Clinical trial NCT00001305
Conditions: Osteogenesis Imperfecta
Keywords: Osteogenesis Imperfecta
Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Start date: 1991-11-05; Completion date: 2017-05-19
Enrollment: 42 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Growth deficiency is a key feature of severe Osteogenesis Imperfecta (OI) and a frequent feature of mild to moderate forms of the disease. The reason that children with OI are short is not fully understood. We do know that details such as the number of fractures suffered or the type of OI do not fully explain the short stature of OI. Growth patterns have been defined for children with OI Types I, III, and IV. At about 12 months of age, children with Types III and IV OI demonstrate a predictable plateau of their linear growth rate. Type IV OI children begin to resume a normal growth rate at about age four to five years, but they will not "catch up" to a normal height, as they have "lost" a significant period of growth. The plateau usually continues for children with Type III OI. The reason for this growth plateau is unknown. There have been no studies which evaluate the growth of OI children in this age range. Our previous studies of growth in OI children have begun at age 5 years.

We have studied growth in OI children for the past 10 years. Different medications have been tried to both stimulate growth and improve bone density. Some children have responded to growth hormone (their growth rate increased by at least 50%) and some did not. The majority of children who did respond were Type IV. However, we need to carefully treat and study more children to try to determine which children will benefit from growth hormone medication.

The Goals of this Study Are:

1. We want to try to find a cause for the growth plateau common in types III and IV OI. Long-term, our goal is to develop a treatment to eliminate this plateau.
2. We want to see how long and how well OI bone will respond to growth stimulation.
3. We hope to find a "predictor" for who will respond to growth hormone and who will not, by measuring your child's endocrine and growth hormone function before receiving any growth hormone treatment.
4. We want to measure the effects of growth stimulation on bone density, and the quality of OI bone.
5. We want to see if there are long term benefits resulting from this treatment in the form of final adult height, trunk height, and possibly improved function of the respiratory system.

Median Subject Age (on p. 1 of webpage): 1-15 years (replaces 0-20)

Detailed description:
Growth deficiency is a cardinal feature of severe Osteogenesis Imperfecta (OI) and a frequent feature of mild to moderate forms of this disease. Despite the prevalence of short stature among people with OI, few studies have examined treatment options for this feature of OI. Recombinant human growth hormone (rGH) is a treatment for growth deficiency which we have investigated. In our initial studies we have found that many OI children are responsive to rGH especially those with type IV OI. The purpose of this protocol is to examine the effect of growth hormone treatment on linear growth of children with types III and IV OI and correlate growth responsiveness with growth hormone-somatomedin axis and histomorphometry parameters of OI bone.

Arms: arm 1: Treatment of children with types III and IV osteogenesis imperfecta with Humatrope
Interventions: intervention 1: Humatrope
Intervention descriptions: intervention 1: Patients receive a subcutaneous injection.

Protocol documents:
Prot_000.pdf: 
IND 37368 
 
Date: April 18th, 2017 
To: 
Karim Calis, Pharm.D., MPH, IRB Chair, NICHD IRB 
Recommended by: 
 
 
 
Joan C. Marini. M.D., Ph.D., Chief, Bone & Extracellular Matrix Branch, NICHD 
 
 
 
Forbes D. Porter, M.D., Ph.D., Clinical Director, NICHD 
 
Project Title: 
Studies of Growth Deficiency and Growth Hormone 
Treatment in Children with Osteogenesis Imperfecta Types 
III and IV 
 
Principal Investigator: 
Joan C. Marini, M.D., Ph.D. 
Chief, Bone and Extracellular Matrix Branch, NICHD, NIH 
 
Associate Investigators: 
Timothy Bhattacharyya, MD, Orthopaedic Surgeon-BC   
Clinical and Investigative Orthopaedics Section of the 
Intramural Research Program, NIAMS 
 
Judith Holt, CRNP, MS, BSN 
Nurse Practitioner, Office of the Clinical Director, NICHD, 
NIH 
 
Outside Collaborators: 
Caren Gundberg, Ph.D., Department of Orthopedics, 
Yale University 
 
Theresa Hefferan, Ph.D., Mayo Clinic, Rochester MN 
Estimated Duration of Study: 
20 years 
Total Patients to be Recruited: 
60 
 
Normal Volunteers: 
None 
 
Description of Patient Population: Children with Osteogenesis Imperfecta (Types III and 
IV), and short stature, ages 3 through 15 years. 


2 
 
 
 
PRECIS: 
 
Growth deficiency is a cardinal feature of severe Osteogenesis Imperfecta (OI) and a 
frequent feature of mild to moderate forms of this disease. Despite the prevalence of short 
stature among people with OI, few studies have examined treatment options for this 
feature of OI. Recombinant human growth hormone (rGH) is a treatment for growth 
deficiency which we have investigated. In our initial studies we have found that many OI 
children are responsive to rGH, especially those with type IV OI. The purpose of this 
protocol is to examine the effect of growth hormone treatment on linear growth of 
children with types III and IV OI and correlate growth responsiveness with growth 
hormone-somatomedin axis and histomorphometry parameters of OI bone. 


