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Trial registered on ANZCTR


Registration number
ACTRN12617001471370
Ethics application status
Approved
Date submitted
11/10/2017
Date registered
18/10/2017
Date last updated
25/07/2019
Date data sharing statement initially provided
25/07/2019
Date results information initially provided
25/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A trial comparing ACP-011 administered as a single dose via a syringe and needle versus an auto-injector
Scientific title
A Single Center, Phase 1, Randomized, Open-Label Bioequivalence Trial in Healthy Volunteers Comparing ACP-011 Administered as a Single Dose via Syringe and Needle vs. Auto-Injector
Secondary ID [1] 293046 0
'Nil known'
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Growth failure in children due to Growth Hormone Deficiency 304954 0
Condition category
Condition code
Metabolic and Endocrine 304287 304287 0 0
Other endocrine disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a single center, phase 1, randomized, open-label, single dose,
crossover study in healthy adult subjects designed to compare the
PK and PD of two injection modalities of ACP-011 to confirm
bioequivalence (BE). PK (hGH) will be evaluated by Cmax and AUC, and the PD (IGF-1) will be evaluated by Emax and AUEC. ACP-011 will be administered at a fixed nominal dose of 13.3 mg hGH corresponding to 0.20 mg hGH/kg subcutaneously (SC) to healthy subjects via syringe and needle versus the auto-injector during two separate periods separated by interval washout period.

The screening period will occur between Days –28 and –2; subjects will be admitted to the clinic site on Day –1.

Two treatments modalities will be available,

ACP-011 administered by syringe and needle (termed ‘A’)
ACP-011 administered by auto-injector (termed ‘B’).

Approximately 26 healthy male subjects will be randomly assigned to receive one of the two treatment modality sequences, AB or BA.

A (or B, depending on sequence) will be given during Period 1, followed by B (or A, depending on sequence) in Period 2 with an interval of at least 14 days in between.

Treatment modality A consists of a single subcutaneous injection of ACP-011 13.3 mg hGH administered via syringe and needle to the abdomen. Treatment modality B consists of a single SC injection of ACP-011 13.3 mg hGH administered via the auto-injector. Both injections will be administered to the same quadrant of the abdomen.

On the morning of Day 1 of Period 1, subjects will receive a single dose of ACP-011 according to the assigned administration method. On the morning of Day 1 of Period 2, subjects will cross over to receive a single dose of ACP-011 via the alternate
administration method. Each dose will be followed by 15 days of PK and PD sampling.

Subjects will be admitted on Day –1 and remain in the clinic until the morning of Day 8. They will return for outpatient visits on Days 9, 11, and 15 in each treatment period for safety, PK, and PD assessments. Discharge from the study will occur after all assessments are completed on Day 15 (cumulative Day 44) of Period 2.
Intervention code [1] 299275 0
Treatment: Drugs
Intervention code [2] 299395 0
Treatment: Devices
Comparator / control treatment
Comparing a needle and syringe against an autoinjection
Control group
Active

Outcomes
Primary outcome [1] 303557 0
To compare the pharmacokinetic (PK) profile of ACP-011, measured as Cmax and Area Under the Curve (AUC) of hGH when administered by syringe and needle versus an auto-injector.
Timepoint [1] 303557 0
For hGH, the following PK parameters will be estimated:

Maximum observed serum concentration (Cmax)
Area under the curve (AUC) from time 0 (predose) to the time of the last measureable concentration postdose
AUC from time 0 (predose) to 168 hours postdose
AUC from time 0 (predose) extrapolated to infinity

PK blood samples will be drawn at 30-60 and at 5-15 minutes predose and at 2, 4, 8, 12, 16, 24, 30, 36, 48, 60, 72, 96, 120, 144, and 168 hours post dose (during inpatient stay).
Secondary outcome [1] 339356 0
To compare the pharmacodynamic profile of ACP-011, measured as Emax and AUEC of insulin-like growth factor-1 (IGF-1) when administered by syringe and needle versus an auto-injector.
Timepoint [1] 339356 0
IGF-1 concentration data, the following PD parameters will be estimated:

