Efficacy and Safety Evaluation of Recombinant Human Growt... | NCT01111019

Name	Class
Merck Serono S.A.S, France	INDUSTRY

Label	Type	Description	Intervention Names
r-hGH (Saizen®)	Experimental		Drug: Recombinant human growth hormone (r-hGH)

Name	Type	Description	Arm Group Labels	Other Names
Recombinant human growth hormone (r-hGH)	Drug	Subjects will receive a single subcutaneous injection of recombinant human growth hormone (r-hGH) equivalent to a dose of 0.057 milligram per kilogram per day (mg/kg/day). The dose will be subsequently adjusted during the trial and subjects will be treated for at least 3 years or until near final height is reached.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Change From Baseline in Height-Standard Deviation Score (H-SDS) of Recombinant Human Growth Hormone (r-hGH) Treated Subjects at Year 3	Height was calculated in standardized units expressed as the standard deviation score (SDS), where SDS = (x - m)/sigma, in which x represents the height variable measured by sex and age, and m and sigma are the statistical parameters (mean and standard deviation) for the Sempe reference population. The reference population was the historical cohort consisting of non-treated subjects with Hypochondroplasia (HCH). SDS indicated how many standard deviations higher (in case of positive SDS) or lower (in case of negative SDS) a participant's value was relative to the mean of the reference population. The scores were centered around zero. Negative score indicated smaller height for the respective age/gender.	Baseline (Month 0), Year 3
Height-Standard Deviation Score (H-SDS) of Recombinant Human Growth Hormone (r-hGH) Treated Subjects at Year 4	Height was calculated in standardized units expressed as the standard deviation score (SDS), where SDS = (x - m)/sigma, in which x represents the height variable measured by sex and age, and m and sigma are the statistical parameters (mean and standard deviation) for the Sempe reference population. The reference population was the historical cohort consisting of non-treated subjects with Hypochondroplasia (HCH). SDS indicated how many standard deviations higher (in case of positive SDS) or lower (in case of negative SDS) a participant's value was relative to the mean of the reference population. The scores were centered around zero. Negative score indicated smaller height for the respective age/gender.	Year 4

Secondary Outcomes

Measure	Description	Time Frame
Height-Standard Deviation Score (H-SDS) of Recombinant Human Growth Hormone (r-hGH) Treated Subjects	Height was calculated in standardized units expressed as the standard deviation score (SDS), where SDS = (x - m)/sigma, in which x represents the height variable measured by sex and age, and m and sigma are the statistical parameters (mean and standard deviation) for the Sempe reference population. The reference population was the historical cohort consisting of non-treated subjects with Hypochondroplasia (HCH). Data was reported by gender. Male subjects were analyzed till 9.5 years and female subjects were analyzed till 8.5 years. SDS indicated how many standard deviations higher (in case of positive SDS) or lower (in case of negative SDS) a participant's value was relative to the mean of the reference population. The scores were centered around zero. Negative score indicated smaller height for the respective age/gender.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Male or female children with hypochondroplasia defined by a disproportional short limb height and a X-ray evidence of shortening of the long bones and failure of increase in the interpedicular distance between lumbar vertebrae L1 and L5
Result of genetic analysis for mutation of gene FGFR3 already known or ongoing analysis at the beginning of the study
Chronological age greater than or equal to 3 years
Height for chronological age less than or equal to - 2 SDS
Bone age less than or equal to 11 years for girls and 13 years for boys
A written informed consent at the beginning of the pre-treatment period must be obtained from the parent(s)/legal guardian(s). Children able to understand the trial should personally sign and date the written informed consent

Additional inclusion criteria for each study prolongation:

Bone age at Month 36 or Month 60 is compatible with treatment prolongation according to investigator opinion
Subject is still under r-hGH treatment with Saizen® at Month 36 or Month 60
Height gain greater than or equal to + 1 SDS after the 2 first years of treatment for treatment prolongation at Month 36 and growth velocity greater than or equal to 5 centimeter (cm) per year, with bone age less than 14 years for females or less than 16 years for males for treatment prolongation at Month 60
According to investigator opinion, gene mutations of the subjects are not in connection with observed side effects during the 3 or 5 first years of treatment
An updated written informed consent must be obtained from the parent(s)/legal guardian(s) before the start of each study prolongation. Children able to understand the trial should personally sign and date the written informed consent

