Long-Term Effectiveness and Safety of Childhood Growth Hormone Treatment in Noonan Syndrome

Tilman R. Rohrer; Jennifer Abuzzahab; Philippe Backeljauw; Anna Camilla Birkegård; Joanne Blair; Jovanna Dahlgren; Pétur Benedikt Júlíusson; Vlady Ostrow; Alberto Pietropoli; Michel Polak; Alicia Romano; Judith Ross; Lars Sävendahl; Bradley S. Miller

doi:10.1159/000512429

Long-Term Effectiveness and Safety of Childhood Growth Hormone Treatment in Noonan Syndrome

Tilman R. Rohrer, Jennifer Abuzzahab, Philippe Backeljauw, Anna Camilla Birkegård, Joanne Blair, Jovanna Dahlgren, Pétur Benedikt Júlíusson, Vlady Ostrow, Alberto Pietropoli, Michel Polak, Alicia Romano, Judith Ross, Lars Sävendahl, Bradley S. Miller

Pediatrics - Endocrine and Diabetes

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Introduction: Few data exist on long-term growth hormone (GH) treatment in patients with Noonan syndrome (NS). Objective: To evaluate the effectiveness and safety of GH treatment in NS in clinical practice. Methods: Height gain, near-adult height (NAH), and safety were assessed in 2 complementary non-interventional studies: NordiNet® IOS and ANSWER. The safety analysis included 412 patients, and the effectiveness analysis included 84 GH-treated patients (male, n = 67) with ≥4 years' height standard deviation score (HSDS) data. HSDS was determined using national reference (NR) and NS-specific (NSS) data. Results: The mean (SD) baseline age was 8.38 (3.57) years; HSDS, -2.76 (1.03); GH dose, 41.6 (11.1) μg/kg/day. The mean (SD) HSDS increase from baseline (ΔHSDS) was 0.49 (0.37) (first year), 0.79 (0.58) (second year), and 1.01 (0.60) (third year) (NR). The mean (SD) HSDS at year 3 was -1.66 (1.00) (NR; 1.06 [1.12] [NSS]). Twenty-four patients achieved NAH. The mean (SD) NAH SDS (NR) was -1.51 (0.60) (154.90 [3.21] cm) in females and -1.79 (1.09) (165.61 [7.19] cm) in males; 70.8% (17/24) had NAH SDS ≥ -2. Adverse drug reactions and GH-unrelated serious adverse events (n = 34) were reported in 22/412 (5.3%) patients. Four neoplasms and 3 cases of scoliosis were reported; no cardiovascular adverse events occurred. Conclusions: GH-treated children with NS achieved substantial height gain during the first 3 years of follow-up. Overall, 24 patients achieved NAH, with 70.8% having NAH SDS ≥ -2. There was no evidence to support a higher prevalence of neoplasm, or cardiac or other comorbidities.

Original language	English (US)
Pages (from-to)	380-395
Number of pages	16
Journal	Hormone Research in Paediatrics
Volume	93
Issue number	6
DOIs	https://doi.org/10.1159/000512429
State	Published - Feb 2021

Bibliographical note

Funding Information:
Tilman R. Rohrer has acted as a consultant for Novo Nordisk and received speaker honoraria from Novo Nordisk. M. Jennifer Abuzzahab has received research grant/research support from As-cendis, Astra Zeneca, Levo, Millendo, Novo Nordisk, Rhythm, and Soleno. She has attended advisory boards for Ascendis and Rhythm and speaker’s bureau for Novo Nordisk, Rhythm, and Sandoz. Philippe Backeljauw has received research grant support from Novo Nordisk, Opko, and Ipsen and is a consultant for Novo Nordisk, Ipsen, Sandoz, and Endo Pharmaceuticals. Anna Camilla Birkegård, Vlady Ostrow, and Alberto Pietropoli are employees of Novo Nordisk. Jo Blair has acted as a consultant for Novo Nordisk, has received speaker honoraria from Novo Nordisk and Sandoz, and has received financial support in the form of registration fees from Novo Nordisk to attend academic meetings. Jovanna Dahlgren has received honoraria from Merck, Novartis, and Pfizer, as well as unrestricted grants from Pfizer for 2 clinical trials. Petur B. Juliusson has received a lecture fee from Novo Nordisk for a presentation at a Novo Nordisk meeting. Michel Polak is a member of the Increlex European registry and Novo Nordisk growth international advisory board and has institutional disclosures from Pfizer France. He has received grants from Ipsen, Novo Nordisk, Pfizer, Lilly, Sanofi, Sandoz, and Merck and government grants (PHRC, PHRIP, and ANR). Alicia Romano has been a consultant for Ascendis Pharma and is a consultant and speaker for Novo Nordisk. Judith Ross is a consultant for Novo Nordisk and Opko and receives research funding from Novo Nordisk. Lars Sävendahl has received consultancy fees from Ascendis, Hexal, Novo Nordisk, Merck, Pfizer, and Sandoz. Bradley S. Miller has been a consultant for Ascendis, BioMarin, Bluebird Bio, Gene-Science, Novo Nordisk, Pfizer, Sandoz, Sanofi Genzyme, Soleno, Takeda, Tolmar, and Versartis and has received research support from AbbVie, Alexion, Ascendis, Novo Nordisk, Opko, Orphan Reach, Sandoz, Sangamo, Sanofi Genzyme, Takeda, and Versartis in the last 3 years.

