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Trial registered on ANZCTR


Registration number
ACTRN12618001157268
Ethics application status
Approved
Date submitted
27/06/2018
Date registered
13/07/2018
Date last updated
13/07/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Trial Evaluating Safety, Tolerability and Pharmacokinetics of Subcutaneous Single Doses of ACP-015 in Healthy Adult Male Subjects.
Scientific title
A Phase 1, Double-Blind, Randomized, Placebo-Controlled, Dose Escalation Trial Evaluating Safety, Tolerability and Pharmacokinetics of Subcutaneous Single Doses of ACP-015 in Healthy Adult Male Subjects.
Secondary ID [1] 295215 0
CNP TCC-101
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Skeletal Dysplasia in Children 308361 0
Achondroplasia 308362 0
Thanatophoric Dysplasia 308363 0
Hypochondroplasia 308364 0
Campomelic Dysplasia 308365 0
Osteogenesis Imperfecta 308366 0
Achondrogenesis 308367 0
Condition category
Condition code
Metabolic and Endocrine 307355 307355 0 0
Other endocrine disorders
Musculoskeletal 307641 307641 0 0
Other muscular and skeletal disorders
Human Genetics and Inherited Disorders 307642 307642 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a single center, phase 1, entry into human, double-blind, placebo-controlled trial of TransCon CNP (ACP-015) given subcutaneously (SC) to healthy adult male subjects.

The trial comprises 6 dosing cohorts [up to 10 subjects per cohort (up to 8 active + 2 placebo)]. Study drug is administered SC in the abdomen in single doses to ascending dose cohorts (3 µg/kg, 10 µg/kg, 25 µg/kg, 75 µg/kg, 150 µg/kg, and 300 µg/kg CNP or
until maximum tolerated dose (MTD) is identified.

Each Single Ascending Dose (SAD) cohort consists of a screening visit (Day -28 to Day -2) to assess eligibility, a subsequent check-in period in which screening is completed and eligibility is confirmed (Day -2 to Day -1), and a dosing period (Day 1) followed by a total safety observational period of 4 weeks after the SAD dose of study drug. Final eligibility for trial enrollment will be determined at check-in to the clinic before randomization (Day -1) and dosing (on Day 1).

Up to ten eligible subjects who have successfully completed screening will be enrolled into the lowest dose cohort that is yet to be filled, and randomly assigned (double-blind) to receive TransCon CNP (ACP-015) or matched placebo (4:1).

Each SAD cohort will be enrolled and completed in a sequential fashion. There will be a sentinel pair of subjects (one receiving TransCon CNP (ACP-015) and the other receiving placebo) for each of the six SAD cohorts who will be dosed first. After a period of approximately 72 hours, and at the discretion of the Principal Investigator, the same TransCon CNP (ACP-015) or placebo dose will be given to the rest of the subjects in the respective SAD cohort.

At the completion of the inpatient period after dosing for each cohort (inclusive of an inpatient period from Day -2 through Day 8), blinded clinical safety and laboratory parameters will be assessed in a Data and Safety Monitoring Board (DSMB) meeting to provide a recommendation on dose escalation either per protocol or with modifications.

After receipt of the DSMB recommendation, the Safety Data Review Committee will make a decision either to continue with dose escalation or to pause (or stop) the dose escalation, after which subject dosing assignments will be unblinded.
Intervention code [1] 301552 0
Treatment: Drugs
Comparator / control treatment
Control group will receive the same treatment as the Intervention group with the exception that they will receive placebo rather than the investigational product.

Placebo product will be a normal saline solution in a suitable container to provide the trial-specified doses to be administered by SC injection via syringe and needle.
Control group
Placebo

Outcomes
Primary outcome [1] 306323 0
To determine the safety and tolerability of single ascending subcutaneous (SC) doses of ACP015 in healthy adult male subjects by observing the frequency of adverse events (AEs) reported after administration of ACP-015. This is a composite outcome.

Safety parameters as assessed by physical examination, vital signs, electrocardiography parameters including the QTc interval, clinical laboratory assessment (hematology, chemistry profiles, antibodies against CNP and mPEG, urinalysis), local tolerability assessment and adverse event data.

