Albright Hereditary Osteodystrophy: Growth Hormone Trial and Cognitive/Behavioral Assessments - Full Text View

Purpose

We, the researchers, have found that growth hormone deficiency is very common in patients with pseudohypoparathyroidism type 1a, which falls under the broader condition termed Albright hereditary osteodystrophy. Patients with pseudohypoparathyroidism type 1a typically are short and obese. Some of these patients are not short during childhood, but due to a combination of factors, they end up short as adults. We are evaluating the effect of growth hormone treatment in those patients with pseudohypoparathyroidism type 1a who are found to be growth hormone deficient. We hypothesize that growth hormone deficiency may contribute to the short stature and obesity found in this condition. We are also evaluating the effect of growth hormone on patients with pseudohypoparathyroidism type 1a who are not growth hormone deficient (i.e., growth hormone sufficient) in those who had been on study drug through R01 FD003409 or who meet the criteria of idiopathic short stature or SGA.

We are also evaluating neurocognitive and psychosocial functioning in participants with AHO in order to determine the specific impairments that are most common in the condition and to determine the best approach toward management.

Funding source -- Growth hormone study: FDA OOPD [R01 FD003409 (which has ended) and R01 FD002568 (which has ended)] Cognitive/behavior: NICHD R21 HD078864

Condition	Intervention	Phase
Pseudohypoparathyroidism Type 1a Albright Hereditary Osteodystrophy	Drug: Growth hormone Drug: Growth Hormone	Phase 2 Phase 3


Study Type:	Interventional
Study Design:	Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Study of Growth Hormone Use in Patients With Pseudohypoparathyroidism Type 1a and Assessment of Cognitive/Behavioral Status in Albright Hereditary Osteodystrophy

Resource links provided by NLM:

MedlinePlus related topics: Hormones

Drug Information available for: Somatropin

Genetic and Rare Diseases Information Center resources: Growth Hormone Deficiency Isolated Growth Hormone Deficiency Pseudohypoparathyroidism Pseudopseudohypoparathyroidism Albright's Hereditary Osteodystrophy Pseudohypoparathyroidism Type 1A

U.S. FDA Resources

Further study details as provided by Hugo W. Moser Research Institute at Kennedy Krieger, Inc.:

Primary Outcome Measures:

PHP1a: Effect of GH on height, growth velocity, final height in children. Effect on weight, BMI, lipids, self-esteem in all ages. [ Time Frame: until achieve final height (approximately 12-15 years) ]
Cognitive and behavioral function in Albright hereditary osteodystrophy [ Time Frame: participant will be assessed on day 1; assessment may extend into day 2 ]


Estimated Enrollment:	300
Study Start Date:	January 2003
Estimated Study Completion Date:	December 2025
Estimated Primary Completion Date:	October 2019 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Growth hormone Growth hormone use in PHP1a. For GH deficient PHP1a participants, the GH use is under FDA-approved indications, and the GH is considered as treatment (not study drug). For GH sufficient PHP1a participants (all are children), the GH use is considered as study drug unless the patient meets the criteria of idiopathic short stature (in which case the GH is considered an FDA-approved treatment).	Drug: Growth hormone Growth hormone Other Names: Nutropin AQ Nutropin Genotropin Saizen Norditropin Humatrope Tev-tropin Omnitrope Drug: Growth Hormone Pseudohypoparathyroidism type 1a (growth hormone deficient): subcutaneous form, 0.15 mg - 0.30 mg per kg per week divided into daily doses, titrated by response and IGF-1 levels. The duration is participant dependent. For phase for growth hormone sufficient participants with PHP1a, dosage may be up to 0.37 mg per kg per week divided into daily doses subcutaneously, titrated by response and IGF-1 levels. The duration is participant dependent and also dependent on length of study and period of active recruitment. For all GH-sufficient participants, the GH use is initiated in patients who are over 3 years of age and who are pre-pubertal provided that there are no contraindications to its use. [Enrollment for study drug has been completed and supply of study drug has ended.] As of now, the growth hormone sufficient participants must meet the criteria of idiopathic short stature or SGA indication in order to be considered for GH. Other Names: Nutropin AQ Nutropin Genotropin Saizen Norditropin Humatrope Tev-tropin Omnitrope

Arms

Assigned Interventions

Growth hormone

Growth hormone use in PHP1a.