3 
 
 
INTRODUCTION: 
 
Osteogenesis Imperfecta (OI) is a heritable disorder of connective tissue with bone 
fragility as the hallmark feature. Classical autosomal dominant OI is caused by structural 
defects in the genes coding for type I collagen (COL1A1 and COL1A2). [1] Growth 
deficiency is the most striking secondary feature of OI.  Severe growth deficiency is 
always present in type III OI and is a frequent feature of moderate (type IV) OI.  In 
general, the degree of growth deficiency parallels the severity of the bone disease in 
morphologic and radiographic features but not in fracture number. [2] 
 
Typical growth patterns have been defined for classical autosomal dominant OI types. 
Many of these children are small to normal size at birth, but virtually all Types III and IV 
patients begin to plateau in length beginning about 12 months. This continues through 
about age 4 years for Type IV, when most of these children begin to grow at normal 
growth rates, but below the lowest percentiles of the standard growth chart curve. It is 
possible that Type IV children could have normal stature if the plateau phase were 
eliminated. Type III children tend to demonstrate only small growth gains. [3] The 
reasons for this plateau phase are unknown. The National Institute of Child Health and 
Development (NICHD)  has produced data addressing growth deficiency in older OI 
children, but there have been no efforts to date focused on the plateau phase in early 
childhood. [4] 
 
At a molecular level, autosomal dominant osteogenesis imperfecta is associated with 
defects in either of the two chains which comprise type I collagen. [5] Type I collagen is 
a heterotrimer, made up of two α1 chains and one α2 chain, which constitutes the most 
abundant protein in bone, skin, and tendon. Inadequate amounts or abnormal forms of 
type I collagen can account for the matrix abnormalities, osteoporosis and bone fragility 
of OI. [6] The role of skeletal matrix abnormalities in short stature is unclear. Possible 
roles include unresponsiveness of the target tissue to local and systemic growth factors or 
abnormal feedback of target tissue on the endocrine axis. 
 
There is now considerable data available on normal growth markers in children. At the 
research level of investigation, unstimulated 12 and 24 hour growth hormone sampling 
and somatomedin generation testing have become routine in the evaluation of growth in 
children. [7] Dr. Rose has also produced data on unstimulated 6 hour growth hormone 
sampling. She has found that the 6 hour sampling corresponds to the 12 hour results. [8] 
The data most applicable to our population of 1-5 years of age were determined in pre- 
pubertal children below the age of 8 years. Unless our results show marked 
inconsistencies, there is no reason not to consider this normative data comparable (S. 
Rose, personal communication). Markers of skeletal formation include osteocalcin, a 
bone specific protein made by osteoblasts, and procollagen peptide type I (PICP). Studies 
have shown that these markers correlate with age and puberty, reflecting higher levels 
during periods of maximum growth, and very low levels as puberty ends and during 
adulthood. [9] 


4 
 
 
 
Markers of bone turnover include bone specific alkaline phosphatase, IGF Binding 
Protein-3 (IGFBP-3), and Growth Hormone Binding Protein (GHBP). We have assessed 
these values in the children currently enrolled in the OI growth hormone study.. Specific 
normative data is available for bone specific alkaline phosphatase and IGFBP-3.  IGFBP- 
3 normative data is available in 2-4 year ranges, beginning at birth. Recently bone 
specific alkaline phosphatase during childhood (i.e., 2 months to 18 years broken down to 
2 year intervals) have been established. [10] In contrast, normative data about GHBP, 
which indirectly measures the circulating portion of the growth hormone receptor, is 
available but the age ranges are very broad, ages 3 to 10 years, and 10 to 15 years 
 
We began investigating the status of hormones related to growth in 28 children with 
osteogenesis imperfecta. [11] This original investigation was prompted by the observation 
that several children with OI, who served as non-endocrine controls in GHD studies, did 
not have normal test results. Our goals were to determine 1. whether there were any 
abnormalities of the growth hormone / somatomedin-C axis in this condition, 2. whether 
any abnormalities correlated with the type of OI, and 3. whether OI bone could be safely 
stimulated to grow. The endocrine evaluation of the OI children included a GRF 
stimulation test, three standard GH provocative tests (Arginine-Insulin tolerance test, L- 
Dopa stimulation test), a 24 hour q 20 minute sampling for measuring basal, unstimulated 
concentrations of GH and a somatomedin generation test. 
 
Endocrine evaluation of 28 patients at the NIH has shown that about half of them have a 
low area under the integrated curve of unstimulated 24 hour growth hormone secretion, 
and fail to respond positively to a growth hormone releasing hormone stimulation test or 
a somatomedin generation test. [12] 
 
Complete evaluation of the hormonal axis related to growth in short children with OI 
revealed subtle deviations from normal in some of the children; there was no pattern of 
response to any test or among any sequence of tests that correlated with the type of OI or 
the degree of growth deficiency. The only significant correlation of test results was that 
12 children, whose response to GRH was comparable to the GRH response of GHD 
children [13], had a significantly lower area under the 24 hour curve of unstimulated 
growth hormone secretion, while 14 children with a normal response to GRH also had a 
normal area under the 24 hour growth hormone secretion curve. Thus, one group 
appeared to have a relatively hypoactive growth hormone axis even though, by standard 
criteria of GH provocative tests and the 24 hour GH sampling, they did not fill the criteria 
of growth hormone deficiency. 
 
