A Post-Marketing Study of the Immunogenicity of Somatropin (Ribosomal Deoxyribo Nucleic Acid [rDNA] Origin) Injection (Nutropin AQ®) in Children With Growth Hormone Deficiency

• Sponsor: Genentech, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02311894
• Collaborator: (none)
• Enrollment: 82
• Locations: 33
• Arm: 1
• Actual Duration (Months): 31.3
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a Phase IV, multicenter, open-label, single-arm study of somatropin (rDNA origin) (Nutropin AQ v1.1) in pre-pubertal children with growth hormone deficiency (GHD) naïve to prior recombinant human growth hormone (rhGH) treatment. The study is designed to characterize the immunogenicity profile of somatropin (rDNA origin) injection when administered daily subcutaneously for 12 months. The clinical impact of immunogenicity will also be assessed.

Condition or Disease	Intervention/Treatment	Phase
Growth Hormone Deficiency	Drug: Somatropin	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 82 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase IV, Multicenter, Open-Label Study of the Immunogenicity of Nutropin AQ® V1.1 [Somatropin (rDNA Origin) Injection] Administered Daily to Naïve Growth Hormone-Deficient Children (iSTUDY)
• Actual Study Start Date: Mar 31, 2015
• Actual Primary Completion Date: Nov 8, 2017
• Actual Study Completion Date: Nov 8, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Somatropin Children will receive daily SC injections of somatropin at a dose of up to 0.043 milligrams per kilogram per day (mg/kg/day) for 1 year.	Drug: Somatropin; Somatropin will be administered as SC injections at a dose of up to 0.043 mg/kg/day. The dose may be adjusted for a change in body weight of at least (plus [+]/minus [-]) 2 kilograms (kg) from baseline at the Month 6 study visit or for a change in insulin-growth factor-1 (IGF-1), as per investigator assessment.; Other Names: Nutropin AQ v1.1

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Develop Anti-GH Antibodies After Treatment With Nutropin AQ v1.1 [Baseline up to 1 year]

   Participants who were tested positive to anti-GH antibody after initiation of study treatment.

Secondary Outcome Measures

1. Percentage of Participants Who Exhibit Functional Growth Attenuation [Baseline up to 1 year]

   Growth attenuation is defined as initial growth response greater than pretreatment velocity followed by reduction in growth response to below the pretreatment velocity in the subsequent 6- to 12-month treatment period or reaching ≤ 2 cm per year.

2. Percentage of Participants With Neutralizing Antibodies [Baseline up to 1 year]

   Among participants who developed positive anti-GH antibody post-baseline, participants who were tested positive to neutralizing anti-GH antibody during study participation.

3. Annualized Growth Velocity at Months 6 and 12 (Change From Baseline) [Months 6, 12]

   Annualized growth velocity is defined as (height - baseline height) / (date of height assessment - date of baseline)*365.25. Results are presented according to anti-GH antibody status (positive included all participants that were anti-GH antibody positive at least once post-baseline visit and anti-GH antibody negative population included all participants that were anti-GH antibody negative at all post-baseline visits).

4. Height Standard Deviation Score (SDS) at Months 6 and 12 (Change From Baseline) [Months 6, 12]

   Height Standard Deviation Score (SDS) allows for the comparison of a participants height to that of others in the same age group. Therefore, the average height for that age group will have the SDS of 0. In this study, the starting Height SDS score was ≤ -1.5 (≤ 5th percentile). Results are presented according to anti-GH antibody status (positive included all participants that were anti-GH antibody positive at least once post-baseline visit and anti-GH antibody negative population included all participants that were anti-GH antibody negative at all post-baseline visits.

