Effect of adherence to growth hormone treatment on 0-2 year catch-up growth in children with growth hormone deficiency

PLoS One. 2018 Oct 24;13(10):e0206009. doi: 10.1371/journal.pone.0206009. eCollection 2018.

Abstract

Background: Quantifying the association between adherence and the growth response to growth hormone (GH) treatment is hampered by suboptimal methods of measuring adherence, confounders associated with the growth response, and restriction of the outcome parameters to yearly growth velocities.

Aim: To investigate the effect of adherence on the two-year growth response to GH treatment in prepubertal children with idiopathic isolated growth hormone deficiency (GHD) participating in the easypod connect observational study (ECOS), a 5-year, Phase IV open-label study to continuously assess real-world adherence via the easypod electronic drug-delivery device.

Patients and methods: Outcome measures were change in height standard deviation score (ΔHSDS), index of responsiveness (IoR), and parameters of two catch-up growth (CUG) curve functions (monomolecular growth curve and second degree polynomial) with adj-HSDS (HSDS minus Target height (TH) SDS) as dependent variable. Inclusion criteria were GHD, naïve to GH treatment, known TH, age <10y in girls and <12y in boys, ≥3 measurements, HSDS <-2 at start, complete data on growth and adherence in the first and second year. Linear regression analyses were performed to test the association between adherence (continuous and high vs. low) and the outcome measures, also adjusted for potential clinical confounders (age at start, adj-HSDS at start, birth weight SDS, gestational age (<37 weeks vs ≥37 weeks), GH dose, GH max (n = 58)). The formula of IoR already adjusts for confounders.

Results: In total, 95 patients complied with the inclusion criteria. The strongest associations were found between high adherence in the second year (≥91% as cut-off value) and IoR 2y (+0.62), and average adherence and high adherence (≥78%) in the first two years and ΔHSDS 0-2y (+0.11 SD per 1 injection/week, and +0.34 SD for high vs. low adherence).

Conclusion: Suboptimal adherence negatively affected the growth response in the first two years of GH treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child
  • Female
  • Growth and Development*
  • Human Growth Hormone / deficiency*
  • Human Growth Hormone / therapeutic use*
  • Humans
  • Linear Models
  • Male
  • Medication Adherence*

Substances

  • Human Growth Hormone

Grants and funding

This study was sponsored by Merck KGaA, Darmstadt, Germany. Medical writing assistance was provided by David Candlish, inScience Communications, Tattenhall, UK, and sponsored by Merck KGaA, Darmstadt, Germany. The data collection was performed via the easypodTM electronic drug-delivery device, which is a product of Merck KGaA. Also, physician data entry of outcome measures were retrospectively and prospectively collected by Merck KGaA. This data collection was part of the ECOS study, which was conducted in accordance with the principles of the Declaration of Helsinki, Good Clinical Practice (ICH-GCP E6) guidelines and applicable national legal and regulatory requirements. The ECOS study was published in Endocrine Connections (Koledova E, Stoyanov G, Ovbude L, Davies PSW (2018) Adherence and long-term growth outcomes: results from the easypod™ connect observational study (ECOS) in paediatric patients with growth disorders. Endocr Connect. 7: 914-923). Post hoc analysis on the ECOS study was performed by PvD from TNO. TNO is an independent RTO from the Netherlands founded by law. TNO’s professionals put their knowledge and experience to work in creating smart solutions to complex issues. These innovations help to sustainably strengthen social wellbeing and industrial competitiveness. The core values of TNO are integrity, independence, professionalism, and engagement with society. TNO’s Code of Conduct, published on the website of TNO (https://www.tno.nl/en/about-tno/mission-and-strategy/tno-code), contains a chapter on scientific integrity. Research is conducted without any undue influence from commercial or other interests. Merck KGaA provided support in the form of salaries for author PvD, but did not have any additional role in performing the post hoc analysis. Merck has provided the ECOS data to TNO for this post hoc analysis. Manuscript was reviewed according to Merck publication procedures. The specific roles of all authors are articulated in the ‘author contributions’ section.