Furthermore, the OI children as a group demonstrated a blunted response in the 
somatomedin generation test, with 21/28 children having a baseline IGF-I below the 
mean for age and 18/28 children having less than a two-fold stimulation in response to 
growth hormone injections. The group with blunted IGF-I response did not correlate with 
the low GRH-low 24 hour area group. This was not surprising since one would not expect 
relatively low growth hormone to be correlated with unresponsiveness of somatomedin to 
growth hormone stimulation. More problematic was the interpretation of IGF-I levels in 
children, whatever their height or bone morphology. IGF-I is known to be responsive to 
GH stimulation and is itself functionally defined in terms of its ability to stimulate 


5 
 
 
 
sulfation in bone. [14] Although the predominant quantity of IGF-I is made in the liver, it 
is also made in multiple other tissues including bone itself, where its synthesis has been 
localized to a region of the growth plate. [15] The tissue of origin of basal and GH- 
stimulated IGF-I is unmeasurable and so the functional significance of the test is difficult 
to assess. In a primary defect of bone matrix, even a successful stimulation of IGF-I level 
may not represent an effective functional increment in terms of growth stimulation. 
 
The study of the growth response of OI bone to growth hormone also allowed us to 
address the effect of hormonal stimulation on the secondary consequences of abnormal 
bone matrix (collagen) by measurement of the histomorphometry of the bone. 
There is in vitro evidence demonstrating that growth hormone stimulates proliferation of 
osteoblasts and increases their production of collagen via IGF-I. [3] In the current 
protocol, we propose to examine iliac crest biopsies to determine if there is an effect of 
growth hormone on bone histomorphometric parameters apart from its effect on linear 
growth. Previous studies [4] on tetracycline-labeled iliac crest biopsies from OI children 
have demonstrated 1. decreased cancellous bone volume and trabecular thickness, 2. no 
evidence of increased resorption, 3. decreased synthesis of an organized matrix in type I 
OI (mild), 4. disorganized matrix in type III OI (severe), consisting of a mixture of 
lamellar and woven structure with irregular tetracycline labeling, and 5. poor 
organization of cortical bone in type III OI, often with absence of Haversian systems. 
 
This protocol has produced some encouraging results for rGH treatment of OI children. 
We have treated 36 children, ages 5-12 years and including 14 type III and 22 type IV OI 
children. During the treatment trial, children receive 0.06mg/kg/day of Humatrope, 6 
days per week for one year. Nineteen of the 36 children demonstrated a positive response 
to treatment. This responder group was composed predominantly of children with type 
IV OI; 13 of the responders have type IV OI and 70% of the treated type IV children 
were growth responders. [9] Overall, half of the treated children responded. 
 
The only bone metabolic marker which differentiated responders from non-responders 
was procollagen peptide type I (p=0.04). Responders had higher PICP than non- 
responders at baseline and after 6 and 12 months of treatment. A cut-off PICP value of 
86 mg/ml is 73% predictive of OI response to rGH. 
 
The total patient group showed significant increases over baseline in IGF-I, IGFBP-3, 
Procollagen Peptide type I, and osteocalcin by 6 months of treatment. Bone specific 
alkaline phosphatase was significantly increased over baseline by one year. [9] 
 
Bone histomorphometrics of responders show a significant increase in bone volume/total 
volume, mineralized bone volume/total volume and bone formation rate/total volume. [9] 
 
Our interpretation of our results is that there is a significant population of OI children, 
especially with type IV OI, who respond to growth hormone treatment with increased 
growth rates and positive changes in bone formation. 


6 
 
 
 
 
 
OBJECTIVES: 
 
(1) 
To determine the range and duration of growth responsiveness of OI bone; 
(2) 
To determine the correlation of this growth responsiveness with the results of the 
endocrine evaluation of the growth hormone somatomedin axis; 
(3) 
To determine the effect of growth hormone on the density and histomorphometric 
parameters of OI bone; 
(4) 
To determine the long term benefits of this therapy for final stature, trunk length, 
and pulmonary function. 
 
STUDY DESIGN AND METHODS: 
 
 
 
PART A 
PRE - TREATMENT YEAR AND EVALUATION OF HORMONAL STATUS 
 
The pre-treatment interval will be a one year time period during which children will be 
serving as their own baseline controls. The visit schedule will be every 3 months. Linear 
growth on each side of the body will be measured at each visit with 5 lengths using a 
supine length board. Other measurements at each visit will include weight, arm span, 
sitting height, upper and lower extremity segments, and head circumference. At 6 month 
intervals, radiographic assessments of spine, and lower extremities will be performed, as 
well as bone density of the lumbar spine. Radiographic assessments of bone age will be 
done annually. 
 