Funding Information:
The authors would like to thank the patients, their families, the nurses and study coordinators, and all investigators involved in this study. Statistical support was provided by Jean-Marc Ferran (Qualiance ApS) and Moshe Fridman (AMF Consulting), both under contract to Novo Nordisk A/S. Medical writing and editorial support were provided by Penny Butcher, PhD, and Helen Marshall of Watermeadow Medical, part of the Ashfield Group, supported by Novo Nordisk Health Care AG. The sponsor was involved in the study design and collection, analysis, and interpretation of data, as well as data checking of information provided in the manuscript. However, ultimate responsibility for opinions, conclusions, and data interpretation lies with the authors. This work was dedicated to the memory of Dr. Jacqueline Noonan (1928–2020).

Publisher Copyright:
© 2020 The Author(s) Published by S. Karger AG, Basel.

Keywords

Adolescent
Effectiveness
Growth hormone therapy
Near-adult height
Noonan syndrome
Puberty
RASopathy
Ras/mitogen-activated protein kinase
Real-world evidence
Safety

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Rohrer, T. R., Abuzzahab, J., Backeljauw, P., Birkegård, A. C., Blair, J., Dahlgren, J., Júlíusson, P. B., Ostrow, V., Pietropoli, A., Polak, M., Romano, A., Ross, J., Sävendahl, L., & Miller, B. S. (2021). Long-Term Effectiveness and Safety of Childhood Growth Hormone Treatment in Noonan Syndrome. Hormone Research in Paediatrics, 93(6), 380-395. https://doi.org/10.1159/000512429

Rohrer, TR, Abuzzahab, J, Backeljauw, P, Birkegård, AC, Blair, J, Dahlgren, J, Júlíusson, PB, Ostrow, V, Pietropoli, A, Polak, M, Romano, A, Ross, J, Sävendahl, L & Miller, BS 2021, 'Long-Term Effectiveness and Safety of Childhood Growth Hormone Treatment in Noonan Syndrome', Hormone Research in Paediatrics, vol. 93, no. 6, pp. 380-395. https://doi.org/10.1159/000512429

@article{589dc3757ba84626a217a5c3ff8a300b,

title = "Long-Term Effectiveness and Safety of Childhood Growth Hormone Treatment in Noonan Syndrome",

abstract = "Introduction: Few data exist on long-term growth hormone (GH) treatment in patients with Noonan syndrome (NS). Objective: To evaluate the effectiveness and safety of GH treatment in NS in clinical practice. Methods: Height gain, near-adult height (NAH), and safety were assessed in 2 complementary non-interventional studies: NordiNet{\textregistered} IOS and ANSWER. The safety analysis included 412 patients, and the effectiveness analysis included 84 GH-treated patients (male, n = 67) with ≥4 years' height standard deviation score (HSDS) data. HSDS was determined using national reference (NR) and NS-specific (NSS) data. Results: The mean (SD) baseline age was 8.38 (3.57) years; HSDS, -2.76 (1.03); GH dose, 41.6 (11.1) μg/kg/day. The mean (SD) HSDS increase from baseline (ΔHSDS) was 0.49 (0.37) (first year), 0.79 (0.58) (second year), and 1.01 (0.60) (third year) (NR). The mean (SD) HSDS at year 3 was -1.66 (1.00) (NR; 1.06 [1.12] [NSS]). Twenty-four patients achieved NAH. The mean (SD) NAH SDS (NR) was -1.51 (0.60) (154.90 [3.21] cm) in females and -1.79 (1.09) (165.61 [7.19] cm) in males; 70.8% (17/24) had NAH SDS ≥ -2. Adverse drug reactions and GH-unrelated serious adverse events (n = 34) were reported in 22/412 (5.3%) patients. Four neoplasms and 3 cases of scoliosis were reported; no cardiovascular adverse events occurred. Conclusions: GH-treated children with NS achieved substantial height gain during the first 3 years of follow-up. Overall, 24 patients achieved NAH, with 70.8% having NAH SDS ≥ -2. There was no evidence to support a higher prevalence of neoplasm, or cardiac or other comorbidities.",

