SAIZEN in SGA: A Trial to Evaluate the Correlation Between Spontaneous Catch-up Growth, Clinical Response to Saizen (Recombinant Human Growth Hormone, r-hGH) and Gene Expression Profiling in Children Small for Gestational Age (SGA)

• Sponsor: Merck KGaA, Darmstadt, Germany (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01067352
• Collaborator: Merck Serono S.P.A., Italy (Industry)
• Enrollment: 25
• Location: 1
• Arms: 3
• Duration (Months): 65
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This open, multicentric, randomized, controlled study is planned to evaluate the correlation between gene expression, spontaneous catch-up growth and therapeutic response to Saizen in SGA children.

Condition or Disease	Intervention/Treatment	Phase
Infant, Small for Gestational Age	Drug: Recombinant human growth hormone (r-hGH)	Phase 3

Detailed Description

This open, multicentric, randomized, controlled study was planned to identify genes activated by hGH in SGA children responders to treatment (making it possible in the near future to better identify SGA children likely to benefit from hGH treatment). Furthermore, the study would hopefully allow to verify which genes were responsible of spontaneous catch-up growth in children with diagnosis of SGA at birth but above the third percentile for height at the age of 24 months, and if these genes were the same activated by hGH during the treatment in participants responders. Sixty children born at term (i.e. after the 37th completed week of gestation) and with a diagnosis of SGA (defined as a length less than tenth percentile according to the Italian reference table published by Bertini and Fabris) were planned to be enrolled in the study. Forty participants (group A) were still less than third percentile for height (according to the Tanner reference table) at the age of 24 months, the remaining 20 (group B) being more than or equal to third percentile (thus showing a spontaneous catch-up growth). Group A was randomized to receive Saizen at the daily dose of 0.067 mg/kg (Group A1) or no treatment (Group A2) for two years. All participants were to undergo full clinical examination and blood chemistry at baseline visit and visit after 1,6,12,18 and 24 months for a period of two years. Gene expression analysis using the Clontech Atlas Human Array was performed in all participants at baseline and after one year in order to identify the possible correlation between catch-up growth (either spontaneous or drug-induced) and expression of some genes.

OBJECTIVES

Primary objective:

• To evaluate the correlation between gene expression profiling and catch-up growth (either spontaneous or drug induced after one year of treatment) in SGA children.

Secondary Objectives:

• To evaluate the percentage of participants not treated who show a spontaneous catch-up growth during the two years of observation.

• To assess the safety and tolerability of early treatment with Saizen

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open, Multicenter, Randomized, Controlled Trial to Evaluate the Correlation Between Spontaneous Catch-up Growth, Clinical Response to Saizen (Recombinant Human Growth Hormone, r-hGH) and Gene Expression Profiling in Children Small for Gestational Age (SGA)
• Study Start Date: Feb 1, 2004
• Actual Primary Completion Date: Jul 1, 2009
• Actual Study Completion Date: Jul 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group A (A1) Participants were allocated to Group A if were still third percentile for height (according to the Tanner reference table) at the age of 4-6 years. Group A would be then randomized to receive Saizen at the daily dose of 0.035 milligram (mg)/kilogram (kg) (Group A1) or no treatment (Group A2) for two years.	Drug: Recombinant human growth hormone (r-hGH); Recombinant human GH were administered subcutaneously (s.c) at the daily dose of 0.067 mg/kg of body weight to Group A1.; Other Names: Saizen
No Intervention: Group A (A2) Participants were allocated to Group A if were still third percentile for height (according to the Tanner reference table) at the age of 4-6 years. Group A would be then randomized to receive no treatment (Group A2) for two years.
No Intervention: Group B Participants were allocated to Group B being third percentile (thus showing a spontaneous catch-up growth).

Outcome Measures

Primary Outcome Measures

1. Correlation Between Gene Expression Profiling and Catch-up Growth in Small for Gestational Age (SGA) Children [Baseline and Week 48]

   Gene expression profiling:analysis of ribonucleic acid (RNA) extracted from body tissue or fluids using Clontech Atlas Human Array to study level of activation of genes in tissue analyzed. Analysis was performed to identify possible correlation between catch-up growth (either spontaneous or drug-induced after Week 48) and therapeutic response to rhGH. Spontaneous catch up growth:shown by SGA participants having length more than third percentile at Week 96 without any treatment;drug induced growth was by SGA participants having length more than third percentile at Week 96 with drug treatment.