Children enrolled in this protocol will be co-enrolled in protocol 97-CH-0064 and will 
undergo pulmonary testing and neurological imaging on the schedule for that protocol. 
For pulmonary function testing, the tests will be completed at Children’s National 
Medical Center. Children too young to cooperate with the procedures of pulmonary 
function testing will not be sedated for these procedures. Additionally, neuroimaging 
studies of the head and neck, including CT and MRI scan, will commence when the child 
is able to cooperate without needing sedation. In our experience, children age 4-5 years 
are able to hold still for the CT scan, which takes approximately 5-10 minutes. If signs of 
Basilar Invagination (BI) are detected, the children progress to having MRI scans every 
year. 
 
An iliac crest bone biopsy will be obtained at the beginning of the treatment year for 
growth hormone. This biopsy will be repeated at the end of the growth hormone 
treatment year. The biopsies will be obtained by Dr. Bhattacharyya for analysis in Dr. 
Hefferan’s laboratory. The procedure will be performed under general anesthesia in the 
operating room at the NIH. 
 
During the pre-treatment year, the following testing will be done for endocrine 
evaluation. 


7 
 
 
 
1. 
Baseline CBC 
1.5cc 
2. 
Somatomedin Generation Test [14] 
3.2 cc / draw (includes discard) 
2.0 cc added to Baseline and Day 5 
20.0 cc total 
 
Our experience with this test in OI children shows that 89% demonstrate a peak 
response beginning at 48 hours after the initial injection. Therefore we plan to do 
the full 6 day test, but only draw blood at baseline (day 0) and days 2-5.  To 
evaluate for the possibility of growth hormone resistance, we will measure GHBP 
and IGFBP-3 at baseline and day 5 of this test. 
 
3. 
IGF-I 
IGFBP-3, GHBP 
3.0 cc 
Bone Specific Alk Phos 
6.0 cc 
Osteocalcin, Type I Collagen Peptide 
4.0 cc 
TSH, FT4, T4 
Glycosylated Hemoglobin 
4.0 cc 
5.0 cc 
Total 
22.0 cc 
These growth factors will be obtained at 6 month intervals. 
4. 
6 hour growth hormone sampling 
1.7 cc/draw (inc. discard); 32.3 cc total 
or 
12 hour growth hormone sampling [17] 
1.7 cc/draw (inc. discard); 62.9 cc total 
 
The 6 hr testing will be used for patients with a minimum weight of 6.5 kg 
through 12.6 kg. The 12-hour evaluation will be done for children 12.7 kg or 
greater. 
 
This endocrine testing will be spread out over the 3-month visit schedule to remain within 
the NIH guidelines for safe amounts of blood withdrawal from children. Scheduled visits 
will be inpatient on the 1 Northwest Pediatric unit when overnight serial blood testing or 
a bone biopsy is scheduled. Other scheduled visits will be outpatient day hospital visits. 
 
VISIT 
Meas 
XR 
BA 
BMD 
Growth 
Factors 
SGT 
Serial 
GH 
CBC 
Bone 
Biopsy 
Pulm/Neuro 
Baseline 
X 
LE, 
spine 
X 
X 
X 
X 
Per 97-CH- 
0064 
3 month 
X 
X 
6 month 
X 
LE, 
spine 
X 
X 
X 
9 month 
X 
12 month 
(baseline 
part B) 
X 
LE, 
spine 
X 
X 
X 
X 
X 


8 
 
 
 
PART B 
GROWTH HORMONE TREATMENT 
 
In this part of the protocol, OI children will be treated with synthetic growth hormone 
(Humatrope
®, generously donated by Eli Lilly and Company) for one year to identify 
responders. Responders will be identified as those children who are able to achieve and 
sustain a 50% increase in growth rate over their baseline. Responders will be treated an 
additional 2 years. After the third year of treatment, responders will be defined as those 
children who demonstrate a sustained increase of 30% or greater from baseline. Children 
who are responders at the 3 year mark will be treated with growth hormone through final 
adult height. Final adult height will be defined as epiphyseal-metaphyseal union of the 
distal femur and proximal tibia growth plates. We will attempt to follow all participants 
through final adult height. 
 
The planned visit schedule is every 3 months starting at the baseline period and 
continuing through treatment completion. 
 
Parameters which will be followed during the treatment year will be a continuation of 
those followed during the pre-treatment year, and are summarized in the following table: 
 
Visit 
Measures 
XR 
Bone Age 
Growth 
Factors 
Bone 
Density 
Bone 
Biopsy 
Pulm/Neuro 
PART B 
BASELINE (Rx 
year, also part A 
12 mo visit) 
X 
X 
X 
X 
X 
X 
Per 97-CH- 
0064 
3 MONTH 
X 
6 MONTH 
X 
X 
X 
X 
9 MONTH 
X 
12 MONTH 
X 
X 
X 
X 
X 
X 
RESPONDERS  6 
MONTH 
X 
X 
X 
X 
12 MONTH 
X 
X 
X 
X 
X 
TREATMENT 
END, 3 YEAR 
NON- 
RESPONDERS 
X 
X 
X 
X 
X 
ADULT 
STATURE 
X 
X 
X 
X 
X 
 
All visits will be outpatient day hospital visits with the exception of those visits when a 
bone biopsy is scheduled. 
 