keywords = "Adolescent, Effectiveness, Growth hormone therapy, Near-adult height, Noonan syndrome, Puberty, RASopathy, Ras/mitogen-activated protein kinase, Real-world evidence, Safety",

author = "Rohrer, {Tilman R.} and Jennifer Abuzzahab and Philippe Backeljauw and Birkeg{\aa}rd, {Anna Camilla} and Joanne Blair and Jovanna Dahlgren and J{\'u}l{\'i}usson, {P{\'e}tur Benedikt} and Vlady Ostrow and Alberto Pietropoli and Michel Polak and Alicia Romano and Judith Ross and Lars S{\"a}vendahl and Miller, {Bradley S.}",

note = "Funding Information: Tilman R. Rohrer has acted as a consultant for Novo Nordisk and received speaker honoraria from Novo Nordisk. M. Jennifer Abuzzahab has received research grant/research support from As-cendis, Astra Zeneca, Levo, Millendo, Novo Nordisk, Rhythm, and Soleno. She has attended advisory boards for Ascendis and Rhythm and speaker{\textquoteright}s bureau for Novo Nordisk, Rhythm, and Sandoz. Philippe Backeljauw has received research grant support from Novo Nordisk, Opko, and Ipsen and is a consultant for Novo Nordisk, Ipsen, Sandoz, and Endo Pharmaceuticals. Anna Camilla Birkeg{\aa}rd, Vlady Ostrow, and Alberto Pietropoli are employees of Novo Nordisk. Jo Blair has acted as a consultant for Novo Nordisk, has received speaker honoraria from Novo Nordisk and Sandoz, and has received financial support in the form of registration fees from Novo Nordisk to attend academic meetings. Jovanna Dahlgren has received honoraria from Merck, Novartis, and Pfizer, as well as unrestricted grants from Pfizer for 2 clinical trials. Petur B. Juliusson has received a lecture fee from Novo Nordisk for a presentation at a Novo Nordisk meeting. Michel Polak is a member of the Increlex European registry and Novo Nordisk growth international advisory board and has institutional disclosures from Pfizer France. He has received grants from Ipsen, Novo Nordisk, Pfizer, Lilly, Sanofi, Sandoz, and Merck and government grants (PHRC, PHRIP, and ANR). Alicia Romano has been a consultant for Ascendis Pharma and is a consultant and speaker for Novo Nordisk. Judith Ross is a consultant for Novo Nordisk and Opko and receives research funding from Novo Nordisk. Lars S{\"a}vendahl has received consultancy fees from Ascendis, Hexal, Novo Nordisk, Merck, Pfizer, and Sandoz. Bradley S. Miller has been a consultant for Ascendis, BioMarin, Bluebird Bio, Gene-Science, Novo Nordisk, Pfizer, Sandoz, Sanofi Genzyme, Soleno, Takeda, Tolmar, and Versartis and has received research support from AbbVie, Alexion, Ascendis, Novo Nordisk, Opko, Orphan Reach, Sandoz, Sangamo, Sanofi Genzyme, Takeda, and Versartis in the last 3 years. Funding Information: The authors would like to thank the patients, their families, the nurses and study coordinators, and all investigators involved in this study. Statistical support was provided by Jean-Marc Ferran (Qualiance ApS) and Moshe Fridman (AMF Consulting), both under contract to Novo Nordisk A/S. Medical writing and editorial support were provided by Penny Butcher, PhD, and Helen Marshall of Watermeadow Medical, part of the Ashfield Group, supported by Novo Nordisk Health Care AG. The sponsor was involved in the study design and collection, analysis, and interpretation of data, as well as data checking of information provided in the manuscript. However, ultimate responsibility for opinions, conclusions, and data interpretation lies with the authors. This work was dedicated to the memory of Dr. Jacqueline Noonan (1928–2020). Publisher Copyright: {\textcopyright} 2020 The Author(s) Published by S. Karger AG, Basel.",