Secondary Outcome Measures

1. Percentage of Untreated Participants Who Showed a Spontaneous Catch-up Growth [Baseline through Week 96]

   Spontaneous catch up growth was the growth shown by SGA participants having length more than third percentile at Week 96 without any study drug treatment.

2. Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation [Baseline through Week 96]

   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. Participants who discontinued from the study due to AE were also recorded.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Years to 6 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• SGA at birth (defined as a length at birth equal or below the tenth percentile according to the Italian reference table of Bertini and Fabris)

• Age of 24 Months

• Caucasic

• Born at term (i.e. after the 37th completed week of gestation)

• Height equal or below (Group A) or up (Group B) the third percentile at the age of 24 months according to the Tanner reference table

• Sufficient GH secretion (more than 10 nanogram (ng)/milliliter (ml)) at least to one of the tests commonly used at that age (glucagon, Levo-dopa, arginine, clonidine, Growth Hormone Releasing Hormone (GHRH), GH integrated secretion)

• Normal level of Thyroid-stimulating hormone (THS), Free Triiodothyronine (FT3), Free Thyroxine (FT4), Insulin-like growth factor 1(IGF-1), insulin and haemoglobin A1c (HbA1c)

• Normal level of Immunoglobulin A (IgA)

• Children parents willing to comply with the protocol for the whole duration of the study

• A written Informed Consent before the baseline visit must be obtained from the parent(s) / legal guardian(s)

Exclusion Criteria:

• Congenital malformations (including Silver-Russel syndrome)

• Known abnormal karyotype, especially in girls

• Twins

• Severe psychomotor retardation

• Previous or ongoing treatment with anabolic steroids or r-hGH

• Treatments interfering with the immune system (including bacterial lysate)

• Severe chronic illnesses

• Autoimmune diseases

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Merck Serono S.p.A.	Roma		Italy

Sponsors and Collaborators

• Merck KGaA, Darmstadt, Germany
• Merck Serono S.P.A., Italy

Investigators

• Study Director: Medical Responsible, Merck Serono S.P.A., Italy

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT01067352
• Other Study ID Numbers: IMP23681
• First Posted: Feb 11, 2010
• Last Update Posted: Dec 27, 2013
• Last Verified: Dec 1, 2013

• Keywords provided by Merck KGaA, Darmstadt, Germany: Infant, small for gestational age; Growth hormone; Saizen
• Additional relevant MeSH terms: Hormones

Study Results

Participant Flow

Recruitment Details	Participants were recruited in 12 study centers in Italy from 20 Feb 2004 to 10 Jul 2009.

Arm/Group Title	Group A, Less Than Third Percentile (Saizen)	Group A2, Less Than Third Percentile (No Treatment)	Group B, More Than Third Percentile (No Treatment)
Arm/Group Description	Participants with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received Saizen (recombinant human growth hormone, r-hGH) subcutaneously (s.c) at the daily dose of 0.035 milligram(mg)/kilogram(kg) for 2 years.	Participants with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years.	Participants with more than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years.
Period Title: Overall Study
STARTED	9	6	10
COMPLETED	8	3	9
NOT COMPLETED	1	3	1

Baseline Characteristics

Arm/Group Title	Group A, Less Than Third Percentile (Saizen)	Group A2, Less Than Third Percentile (No Treatment)	Group B, More Than Third Percentile (No Treatment)	Total
Arm/Group Description	Participants with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received Saizen (recombinant human growth hormone, r-hGH) subcutaneously (s.c) at the daily dose of 0.035 milligram(mg)/kilogram(kg) for 2 years.	Participants with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years.	Participants with more than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years.	Total of all reporting groups
Overall Participants	9	6	10	25
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	5.7 (1.2)	5.0 (0.7)	5.2 (0.4)	5.3 (0.9)
Sex: Female, Male (Count of Participants)
Female	4 44.4%	4 66.7%	5 50%	13 52%
Male	5 55.6%	2 33.3%	5 50%	12 48%

Outcome Measures

1. Primary Outcome

Title	Correlation Between Gene Expression Profiling and Catch-up Growth in Small for Gestational Age (SGA) Children
Description	Gene expression profiling:analysis of ribonucleic acid (RNA) extracted from body tissue or fluids using Clontech Atlas Human Array to study level of activation of genes in tissue analyzed. Analysis was performed to identify possible correlation between catch-up growth (either spontaneous or drug-induced after Week 48) and therapeutic response to rhGH. Spontaneous catch up growth:shown by SGA participants having length more than third percentile at Week 96 without any treatment;drug induced growth was by SGA participants having length more than third percentile at Week 96 with drug treatment.
Time Frame	Baseline and Week 48

Outcome Measure Data

Analysis Population Description

Gene expression profiling was not performed due to RNA degradation in nearly all of the blood samples and hence no comparison between gene expression and growth was made.

Arm/Group Title	Group A, Less Than Third Percentile (Saizen)	Group A2, Less Than Third Percentile (No Treatment)	Group B, More Than Third Percentile (No Treatment)
Arm/Group Description	Participants with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received Saizen (recombinant human growth hormone, r-hGH) subcutaneously (s.c) at the daily dose of 0.035 milligram(mg)/kilogram(kg) for 2 years.	Participants with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years.	Participants with more than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years.
Measure Participants	0	0	0

2. Secondary Outcome

Title	Percentage of Untreated Participants Who Showed a Spontaneous Catch-up Growth
Description	Spontaneous catch up growth was the growth shown by SGA participants having length more than third percentile at Week 96 without any study drug treatment.
Time Frame	Baseline through Week 96

Outcome Measure Data

Analysis Population Description

Data was not analyzed due to small number of evaluable participants.

Arm/Group Title	Group A, Less Than Third Percentile (Saizen)	Group A2, Less Than Third Percentile (No Treatment)	Group B, More Than Third Percentile (No Treatment)
Arm/Group Description	Participants with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received Saizen (recombinant human growth hormone, r-hGH) subcutaneously (s.c) at the daily dose of 0.035 milligram(mg)/kilogram(kg) for 2 years.	Participants with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years.	Participants with more than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years.
Measure Participants	0	0	0

3. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and AEs Leading to Study Drug Discontinuation
Description	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. Participants who discontinued from the study due to AE were also recorded.
Time Frame	Baseline through Week 96

Outcome Measure Data

Analysis Population Description

Safety analysis population included all randomized participants with at least 1 post-baseline assessment.

Arm/Group Title	Group A, Less Than Third Percentile (Saizen)	Group A2, Less Than Third Percentile (No Treatment)	Group B, More Than Third Percentile (No Treatment)
Arm/Group Description	Participants with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received Saizen (recombinant human growth hormone, r-hGH) subcutaneously (s.c) at the daily dose of 0.035 milligram(mg)/kilogram(kg) for 2 years.	Participants with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years.	Participants with more than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years.
Measure Participants	8	4	10
AEs	6 66.7%	4 66.7%	9 90%
SAEs	0 0%	0 0%	0 0%
Discontinuation due to AEs	0 0%	0 0%	0 0%