MONITORING SUBJECTS, DOSAGE, AND CRITERIA FOR WITHDRAWAL OF  
SUBJECTS FROM THE STUDY 
 
Treatment with Humatrope
®   will begin at the 12 month pretreatment visit/baseline 
treatment visit. The accompanying parent will learn how to reconstitute the drug and 
administer the subcutaneous injections. The dose will be 0.06 mg/kg/day for 6 days of the 
week. At the end of 12 months of treatment, those children who have responded with a 


9 
 
 
 
sustained 50% increase in growth rate will remain on Humatrope
®   injections for an 
additional 2 years. After the third year of treatment, responders will be defined as those 
children who demonstrate a sustained increase of 30% or greater above baseline. These 
responders will be treated through attainment of final adult height as defined above. 
 
STRATIFICATION AND RANDOMIZATION 
 
All patients entering this study will undergo the same protocol as described above. There 
will be no randomization. 
 
HUMAN SUBJECTS PROTECTIONS 
 
Children enrolled in this study will be limited to those with Sillence Types III and IV OI, 
as determined by clinical and genetic criteria. This disorder is autosomal dominant, and 
occurs with equal distribution in males and females. The disorder has been described in 
all races and has no ethnic preference. There are no exclusionary criteria related to race 
or gender for this protocol. 
 
CRITERIA FOR PATIENT SELECTION 
 
Patients will be recruited with the goal of including at least 10 each of individuals with 
clinical/biochemical criteria of types III and IV OI who are between 3 and 8 years of age. 
 
1.   Height: Individuals with type III OI have severe short stature by definition; 
individuals with type IV OI recruited to the study will have height less than the 3rd 
percentile for age. All individuals will be required to furnish growth records, especially 
height and head circumference, from at least the preceding two years. 
 
2.   Long bone status: Participants must have radiographic evidence that long bone 
epiphyses have not yet fused. In addition, 60° or greater angulation of a femur will 
exclude a child, pending surgical management or medical clearance. 
 
3.   Spine: Prospective participants will be evaluated for scoliosis and spinal 
compressions. Participants with scoliosis greater than 40° will be excluded unless 
evidence is presented that the scoliosis has been stable for the prior two years. 
Participants with corrective rods in their spine will be excluded. 
 
4.   Neuro status: All patients will be co-enrolled in 97-CH-0064, and will be screened for 
Basilar Invagination through that protocol. Children who are initially screened by spiral 
CT scan with MRI confirmation and determined to have severe BI will be excluded from 
participation in this study. Severe BI is defined by NIH data as distortion of the angle 
between the pons and medulla and or compression of posterior fossa contents. [18] We 
are only beginning to define the parameters of BI in this population, and we do not know 
why some children with BI progress in severity and some do not. Until those questions 
are answered, we feel it would not be prudent to stimulate growth in a child we know to 
have a severe form of BI at enrollment. 


10 
 
 
 
 
 
5.  Pulmonary status: All children will be co-enrolled in 97-CH-0064, and will have 
pulmonary function testing through that protocol. Tests will be scheduled as required for 
that protocol; namely, PFTs every 2 years if normal, every year if abnormal. 
 
OFF STUDY CRITERIA 
 
1. Patients who develop scoliosis greater than 40° and/or patients who progress to severe 
basilar invagination during the study will be removed from the study. 
Failure to comply with the outlined procedures (blood draws, endocrine testing, bone 
biopsies, and visit schedule) is also a criterion for withdrawal from the protocol. 
2. Patients who become pregnant. 
NATURE OF PROCEDURES 
 
6 or 12 hour growth hormone evaluation: A heparin lock will be inserted prior to the 
overnight unstimulated growth hormone evaluation. Blood samples will be collected for 
growth hormone every 20 minutes for 6 or 12 hours. [17] We anticipate that the majority 
of patients will weigh enough for either the 6 or 12 hour test. 
 
Somatomedin generation test: Patients will be given a daily subcutaneous injection of 
synthetic growth hormone, 0.033 mg/kg, for 5 days. [14] Blood will be drawn as 
described in the protocol section of this document. 
 
Tetracycline-labeled iliac crest biopsy: To assess dynamic parameters of bone formation, 
tetracycline, which has high affinity for hydroxyapatite in its early states of organization), 
will be administered orally at a dose of 15-20 mg/kg/d (max 900 mg/d) for two 2-day 
courses separated by a 10-day free period. This generates two distinct fluorescent lines 
along the actively forming bone surfaces and allows exact assessment of the bone 
formation and mineral apposition rates. Bone cores will be taken from alternate iliac 
crests using a 5 mm Bordier trephine. Careful procedure will allow collection of 
specimens in which the architecture of trabecular and cortical bone is maintained. 
Dynamic and static histomorphometric parameters of bone formation and resorption will 
be measured according to the guidelines of the ASBMR Histomorphometric 
Nomenclature Committee. [19] 
 
Growth Hormone Injections: Humatrope
®   is the synthetic human growth hormone 
manufactured by Eli Lilly and Company. It is identical in amino sequence to the natural 
human hormone. There is now considerable experience with this drug. Parents will be 
informed of the potential risks of insulin-resistant hyperglycemia, decreased serum 
thyroxine, slipped capital femoral epiphysis and allergic reactions. A comprehensive, 
detailed list of all potential risks is included in the informed consent form. All patients 
will be given the dose 0.06 mg/kg/day for six days/week. 


