nonadherence 3.6
Healthcare provider recommendation 3.3
Adverse events 2.5
Change of physicians or patient moved 1.5
Lack of response 0.1
In Rosenfeld and Bakker’s study, the lack of GH persistence was attributed to physician’s advice, GH cost, insurance coverage changes, painful injections, and patient-parent perception that growth has finished.1

Consider the impact of treatment-associated burden on the patient and caregiver4

Brod et al explored the burden associated with daily rhGH for children, adolescents, and parents using qualitative interviews conducted with 70 respondents, which included children ages 8 to <13 with GHD and parents of children ages 4 to <13 with GHD. An analysis of interview transcripts was also used to identify themes with which to develop a disease-specific model of the impact of GHD.

The table below shows the percentage of patients and caregivers who endorsed each major domain subtheme related to treatment burden of GHD. Themes were considered major if they were endorsed by >15% of either child or parent respondents.

Patients and caregivers alike experience treatment burden across all domains.

Percentage of children and parents who endorsed each major domain subtheme

Treatment burden domains and subthemes (children) Children (%) Parents (%)
Child emotional well-being domain
Worry about injections, worry about remembering 23 53
Unhappiness about injection frequency 26 24
Fear of injections 8 38
Embarrassment about treatment 15 29
Annoyance about injections 15 6
Feeling different from other children 13 6
Child interference domain
Interference with overnight or other activities 33 24
Time needed emotionally to prepare for shot (avoiding or delaying the injections) 8 41
Needing to stop/interrupt what your are doing (daily routine) 21 18
Child physical domain
Pain 41 24
Bruising 21 18
Burning/stinging 10 6
Soreness 15 0
Treatment burden domains and subthemes (parents) n (N=31) Parents (%)
Parent emotional well-being domain
Worry or anxiety about treatment or treatment administration 18 58
Worry about causing child pain 13 42
Feeling guilt 7 23
Feeling sadness 5 16
Feeling frustration 3 10
Parent interference domain
Interference/time needed to prepare/administer injection (logistics) OR prepare child for injections 13 42
Interference with travel plans/vacations 13 42
Scheduling time around daily/family routines 11 35
Interfere with social life 5 16

Innovation in currently available GH therapies could potentially improve treatment adherence by reducing aspects of treatment burden.8

Clinical review:
Understanding causes of nonadherence to current rhGH treatment

A review article that examines methods of measuring adherence, prevalence of nonadherence, factors affecting adherence, and interventions to improve adherence.2

Understanding the Growth Hormone Therapy Adherence Paradigm: A Systematic Review

Download the paper

Somavaratan is an investigational new drug that has not been approved for sale in any country.

 

References
1. Rosenfeld RG, Bakker B. Compliance and persistence in pediatric and adult patients receiving growth hormone therapy. Endocr Pract. 2008;14(2):143-154. doi:10.4158/EP.14.2.143.
2. Fisher BG, Acerini CL. Understanding the growth hormone therapy adherence paradigm: a systematic review. Horm Res Paediatr. 2013;79(4):189-196. doi:10.1159/000350251.
3. Cutfield WS, Derraik JGB, Gunn AJ, et al. Non-compliance with growth hormone treatment in children is common and impairs linear growth. PLoS One. 2011;6(1):e16223. doi:10.1371/journal.pone.0016223.
4. Brod M, Højbjerre L, Alolga SL, Nacson A, Nordholm L, Rasmussen MH. Disease and treatment burden in children and adolescents with growth hormone deficiency (GHD). Poster presented at: 54th Annual Meeting of European Society for Paediatric Endocrinology (ESPE); October 1-3, 2015; Barcelona, Spain.
5. De Pedro S, Murillo M, Salinas I, et al. Variability in adherence to rhGH treatment: socioeconomic causes and effect on children’s growth. Growth Horm IGF Res. 2016;26:32-35. doi:10.1016/j.ghir.2015.12.002.
6. Haverkamp F, Johansson L, Dumas H, et al. Observations of nonadherence to recombinant human growth hormone therapy in clinical practice. Clin Ther. 2008;30(2):307-316. doi:10.1016/j.clinthera.2008.02.017.
7. Miller BS, Rotenstein D, Deeb LC, Germak J, Wisniewski T. Persistence with growth hormone therapy in pediatric patients. Am J Pharm Benefits. 2014;6(1):e9-e17.
8. Christiansen JS, Backeljauw PF, Bidlingmaier M, et al. Growth Hormone Research Society perspective on the development of long-acting growth hormone preparations. Eur J Endocrinol. 2016;174(6):C1-8. doi:10.1530/EJE-16-0111.