ClinicalTrials.gov
ClinicalTrials.gov Menu

A Phase 3 Study to Evaluate the Safety and Efficacy of Saizen® in Children With Idiopathic Short Stature (ISS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01746862
Recruitment Status : Completed
First Posted : December 11, 2012
Results First Posted : October 18, 2016
Last Update Posted : October 18, 2016
Sponsor:
Information provided by (Responsible Party):
Merck KGaA, Darmstadt, Germany

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Idiopathic Short Stature
Intervention Drug: Saizen®
Enrollment 90
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Saizen Test Group Saizen Control Group
Hide Arm/Group Description Subjects in the Saizen test group received Saizen (recombinant-human growth hormone [r-hGH]) subcutaneously 6 days per week at a weight based dose of 0.067 milligram per kilogram of body weight per day (mg/kg/day) for 12 months. Subjects in the Saizen control group received no treatment for the first 6 months and thereafter received Saizen (r-hGH) subcutaneously 6 days per week at a weight based dose of 0.067 mg/kg/day for the next 6 months.
Period Title: Overall Study
Started 60 30
Treated 59 30
Completed 52 27
Not Completed 8 3
Reason Not Completed
Withdrawal by Subject             1             1
Protocol Violation             1             0
Consent withdrawal by parent’s guardian             5             2
Entered puberty during the study             1             0
Arm/Group Title Saizen Test Group Saizen Control Group Total
Hide Arm/Group Description Subjects in the Saizen test group received Saizen (recombinant-human growth hormone [r-hGH]) subcutaneously 6 days per week at a weight based dose of 0.067 milligram per kilogram of body weight per day (mg/kg/day) for 12 months. Subjects in the Saizen control group received no treatment for the first 6 months and thereafter received Saizen (r-hGH) subcutaneously 6 days per week at a weight based dose of 0.067 mg/kg/day for the next 6 months. Total of all reporting groups
Overall Number of Baseline Participants 59 30 89
Hide Baseline Analysis Population Description
Safety analysis set (SAS) included all randomized subjects who received at least 1 dose of planned trial treatment and had follow-up safety data. SAS also included the safety data for all subjects during non-treatment (the first 6 months after enrollment) period who belonged to control group.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 59 participants 30 participants 89 participants
6.79  (1.54) 6.83  (1.61) 6.80  (1.55)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 59 participants 30 participants 89 participants
Female
29
  49.2%
13
  43.3%
42
  47.2%
Male
30
  50.8%
17
  56.7%
47
  52.8%
1.Primary Outcome
Title Change From Baseline in Height Velocity at Month 6 Using Last Observation Carried Forward (LOCF) Method
Hide Description Baseline height is defined as the last available height measurement before randomization. Baseline height velocity = ([Baseline height minus height measurement obtained at least 6 months prior] / 6) * 12. Height velocity at Month 6 = ([Month 6 height minus height measurement obtained at least 6 months prior] / 6) * 12.
Time Frame Baseline, Month 6
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat (ITT) analysis set included all randomized subjects, regardless of whether or not they received the treatment to which they were randomized, completed the study or had any protocol deviations. Here ”n” signifies those subjects who were evaluable for this outcome measure at the specified time points.
Arm/Group Title Saizen Test Group Saizen Control Group
Hide Arm/Group Description:
Subjects in the Saizen test group received Saizen (recombinant-human growth hormone [r-hGH]) subcutaneously 6 days per week at a weight based dose of 0.067 milligram per kilogram of body weight per day (mg/kg/day) for 12 months.
Subjects in the Saizen control group received no treatment for the first 6 months and thereafter received Saizen (r-hGH) subcutaneously 6 days per week at a weight based dose of 0.067 mg/kg/day for the next 6 months.
Overall Number of Participants Analyzed 60 30
Mean (Standard Deviation)
Unit of Measure: centimeter/year (cm/yr)
Baseline (n=59,30) 5.63  (1.62) 4.94  (1.91)
Change at Month 6 (n=59,29) 4.45  (2.70) 1.01  (3.15)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Saizen Test Group, Saizen Control Group
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANCOVA
Comments Analysis was performed using analysis of covariance (ANCOVA) with baseline age and baseline height as the covariates.