11 
 
 
 
HAZARDS AND DISCOMFORTS 
 
Endocrine evaluation for Parts A and B: Participants in this study will have a heparin 
lock inserted prior to the overnight serial growth hormone sampling. This heparin lock 
will be used to withdraw blood samples for the pulsatile growth hormone study. 
 
Our experience with the somatomedin generation test has been more positive with 
separate venipunctures for each sample; we are not planning heparin lock insertion for 
this stimulation test. During the somatomedin generation test the patient will have the 
discomfort of daily subcutaneous injections. No additional side effects are expected from 
this short-term administration of synthetic growth hormone. 
 
The maximum blood volume required for the endocrine evaluation when all testing is done 
in one visit is 76 cc, which can safely be obtained from a 15.2 kg child. We expect to do 
this testing in 2 separate visits, 6 months apart so as not to exceed the safe blood limit 
parameters defined by Clinical Center policy. NIH policy limits the volume of blood 
drawn from children to 9.5 milliliters per kilogram of body weight in any 8-week period 
of time and 5 milliliters per kilogram of body weight at any one time. 
 
Iliac Crest Bone Biopsy: Bone biopsies are now performed in the operating room at the 
NIH with patients under general anesthesia. Anesthesiologists from the Department of 
Anesthesia and Surgical Services at the NIH clinical center manage general anesthesia 
and closely monitor risks associated with general anesthesia such as suppression of 
respiratory and cardiac function. With appropriate sedation, an iliac crest biopsy is a 
relatively simple procedure. Plugging of the biopsy site with Surgicel or gel foam, 
together with placement of a compressive dressing, prevents bleeding and also 
encourages rapid clot organization. Two small stitches will be used to close the skin 
wound. In our experience, the short course of tetracycline administration has never 
provoked tooth staining. The drug should be administered after meals and long duration 
exposure to sunlight prevented during those days. Rarely, the drug causes skin 
hypersensitivity to sunlight that may induce first degree sunburn. Discomfort in the hours 
following the biopsy is easily controlled with pain relievers such as Tylenol or Tylenol 
with codeine. 
 
Humatrope
®   injections: Parents will be taught to administer subcutaneous injections of 
Humatrope
®. They will use an insulin syringe and needle for this daily procedure. There 
is no discomfort connected with the delivery of the hormone itself. The discomfort will 
consist of the insertion of a very small needle under the skin and should be minimal. 
 
 
 
ADVERSE EVENTS 
 
All serious, unexpected adverse events (those not included in the investigators brochure), 
related to the use of Humatrope
®   will be reported to Eli Lilly and Company. Unexpected, 
serious adverse events will be reported to the FDA as well, within 15 days of the event, 
and within 7 days in the case of a death or life-threatening event. The known risks of 


12 
 
 
 
growth hormone administration are listed in attachment I. These are expected risks and 
therefore will not be considered reportable to the FDA. 
 
Adverse events that will be reported to the NICHD IRB will include those events 
reportable to the FDA and Eli Lilly. In addition, we will report the following adverse 
events related to the bone biopsy procedure: 
 
1. 
Prolonged bleeding at the biopsy site, which we define as bleeding lasting longer 
than 24 hours post biopsy 
2. 
Post biopsy infection at the biopsy site; defined as an infection diagnosed and 
treated by the private physician at home within 7 days of the biopsy. 
 
Frequent fractures are a cardinal feature of patients with OI.  Fractures may not be 
consistently documented by x-ray or history, and can occur in clusters. For these reasons, 
fracture incidence is not an accurate measure of progression or worsening of osteogenesis 
imperfecta. Fractures are not defined as reportable adverse events. 
 
RADIATION EXPOSURE 
 
The effective dose calculation for the radiographic studies involved in this protocol is 
0.43 rem. The amount of radiation in this study is within the dose guideline (0.5 rem) 
established by the NIH Radiation Safety Committee for pediatric research subjects, and is 
deemed a slight increment above minimal risk. The amount of radiation that patients will 
receive in this protocol is equivalent to the amount of radiation exposure from natural 
background sources in about a year and a half. The highest individual organ exposures 
will be to the skin, muscle, and bone surfaces (4 rem each). The radiographic studies 
described in this study are acceptable to obtain the desired research information, and 
present the prospect of direct benefit to the individual subjects. The radiographic 
procedures will be performed by or under the supervision of a radiologist in the NIH CC 
Radiology Department. 
 
We invite the parents of our patients to bring recent films taken at home which can be 
copied at the Clinical Center and returned to them, thus eliminating the need for repeat 
films. All parents will be informed that this is a possibility, and told to request that a 
ruler be placed on the long bone films. 
 