For GH deficient PHP1a participants, the GH use is under FDA-approved indications, and the GH is considered as treatment (not study drug).

For GH sufficient PHP1a participants (all are children), the GH use is considered as study drug unless the patient meets the criteria of idiopathic short stature (in which case the GH is considered an FDA-approved treatment).

Drug: Growth hormone

Growth hormone

Other Names:

Nutropin AQ
Nutropin
Genotropin
Saizen
Norditropin
Humatrope
Tev-tropin
Omnitrope

Drug: Growth Hormone

Pseudohypoparathyroidism type 1a (growth hormone deficient): subcutaneous form, 0.15 mg - 0.30 mg per kg per week divided into daily doses, titrated by response and IGF-1 levels. The duration is participant dependent.

For phase for growth hormone sufficient participants with PHP1a, dosage may be up to 0.37 mg per kg per week divided into daily doses subcutaneously, titrated by response and IGF-1 levels. The duration is participant dependent and also dependent on length of study and period of active recruitment.

For all GH-sufficient participants, the GH use is initiated in patients who are over 3 years of age and who are pre-pubertal provided that there are no contraindications to its use. [Enrollment for study drug has been completed and supply of study drug has ended.] As of now, the growth hormone sufficient participants must meet the criteria of idiopathic short stature or SGA indication in order to be considered for GH.

Other Names:

Nutropin AQ
Nutropin
Genotropin
Saizen
Norditropin
Humatrope
Tev-tropin
Omnitrope

Detailed Description:

Pseudohypoparathyroidism type 1a (PHP1a) is a disorder that causes many endocrine and developmental problems. To date, medical treatment has focused primarily on maintenance of normal serum levels of calcium, phosphorous, and thyroid hormone. However, these therapeutic interventions do not address the problems of short stature, obesity, and subcutaneous ossifications, which for many are a source of considerable morbidity and personal distress. These patients require frequent medical care, blood tests, and medication adjustments. PHP1a is an inherited condition with an estimated prevalence in the United States of 1:15,000- 20,000, and the studies that we propose provide an opportunity to improve the quality of life in affected patients. We have found that growth hormone (GH) deficiency is common in these patients, and our data suggest that GH testing should be part of their routine standard of care. We are investigating whether GH treatment can increase linear growth velocity and final adult height in children. We are also investigating whether GH treatment can reduce weight and improve a variety of metabolic disturbances and overall health in both children and adults.

GH deficiency not only leads to short stature and obesity, but also to osteoporosis, hyperlipidemia, depressed cardiac and renal function, as well as an overall lack of energy. It is quite possible that treatment of GH-deficient patients with PHP1a could improve any or all of the above problems. GH treatment has been FDA approved for use in both children and adults with GH deficiency. Therefore, it may be possible to provide improvement in health and overall quality of life in these patients.

Additionally, we have initiated a research study for which we are treating children with PHP1a who are not GH deficient (i.e., GH sufficient). The rationale is that GH treatment could maximize linear growth velocity prior to the premature bone fusion that occurs in this condition and potentially improve final adult height. The supply of growth hormone has ended for this study, and we are following those participants who were in this study and received the growth hormone supply.

This study also seeks to define the specific neurocognitive and psychosocial disabilities in individuals with AHO in order to develop therapies and improve quality of life.

Eligibility


Ages Eligible for Study:	2 Months to 89 Years (Child, Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria for GH study:

Diagnosis of pseudohypoparathyroidism type 1a
For the portion of the study in which growth hormone is used for participants who are not growth hormone deficient (ie., growth hormone sufficient), the patient must be over 3 years of age (ie., after 3rd birthday) AND also be pre-pubertal at the time of GH initiation. As of now, the growth hormone sufficient participants must meet the criteria of idiopathic short stature or SGA indication.

Exclusion Criteria:

Absence of above diagnosis

Inclusion for cognitive/behavioral studies:

Confirmed diagnosis of Pseudohypoparathyroidism type 1a and Pseudopseudohypoparathyroidism
Ages 6 - 65 yrs

Exclusion:

Absence of above

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00209235

Contacts


Contact: Emily L Germain-Lee, MD	443-923-2703	germainlee@kennedykrieger.org

Locations


United States, Maryland
Kennedy Krieger Institute and Johns Hopkins Hospital	Recruiting
Baltimore, Maryland, United States, 21205
Contact: Emily L Germain-Lee, MD 443-923-2703 germainlee@kennedykrieger.org
Principal Investigator: Emily L Germain-Lee, MD

Sponsors and Collaborators

Hugo W. Moser Research Institute at Kennedy Krieger, Inc.

Johns Hopkins University

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators


Principal Investigator:	Emily L Germain-Lee, MD	Kennedy Krieger Institute and Johns Hopkins University School of Medicine

More Information

Publications:

Germain-Lee EL. Short stature, obesity, and growth hormone deficiency in pseudohypoparathyroidism type 1a. Pediatr Endocrinol Rev. 2006 Apr;3 Suppl 2:318-27. Review.

Long DN, Levine MA, Germain-Lee EL. Bone mineral density in patients with pseudohypoparathyroidism type 1a. EndoTrends 12(4):4,2006.

Long DN, McGuire S, Levine MA, Weinstein LS, Germain-Lee EL. Body mass index differences in pseudohypoparathyroidism type 1a versus pseudopseudohypoparathyroidism may implicate paternal imprinting of Galpha(s) in the development of human obesity. J Clin Endocrinol Metab. 2007 Mar;92(3):1073-9. Epub 2006 Dec 12.

Hsu SC, Groman JD, Merlo CA, Naughton K, Zeitlin PL, Germain-Lee EL, Boyle MP, Cutting GR. Patients with mutations in Gsalpha have reduced activation of a downstream target in epithelial tissues due to haploinsufficiency. J Clin Endocrinol Metab. 2007 Oct;92(10):3941-8. Epub 2007 Jul 24.

Plagge A, Kelsey G, Germain-Lee EL. Physiological functions of the imprinted Gnas locus and its protein variants Galpha(s) and XLalpha(s) in human and mouse. J Endocrinol. 2008 Feb;196(2):193-214. doi: 10.1677/JOE-07-0544. Review.

Long DN, Levine MA, Germain-Lee EL. Bone mineral density in pseudohypoparathyroidism type 1a. J Clin Endocrinol Metab. 2010 Sep;95(9):4465-75. doi: 10.1210/jc.2010-0498. Epub 2010 Jul 7.

Joseph AW, Shoemaker AH, Germain-Lee EL. Increased prevalence of carpal tunnel syndrome in albright hereditary osteodystrophy. J Clin Endocrinol Metab. 2011 Jul;96(7):2065-73. doi: 10.1210/jc.2011-0013. Epub 2011 Apr 27.

Muniyappa R, Warren MA, Zhao X, Aney SC, Courville AB, Chen KY, Brychta RJ, Germain-Lee EL, Weinstein LS, Skarulis MC. Reduced insulin sensitivity in adults with pseudohypoparathyroidism type 1a. J Clin Endocrinol Metab. 2013 Nov;98(11):E1796-801. doi: 10.1210/jc.2013-1594. Epub 2013 Sep 12.