Exclusion Criteria:

Turner's Syndrome in girls
Active malignant neoplastic disease
Severe congenital malformations
Proliferative or preproliferative diabetic retinopathy
Evidence of any progression or recurrence of an underlying intra-cranial space occupying lesion
Severe psychomotor retardation
Diabetes mellitus or history of significant glucose intolerance as defined by a fasting blood glucose greater than 6.4 millimole per liter (mmol/L)
Known renal insufficiency as defined by serum creatinine level 1.0 milligram per deciliter (mg/dL) (88 micromole per liter [mcmol/L])
Known hepatic disease as defined by elevated liver enzymes or total bilirubin (* 2 Normal)
Current congestive heart failure, untreated hypertension, serious chronic edema of any cause
Chronic infectious disease
History of intracranial hypertension with papilledema
Previous or ongoing treatment with sex steroid therapy such as estrogens or testosterone
Previous or ongoing treatment with any therapy that may directly influence growth, including Growth Hormone (GH), Growth Hormone Releasing Hormone (GHRH) and long duration corticosteroids therapy
Known hypersensitivity to somatropin or any of the excipients
Epiphyseal fusion
Participation to any clinical study within the 30 days preceding study entry
Pregnant females

Name	Affiliation	Role
Medical Responsible	Merck KGaA, Darmstadt, Germany	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Endocrinologie Pédiatrique - centre des maladies rares de la croissance -Hôpital Necker Enfants Malades		Paris		75015	France

PubMed Identifier	Type	Citation	Retractions
25323764	Derived	Pinto G, Cormier-Daire V, Le Merrer M, Samara-Boustani D, Baujat G, Fresneau L, Viaud M, Souberbielle JC, Pineau JC, Polak M. Efficacy and safety of growth hormone treatment in children with hypochondroplasia: comparison with an historical cohort. Horm Res Paediatr. 2014;82(6):355-63. doi: 10.1159/000364807. Epub 2014 Oct 15.

ID	Title	Description
FG000	r-hGH (Saizen®)	Subjects received a single subcutaneous injection of recombinant human growth hormone (r-hGH) equivalent to dose of 0.057 milligram per kilogram per day (mg/kg/day). The dose was subsequently reduced to 0.035 mg/kg/day for subjects, who continued treatment after 31 January 2011. Subjects were treated for at least 3 years or until near final height was reached.

ID	Title	Description
BG000	r-hGH (Saizen®)	Subjects received a single subcutaneous injection of recombinant human growth hormone (r-hGH) equivalent to dose of 0.057 milligram per kilogram per day (mg/kg/day). The dose was subsequently reduced to 0.035 mg/kg/day for subjects, who continued treatment after 31 January 2011. Subjects were treated for at least 3 years or until near final height was reached.

Units	Counts
Participants	BG00019

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change From Baseline in Height-Standard Deviation Score (H-SDS) of Recombinant Human Growth Hormone (r-hGH) Treated Subjects at Year 3

Height was calculated in standardized units expressed as the standard deviation score (SDS), where SDS = (x - m)/sigma, in which x represents the height variable measured by sex and age, and m and sigma are the statistical parameters (mean and standard deviation) for the Sempe reference population. The reference population was the historical cohort consisting of non-treated subjects with Hypochondroplasia (HCH). SDS indicated how many standard deviations higher (in case of positive SDS) or lower (in case of negative SDS) a participant's value was relative to the mean of the reference population. The scores were centered around zero. Negative score indicated smaller height for the respective age/gender.

Intention to Treat (ITT) population included all subjects who received at least one dose of treatment with at least an efficacy assessment available during the treatment period.

Posted

Mean

Standard Deviation

Standard Deviation Score (SDS)

Baseline (Month 0), Year 3

ID	Title	Description
OG000	r-hGH (Saizen®)	Subjects received a single subcutaneous injection of recombinant human growth hormone (r-hGH) equivalent to dose of 0.057 milligram per kilogram per day (mg/kg/day). The dose was subsequently reduced to 0.035 mg/kg/day for subjects, who continued treatment after 31 January 2011. Subjects were treated for at least 3 years or until near final height was reached.

Units	Counts
Participants	OG00019

Title

Denominators

Categories

Title	Measurements
	OG0001.39± 0.9

Primary

Height-Standard Deviation Score (H-SDS) of Recombinant Human Growth Hormone (r-hGH) Treated Subjects at Year 4

Intention to Treat (ITT) population included all subjects who received at least one dose of treatment with at least an efficacy assessment available during the treatment period.

Posted

Mean

Standard Deviation

Standard Deviation Score (SDS)

Year 4

ID	Title	Description
OG000	r-hGH (Saizen®)	Subjects received a single subcutaneous injection of recombinant human growth hormone (r-hGH) equivalent to dose of 0.057 milligram per kilogram per day (mg/kg/day). The dose was subsequently reduced to 0.035 mg/kg/day for subjects, who continued treatment after 31 January 2011. Subjects were treated for at least 3 years or until near final height was reached.

Secondary

Height-Standard Deviation Score (H-SDS) of Recombinant Human Growth Hormone (r-hGH) Treated Subjects

Height was calculated in standardized units expressed as the standard deviation score (SDS), where SDS = (x - m)/sigma, in which x represents the height variable measured by sex and age, and m and sigma are the statistical parameters (mean and standard deviation) for the Sempe reference population. The reference population was the historical cohort consisting of non-treated subjects with Hypochondroplasia (HCH). Data was reported by gender. Male subjects were analyzed till 9.5 years and female subjects were analyzed till 8.5 years. SDS indicated how many standard deviations higher (in case of positive SDS) or lower (in case of negative SDS) a participant's value was relative to the mean of the reference population. The scores were centered around zero. Negative score indicated smaller height for the respective age/gender.

Intention to Treat (ITT) population included all subjects who received at least one dose of treatment with at least an efficacy assessment available during the treatment period. Here "Number analyzed" signifies those subjects who were evaluable for this outcome measure for specified category.

Posted

Median

Full Range

Standard Deviation Score (SDS)

Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 8.5 (only for female), 9 (only for male) and 9.5 (only for male)

ID	Title	Description
OG000	r-hGH (Saizen®)	Subjects received a single subcutaneous injection of recombinant human growth hormone (r-hGH) equivalent to dose of 0.057 milligram per kilogram per day (mg/kg/day). The dose was subsequently reduced to 0.035 mg/kg/day for subjects, who continued treatment after 31 January 2011. Subjects were treated for at least 3 years or until near final height was reached.

Secondary

Change From Baseline in Height of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) up to 9.5 Years

Body proportion was measured in terms of height. Data was reported by gender. Male subjects were analyzed till 9.5 years and female subjects were analyzed till 8.5 years.

Intention to Treat (ITT) population included all subjects who received at least one dose of treatment with at least an efficacy assessment available during the treatment period. Here "Number Analyzed" signifies those subjects who were evaluable for the specified category.

Posted

Mean

Standard Deviation

Centimeter (cm)

Baseline (Month 0), Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 8.5 (only for female), 9 (only for male) and 9.5 (only for male)

ID	Title	Description
OG000	r-hGH (Saizen®)	Subjects received a single subcutaneous injection of recombinant human growth hormone (r-hGH) equivalent to dose of 0.057 milligram per kilogram per day (mg/kg/day). The dose was subsequently reduced to 0.035 mg/kg/day for subjects, who continued treatment after 31 January 2011. Subjects were treated for at least 3 years or until near final height was reached.

Units	Counts
Participants

Secondary

Change From Baseline in Upper Segment (Superior) of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) up to 9.5 Years

Body proportion was measured in terms of upper segment for standing and sitting position. Data was reported by gender. Male subjects were analyzed till 9.5 years and female subjects were analyzed till 8.5 years.

ITT population. Here "Number analyzed" signifies those subjects who were evaluable for this outcome measure for specified category. Number Analyzed was "0" at certain time points because there was no data collected at the specified time points.

Posted

Mean

Standard Deviation

Centimeter (cm)

Baseline (Month 0), Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 8.5 (only for female), 9 (only for male) and 9.5 (only for male)

ID	Title	Description
OG000	r-hGH (Saizen®)	Subjects received a single subcutaneous injection of recombinant human growth hormone (r-hGH) equivalent to dose of 0.057 milligram per kilogram per day (mg/kg/day). The dose was subsequently reduced to 0.035 mg/kg/day for subjects, who continued treatment after 31 January 2011. Subjects were treated for at least 3 years or until near final height was reached.

Units	Counts
Participants

Secondary

Change From Baseline in Weight of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) up to 9.5 Years

The body weight was measured on a certified and calibrated hospital scale. Data was reported by gender. Male subjects were analyzed till 9.5 years and female subjects were analyzed till 8.5 years.

ITT population. Here "Number analyzed" signifies those subjects who were evaluable for this outcome measure for specified category.

Posted

Mean

Standard Deviation

Kilogram (kg)

Baseline (Month 0), Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 8.5 (only for female), 9 (only for male) and 9.5 (only for male)

ID	Title	Description
OG000	r-hGH (Saizen®)	Subjects received a single subcutaneous injection of recombinant human growth hormone (r-hGH) equivalent to dose of 0.057 milligram per kilogram per day (mg/kg/day). The dose was subsequently reduced to 0.035 mg/kg/day for subjects, who continued treatment after 31 January 2011. Subjects were treated for at least 3 years or until near final height was reached.

Units	Counts
Participants	OG000

Secondary

Change From Baseline in Body Mass Index (BMI) of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) up to 9.5 Years

Body proportion measured as BMI. It was calculated according to the formula BMI = Weight (kilogram)/Height square (meter square). Data was reported by gender. Male subjects were analyzed till 9.5 years and female subjects were analyzed till 8.5 years.

Posted

Mean

Standard Deviation

Kilogram per meter square (kg/m^2)

Baseline (Month 0), Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 8.5 (only for female), 9 (only for male) and 9.5 (only for male)

ID	Title	Description
OG000	r-hGH (Saizen®)	Subjects received a single subcutaneous injection of recombinant human growth hormone (r-hGH) equivalent to dose of 0.057 milligram per kilogram per day (mg/kg/day). The dose was subsequently reduced to 0.035 mg/kg/day for subjects, who continued treatment after 31 January 2011. Subjects were treated for at least 3 years or until near final height was reached.

Units	Counts
Participants

Secondary

Change From Baseline in Bone Mineral Density (BMD) of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) up to 9 Years

Body composition measured as BMD. It was examined at the lumbar spine (L1-L4) and determined annually by dual-energy X-ray absorptiometry. Data was reported by gender. Male subjects were analyzed till 9 years and female subjects were analyzed till 8 years.

Posted

Mean

Standard Deviation

Gram per square centimeter (g/cm^2)

Baseline (Month 0), Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 9 (only for male)

ID	Title	Description
OG000	r-hGH (Saizen®)	Subjects received a single subcutaneous injection of recombinant human growth hormone (r-hGH) equivalent to dose of 0.057 milligram per kilogram per day (mg/kg/day). The dose was subsequently reduced to 0.035 mg/kg/day for subjects, who continued treatment after 31 January 2011. Subjects were treated for at least 3 years or until near final height was reached.

Units	Counts
Participants

Secondary

Change From Baseline in Percent Body Fat Mass of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) up to 9 Years

Body composition measured as percentage of body fat mass. It was measured by Dual X-ray absorptiometry. Data was reported by gender. Male subjects were analyzed till 9 years and female subjects were analyzed till 8 years.

Posted

Mean

Standard Deviation

Percentage (%) of body fat mass

Baseline (Month 0), Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 9 (only for male)

ID	Title	Description
OG000	r-hGH (Saizen®)	Subjects received a single subcutaneous injection of recombinant human growth hormone (r-hGH) equivalent to dose of 0.057 milligram per kilogram per day (mg/kg/day). The dose was subsequently reduced to 0.035 mg/kg/day for subjects, who continued treatment after 31 January 2011. Subjects were treated for at least 3 years or until near final height was reached.

Units	Counts
Participants

Secondary

Change From Baseline in Lean Body Mass (LBM) of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) up to 9 Years

Body composition measured as LBM. It was measured by Dual X-ray absorptiometry. Data was reported by gender. Male subjects were analyzed till 9 years and female subjects were analyzed till 8 years.

Posted

Mean

Standard Deviation

Gram (g)

Baseline (Month 0), Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 9 (only for male)

ID	Title	Description
OG000	r-hGH (Saizen®)	Subjects received a single subcutaneous injection of recombinant human growth hormone (r-hGH) equivalent to dose of 0.057 milligram per kilogram per day (mg/kg/day). The dose was subsequently reduced to 0.035 mg/kg/day for subjects, who continued treatment after 31 January 2011. Subjects were treated for at least 3 years or until near final height was reached.

Units	Counts
Participants	OG000

Secondary

Growth (Height) Velocity of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) From Year 1 up to 9.5 Years

Growth velocity was calculated in terms of height velocity. It corresponded to a difference in height between current and baseline values divided by the time interval between both evaluations. Data was reported by gender. Male subjects were analyzed till 9.5 years and female subjects were analyzed till 8.5 years.

Posted

Mean

Standard Deviation

Centimeter per year (cm/year)

Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 8.5 (only for female), 9 (only for male) and 9.5 (only for male)

ID	Title	Description
OG000	r-hGH (Saizen®)	Subjects received a single subcutaneous injection of recombinant human growth hormone (r-hGH) equivalent to dose of 0.057 milligram per kilogram per day (mg/kg/day). The dose was subsequently reduced to 0.035 mg/kg/day for subjects, who continued treatment after 31 January 2011. Subjects were treated for at least 3 years or until near final height was reached.

Units	Counts
Participants

Secondary

Head Circumference Values of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) From Year 1 up to 9.5 Years

Body proportion was measured in terms of head circumference with a tape measure. Data was reported by gender. Male subjects were analyzed till 9.5 years and female subjects were analyzed till 8.5 years.

Posted

Mean

Standard Deviation

Centimeter (cm)

Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 8.5 (only for female), 9 (only for male) and 9.5 (only for male)

ID	Title	Description
OG000	r-hGH (Saizen®)	Subjects received a single subcutaneous injection of recombinant human growth hormone (r-hGH) equivalent to dose of 0.057 milligram per kilogram per day (mg/kg/day). The dose was subsequently reduced to 0.035 mg/kg/day for subjects, who continued treatment after 31 January 2011. Subjects were treated for at least 3 years or until near final height was reached.

Units	Counts
Participants

Secondary

Osteocalcin Values of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) From Year 1 up to 9.5 Years

Osteocalcin as bone marker was analyzed with the Immunology system Elecsys. Data was reported by gender. Male subjects were analyzed till 9.5 years and female subjects were analyzed till 8.5 years.

Posted

Mean

Standard Deviation

Nanogram per milliliter (ng/mL)

Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 8.5 (only for female), 9 (only for male), 9.5 (only for male)

ID	Title	Description
OG000	r-hGH (Saizen®)	Subjects received a single subcutaneous injection of recombinant human growth hormone (r-hGH) equivalent to dose of 0.057 milligram per kilogram per day (mg/kg/day). The dose was subsequently reduced to 0.035 mg/kg/day for subjects, who continued treatment after 31 January 2011. Subjects were treated for at least 3 years or until near final height was reached.

Units	Counts
Participants

Secondary

C-terminal Telopeptide (CTX) Values of Recombinant Human Growth Hormone (r-hGH) Treated Subjects With Hypochondroplasia (HCH) From Year 1 up to 9.5 Years

CTX (Blood) as bone marker was analyzed with the Immunology system Elecsys. Data was reported by gender. Male subjects were analyzed till 9.5 years and female subjects were analyzed till 8.5 years.

Posted

Mean

Standard Deviation

picomole per liter (pmol/L)

Year 1, 2, 3, 4, 5, 6, 7, 8 (both male and female); 8.5 (only for female), 9 (only for male), 9.5 (only for male)

ID	Title	Description
OG000	r-hGH (Saizen®)	Subjects received a single subcutaneous injection of recombinant human growth hormone (r-hGH) equivalent to dose of 0.057 milligram per kilogram per day (mg/kg/day). The dose was subsequently reduced to 0.035 mg/kg/day for subjects, who continued treatment after 31 January 2011. Subjects were treated for at least 3 years or until near final height was reached.

Units	Counts
Participants

Secondary

Number of Subjects With Fibroblast Growth Factor Receptor (FGFR3) Mutation

Genetic analysis was performed to record FGFR3 gene mutation. Genomic DNA was extracted from lymphocytes of collected blood samples using standard procedures. A set of intronic primers was designed based on the genomic sequence of the human FGFR3 gene and used to amplify exons 2-19. Number of subjects with FGFR3 mutation were reported.

Intention to Treat (ITT) population included all subjects who received at least one dose of treatment with at least an efficacy assessment available during the treatment period.

Posted

Number

Subjects

Baseline up to 3 years

ID	Title	Description
OG000	r-hGH (Saizen®)	Subjects received a single subcutaneous injection of recombinant human growth hormone (r-hGH) equivalent to dose of 0.057 milligram per kilogram per day (mg/kg/day). The dose was subsequently reduced to 0.035 mg/kg/day for subjects, who continued treatment after 31 January 2011. Subjects were treated for at least 3 years or until near final height was reached.

Units	Counts
Participants	OG000

Secondary

Number of Subjects With Adverse Event (AE) and Serious Adverse Event (SAE)

AEs: any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug , SAE: any AE that resulted in death; was life threatening; resulted in persistent/significant disability/incapacity; resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; or was an overdose.

Intention to Treat (ITT) population included all subjects who received at least one dose of treatment with at least an efficacy assessment available during the treatment period.

Posted

Number

Subjects

Baseline up to 9.5 years

ID	Title	Description
OG000	r-hGH (Saizen®)	Subjects received a single subcutaneous injection of recombinant human growth hormone (r-hGH) equivalent to dose of 0.057 milligram per kilogram per day (mg/kg/day). The dose was subsequently reduced to 0.035 mg/kg/day for subjects, who continued treatment after 31 January 2011. Subjects were treated for at least 3 years or until near final height was reached.