The most obvious potential benefit that participants in this study might expect is 
improved linear growth rate, leading to, over time, an improved final adult stature. At 
this time, we cannot predict who will and will not respond, so this benefit is a potential 
for all participants. For those children who respond to the growth hormone, our earlier 
data showed an improved quality of bone after 1 year of growth hormone treatment, as 
well as improved bone density. [9] By adolescence and adulthood, many people affected 
with OI begin to develop cardiac and pulmonary abnormalities that may be secondary to 
a small thoracic cage. By increasing linear length, to include trunk height, we expect a 
final potential benefit to be prevention of possible cardiac and pulmonary deficiencies. 


13 
 
 
 
Informed consent will be obtained from a parent or legal guardian of all children 
participating in this study, by the principal investigator or an associate investigator. For 
children who are 7- 8 years old, an assent will be obtained by the principal investigator or 
an associate investigator. Children under the age of 7 years will be given age appropriate 
teaching for each procedure they will be having. 
 
 
DATA and SAFETY MONIORIN PLAN  
 
Study Staff Responsibilities  
The Principal Investigator, Joan Marini, is responsible for all aspects of the study.  
 
Source Documentation  
Joan Marini, MD, PhD, is responsible for coordinating data collection and will review the data for accuracy 
and completeness within 2 months of each subject visit, including review of patient consent 
documents. An evaluation of patient recruitment, accrual, and retention as specified in the 
protocol will be ongoing. Review of literature and results of related studies will be assessed 
throughout the study for any impact on patient safety or ethical questions.   
IRB and DSMC Documentation  
All IRB documentation can be found in PTMS. The Principal Investigator, Joan Marini, is responsible 
for maintaining IRB documentation, including records of all reviews of the study and submissions 
to the IRB. This protocol does not meet the criteria as outlined in the NIH HRPP SOP 17 for data to 
be submitted to a data safety monitoring committee.   Clinical Trial Studies (non IND/IDE) will have 
random audits performed by the NICHD Office of the Clinical Director (policy: 
https://science.nichd.nih.gov/confluence/display/ocd/Protocol+Navigation). 
Consent:  
“For subjects who were minors at the time of consent and are now age 18 
years or older, the PI has requested a waiver of consent (45 CFR.46.117) 
for continued analysis of their data. The research involves no more than 
minimal risk and a waiver will not adversely affect the rights and welfare of 
the subjects. The only record linking the subject and the research would be 
the consent document and the principal risk would be potential harm 
resulting from breach of confidentiality. Continued research could not be 
carried out without the waiver as several protocol participants signed their 
assent more than 10 years ago and the PI has lost touch with about 3/4 of 
the patients. Wherever appropriate, subjects will be provided with additional 
pertinent information regarding any findings learned from the analysis of 
their data”. 
 
Adverse Event Procedures and Documentation  
All Unanticipated Problems (UP), Unanticipated Adverse Device Effects (UADE), Protocol 
Deviations (PD), deaths, and Adverse Events (AE) will be reported to the IRB or the Clinical 
Director (CD) using PTMS, in accordance with SOP 16. When PTMS is not available, the NIH 
Problem Report Form will be used. 


14 
 
(https://federation.nih.gov/ohsr/nih/ohrdocs/NIH_Problem_Report_Form_Fillable_DDIR_v1_6-
11-13_508.pdf).   
All serious UP’s and Serious PD’s, and will be reported to the IRB and CD as soon as possible 
but not more than 7 days after the PI first learns of the event. Non-serious UP’s will be reported 
to the IRB and CD, and non-serious PD’s to the IRB not more than 14 days after the PI first 
learns of the event. Deaths will be reported to the Clinical Director within 7 days after the PI 
first learns of the event. An aggregated summary of all UP’s, PD’s,  and AE’s will be reported to 
the IRB at the time of Continuing Review (CR). 
 
 Study Completion 
Principal Investigator will maintain subjects’ records for at least three years after completion 
of the study.   
 
 
EVALUATION OF RESULTS 
 
The primary outcome is the change in growth rate from untreated to treated status. For 
the first year, a 50% increase in growth rate is considered a positive response. We 
suppose that growth rate is approximately normally distributed. From random chance, 
we estimate that the probability of observing a 50% increase in growth without 
intervention is less than 0.2. Therefore, we would like to test the null hypothesis that the 
proportion of responders in the population is less than or equal to 0.2 against the 
alternative that the proportion exceeds 0.2. Using a normal approximation to the binomial 
and assuming the true action of GH is to result in a population with mean 50% more than 
the untreated mean, we have 91% power with the sample size of 20. 
 
Other protocol parameters will be correlated with linear growth responders versus non- 
responders, as well as being analyzed for the group as a whole. These correlations will 
be made for both 6 month and one-year treatment intervals throughout the study. 
 
NATURE OF FINANCIAL COMPENSATION 
 
No financial payments will be offered to patients or their families. 


15 
 
 
 
References 
 
1. 
Marini JC, C.E., Osteogenesis Imperfecta, in Management of Genetic Syndromes, A.J. Cassidy 
SB, Editor. 2001, Wiley-Liss: New York. p. 281-300. 
2. 
Marini, J.C., Osteogenesis imperfecta: comprehensive management. Adv Pediatr, 1988. 35: p. 
391-426. 
3. 
Ernst, M. and E.R. Froesch, Growth hormone dependent stimulation of osteoblast-like cells in 
serum-free cultures via local synthesis of insulin-like growth factor I. Biochem Biophys Res 
Commun, 1988. 151(1): p. 142-7. 
4. 
Rauch, F., et al., Static and dynamic bone histomorphometry in children with osteogenesis 
imperfecta. Bone, 2000. 26(6): p. 581-9. 
5. 
Prockop, D.J. and K.I. Kivirikko, Heritable diseases of collagen. N Engl J Med, 1984. 311(6): p. 
376-86. 
6. 
Prockop, D.J., et al., The biosynthesis of collagen and its disorders (first of two parts). N Engl J 
Med, 1979. 301(1): p. 13-23. 
7. 
Cohen, P., et al., 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. J Clin 
Endocrinol Metab, 2008. 93(11): p. 4210-7. 
8. 
Rose, S.R. and G. Municchi, Six-hour and four-hour nocturnal sampling for growth hormone. J 
Pediatr Endocrinol Metab, 1999. 12(2): p. 167-73. 
9. 
Marini, J.C., et al., Positive linear growth and bone responses to growth hormone treatment in 
children with types III and IV osteogenesis imperfecta: High predictive value of the 
carboxyterminal propeptide of type I procollagen. Journal of Bone and Mineral Research, 2003. 
18(2): p. 237-243. 
10. 
Rauchenzauner, M., et al., Sex- and age-specific reference curves for serum markers of bone 
turnover in healthy children from 2 months to 18 years. J Clin Endocrinol Metab, 2007. 92(2): p. 
443-9. 
11. 
Marini, J.C., et al., The growth hormone and somatomedin axis in short children with osteogenesis 
imperfecta. Journal of Clinical Endocrinology and Metabolism, 1993. 76: p. 251-256. 
12. 
Cotterill, A.M., et al., The insulin-like growth factor I generation test in the investigation of short 
stature. Acta Paediatr Suppl, 1994. 399: p. 128-30. 
13. 
Gelato, M.C., et al., Growth hormone (GH) responses to GH-releasing hormone during pubertal 
development in normal boys and girls: comparison to idiopathic short stature and GH deficiency. 
J Clin Endocrinol Metab, 1986. 63(1): p. 174-9. 
14. 
Copeland, K.C., L.E. Underwood, and J.J. Van Wyk, Induction of immunoreaactive somatomedin 
C human serum by growth hormone: dose-response relationships and effect on chromatographic 
profiles. Journal of Clinical Endocrinology and Metabolism, 1980. 50(4): p. 690-697. 
15. 
Nilsson, A., et al., Regulation by growth hormone of number of chondrocytes containing IGF-I in 
rat growth plate. Science, 1986. 233(4763): p. 571-4. 
16. 
Pintor, C., et al., Clonidine accelerates growth in children with impaired growth hormone 
secretion. Lancet, 1985. 1(8444): p. 1482-5. 
17. 
Rose, S.R., et al., Overnight growth hormone concentrations are usually normal in pubertal 
children with idiopathic short stature--a Clinical Research Center study. J Clin Endocrinol Metab, 
1996. 81(3): p. 1063-8. 
18. 
Charnas, L.R., E. Hopkins, and J.C. Marini. The Dynamic Deformation Sequence of Basilar 
Invagination in Osteogenesis Imperfecta (Abstract). in American Society of Human Genetics 
Annual Meeting. 1997. Baltimore MD. 
19. 
Parfitt, A.M., et al., Bone histomorphometry:  standardization of nomenclature, symbols, and units. 
Report of the ASBMR Histomorphometry  Nomenclature Committee. J Bone Miner Res, 1987. 2(6): 
p. 595-610. 

SAP_001.pdf: 
Date: April 18th, 2017 
 
Project Title: Studies of Growth Deficiency and Growth Hormone Treatment in Children with 
Osteogenesis Imperfecta Types III and IV  
 
Principal Investigator: Joan C. Marini, M.D., Ph.D. Chief, Bone and Extracellular Matrix Branch, NICHD, 
NIH 
 
Statistical Analysis Plan: 
For each patient, they were seen at the NIH CC for a full year prior to treatment.  
Baseline growth rate was set for each patient at NIH CC: At 1 yr prior and 6 months prior to treatment, 
as well as at t=0, patients length was measured on a stadiometer board by genetics and endocrine 
nurses trained to take accurate repetitive measurements. 10 measurements were taken and averaged 
for each date. The growth in cc from 1 year prior to treatment to treatment start in cm/yr was the 
baseline growth rate for that patient. 
 
Treatment growth rate: Measurements taken on each patient at treatment time=0, 6 and 12 months 
were taken in the same way and a treatment year (cm/yr) growth rate was calculated.  
 
Response to treatment: For each patient, their rate of growth during treatment was compared to the 
baseline growth rate. A positive response was scored if treatment growth rate was 50% or more 
increased over baseline rate. The percent of patients in the full treatment group with a positive linear 
growth rate response was scored as the % responders.