year = "2021",

month = feb,

doi = "10.1159/000512429",

language = "English (US)",

volume = "93",

pages = "380--395",

journal = "Hormone Research in Paediatrics",

issn = "1663-2818",

publisher = "S. Karger AG",

number = "6",

}

TY - JOUR

T1 - Long-Term Effectiveness and Safety of Childhood Growth Hormone Treatment in Noonan Syndrome

AU - Rohrer, Tilman R.

AU - Abuzzahab, Jennifer

AU - Backeljauw, Philippe

AU - Birkegård, Anna Camilla

AU - Blair, Joanne

AU - Dahlgren, Jovanna

AU - Júlíusson, Pétur Benedikt

AU - Ostrow, Vlady

AU - Pietropoli, Alberto

AU - Polak, Michel

AU - Romano, Alicia

AU - Ross, Judith

AU - Sävendahl, Lars

AU - Miller, Bradley S.

N1 - Funding Information: Tilman R. Rohrer has acted as a consultant for Novo Nordisk and received speaker honoraria from Novo Nordisk. M. Jennifer Abuzzahab has received research grant/research support from As-cendis, Astra Zeneca, Levo, Millendo, Novo Nordisk, Rhythm, and Soleno. She has attended advisory boards for Ascendis and Rhythm and speaker’s bureau for Novo Nordisk, Rhythm, and Sandoz. Philippe Backeljauw has received research grant support from Novo Nordisk, Opko, and Ipsen and is a consultant for Novo Nordisk, Ipsen, Sandoz, and Endo Pharmaceuticals. Anna Camilla Birkegård, Vlady Ostrow, and Alberto Pietropoli are employees of Novo Nordisk. Jo Blair has acted as a consultant for Novo Nordisk, has received speaker honoraria from Novo Nordisk and Sandoz, and has received financial support in the form of registration fees from Novo Nordisk to attend academic meetings. Jovanna Dahlgren has received honoraria from Merck, Novartis, and Pfizer, as well as unrestricted grants from Pfizer for 2 clinical trials. Petur B. Juliusson has received a lecture fee from Novo Nordisk for a presentation at a Novo Nordisk meeting. Michel Polak is a member of the Increlex European registry and Novo Nordisk growth international advisory board and has institutional disclosures from Pfizer France. He has received grants from Ipsen, Novo Nordisk, Pfizer, Lilly, Sanofi, Sandoz, and Merck and government grants (PHRC, PHRIP, and ANR). Alicia Romano has been a consultant for Ascendis Pharma and is a consultant and speaker for Novo Nordisk. Judith Ross is a consultant for Novo Nordisk and Opko and receives research funding from Novo Nordisk. Lars Sävendahl has received consultancy fees from Ascendis, Hexal, Novo Nordisk, Merck, Pfizer, and Sandoz. Bradley S. Miller has been a consultant for Ascendis, BioMarin, Bluebird Bio, Gene-Science, Novo Nordisk, Pfizer, Sandoz, Sanofi Genzyme, Soleno, Takeda, Tolmar, and Versartis and has received research support from AbbVie, Alexion, Ascendis, Novo Nordisk, Opko, Orphan Reach, Sandoz, Sangamo, Sanofi Genzyme, Takeda, and Versartis in the last 3 years. Funding Information: The authors would like to thank the patients, their families, the nurses and study coordinators, and all investigators involved in this study. Statistical support was provided by Jean-Marc Ferran (Qualiance ApS) and Moshe Fridman (AMF Consulting), both under contract to Novo Nordisk A/S. Medical writing and editorial support were provided by Penny Butcher, PhD, and Helen Marshall of Watermeadow Medical, part of the Ashfield Group, supported by Novo Nordisk Health Care AG. The sponsor was involved in the study design and collection, analysis, and interpretation of data, as well as data checking of information provided in the manuscript. However, ultimate responsibility for opinions, conclusions, and data interpretation lies with the authors. This work was dedicated to the memory of Dr. Jacqueline Noonan (1928–2020). Publisher Copyright: © 2020 The Author(s) Published by S. Karger AG, Basel.