Method of Estimation Estimation Parameter Least Squares (LS) Mean Difference
Estimated Value 3.47
Confidence Interval (2-Sided) 95%
2.17 to 4.78
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change From Baseline in Height Velocity at Month 12
Hide Description Baseline height is defined as the last available height measurement before randomization. Baseline height velocity = ([Baseline height minus height measurement obtained at least 12 months prior] / 12) * 12. Height velocity at Month 12 = ([Month 12 height minus height measurement obtained at least 12 months prior] / 12) * 12.
Time Frame Baseline, Month 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all randomized subjects, regardless of whether or not they received the treatment to which they were randomized, completed the study or had any protocol deviations. Here “Number of participants analyzed” signifies those subjects who were evaluable for this outcome measure.
Arm/Group Title Saizen Test Group Saizen Control Group
Hide Arm/Group Description:
Subjects in the Saizen test group received Saizen (recombinant-human growth hormone [r-hGH]) subcutaneously 6 days per week at a weight based dose of 0.067 milligram per kilogram of body weight per day (mg/kg/day) for 12 months.
Subjects in the Saizen control group received no treatment for the first 6 months and thereafter received Saizen (r-hGH) subcutaneously 6 days per week at a weight based dose of 0.067 mg/kg/day for the next 6 months.
Overall Number of Participants Analyzed 52 27
Mean (Standard Deviation)
Unit of Measure: cm/year
3.77  (2.21) 2.86  (1.95)
3.Secondary Outcome
Title Change From Baseline in Height at Month 6 and 12
Hide Description [Not Specified]
Time Frame Baseline, Month 6, Month 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all randomized subjects, regardless of whether or not they received the treatment to which they were randomized, completed the study or had any protocol deviations. Here ”n” signifies those subjects who were evaluable for this outcome measure at the specified time points.
Arm/Group Title Saizen Test Group Saizen Control Group
Hide Arm/Group Description:
Subjects in the Saizen test group received Saizen (recombinant-human growth hormone [r-hGH]) subcutaneously 6 days per week at a weight based dose of 0.067 milligram per kilogram of body weight per day (mg/kg/day) for 12 months.
Subjects in the Saizen control group received no treatment for the first 6 months and thereafter received Saizen (r-hGH) subcutaneously 6 days per week at a weight based dose of 0.067 mg/kg/day for the next 6 months.
Overall Number of Participants Analyzed 60 30
Mean (Standard Deviation)
Unit of Measure: centimeter (cm)
Baseline (n=60, 30) 108.27  (7.67) 108.07  (8.36)
Change at Month 6 (n=55, 27) 5.41  (1.04) 3.10  (0.84)
Change at Month 12 (n=52, 27) 9.78  (1.35) 8.24  (1.47)
4.Secondary Outcome
Title Change From Baseline in Height Standard Deviation Score (SDS) at Month 6 and 12
Hide Description Height SDS was calculated as: Height SDS = (measured height – population mean) / population standard deviation, where mean and standard deviation were based on the Korean standard growth charts. SDS indicated how many standard deviations higher (in case of positive SDS) or lower (in case of negative SDS) a subject’s value was relative to the mean of the reference population. The scores were centred around zero. Negative score indicated a subject was smaller for their age/gender.
Time Frame Baseline, Month 6, Month 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all randomized subjects, regardless of whether or not they received the treatment to which they were randomized, completed the study or had any protocol deviations. Here ”n” signifies those subjects who were evaluable for this outcome measure at the specified time points.
Arm/Group Title Saizen Test Group Saizen Control Group
Hide Arm/Group Description:
Subjects in the Saizen test group received Saizen (recombinant-human growth hormone [r-hGH]) subcutaneously 6 days per week at a weight based dose of 0.067 milligram per kilogram of body weight per day (mg/kg/day) for 12 months.
Subjects in the Saizen control group received no treatment for the first 6 months and thereafter received Saizen (r-hGH) subcutaneously 6 days per week at a weight based dose of 0.067 mg/kg/day for the next 6 months.
Overall Number of Participants Analyzed 60 30
Mean (Standard Deviation)
Unit of Measure: standard deviation score
Baseline (n=60,30) -2.26  (0.36) -2.34  (0.34)
Change at Month 6 (n=55, 27) 0.59  (0.21) 0.08  (0.19)
Change at Month 12 (n=52, 27) 0.96  (0.27) 0.62  (0.27)
5.Secondary Outcome
Title Change From Baseline in Serum Concentration of Insulin-like Growth Factor-I (IGF-I) at Month 6 and 12
Hide Description [Not Specified]
Time Frame Baseline, Month 6, Month 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all randomized subjects, regardless of whether or not they received the treatment to which they were randomized, completed the study or had any protocol deviations. Here ”n” signifies those subjects who were evaluable for this outcome measure at the specified time points.