Maximum observed response

Area Under the Effect Time Curve (AUEC) from time 0 (predose) to 168 hours postdose

AUEC from time 0 (predose) to 336 hours postdose

PD blood samples will be drawn at 30-60 and at 5-15 minutes predose and at 2, 4, 8, 12, 16, 24, 30, 36, 48, 60, 72, 96, 120, 144, and 168 hours post dose during the inpatient stay. PD samples will also be drawn at 192 hours (Day 9), 240 hours (Day 11), and 336 hours (Day 15) postdose during outpatient visits.
Secondary outcome [2] 339357 0
To characterize the safety and tolerability profile of ACP-011 administered by syringe and needle or an auto-injector
Timepoint [2] 339357 0
Vital signs will be measured at approximately -1 hours predose and 4, 12, 24, 36, 48, 72, 96, 168, and 336 hours postdose (± 15 mins).

Limited physical examination Limited physical examination on Day -1 (pre-does) and Day 8.

Clinical laboratory results (hematology and serum chemistry) to be drawn after at least 10 hour fast) will be measured at approximately predose (-1 Day), and 168 hours, 336 hours postdose (± 15 mins).

Injection site reactions/local tolerability assessments will be made at 2, 4, 12, and 24 hours postdose (± 15 mins).

Incidence of Adverse Events (AEs) will be made at 0, 2, 4, 12, 24, 36, 48, 60, 72, 96, 120, 144, 168, 192,
240, and 336 hours postdose (± 15 mins).


Secondary outcome [3] 339358 0
To characterize the immunogenicity of ACP-011 after two single doses including:

- Incidence of antibodies against hGH, including neutralizing antibodies
- Incidence of antibodies against PEG
Timepoint [3] 339358 0
Samples for antibodies against hGH and PEG will be drawn approximately at predose
and 336 hours postdose (± 15 mins).

Eligibility
Key inclusion criteria
1) Healthy Male Adults aged between 18 and 65 years at time of informed consent
2) Body weight between 60.50 and 73.90 kg
3) Body mass index (BMI) between19 and 29 kg/m2
4) Considered to be in good general health at screening as determined by investigator
5) Able to comply with all protocol requirements.
6) Able to provide written informed consent.
Minimum age
18 Years
Maximum age
65 Years
Gender
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
1) History of clinically significant (in the opinion of the investigator) endocrine disease; history or presence of endocrine tumors, thyroid disease, diabetes, or impaired glucose tolerance.
2) History of malignancy of any organ system (other than localized basal or squamous cell carcinomas of the skin), treated or untreated within the past 5 years.
3) Clinically significant (in the opinion of the investigator) history of neurological, cardiovascular, respiratory, hematological, hepatic, renal, gastrointestinal, genitourinary, pulmonary, and/or musculoskeletal disease, glaucoma, a psychiatric disorder, or any other chronic disease, whether controlled by medication or not.
4) On a 12-lead ECG, the subject has any of the following at screening, confirmed by repeat assessment:
- PR greater than or equal to 221 ms
- QRS greater than or equal to 120 ms
- QTcF greater than or equal to 451 ms
5) Systolic blood pressure <90 mmHg and >140 mmHg; diastolic blood pressure <40 mmHg and > 90 mmHg
6) Known or suspected HIV-positive status
7) Known or suspected infection with hepatitis B or C
8) Use of any prescription or over-the-counter medications (including herbal or nutritional supplements) within 14 days before the first dose of study drug.
9) Consumption of alcohol-containing products within 48 hours before dosing with study drug.
10) Social smokers who are otherwise healthy may be enrolled if they have not used nicotine containing products within 2 weeks prior to dosing.
11) History of alcohol or drug abuse
12) Strenuous activity or contact sports within 24 hours before dosing with study drug or during the study.
13) Donation of blood or blood products >450 mL within 30 days before dosing with study drug.
14) Presence of contraindications to hGH treatment
15) Known hypersensitivity to the components of the trial medication
16) Any medical abnormality unless approved by Medical Monitor
17) History of relevant drug and/or allergies (ie, allergy to ACP-011, or excipients, or any significant food allergy that would preclude a standard diet in the clinic).
18) Participation in drug trial in which receipt of a study drug occurred within 5 half-lives or 30 days, whichever is longer, prior to study entry
19) Any other reason that in the opinion of the investigator would prevent the subject from completing participation or following the trial schedule.



Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
An external data management CRO will be used to randomise subjects randomly to either Cohort 1 or Cohort 2.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A simple computer generated randomisation schedule will be used to randomise patients to either cohort on a 1 to 1 ratio.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint(s)
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
A total of 26 subjects evaluable for bioequivalence are planned for the study to provide 95% power to demonstrate bioequivalence with 0.25 coefficient of variance (CV), and 84% power with 0.30 CV, assuming equal PK profile between the two drug administration methods.

For categorical variables, frequencies and percentages will be presented. Continuous variables will be summarised using descriptive statistics (number of subjects, mean, median, SD, minimum, and maximum). Baseline demographic and background variables will be summarized for all subjects. The number of subjects who enroll in the study and the number and percentage of subjects who complete the study will be presented. Frequency and percentage of subjects who withdraw or discontinue from the study, and the reason for withdrawal or discontinuation, will also be summarised.

Pharmacokinetic and Pharmacodynamic Anlysis

hGH serum concentration data will be listed and summarized by time point for each dose and analyte using descriptive statistics, including but not limited to: number of subjects, mean, SD, coefficient of variation (CV), median, minimum, and maximum. HGH serum concentration versus time profiles for each subject will be presented graphically using actual sampling times.

The PK parameters of hGH will be analyzed using non-compartmental modelling based on the actual sampling times. Pharmacokinetic parameters will be summarized using descriptive statistics (including, but not limited to: number of subjects, mean, SD, CV, median, minimum, and maximum).

Geometric means will be reported for at least Cmax and all AUCs. Actual sampling times, rather than scheduled sampling times, will be used in all calculations of PK parameters. However, for ease of presentation, scheduled sampling times will be used to present results in tables, listings, and figures.

The PD parameters of IGF-1, IGF-1 SDS will be summarized by time point for each dose using descriptive statistics, including, but not limited to number of subjects, mean, SD, CV, median, minimum, and maximum.

Geometric means will be reported for at least Emax and all AUECs. Actual sampling times, rather than scheduled sampling times, will be used in all calculations of PD parameters. However, for ease of presentation, scheduled sampling times will be used to present results in tables, listings,
and figures.

The primary PK endpoints to determine bioequivalence are AUC0-168 and Cmax of hGH.. The primary PD parameters to determine PD bioequivalence are AUEC0-336 and Emax of IGF-1. An analysis of variance model (ANOVA) will be used to compare the two administration methods
(intra-subject) for each of the log transformed PK/PD endpoints. A 90% confidence interval (CI) will be calculated for the ratio of population geometric means of exponentiated LS means (Treatments B/A). PK and PD bioequivalence will be concluded if the 90% confidence limits
fall within 80-125% for the corresponding primary endpoints.

Safety Analysis

Adverse events will be coded by preferred term and system organ class using the latest version of MedDRA and summarized by treatment and overall. Adverse events will also be summarized by severity, relationship to study drug, SAEs, TEAEs, and AEs leading to discontinuation of study
drug. The incidence and quality of injection site reactions and positive immunogenicity results will be summarized by treatment.Actual values and changes from Baseline for clinical laboratory results and vital sign measurement results will be summarized by treatment at each time point using descriptive statistics (number of subjects, mean, SD, median, minimum, and maximum). Clinical laboratory data, vital sign measurements, physical examination findings, injection site reactions, and immunogenicity results will be presented in data listings.


Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 9152 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 17664 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 297662 0
Commercial sector/Industry
Name [1] 297662 0
Ascendis Pharma Endocrinology Division A/S
Address [1] 297662 0
Tuborg Boulevard 5, DK-2900
Hellerup, Denmark
Country [1] 297662 0
Denmark
Primary sponsor type
Commercial sector/Industry
Name
Ascendis Pharma Endocrinology Division A/S
Address
Tuborg Boulevard 5, DK-2900
Hellerup, Denmark
Country
Denmark
Secondary sponsor category [1] 296688 0
Commercial sector/Industry
Name [1] 296688 0
Pharmaceutical Solutions Australia Pty Ltd
Address [1] 296688 0
Level 9
Avaya House
123 Epping Road North
North Ryde
NSW 2113
Country [1] 296688 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298744 0
The Alfred Hospital Ethics Committee
Ethics committee address [1] 298744 0
The Alfred
55 Commercial Rd,
Melbourne
VIC 3004
Ethics committee country [1] 298744 0
Australia
Date submitted for ethics approval [1] 298744 0
24/08/2017
Approval date [1] 298744 0
15/09/2017
Ethics approval number [1] 298744 0
370/17

Summary
Brief summary
This study aims to investigate an alternative method of administration, an auto-injector device containing ACP-011 compared to the usual needle and syringe.

This research project is testing and comparing the safety, tolerability, pharmacokinetics (the amount of study drug and it’s breakdown products in your blood), pharmacodynamics (how your body is affected by the study drug) and immunogenicity (how your immune system is affected by the study drug) of ACP-011.

Approximately 26 healthy male participants will be enrolled across 2 cohorts (groups). Each cohort will consist of 13 participants.

The study medication will be administered through two methods over two periods, Particpants will receive both treatment methods in a particular sequence. The dose of study drug will be the same for each method.

Participants will not have a choice as to which method or treatment sequence assigned, this will random (like flipping a coin). After the first treatment period, there will be a 14 day period where there will not be any study medication given. This period is known as a wash-out period.

Treatment A: consists of a single subcutaneous (SC) (just under the skin) injection to the abdomen administered via syringe and needle.
Treatment B: consists of a single SC injection administered via the auto-injector to the same quadrant of the abdomen as the previous injection (depending on sequence).

Total participation in the study consists of 45 days which is broken up into 3 phases:

- Screening Phase: During which participants will undergo suitability assessments
- Treatment Phase: During which participants will be required to stay overnight in the unit for 8 consecutive nights on two separate occasions. Following this participants will be required to attend the study centre on 3 separate occasions
- Washout Phase: in between the inpatient stays, where no study visits are required.




Trial website
http://clinicalstudies.com.au/

Trial related presentations / publications
Public notes
Register interest in the study at http://clinicalstudies.com.au/

Contacts
Principal investigator
Name 78086 0
Dr Jason Lickliter
Address 78086 0
Nucleus Network
Level 5
89 Commercial Road
Melbourne
Victoria 3005
Country 78086 0
Australia
Phone 78086 0
+61385939860
Fax 78086 0
+61390768911
Email 78086 0
m.ludusan@nucleusnetwork.com.au
Contact person for public queries
Name 78087 0
Ms Jessica Faggian
Address 78087 0
Nucleus Network
Level 5
89 Commercial Road
Melbourne
Victoria 3005
Country 78087 0
Australia
Phone 78087 0
+ 613 9076 8900
Fax 78087 0
+61 3 90768911
Email 78087 0
J.Faggian@nucleusnetwork.com.au
Contact person for scientific queries
Name 78088 0
Dr Jason Lickliter
Address 78088 0
Nucleus Network
Level 5
89 Commercial Road
Melbourne
Victoria 3005
Country 78088 0
Australia
Phone 78088 0
+61385939860
Fax 78088 0
+61390768911
Email 78088 0
m.ludusan@nucleusnetwork.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary