Clinical Trial Results:
A randomised, open-labelled, active-controlled, multinational, dose-escalation trial investigating safety, tolerability, pharmacokinetics and pharmacodynamics of a single dose of long-acting growth hormone (NNC0195-0092) compared to daily dosing of Norditropin® SimpleXx® in children with growth hormone deficiency

Trial information Top of page
Trial identification
Sponsor protocol code	NN8640-4042
Additional study identifiers
ISRCTN number	-
US NCT number	NCT01973244
WHO universal trial number (UTN)	U1111-1138-2206
Sponsors
Sponsor organisation name	Novo Nordisk A/S
Sponsor organisation address	Novo Allé, Bagsvaerd, Denmark, 2880
Public contact	Global Clinical Registry (GCR,1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
Scientific contact	Global Clinical Registry (GCR,1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	Yes
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	19 Mar 2015
Is this the analysis of the primary completion data?	Yes
Primary completion date	04 Nov 2014
Global end of trial reached?	Yes
Global end of trial date	04 Nov 2014
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	To evaluate safety and tolerability of a single subcutaneous (s.c.) dose of NNC0195-0092 compared to daily dosing of Norditropin® SimpleXx® for seven days in children with growth hormone deficiency (GHD)
Protection of trial subjects	The trial was conducted in accordance with the Declaration of Helsinki (Oct 2013), ICH Good Clinical Practice (GCP) (1996) and FDA 21 CFR 312.120.
Background therapy	Not applicable.
Evidence for comparator	Not applicable.
Actual start date of recruitment	16 Dec 2013
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Slovenia: 6
Country: Number of subjects enrolled	Spain: 5
Country: Number of subjects enrolled	Sweden: 2
Country: Number of subjects enrolled	Austria: 1
Country: Number of subjects enrolled	Belgium: 6
Country: Number of subjects enrolled	France: 3
Country: Number of subjects enrolled	Israel: 5
Country: Number of subjects enrolled	Macedonia, the former Yugoslav Republic of: 4
Worldwide total number of subjects	32
EEA total number of subjects	23
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	32
Adolescents (12-17 years)	0
Adults (18-64 years)	0
From 65 to 84 years	0
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	The trial was conducted at 14 sites in 8 countries.
Pre-assignment
Screening details	Not applicable.
Period 1
Period 1 title	Overall Study (overall period)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Not blinded
Blinding implementation details	Not applicable.
Arms
Are arms mutually exclusive	Yes
Arm title	0.02 mg/Kg - NNC0195-0092
Arm description	0.02 mg/Kg, single dose of NNC0195-0092 was administered to subjects subcutaneously.
Arm type	Experimental
Investigational medicinal product name	NNC0195-0092
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for injection in cartridge
Routes of administration	Subcutaneous use
Dosage and administration details	0.02 mg/Kg, single dose of NNC0195-0092 was administered to subjects subcutaneously.
Arm title	0.04 mg/Kg - NNC0195-0092
Arm description	0.04 mg/Kg, single dose of NNC0195-0092 was administered to subjects subcutaneously.
Arm type	Experimental
Investigational medicinal product name	NNC0195-0092
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for injection in cartridge
Routes of administration	Subcutaneous use
Dosage and administration details	0.04 mg/Kg, single dose of NNC0195-0092 was administered to subjects subcutaneously.
Arm title	0.08 mg/Kg - NNC0195-0092
Arm description	0.08 mg/Kg, single dose of NNC0195-0092 was administered to subjects subcutaneously.
Arm type	Experimental
Investigational medicinal product name	NNC0195-0092
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for injection in cartridge
Routes of administration	Subcutaneous use
Dosage and administration details	0.08 mg/Kg, single dose of NNC0195-0092 was administered to subjects subcutaneously.
Arm title	0.16 mg/Kg - NNC0195-0092
Arm description	0.16 mg/Kg, single dose of NNC0195-0092 was administered to subjects subcutaneously.
Arm type	Experimental
Investigational medicinal product name	NNC0195-0092
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for injection in cartridge
Routes of administration	Subcutaneous use
Dosage and administration details	0.16 mg/Kg, single dose of NNC0195-0092 was administered to subjects subcutaneously.
Arm title	0.03 mg/Kg - Norditropin® SimpleXx®
Arm description	0.03 mg/Kg, once daily dose of Norditropin® SimpleXx® was administered to subjects subcutaneously, for 7 days.
Arm type	Active comparator
Investigational medicinal product name	Norditropin® SimpleXx®
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for injection in cartridge
Routes of administration	Subcutaneous use
Dosage and administration details	0.03 mg/Kg, once daily dose of Norditropin® SimpleXx® was administered to subjects subcutaneously, for 7 days.
Number of subjects in period 1 0.02 mg/Kg - NNC0195-0092 0.04 mg/Kg - NNC0195-0092 0.08 mg/Kg - NNC0195-0092 0.16 mg/Kg - NNC0195-0092 0.03 mg/Kg - Norditropin® SimpleXx® Started 6 6 6 6 8 Completed 6 6 6 6 8

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	0.02 mg/Kg - NNC0195-0092
Reporting group description	0.02 mg/Kg, single dose of NNC0195-0092 was administered to subjects subcutaneously.
Reporting group title	0.04 mg/Kg - NNC0195-0092
Reporting group description	0.04 mg/Kg, single dose of NNC0195-0092 was administered to subjects subcutaneously.
Reporting group title	0.08 mg/Kg - NNC0195-0092
Reporting group description	0.08 mg/Kg, single dose of NNC0195-0092 was administered to subjects subcutaneously.
Reporting group title	0.16 mg/Kg - NNC0195-0092
Reporting group description	0.16 mg/Kg, single dose of NNC0195-0092 was administered to subjects subcutaneously.
Reporting group title	0.03 mg/Kg - Norditropin® SimpleXx®
Reporting group description	0.03 mg/Kg, once daily dose of Norditropin® SimpleXx® was administered to subjects subcutaneously, for 7 days.
Reporting group values 0.02 mg/Kg - NNC0195-0092 0.04 mg/Kg - NNC0195-0092 0.08 mg/Kg - NNC0195-0092 0.16 mg/Kg - NNC0195-0092 0.03 mg/Kg - Norditropin® SimpleXx® Total Number of subjects 6 6 6 6 8 32 Age categorical Units: Subjects     Children (2-11 years) 6 6 6 6 8 32 Gender categorical Units: Subjects     Female 2 5 1 1 0 9     Male 4 1 5 5 8 23 Height Units: meter     arithmetic mean (standard deviation) 1.2 ( 0.1 ) 1.3 ( 0.1 ) 1.3 ( 0.1 ) 1.3 ( 0.1 ) 1.3 ( 0.2 ) - Body weight Units: Kg     arithmetic mean (standard deviation) 23.1 ( 8.9 ) 27.8 ( 5.6 ) 27.1 ( 7.4 ) 26.7 ( 6.9 ) 26.1 ( 7.5 ) - Body mass index (BMI) Units: Kg/m2     arithmetic mean (standard deviation) 15.8 ( 2.2 ) 17.4 ( 3.4 ) 16.6 ( 1.9 ) 15.6 ( 1.9 ) 16.2 ( 1.4 ) -

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	0.02 mg/Kg - NNC0195-0092
Reporting group description	0.02 mg/Kg, single dose of NNC0195-0092 was administered to subjects subcutaneously.
Reporting group title	0.04 mg/Kg - NNC0195-0092
Reporting group description	0.04 mg/Kg, single dose of NNC0195-0092 was administered to subjects subcutaneously.
Reporting group title	0.08 mg/Kg - NNC0195-0092
Reporting group description	0.08 mg/Kg, single dose of NNC0195-0092 was administered to subjects subcutaneously.
Reporting group title	0.16 mg/Kg - NNC0195-0092
Reporting group description	0.16 mg/Kg, single dose of NNC0195-0092 was administered to subjects subcutaneously.
Reporting group title	0.03 mg/Kg - Norditropin® SimpleXx®
Reporting group description	0.03 mg/Kg, once daily dose of Norditropin® SimpleXx® was administered to subjects subcutaneously, for 7 days.