Arm/Group Title Saizen Test Group Saizen Control Group
Hide Arm/Group Description:
Subjects in the Saizen test group received Saizen (recombinant-human growth hormone [r-hGH]) subcutaneously 6 days per week at a weight based dose of 0.067 milligram per kilogram of body weight per day (mg/kg/day) for 12 months.
Subjects in the Saizen control group received no treatment for the first 6 months and thereafter received Saizen (r-hGH) subcutaneously 6 days per week at a weight based dose of 0.067 mg/kg/day for the next 6 months.
Overall Number of Participants Analyzed 60 30
Mean (Standard Deviation)
Unit of Measure: microgram/liter (mcg/L)
Baseline (n=60,30) 112.62  (43.06) 125.01  (65.68)
Change at Month 6 (n=55, 27) 122.57  (96.99) 8.30  (41.57)
Change at Month 12 (n=52, 27) 164.48  (95.69) 142.17  (112.94)
6.Secondary Outcome
Title Change From Baseline in Serum Concentration of Insulin Like Growth Factor Binding Protein-3 (IGFBP-3) at Month 6 and 12
Hide Description [Not Specified]
Time Frame Baseline, Month 6, Month 12
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all randomized subjects, regardless of whether or not they received the treatment to which they were randomized, completed the study or had any protocol deviations. Here ”n” signifies those subjects who were evaluable for this outcome measure at the specified time points.
Arm/Group Title Saizen Test Group Saizen Control Group
Hide Arm/Group Description:
Subjects in the Saizen test group received Saizen (recombinant-human growth hormone [r-hGH]) subcutaneously 6 days per week at a weight based dose of 0.067 milligram per kilogram of body weight per day (mg/kg/day) for 12 months.
Subjects in the Saizen control group received no treatment for the first 6 months and thereafter received Saizen (r-hGH) subcutaneously 6 days per week at a weight based dose of 0.067 mg/kg/day for the next 6 months.
Overall Number of Participants Analyzed 60 30
Mean (Standard Deviation)
Unit of Measure: mcg/L
Baseline (n=60, 30) 3,783.33  (915.20) 3,935.67  (866.42)
Change at Month 6 (n=55, 27) 857.64  (761.28) -38.89  (616.88)
Change at Month 12 (n=52, 27) 932.31  (666.13) 545.56  (599.52)
7.Secondary Outcome
Title Percentage of Adherence to Study Treatment
Hide Description Percentage of adherence to study treatment (adherence rate) was defined as the actual number of received treatments divided by the scheduled number of treatments multiplied by 100. The adherence rate for 6 months was calculated from Baseline to 6 months for the Saizen Test Group and from Month 6 to Month 12 for the Saizen Control Group.
Time Frame 6 months post-dose (Saizen Test Group and Saizen Control Group); 12 months post-dose (Saizen Test Group)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT analysis set included all randomized subjects, regardless of whether or not they received the treatment to which they were randomized, completed the study or had any protocol deviations. Here ”n” signifies those subjects who were evaluable for this outcome measure at the specified time points.
Arm/Group Title Saizen Test Group Saizen Control Group
Hide Arm/Group Description:
Subjects in the Saizen test group received Saizen (recombinant-human growth hormone [r-hGH]) subcutaneously 6 days per week at a weight based dose of 0.067 milligram per kilogram of body weight per day (mg/kg/day) for 12 months.
Subjects in the Saizen control group received no treatment for the first 6 months and thereafter received Saizen (r-hGH) subcutaneously 6 days per week at a weight based dose of 0.067 mg/kg/day for the next 6 months.
Overall Number of Participants Analyzed 60 30
Mean (Standard Deviation)
Unit of Measure: percentage of adherance
Adherence for 6 months (n=60, 27) 94.38  (14.12) 95.69  (5.04)
Adherence for 12 months (n=60, 0) 93.27  (14.67) NA [1]   (NA)
[1]
Data was not available as control group received the treatment for only 6 months
8.Secondary Outcome
Title Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs
Hide Description An adverse event (AE) was defined as any untoward medical occurrence which does not necessarily have a causal relationship with this the study drug. An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. For the Saizen Test Group, TEAEs were defined as events that occurred or worsened at or after the first administration of treatment and for the Saizen Control Group, TEAEs were defined as events that occurred or worsened at or after the randomization.