PY - 2021/2

Y1 - 2021/2

N2 - Introduction: Few data exist on long-term growth hormone (GH) treatment in patients with Noonan syndrome (NS). Objective: To evaluate the effectiveness and safety of GH treatment in NS in clinical practice. Methods: Height gain, near-adult height (NAH), and safety were assessed in 2 complementary non-interventional studies: NordiNet® IOS and ANSWER. The safety analysis included 412 patients, and the effectiveness analysis included 84 GH-treated patients (male, n = 67) with ≥4 years' height standard deviation score (HSDS) data. HSDS was determined using national reference (NR) and NS-specific (NSS) data. Results: The mean (SD) baseline age was 8.38 (3.57) years; HSDS, -2.76 (1.03); GH dose, 41.6 (11.1) μg/kg/day. The mean (SD) HSDS increase from baseline (ΔHSDS) was 0.49 (0.37) (first year), 0.79 (0.58) (second year), and 1.01 (0.60) (third year) (NR). The mean (SD) HSDS at year 3 was -1.66 (1.00) (NR; 1.06 [1.12] [NSS]). Twenty-four patients achieved NAH. The mean (SD) NAH SDS (NR) was -1.51 (0.60) (154.90 [3.21] cm) in females and -1.79 (1.09) (165.61 [7.19] cm) in males; 70.8% (17/24) had NAH SDS ≥ -2. Adverse drug reactions and GH-unrelated serious adverse events (n = 34) were reported in 22/412 (5.3%) patients. Four neoplasms and 3 cases of scoliosis were reported; no cardiovascular adverse events occurred. Conclusions: GH-treated children with NS achieved substantial height gain during the first 3 years of follow-up. Overall, 24 patients achieved NAH, with 70.8% having NAH SDS ≥ -2. There was no evidence to support a higher prevalence of neoplasm, or cardiac or other comorbidities.

AB - Introduction: Few data exist on long-term growth hormone (GH) treatment in patients with Noonan syndrome (NS). Objective: To evaluate the effectiveness and safety of GH treatment in NS in clinical practice. Methods: Height gain, near-adult height (NAH), and safety were assessed in 2 complementary non-interventional studies: NordiNet® IOS and ANSWER. The safety analysis included 412 patients, and the effectiveness analysis included 84 GH-treated patients (male, n = 67) with ≥4 years' height standard deviation score (HSDS) data. HSDS was determined using national reference (NR) and NS-specific (NSS) data. Results: The mean (SD) baseline age was 8.38 (3.57) years; HSDS, -2.76 (1.03); GH dose, 41.6 (11.1) μg/kg/day. The mean (SD) HSDS increase from baseline (ΔHSDS) was 0.49 (0.37) (first year), 0.79 (0.58) (second year), and 1.01 (0.60) (third year) (NR). The mean (SD) HSDS at year 3 was -1.66 (1.00) (NR; 1.06 [1.12] [NSS]). Twenty-four patients achieved NAH. The mean (SD) NAH SDS (NR) was -1.51 (0.60) (154.90 [3.21] cm) in females and -1.79 (1.09) (165.61 [7.19] cm) in males; 70.8% (17/24) had NAH SDS ≥ -2. Adverse drug reactions and GH-unrelated serious adverse events (n = 34) were reported in 22/412 (5.3%) patients. Four neoplasms and 3 cases of scoliosis were reported; no cardiovascular adverse events occurred. Conclusions: GH-treated children with NS achieved substantial height gain during the first 3 years of follow-up. Overall, 24 patients achieved NAH, with 70.8% having NAH SDS ≥ -2. There was no evidence to support a higher prevalence of neoplasm, or cardiac or other comorbidities.

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KW - Effectiveness

KW - Growth hormone therapy

KW - Near-adult height

KW - Noonan syndrome

KW - Puberty

KW - RASopathy

KW - Ras/mitogen-activated protein kinase

KW - Real-world evidence

KW - Safety

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Long-Term Effectiveness and Safety of Childhood Growth Hormone Treatment in Noonan Syndrome

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