End points Top of page

Primary: Incidence of adverse events (AEs) Top of page
End point title	Incidence of adverse events (AEs) [1]
End point description	Incidence of adverse events (AEs) from first administration of trial product and up until day 35 (final visit).
End point type	Primary
End point timeframe	From first administration of trial product and up until day 35 (final visit).
Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoint investigates safety and is analysed using descriptive statistics, and thus no statistical analysis is performed.
End point values 0.02 mg/Kg - NNC0195-0092 0.04 mg/Kg - NNC0195-0092 0.08 mg/Kg - NNC0195-0092 0.16 mg/Kg - NNC0195-0092 0.03 mg/Kg - Norditropin® SimpleXx® Number of subjects analysed 6 [2] 6 [3] 6 [4] 6 [5] 8 [6] Units: Number of adverse events 3 9 3 4 2
Notes [2] - 3 events were reported in 2 subjects [3] - 9 events were reported in 4 subjects [4] - 3 events were reported in 2 subjects [5] - 4 events were reported in 3 subjects [6] - 2 events were reported in 1 subject
No statistical analyses for this end point

Primary: Incidence of adverse events (AEs) Top of page

Secondary: The area under the insulin-like growth factor I (IGF-I) concentration-time curve (AUC 0-168h) Top of page
End point title	The area under the insulin-like growth factor I (IGF-I) concentration-time curve (AUC 0-168h)
End point description	The area under the insulin-like growth factor I (IGF-I) concentration-time curve (AUC 0-168h)
End point type	Secondary
End point timeframe	From 0 to 168 hours after dosing.
End point values 0.02 mg/Kg - NNC0195-0092 0.04 mg/Kg - NNC0195-0092 0.08 mg/Kg - NNC0195-0092 0.16 mg/Kg - NNC0195-0092 0.03 mg/Kg - Norditropin® SimpleXx® Number of subjects analysed 6 6 6 6 8 Units: ng*h/mL     geometric mean (geometric coefficient of variation) 16153 ( 57 ) 24199 ( 86.6 ) 42218 ( 28.1 ) 34350 ( 13.5 ) 34989 ( 59.4 )
No statistical analyses for this end point