Time Frame Baseline up to Month 13
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set (SAS) included all randomized subjects who received at least 1 dose of planned trial treatment and had follow-up safety data. SAS also included the safety data for all subjects during non-treatment (the first 6 months after enrollment) period who belonged to control group.
Arm/Group Title Saizen Test Group Saizen Control Group
Hide Arm/Group Description:
Subjects in the Saizen control group received no treatment for the first 6 months and thereafter received Saizen (r-hGH) subcutaneously 6 days per week at a weight based dose of 0.067 mg/kg/day for the next 6 months.
Subjects in the Saizen control group received no treatment for the first 6 months and thereafter received Saizen (r-hGH) subcutaneously 6 days per week at a weight based dose of 0.067 mg/kg/day for the next 6 months.
Overall Number of Participants Analyzed 59 30
Measure Type: Number
Unit of Measure: subjects
TEAEs 42 18
Serious TEAEs 3 1
Time Frame Baseline up to Month 13
Adverse Event Reporting Description Safety analysis set (SAS) included all randomized subjects who received at least 1 dose of planned trial treatment and had follow-up safety data. SAS also included the safety data for all subjects during non-treatment (the first 6 months after enrollment) period who belonged to control group.
 
Arm/Group Title Saizen Test Group Saizen Control Group
Hide Arm/Group Description Subjects in the Saizen test group received Saizen (recombinant-human growth hormone [r-hGH]) subcutaneously 6 days per week at a weight based dose of 0.067 milligram per kilogram of body weight per day (mg/kg/day) for 12 months. Subjects in the Saizen control group received no treatment for the first 6 months and thereafter received Saizen (r-hGH) subcutaneously 6 days per week at a weight based dose of 0.067 mg/kg/day for the next 6 months.
All-Cause Mortality
Saizen Test Group Saizen Control Group
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Saizen Test Group Saizen Control Group
Affected / at Risk (%) Affected / at Risk (%)
Total   3/59 (5.08%)   1/30 (3.33%) 
General disorders     
Pyrexia * 1  0/59 (0.00%)  1/30 (3.33%) 
Infections and infestations     
Chronic sinusitis * 1  0/59 (0.00%)  1/30 (3.33%) 
Chronic tonsillitis * 1  1/59 (1.69%)  0/30 (0.00%) 
Croup infectious * 1  1/59 (1.69%)  0/30 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
T-cell lymphoma * 1  0/59 (0.00%)  1/30 (3.33%) 
Respiratory, thoracic and mediastinal disorders     
Adenoidal hypertrophy * 1  2/59 (3.39%)  0/30 (0.00%) 
Tonsillar hypertrophy * 1  1/59 (1.69%)  0/30 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 18.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Saizen Test Group Saizen Control Group
Affected / at Risk (%) Affected / at Risk (%)
Total   42/59 (71.19%)   18/30 (60.00%) 
Congenital, familial and genetic disorders     
Pectus carinatum * 1  1/59 (1.69%)  0/30 (0.00%) 
Ear and labyrinth disorders     
Motion sickness * 1  0/59 (0.00%)  1/30 (3.33%) 
Endocrine disorders     
Hypothyroidism * 1  0/59 (0.00%)  1/30 (3.33%) 
Eye disorders     
Chalazion * 1  1/59 (1.69%)  0/30 (0.00%) 
Conjunctivitis allergic * 1  0/59 (0.00%)  1/30 (3.33%) 
Eye inflammation * 1  1/59 (1.69%)  0/30 (0.00%) 
Gastrointestinal disorders     
Abdominal pain * 1  2/59 (3.39%)  0/30 (0.00%) 
Enteritis * 1  1/59 (1.69%)  1/30 (3.33%) 
Abdominal pain upper * 1  0/59 (0.00%)  1/30 (3.33%) 