5. Percentage of Participants With Adverse Events [Baseline up to 1 year]

   Among participants who received at least one dose of study drug, those who reported at least one adverse event during study participation.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 14 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Bone age less than equal to (</=) 9 years (females) or </= 11 years (males) as determined by X-ray of the left hand and wrist using Greulich and Pyle method and obtained within the 12 months prior to enrollment

• Prepubertal (Tanner I) males and females by physical examination

• Diagnosis of GHD (stimulated GH less than [<] 10 nanograms per milliliter [ng/mL]) by two standard pharmacologic tests obtained up to 12 months prior to informed consent/assent

• Normal thyroid function test within the 12 months prior to informed consent/assent

• Normal complete blood counts within 12 months prior to informed consent/assent

• Documentation of prior height and weight measurements, with height standard deviation score (SDS) </= 5th percentile for idiopathic isolated GHD participants

Exclusion Criteria:

• Any previous rhGH treatment

• Short stature etiologies other than GHD

• Acute critical illness or uncontrolled chronic illness, which in the opinion of the investigator and medical monitor, would interfere with participation in this study, interpretation of the data, or pose a risk to participant safety

• Chronic illnesses such as inflammatory bowel disease, celiac disease, heart disease, and diabetes

• Bone diseases such as achondroplasia or hypochondroplasia, intracranial tumor, irradiation, and traumatic brain injury

• Participants receiving oral or inhaled chronic corticosteroid therapy (greater than [>] 3 months) for other medical conditions other than central adrenal insufficiency

• Participants who require higher (2 times or greater than maintenance) doses of corticosteroids for more than 5 days in the 6 months prior to enrollment in the study

• Participants with active malignancy or any other condition that the investigator believes would pose a significant hazard to the participant if rhGH were initiated

• Females with Turner syndrome regardless of their GH status

• Prader-Willi syndrome regardless of GH status

• Born small for gestational age regardless of GH status

• Presence of scoliosis requiring monitoring

• Previous participation in another clinical trial or investigation of GH, treatment for growth failure, or treatment with a biologic agent

• Participants with closed epiphyses

• Participants with a known hypersensitivity to somatropin, excipients, or diluent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arkansas Children's Hospital Research Institute	Little Rock	Arkansas	United States	72202
2	Children'S Hospital of Orange County	Orange	California	United States	92868-3874
3	Center of Excellence in Diabetes & Endocrinology	Sacramento	California	United States	95821
4	San Diego Medical Group; Pediatric Endocrinology	San Diego	California	United States	92123
5	Rocky Mountain Pediatric Endocrinology, PC	Centennial	Colorado	United States	80112
6	Pediatric Endocrine Associates	Greenwood Village	Colorado	United States	80111
7	Nemours Children's Clinic - of the Nemours Foundation	Jacksonville	Florida	United States	32207
8	Miami Children's Hospital	Miami	Florida	United States	33155-3009
9	Nemours Childrens Clinic	Orlando	Florida	United States	32801
10	The Pediatric Endocrine Office of Larry C. Deeb	Tallahassee	Florida	United States	32308
11	Pediatric Endrocine Assoc	Tampa	Florida	United States	33607
12	USF Diabetes Center	Tampa	Florida	United States	33612
13	Emory Children's Center	Atlanta	Georgia	United States	20010
14	University of Louisville	Louisville	Kentucky	United States	40202
15	Barry J Reiner, MD, LLC	Baltimore	Maryland	United States	21229
16	Boston Childrens Hospital	Boston	Massachusetts	United States	02115
17	Baystate Endocrinology and Diabetes; Baystate Children's Specialty Center, Pediatric Endocrinology	Springfield	Massachusetts	United States	01199
18	University of Michigan	Ann Arbor	Michigan	United States	48109-0934
19	University of Minnesota Childrens' Hospital	Minneapolis	Minnesota	United States	55455
20	Children's Healthcare d.b.a Children's Hospitals and Clinics of Minnesota	Saint Paul	Minnesota	United States	55102
21	Children's Mercy Hospitals & Clinics; Pulmonology	Kansas City	Missouri	United States	64108
22	Hackensack University Medical Center PARTNER	Hackensack	New Jersey	United States	07601
23	New York Presbyterian Hospital	New York	New York	United States	10021
24	UNC General Pediatrics Clinic	Chapel Hill	North Carolina	United States	27514
25	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
26	Oregon Health and Science University	Portland	Oregon	United States	97239
27	Milton S Hershey Ped Sub Spclt	Hershey	Pennsylvania	United States	17033
28	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
29	Medical University of South Carolina; MUSC Pediatric Endocrinology	Charleston	South Carolina	United States	29425
30	Endocrine Associates of Dallas	Dallas	Texas	United States	75231
31	Cook Children's Hospital	Fort Worth	Texas	United States	76104
32	MultiCare Health System Institute for Research and Innovation	Tacoma	Washington	United States	98405
33	MultiCare Institute for Research and Innovation	Tacoma	Washington	United States	98405

Sponsors and Collaborators

• Genentech, Inc.