Adverse Events

Time Frame	AEs were collected on an ongoing basis from day of written informed consent. All new AEs were recorded until the post-treatment safety, on Day 30 post-drug administration.
Arm/Group Title	Group A, Less Than Third Percentile (Saizen)		Group A2, Less Than Third Percentile (No Treatment)		Group B, More Than Third Percentile (No Treatment)
Arm/Group Description	Participants with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received Saizen (recombinant human growth hormone, r-hGH) subcutaneously (s.c) at the daily dose of 0.035 milligram(mg)/kilogram(kg) for 2 years.		Participants with less than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years.		Participants with more than third percentile for height (according to the Tanner reference table) at the age of 4-6 years received no drug treatment for 2 years.
All Cause Mortality
	Group A, Less Than Third Percentile (Saizen)		Group A2, Less Than Third Percentile (No Treatment)		Group B, More Than Third Percentile (No Treatment)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Group A, Less Than Third Percentile (Saizen)		Group A2, Less Than Third Percentile (No Treatment)		Group B, More Than Third Percentile (No Treatment)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/4 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Group A, Less Than Third Percentile (Saizen)		Group A2, Less Than Third Percentile (No Treatment)		Group B, More Than Third Percentile (No Treatment)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/8 (75%)		4/4 (100%)		9/10 (90%)
Blood and lymphatic system disorders
Iron deficiency anaemia	1/8 (12.5%)	1	0/4 (0%)	0	0/10 (0%)	0
Microcytic anaemia	1/8 (12.5%)	2	0/4 (0%)	0	0/10 (0%)	0
Lymphadenopathy	0/8 (0%)	0	0/4 (0%)	0	1/10 (10%)	1
Eye disorders
Conjunctivitis	1/8 (12.5%)	1	0/4 (0%)	0	0/10 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/8 (12.5%)	1	0/4 (0%)	0	0/10 (0%)	0
Stomatitis	1/8 (12.5%)	1	0/4 (0%)	0	0/10 (0%)	0
Diarrhoea	0/8 (0%)	0	1/4 (25%)	1	0/10 (0%)	0
Constipation	0/8 (0%)	0	0/4 (0%)	0	1/10 (10%)	2
General disorders
Cyst	1/8 (12.5%)	1	0/4 (0%)	0	0/10 (0%)	0
Pyrexia	6/8 (75%)	15	2/4 (50%)	6	4/10 (40%)	6
Immune system disorders
Milk allergy	0/8 (0%)	0	1/4 (25%)	1	0/10 (0%)	0
Infections and infestations
Ear infection	1/8 (12.5%)	3	0/4 (0%)	0	1/10 (10%)	1
Bronchitis	2/8 (25%)	2	1/4 (25%)	1	3/10 (30%)	4
Pharyngitis	1/8 (12.5%)	4	2/4 (50%)	2	2/10 (20%)	2
Rhinitis	1/8 (12.5%)	1	0/4 (0%)	0	1/10 (10%)	1
Gastroenteritis	0/8 (0%)	0	1/4 (25%)	2	0/10 (0%)	0
Tonsillitis	0/8 (0%)	0	1/4 (25%)	2	1/10 (10%)	1
Varicella	0/8 (0%)	0	2/4 (50%)	2	2/10 (20%)	2
Enterocolitis infectious	0/8 (0%)	0	0/4 (0%)	0	1/10 (10%)	1
Influenza	0/8 (0%)	0	0/4 (0%)	0	3/10 (30%)	3
Laryngitis	0/8 (0%)	0	0/4 (0%)	0	1/10 (10%)	1
Injury, poisoning and procedural complications
Road traffic accident	0/8 (0%)	0	0/4 (0%)	0	1/10 (10%)	1
Investigations
Blood alkaline phosphatase increased	0/8 (0%)	0	1/4 (25%)	1	0/10 (0%)	0
Blood cholesterol increased	0/8 (0%)	0	1/4 (25%)	1	0/10 (0%)	0
Lipoprotein (a) abnormal	0/8 (0%)	0	1/4 (25%)	1	0/10 (0%)	0
Blood insulin decreased	0/8 (0%)	0	0/4 (0%)	0	1/10 (10%)	1
Metabolism and nutrition disorders
Hypercholesterolaemia	0/8 (0%)	0	0/4 (0%)	0	1/10 (10%)	2
Musculoskeletal and connective tissue disorders
Neck pain	1/8 (12.5%)	1	0/4 (0%)	0	0/10 (0%)	0
Nervous system disorders
Headache	1/8 (12.5%)	1	0/4 (0%)	0	1/10 (10%)	1
Renal and urinary disorders
Proteinuria	0/8 (0%)	0	0/4 (0%)	0	1/10 (10%)	2
Respiratory, thoracic and mediastinal disorders
Adenoidal hypertrophy	1/8 (12.5%)	1	0/4 (0%)	0	0/10 (0%)	0
Cough	1/8 (12.5%)	4	0/4 (0%)	0	2/10 (20%)	2
Oropharyngeal pain	1/8 (12.5%)	1	0/4 (0%)	0	0/10 (0%)	0
Rhinitis allergic	2/8 (25%)	2	0/4 (0%)	0	0/10 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	1/8 (12.5%)	1	0/4 (0%)	0	0/10 (0%)	0
Acute generalised exanthematous pustulosis	0/8 (0%)	0	0/4 (0%)	0	1/10 (10%)	1
Pruritus	0/8 (0%)	0	0/4 (0%)	0	1/10 (10%)	1

Limitations/Caveats

The primary and secondary efficacy objectives were not met because of poor participant enrollment and no quality RNA samples obtained to evaluate (RNA degradation in nearly all of the blood samples).

More Information

Certain Agreements

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