Secondary: The area under the insulin-like growth factor I (IGF-I) concentration-time curve (AUC 0-168h) Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	From the first trial-related activity after the subject has signed the informed consent until the end of the post-treatment follow-up period (up until day 35).
Adverse event reporting additional description	An adverse event is any unfavourable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a product, whether or not considered related to the product.
Assessment type	Non-systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	17.1
Reporting groups
Reporting group title	0.04 mg/Kg - NNC0195-0092
Reporting group description	0.04 mg/Kg, single dose of NNC0195-0092 was administered to subjects subcutaneously.
Reporting group title	0.08 mg/Kg - NNC0195-0092
Reporting group description	0.08 mg/Kg, single dose of NNC0195-0092 was administered to subjects subcutaneously.
Reporting group title	0.16 mg/Kg - NNC0195-0092
Reporting group description	0.16 mg/Kg, single dose of NNC0195-0092 was administered to subjects subcutaneously..
Reporting group title	0.03 mg/Kg - Norditropin® SimpleXx®
Reporting group description	0.03 mg/Kg, once daily dose of Norditropin® SimpleXx® was administered to subjects subcutaneously, for 7 days.
Reporting group title	0.02 mg/Kg - NNC0195-0092
Reporting group description	0.02 mg/Kg, single dose of NNC0195-0092 was administered to subjects subcutaneously.
Serious adverse events 0.04 mg/Kg - NNC0195-0092 0.08 mg/Kg - NNC0195-0092 0.16 mg/Kg - NNC0195-0092 0.03 mg/Kg - Norditropin® SimpleXx® 0.02 mg/Kg - NNC0195-0092 Total subjects affected by serious adverse events      subjects affected / exposed 0 / 6 (0.00%) 0 / 6 (0.00%) 0 / 6 (0.00%) 0 / 8 (0.00%) 0 / 6 (0.00%)      number of deaths (all causes) 0 0 0 0 0      number of deaths resulting from adverse events 0 0 0 0 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events 0.04 mg/Kg - NNC0195-0092 0.08 mg/Kg - NNC0195-0092 0.16 mg/Kg - NNC0195-0092 0.03 mg/Kg - Norditropin® SimpleXx® 0.02 mg/Kg - NNC0195-0092 Total subjects affected by non serious adverse events      subjects affected / exposed 4 / 6 (66.67%) 2 / 6 (33.33%) 3 / 6 (50.00%) 1 / 8 (12.50%) 2 / 6 (33.33%) Nervous system disorders Headache      subjects affected / exposed 0 / 6 (0.00%) 1 / 6 (16.67%) 1 / 6 (16.67%) 0 / 8 (0.00%) 0 / 6 (0.00%)      occurrences all number 0 1 1 0 0 Dizziness      subjects affected / exposed 1 / 6 (16.67%) 0 / 6 (0.00%) 0 / 6 (0.00%) 0 / 8 (0.00%) 0 / 6 (0.00%)      occurrences all number 1 0 0 0 0 General disorders and administration site conditions Fatigue      subjects affected / exposed 1 / 6 (16.67%) 0 / 6 (0.00%) 0 / 6 (0.00%) 0 / 8 (0.00%) 0 / 6 (0.00%)      occurrences all number 1 0 0 0 0 Injection site pain      subjects affected / exposed 0 / 6 (0.00%) 0 / 6 (0.00%) 1 / 6 (16.67%) 0 / 8 (0.00%) 0 / 6 (0.00%)      occurrences all number 0 0 1 0 0 Injection site swelling      subjects affected / exposed 1 / 6 (16.67%) 0 / 6 (0.00%) 0 / 6 (0.00%) 0 / 8 (0.00%) 0 / 6 (0.00%)      occurrences all number 2 0 0 0 0 Gastrointestinal disorders Vomiting      subjects affected / exposed 1 / 6 (16.67%) 0 / 6 (0.00%) 1 / 6 (16.67%) 1 / 8 (12.50%) 0 / 6 (0.00%)      occurrences all number 1 0 1 1 0 Nausea      subjects affected / exposed 0 / 6 (0.00%) 0 / 6 (0.00%) 0 / 6 (0.00%) 1 / 8 (12.50%) 0 / 6 (0.00%)      occurrences all number 0 0 0 1 0 Respiratory, thoracic and mediastinal disorders Epistaxis      subjects affected / exposed 0 / 6 (0.00%) 0 / 6 (0.00%) 0 / 6 (0.00%) 0 / 8 (0.00%) 1 / 6 (16.67%)      occurrences all number 0 0 0 0 1 Skin and subcutaneous tissue disorders Pruritus      subjects affected / exposed 0 / 6 (0.00%) 1 / 6 (16.67%) 0 / 6 (0.00%) 0 / 8 (0.00%) 0 / 6 (0.00%)      occurrences all number 0 1 0 0 0 Renal and urinary disorders Haematuria      subjects affected / exposed 0 / 6 (0.00%) 0 / 6 (0.00%) 0 / 6 (0.00%) 0 / 8 (0.00%) 1 / 6 (16.67%)      occurrences all number 0 0 0 0 1 Musculoskeletal and connective tissue disorders Myalgia      subjects affected / exposed 0 / 6 (0.00%) 0 / 6 (0.00%) 1 / 6 (16.67%) 0 / 8 (0.00%) 0 / 6 (0.00%)      occurrences all number 0 0 1 0 0 Infections and infestations Nasopharyngitis      subjects affected / exposed 1 / 6 (16.67%) 0 / 6 (0.00%) 0 / 6 (0.00%) 0 / 8 (0.00%) 1 / 6 (16.67%)      occurrences all number 1 0 0 0 1 Conjunctivitis      subjects affected / exposed 1 / 6 (16.67%) 0 / 6 (0.00%) 0 / 6 (0.00%) 0 / 8 (0.00%) 0 / 6 (0.00%)      occurrences all number 1 0 0 0 0 Enterobiasis      subjects affected / exposed 0 / 6 (0.00%) 1 / 6 (16.67%) 0 / 6 (0.00%) 0 / 8 (0.00%) 0 / 6 (0.00%)      occurrences all number 0 1 0 0 0 Otitis media      subjects affected / exposed 1 / 6 (16.67%) 0 / 6 (0.00%) 0 / 6 (0.00%) 0 / 8 (0.00%) 0 / 6 (0.00%)      occurrences all number 1 0 0 0 0 Varicella      subjects affected / exposed 1 / 6 (16.67%) 0 / 6 (0.00%) 0 / 6 (0.00%) 0 / 8 (0.00%) 0 / 6 (0.00%)      occurrences all number 1 0 0 0 0

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? No
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
Not applicable.

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