Units	Counts
Participants	OG000

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Neutropenia	Blood and lymphatic system disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Thrombopenia	Blood and lymphatic system disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Leucopenia	Blood and lymphatic system disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Lymphopenia	Blood and lymphatic system disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Angina pectoris	Cardiac disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Precocious puberty	Endocrine disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Hypothyroidism	Endocrine disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Dental cyst	Gastrointestinal disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Constipation	Gastrointestinal disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Abdominal Pain	Gastrointestinal disorders	MedDRA version 20.0	Non-systematic Assessment	EG0005 affected19 at risk
Diarrhea	Gastrointestinal disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Pyrexia	General disorders	MedDRA version 20.0	Non-systematic Assessment	EG0003 affected19 at risk
Fatigue	General disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Oedema peripheral	General disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Tooth abscess	Infections and infestations	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Pharyngitis	Infections and infestations	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Vulvitis	Infections and infestations	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Bronchitis	Infections and infestations	MedDRA version 20.0	Non-systematic Assessment	EG0003 affected19 at risk
Gastroenteritis	Infections and infestations	MedDRA version 20.0	Non-systematic Assessment	EG0003 affected19 at risk
Rhinitis	Infections and infestations	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Tonsillitis	Infections and infestations	MedDRA version 20.0	Non-systematic Assessment	EG0002 affected19 at risk
Meningitis viral	Infections and infestations	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Influenza	Infections and infestations	MedDRA version 20.0	Non-systematic Assessment	EG0002 affected19 at risk
Appendicitis	Infections and infestations	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Conjunctivitis	Infections and infestations	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Infection	Infections and infestations	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Herpes zoster	Infections and infestations	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Ear infection	Infections and infestations	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Nasopharyngitis	Infections and infestations	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Meniscus injury	Injury, poisoning and procedural complications	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Insulin-like growth factor increased	Investigations	MedDRA version 20.0	Non-systematic Assessment	EG0003 affected19 at risk
Vitamin D deficiency	Metabolism and nutrition disorders	MedDRA version 20.0	Non-systematic Assessment	EG0003 affected19 at risk
Insulin resistance	Metabolism and nutrition disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Hypertriglyceridaemia	Metabolism and nutrition disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA version 20.0	Non-systematic Assessment	EG0002 affected19 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA version 20.0	Non-systematic Assessment	EG0007 affected19 at risk
Foot deformity	Musculoskeletal and connective tissue disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Knee deformity	Musculoskeletal and connective tissue disorders	MedDRA version 20.0	Non-systematic Assessment	EG0004 affected19 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA version 20.0	Non-systematic Assessment	EG0002 affected19 at risk
Torticollis	Musculoskeletal and connective tissue disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Scoliosis	Musculoskeletal and connective tissue disorders	MedDRA version 20.0	Non-systematic Assessment	EG0005 affected19 at risk
Limb deformity	Metabolism and nutrition disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Deformity thorax	Musculoskeletal and connective tissue disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Musculoskeletal stiffness	Musculoskeletal and connective tissue disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Lordosis	Musculoskeletal and connective tissue disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Skin papilloma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Headache	Nervous system disorders	MedDRA version 20.0	Non-systematic Assessment	EG0004 affected19 at risk
Sciatica	Nervous system disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Syncope	Nervous system disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Dizziness	Nervous system disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Loss of consciousness	Nervous system disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Anger	Psychiatric disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Gynaecomastia	Reproductive system and breast disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA version 20.0	Non-systematic Assessment	EG0003 affected19 at risk
Bronchial obstruction	Respiratory, thoracic and mediastinal disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Nasal congestion	Respiratory, thoracic and mediastinal disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Dyspnoea exertional	Respiratory, thoracic and mediastinal disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Rhinitis allergic	Respiratory, thoracic and mediastinal disorders	MedDRA version 20.0	Non-systematic Assessment	EG0002 affected19 at risk
Pigmentation disorder	Skin and subcutaneous tissue disorders	MedDRA version 20.0	Non-systematic Assessment	EG0002 affected19 at risk
Eczema	Skin and subcutaneous tissue disorders	MedDRA version 20.0	Non-systematic Assessment	EG0002 affected19 at risk
Acne	Skin and subcutaneous tissue disorders	MedDRA version 20.0	Non-systematic Assessment	EG0002 affected19 at risk
Skin lesion	Skin and subcutaneous tissue disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Corrective lens user	Social circumstances	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk
Mole excision	Surgical and medical procedures	MedDRA version 20.0	Non-systematic Assessment	EG0001 affected19 at risk

ID	Term
D009083	Mucopolysaccharidoses
D002239	Carbohydrate Metabolism, Inborn Errors
D008661	Metabolism, Inborn Errors
D030342	Genetic Diseases, Inborn
D009358	Congenital, Hereditary, and Neonatal Diseases and Abnormalities
D016464	Lysosomal Storage Diseases
D017520	Mucinoses
D003240	Connective Tissue Diseases
D017437	Skin and Connective Tissue Diseases
D008659	Metabolic Diseases
D009750	Nutritional and Metabolic Diseases

ID	Term
D010908	Pituitary Hormones, Anterior
D010907	Pituitary Hormones
D036361	Peptide Hormones
D006728	Hormones
D006730	Hormones, Hormone Substitutes, and Hormone Antagonists
D010455	Peptides
D000602	Amino Acids, Peptides, and Proteins