Lin MH, Numbenjapon N, Germain-Lee EL, Pitukcheewanont P. Progressive osseous heteroplasia, as an isolated entity or overlapping with Albright hereditary osteodystrophy. J Pediatr Endocrinol Metab. 2015 Jul;28(7-8):911-8. doi: 10.1515/jpem-2014-0435.

Germain-Lee EL, Groman J, Crane JL, Jan de Beur SM, Levine MA. Growth hormone deficiency in pseudohypoparathyroidism type 1a: another manifestation of multihormone resistance. J Clin Endocrinol Metab. 2003 Sep;88(9):4059-69.

Germain-Lee EL, Ding CL, Deng Z, Crane JL, Saji M, Ringel MD, Levine MA. Paternal imprinting of Galpha(s) in the human thyroid as the basis of TSH resistance in pseudohypoparathyroidism type 1a. Biochem Biophys Res Commun. 2002 Aug 9;296(1):67-72.

Germain-Lee EL, Schwindinger W, Crane JL, Zewdu R, Zweifel LS, Wand G, Huso DL, Saji M, Ringel MD, Levine MA. A mouse model of albright hereditary osteodystrophy generated by targeted disruption of exon 1 of the Gnas gene. Endocrinology. 2005 Nov;146(11):4697-709. Epub 2005 Aug 11.

Levine MA, Germain-Lee E, Jan de Beur S. Genetic basis for resistance to parathyroid hormone. Horm Res. 2003;60 Suppl 3:87-95. Review.

Jan de Beur S, Ding C, Germain-Lee E, Cho J, Maret A, Levine MA. Discordance between genetic and epigenetic defects in pseudohypoparathyroidism type 1b revealed by inconsistent loss of maternal imprinting at GNAS1. Am J Hum Genet. 2003 Aug;73(2):314-22. Epub 2003 Jul 11.

Crane JL, Shamblott MJ, Axelman J, Hsu S, Levine MA, Germain-Lee EL. Imprinting status of Galpha(s), NESP55, and XLalphas in cell cultures derived from human embryonic germ cells: GNAS imprinting in human embryonic germ cells. Clin Transl Sci. 2009 Oct;2(5):355-60. doi: 10.1111/j.1752-8062.2009.00148.x.

Huso DL, Edie S, Levine MA, Schwindinger W, Wang Y, Jüppner H, Germain-Lee EL. Heterotopic ossifications in a mouse model of albright hereditary osteodystrophy. PLoS One. 2011;6(6):e21755. doi: 10.1371/journal.pone.0021755. Epub 2011 Jun 29.

Myllylä RM, Haapasaari KM, Palatsi R, Germain-Lee EL, Hägg PM, Ignatius J, Tuukkanen J. Multiple miliary osteoma cutis is a distinct disease entity: four case reports and review of the literature. Br J Dermatol. 2011 Mar;164(3):544-52. doi: 10.1111/j.1365-2133.2010.10121.x. Epub 2011 Feb 17. Review.


Responsible Party:	Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
ClinicalTrials.gov Identifier:	NCT00209235 History of Changes
Other Study ID Numbers:	NA_00044877 R01FD002568 ( US NIH Grant/Contract Award Number ) R01FD003409 ( US NIH Grant/Contract Award Number ) R21HD078864 ( US NIH Grant/Contract Award Number )
Study First Received:	September 13, 2005
Last Updated:	August 23, 2016

Keywords provided by Hugo W. Moser Research Institute at Kennedy Krieger, Inc.:


Pseudohypoparathyroidism Type 1a (PHP 1a) Albright Hereditary Osteodystrophy Growth Hormone Deficiency

Additional relevant MeSH terms:


Pseudohypoparathyroidism Pseudopseudohypoparathyroidism Bone Diseases, Metabolic Bone Diseases Musculoskeletal Diseases Metal Metabolism, Inborn Errors Metabolism, Inborn Errors	Genetic Diseases, Inborn Calcium Metabolism Disorders Metabolic Diseases Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs

ClinicalTrials.gov processed this record on May 25, 2017