Colitis * 1  1/59 (1.69%)  0/30 (0.00%) 
Constipation * 1  1/59 (1.69%)  0/30 (0.00%) 
Diarrhoea * 1  1/59 (1.69%)  0/30 (0.00%) 
Oral mucosal eruption * 1  0/59 (0.00%)  1/30 (3.33%) 
Vomiting * 1  1/59 (1.69%)  0/30 (0.00%) 
General disorders     
Pyrexia * 1  4/59 (6.78%)  3/30 (10.00%) 
Infections and infestations     
Nasopharyngitis * 1  24/59 (40.68%)  9/30 (30.00%) 
Upper respiratory tract infection * 1  14/59 (23.73%)  9/30 (30.00%) 
Rhinitis * 1  4/59 (6.78%)  2/30 (6.67%) 
Bronchitis * 1  2/59 (3.39%)  3/30 (10.00%) 
Conjunctivitis * 1  4/59 (6.78%)  0/30 (0.00%) 
Gastroenteritis * 1  4/59 (6.78%)  0/30 (0.00%) 
Otitis media * 1  2/59 (3.39%)  2/30 (6.67%) 
Influenza * 1  2/59 (3.39%)  1/30 (3.33%) 
Pharyngitis * 1  2/59 (3.39%)  1/30 (3.33%) 
Acute tonsillitis * 1  1/59 (1.69%)  0/30 (0.00%) 
Hand-foot-and-mouth disease * 1  1/59 (1.69%)  0/30 (0.00%) 
Hordeolum * 1  1/59 (1.69%)  0/30 (0.00%) 
Impetigo * 1  1/59 (1.69%)  0/30 (0.00%) 
Laryngitis * 1  0/59 (0.00%)  1/30 (3.33%) 
Lower respiratory tract infection * 1  0/59 (0.00%)  1/30 (3.33%) 
Molluscum contagiosum * 1  1/59 (1.69%)  0/30 (0.00%) 
Otitis media acute * 1  1/59 (1.69%)  0/30 (0.00%) 
Perineal infection * 1  1/59 (1.69%)  0/30 (0.00%) 
Pulpitis dental * 1  1/59 (1.69%)  0/30 (0.00%) 
Subcutaneous abscess * 1  0/59 (0.00%)  1/30 (3.33%) 
Tinea infection * 1  1/59 (1.69%)  0/30 (0.00%) 
Tonsillitis * 1  1/59 (1.69%)  0/30 (0.00%) 
Tooth abscess * 1  1/59 (1.69%)  0/30 (0.00%) 
Tracheitis * 1  1/59 (1.69%)  0/30 (0.00%) 
Urinary tract infection * 1  1/59 (1.69%)  0/30 (0.00%) 
Varicella * 1  1/59 (1.69%)  0/30 (0.00%) 
Injury, poisoning and procedural complications     
Contusion * 1  1/59 (1.69%)  0/30 (0.00%) 
Joint injury * 1  1/59 (1.69%)  0/30 (0.00%) 
Ligament sprain * 1  1/59 (1.69%)  0/30 (0.00%) 
Radius fracture * 1  1/59 (1.69%)  0/30 (0.00%) 
Skin abrasion * 1  0/59 (0.00%)  1/30 (3.33%) 
Investigations     
Blood thyroid stimulating hormone increased * 1  1/59 (1.69%)  0/30 (0.00%) 
Haemoglobin decreased * 1  1/59 (1.69%)  0/30 (0.00%) 
Metabolism and nutrition disorders     
Dehydration * 1  1/59 (1.69%)  0/30 (0.00%) 
Musculoskeletal and connective tissue disorders     
Scoliosis * 1  1/59 (1.69%)  0/30 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Skin papilloma * 1  1/59 (1.69%)  0/30 (0.00%) 
Nervous system disorders     
Headache * 1  0/59 (0.00%)  1/30 (3.33%) 
Reproductive system and breast disorders     
Breast mass * 1  1/59 (1.69%)  0/30 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Rhinitis allergic * 1  3/59 (5.08%)  2/30 (6.67%) 
Oropharyngeal pain * 1  1/59 (1.69%)  1/30 (3.33%) 
Rhinorrhoea * 1  0/59 (0.00%)  1/30 (3.33%) 
Cough * 1  1/59 (1.69%)  0/30 (0.00%) 
Skin and subcutaneous tissue disorders     
Urticaria * 1  2/59 (3.39%)  1/30 (3.33%) 
Rash * 1  1/59 (1.69%)  1/30 (3.33%) 
Rash generalised * 1  0/59 (0.00%)  1/30 (3.33%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 18.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Merck KGaA Communication Center
Organization: Merck Healthcare, a business of Merck KGaA, Darmstadt, Germany
Phone: +49-6151-72-5200
Responsible Party: Merck KGaA, Darmstadt, Germany
ClinicalTrials.gov Identifier: NCT01746862     History of Changes
Other Study ID Numbers: EMR200104-533
First Submitted: November 30, 2012
First Posted: December 11, 2012
Results First Submitted: August 24, 2016
Results First Posted: October 18, 2016
Last Update Posted: October 18, 2016