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol - Apr 22, 2015
• Statistical Analysis Plan - Mar 28, 2018

More Information

Publications

None provided.

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT02311894
• Other Study ID Numbers: ML29543
• First Posted: Dec 9, 2014
• Last Update Posted: Jan 8, 2019
• Last Verified: Dec 1, 2018

• Additional relevant MeSH terms: Dwarfism, Pituitary

Study Results

Participant Flow

Arm/Group Title	Somatropin
Arm/Group Description	Children will receive daily subcutaneous (SC) injections of somatropin at a dose of up to 0.043 milligrams per kilogram per day (mg/kg/day) for 1 year.
Period Title: Overall Study
STARTED	82
Modified ITT Population	81
COMPLETED	78
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Somatropin
Arm/Group Description	Children will receive daily subcutaneous (SC) injections of somatropin at a dose of up to 0.043 milligrams per kilogram per day (mg/kg/day) for 1 year.
Overall Participants	82
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	9.0 (1.91)
Sex: Female, Male (Count of Participants)
Female	17 20.7%
Male	65 79.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	11 13.4%
Not Hispanic or Latino	70 85.4%
Unknown or Not Reported	1 1.2%
Race/Ethnicity, Customized (participants) [Number]
Asian	5 6.1%
Black or African American	2 2.4%
Multiple	1 1.2%
Other	3 3.7%
Unknown	3 3.7%
White	68 82.9%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Who Develop Anti-GH Antibodies After Treatment With Nutropin AQ v1.1
Description	Participants who were tested positive to anti-GH antibody after initiation of study treatment.
Time Frame	Baseline up to 1 year

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least one dose of study drug and who had at least one post-baseline assessment

Arm/Group Title	Somatropin
Arm/Group Description	Children will receive daily subcutaneous (SC) injections of somatropin at a dose of up to 0.043 milligrams per kilogram per day (mg/kg/day) for 1 year.
Measure Participants	81
Number (95% Confidence Interval) [percentage of participants]	3.7 4.5%

2. Secondary Outcome

Title	Percentage of Participants Who Exhibit Functional Growth Attenuation
Description	Growth attenuation is defined as initial growth response greater than pretreatment velocity followed by reduction in growth response to below the pretreatment velocity in the subsequent 6- to 12-month treatment period or reaching ≤ 2 cm per year.
Time Frame	Baseline up to 1 year

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least one dose of study drug and who had at least one post-baseline assessment

Arm/Group Title	Somatropin
Arm/Group Description	Children will receive daily subcutaneous (SC) injections of somatropin at a dose of up to 0.043 milligrams per kilogram per day (mg/kg/day) for 1 year.
Measure Participants	81
Number (95% Confidence Interval) [percentage of participants]	2.6 3.2%

3. Secondary Outcome

Title	Percentage of Participants With Neutralizing Antibodies
Description	Among participants who developed positive anti-GH antibody post-baseline, participants who were tested positive to neutralizing anti-GH antibody during study participation.
Time Frame	Baseline up to 1 year

Outcome Measure Data

Analysis Population Description

Included only patients who had positive anti-GH antibody.

Arm/Group Title	Somatropin
Arm/Group Description	Children will receive daily subcutaneous (SC) injections of somatropin at a dose of up to 0.043 milligrams per kilogram per day (mg/kg/day) for 1 year.
Measure Participants	3
Number [percentage of participants]	0 0%

4. Secondary Outcome

Title	Annualized Growth Velocity at Months 6 and 12 (Change From Baseline)
Description	Annualized growth velocity is defined as (height - baseline height) / (date of height assessment - date of baseline)*365.25. Results are presented according to anti-GH antibody status (positive included all participants that were anti-GH antibody positive at least once post-baseline visit and anti-GH antibody negative population included all participants that were anti-GH antibody negative at all post-baseline visits).
Time Frame	Months 6, 12

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least one dose of study drug and who had at least one post-baseline assessment

Arm/Group Title	Somatropin
Arm/Group Description	Children will receive daily subcutaneous (SC) injections of somatropin at a dose of up to 0.043 milligrams per kilogram per day (mg/kg/day) for 1 year.
Measure Participants	81
6 months (Anti-GH Antibody Positive)	5.3 (2.89)
6 months (Anti-GH Antibody Negative)	5.5 (2.64)
12 months (Anti-GH Antibody Positive)	5.2 (3.61)
12 months (Anti-GH Antibody Negative)	4.9 (2.40)

5. Secondary Outcome

Title	Height Standard Deviation Score (SDS) at Months 6 and 12 (Change From Baseline)
Description	Height Standard Deviation Score (SDS) allows for the comparison of a participants height to that of others in the same age group. Therefore, the average height for that age group will have the SDS of 0. In this study, the starting Height SDS score was ≤ -1.5 (≤ 5th percentile). Results are presented according to anti-GH antibody status (positive included all participants that were anti-GH antibody positive at least once post-baseline visit and anti-GH antibody negative population included all participants that were anti-GH antibody negative at all post-baseline visits.
Time Frame	Months 6, 12

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least one dose of study drug and who had at least one post-baseline assessment

Arm/Group Title	Somatropin
Arm/Group Description	Children will receive daily subcutaneous (SC) injections of somatropin at a dose of up to 0.043 milligrams per kilogram per day (mg/kg/day) for 1 year.
Measure Participants	81
6 months (Anti-GH Antibody Positive)	0.3 (0.11)
6 months (Anti-GH Antibody Negative)	0.4 (0.17)
12 months (Anti-GH Antibody Positive)	0.8 (0.15)
12 months (Anti-GH Antibody Negative)	0.7 (0.25)

6. Secondary Outcome

Title	Percentage of Participants With Adverse Events
Description	Among participants who received at least one dose of study drug, those who reported at least one adverse event during study participation.
Time Frame	Baseline up to 1 year

Outcome Measure Data

Analysis Population Description

Include all participants who received at least one dose of study drug.

Arm/Group Title	Somatropin
Arm/Group Description	Children will receive daily subcutaneous (SC) injections of somatropin at a dose of up to 0.043 milligrams per kilogram per day (mg/kg/day) for 1 year.
Measure Participants	82
Number [percentage of participants]	69.5 84.8%

Adverse Events

Time Frame	Adverse events (AEs) were reported from Day 1 until 28 days after last dose of study medication for up to 12 months.
Adverse Event Reporting Description	The safety population included all participants who received at least 1 dose of the investigational product.
Arm/Group Title	Somatropin
Arm/Group Description	Children will receive daily subcutaneous (SC) injections of somatropin at a dose of up to 0.043 milligrams per kilogram per day (mg/kg/day) for 1 year.
All Cause Mortality
	Somatropin
	Affected / at Risk (%)	# Events
Total	0/82 (0%)
Serious Adverse Events
	Somatropin
	Affected / at Risk (%)	# Events
Total	0/82 (0%)
Other (Not Including Serious) Adverse Events
	Somatropin
	Affected / at Risk (%)	# Events
Total	40/82 (48.8%)
Gastrointestinal disorders
Vomiting	12/82 (14.6%)
General disorders
Injection site bruising	7/82 (8.5%)
Pyrexia	5/82 (6.1%)
Infections and infestations
Upper respiratory tract infection	8/82 (9.8%)
Pharyngitis streptococcal	6/82 (7.3%)
Nasopharyngitis	5/82 (6.1%)
Nervous system disorders
Headache	17/82 (20.7%)
Skin and subcutaneous tissue disorders
Rash	6/82 (7.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.