Adverse event data will be collected from patient results, medical records and patient reporting.

Local tolerability assessments to be completed will include, redness, bruising, swelling, and pain. Any local reaction evaluated as moderate or severe must be graded by a medical doctor.

No identified or potential risks for use of ACP-015 in humans has been established as no data is available in humans. However, risks include cardiovascular changes (decrease in blood pressure), and skeletal overgrowth and bone abnormalities (may affect musculoskeletal system and markers of bone turnover will be collected).
Timepoint [1] 306323 0
Patient medical records will be recorded up to 4 weeks prior to enrollment.

Clinical laboratory tests and vital signs will be collected up to the end of the trial on Day 28.

Urine will be collected daily as 24hr collections within 1 hour pre dose, day 2, and day 8

Blood samples to be collected pre dose, 30min post dose, 2hr, 4hr, 8hr, 12hr, 15hr, 18hr, 24hr, 30hr, 36hr, 48hr, 54hr, 72hr, 96hr, 120hr, 144hr, 168hr, day 15, day 22, and day 28

Vital signs will be collected -90min and -10 min pre dose, hourly for the first 6hrs post dose, 12hrs post dose, 3 times daily from day 2 to day 8, day 15, day 22 and day 28.
Secondary outcome [1] 348186 0
To evaluate the pharmacokinetic (PK) properties of single ascending SC doses of ACP-015 in healthy adult male subjects
Timepoint [1] 348186 0
Pharmacokinetic parameters for TransCon CNP (ACP-015) including when applicable Cmax, Tmax, t1/2,CL/F, VZ,/F , AUC (at specified time intervals)

Blood samples for PK assessment will be collected at the following time-points with windows where allowed. PK samples will be drawn within approximately 5 min after the nominal ECG time points when applicable:
- Within 1 h (pre-dose)
- 30 min post-dose (± 5 min)
- 2 h, 4 h, 8 h, 12 h, 15 h, 18 h, 24 h (± 15 min at all time points)
- 30 h, 36 h , 48 h, 54 h, 60 h, 72 h , 96 h, 120 h , 144 h and 168 h (± 25 min at all time points)
- Outpatient visits at 336 h (Day 15), 504 h (Day 22) and 672 h (Day 28) (± 24 h on Days 15 and 22, ± 72 h on Day 28)
Secondary outcome [2] 348187 0
To evaluate cGMP levels in urine circulation after single ascending SC doses of TransCon CNP (ACP-015) in healthy adult male subjects
Timepoint [2] 348187 0
Urine will be collected daily as 24hr collections within 1 hour pre dose, day 2, and day 8
Secondary outcome [3] 349060 0
To evaluate cGMP levels in systemic circulation after single ascending SC doses of TransCon CNP (ACP-015) in healthy adult male subjects
Timepoint [3] 349060 0
Blood samples to be collected pre dose, 30min post dose, 2hr, 4hr, 8hr, 12hr, 15hr, 18hr, 24hr, 30hr, 36hr, 48hr, 54hr, 72hr, 96hr, 120hr, 144hr, 168hr, day 15, day 22, and day 28
Secondary outcome [4] 349180 0
Changes in urine biomarkers circulation, which may include, but are not limited to, BSAP, P1NP, CTx and NTproCNP.
Timepoint [4] 349180 0
Urine will be collected daily as 24hr collections within 1 hour pre dose, day 2, and day 8
Secondary outcome [5] 349181 0
Changes in systemic biomarkers circulation, which may include, but are not limited to, BSAP, P1NP, CTx and NTproCNP.
Timepoint [5] 349181 0
Blood samples to be collected pre dose, 30min post dose, 2hr, 4hr, 8hr, 12hr, 15hr, 18hr, 24hr, 30hr, 36hr, 48hr, 54hr, 72hr, 96hr, 120hr, 144hr, 168hr, day 15, day 22, and day 28

Eligibility
Key inclusion criteria
- Able to give Informed consent
- Able to comply with study protocol per investigator judgement
- Healthy adult males aged 25-60 years at time of Screening
- Attainment of adult height (defined as subject’s confirmation of no change in standing height within 12 months of screening)
- BMI 18 – 27 kg/m2
- Body weight <100 kg
- In good general health as determined by medical history, physical exams and laboratory evaluation at time of screening
- Screening chemistry and hematology laboratory results in the normal range of the reference laboratory (or considered not clinically significant by the investigator)
- Subject must agree to not father a baby while on this study and for 90 days following the end of the study.. Males with female partners of child bearing potential must agree to use a barrier method of contraception (ie, condom) for the entire study period and for 90 days following the end of the study. Female partners must use a highly effective form of contraception (including oral, injectable or implantable contraception, or IUD) for the entire study period and for 90 days post end of the study.
- Agreement to refrain from donating sperm during clinical trial participation and for 90 days following the end of the study
Minimum age
25 Years
Maximum age
60 Years
Gender
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Participation in any investigational medication or device trials within 90 days or 5 half-lives (whichever is longer) prior to screening (and during enrollment in current trial)
2. Prior participation in investigation trial (at any time) involving use of vosoritide
3. History or presence of malignant disease, other than basal cell epithelioma/carcinoma or completely resected squamous skin cancer with no recurrence for 12 months
4. Any history of significant bone disorders including (but not limited to) osteoporosis, hypo- or hyperparathyroidism, or inherited skeletal dysplasias
5. Baseline systolic blood pressure less than 90 mm Hg
6. Past history of, or presence of orthostatic hypotension defined as a decrease of more than or equal to 20 mm Hg systolic blood pressure or more than 20 bpm increase in heart rate at 3 minutes of standing), or with symptoms of lightheadedness, dizziness, or fainting upon standing at screening. the more than 20bpm increase in heart rate upon standing must result in a heart rate of more than 120 bpm or be considered clinically significant by the investigator.
7. Subject has electrographically significant abnormalities that might interfere with ECG analysis including evidence of a previous MI, LVH, flat T waves (particularly in the inferior leads) or more than minor non- specific ST-T wave changes or:
- QRS more than 110 msec
- QT interval corrected using Fridericia’s formula (QTcF) more than 440 msec (men and women)
- PR interval more than 220 msec
- Heart rate less than 50 BPM or more than 90 BPM
- Complete right bundle branch block or left bundle branch block.
8. Subject has a history of, disease or dysfunction of the pulmonary, cardiovascular, endocrine, hematologic, neurological, immune, gastrointestinal, genitourinary, or other body system, that is clinically significant in the opinion of the Investigator, including
- Anemia
- Pathologic factures
- Diabetes mellitus, Type I or II
- History of drug abuse (including alcoholism) or positive drug screen during screening
- History of cardiac or valvular disease (including hypertension or hypotension)
9. Acute illness that can affect hydration or volume status [such as that associated with decreased nutritional intake or increased volume loss (such as diarrhea)]
10. Known hypersensitivity to the components of the trial medication (trehalose, tris(hydroxymethyl)aminomethane, succinate and PEG)
11. Poor peripheral venous access
12. Planned procedure or surgery during the course of the study
13. Any other reason that in the opinion of the investigator would prevent the subject from completing participation or following the trial schedule (including non-compliance)
14. Subject uses any prescription drug or over-the-counter medication, including herbals or routine vitamins or minerals, within 7 days prior to check-in (or 14 days if the drug is a potential inducer or inhibitor of cytochrome P450 [CYP] 3A4 or P-glycoprotein [P gp] [eg, St. John’s Wort, rifampin, cyclosporine, or ritonavir]) or 5 half-lives (whichever is longer) or subject requires continued use of a prescription drug or over-the-counter medication during study participation, with the exception of over-the-counter analgesics (eg, occasional [less than 2 times/week] acetaminophen, ibuprofen, naproxen]
15. Subject is unwilling to refrain from strenuous exercise from 7 days prior to check-in through completion of the study
16. Subject is unwilling to abstain from ingestion of caffeine or xanthine-containing products (eg, tea, coffee, chocolate, cola, etc.) beginning 96 hours prior to check-in until discharge and within 96 hours prior to each visit
17. Subject is unwilling to abstain from alcohol beginning 48 hours prior to check-in through completion of the study
18. Subject has a history of high alcohol consumption within 6 months prior to Screening, defined as an average weekly intake of >14 units. One unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine, or 1 measure (25 mL) of spirits
19. Subject uses or has used nicotine-containing products (eg, cigarettes, cigars, chewing tobacco, snuff, etc.) within 6 months prior to Screening and/or is unwilling to abstain from using nicotine-containing products until the end of the study
20. Subject is unwilling to abstain from consuming grapefruit and/or grapefruit juice within 14 days prior to check-in and is unwilling to abstain from consuming grapefruit and/or grapefruit juice until the end of the study.
21. Subject is unwilling to abstain from consuming other fruit juices within 48 hours prior to check-in and is unwilling to abstain from these items within 48 hours prior to each study visit
22. Subject is unwilling to abstain from consuming cruciferous vegetables (eg, kale, broccoli, watercress, collard greens, kohlrabi, Brussel sprouts, or mustard greens) or charbroiled meats within 7 days prior to check-in and is unwilling to abstain from these items until the end of the study

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
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

Funding & Sponsors
Funding source category [1] 299803 0
Commercial sector/Industry
Name [1] 299803 0
Ascendis Pharma Growth Disorders A/S
Address [1] 299803 0
CVR 3232 3677
Tuborg Boulevard 5, Dk-2900
Hellerup, Denmark
Country [1] 299803 0
Denmark
Primary sponsor type
Commercial sector/Industry
Name
Ascendis Pharma Growth Disorders A/S
Address
CVR 3232 3677
Tuborg Boulevard 5, Dk-2900
Hellerup, Denmark
Country
Denmark
Secondary sponsor category [1] 299151 0
Commercial sector/Industry
Name [1] 299151 0
Pharmaceutical Solutions Australia Pty Ltd
Address [1] 299151 0
Level 9
Avaya House
123 Epping Road North
North Ryde
NSW 2113
Country [1] 299151 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300685 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 300685 0
129 Glen Osmond Road
Eastwood SA 5063
Ethics committee country [1] 300685 0
Australia
Date submitted for ethics approval [1] 300685 0
26/04/2018
Approval date [1] 300685 0
16/05/2018
Ethics approval number [1] 300685 0
2017-12-960-A-2

Summary
Brief summary
The aim of the trial is to evaluate the safety and pharmacokinetics of ACP-015 in healthy male subjects. Such data will be descriptive rather than based on a statistical approach.

ACP-015 is designed to provide long-term CNP exposure with the goal of optimizing efficacy with a well-tolerated and convenient once weekly dose.

No identified or potential risks for use of ACP-015 in humans have been
established as no data is available regarding the use of ACP-015 in humans.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 84470 0
Dr Ben Snyder
Address 84470 0
Nucleus Network Limited
Level 5 Burnet Tower,
AMREP Precinct
89 Commercial Road
Melbourne
Victoria 3004
Country 84470 0
Australia
Phone 84470 0
+61 3 9076 8960
Fax 84470 0
Email 84470 0
b.snyder@nucleusnetwork.com.au
Contact person for public queries
Name 84471 0
Dr Ben Snyder
Address 84471 0
Nucleus Network Limited
Level 5 Burnet Tower,
AMREP Precinct
89 Commercial Road
Melbourne
Victoria 3004
Country 84471 0
Australia
Phone 84471 0
+61 3 9076 8960
Fax 84471 0
Email 84471 0
b.snyder@nucleusnetwork.com.au
Contact person for scientific queries
Name 84472 0
Mr Jeffery Wong
Address 84472 0
Nucleus Network Limited
Level 5 Burnet Tower,
AMREP Precinct
89 Commercial Road
Melbourne
Victoria 3004
Country 84472 0
Australia
Phone 84472 0
+61 3 8593 9899
Fax 84472 0
Email 84472 0
j.wong@nucleusnetwork.com.au

No information has been provided regarding IPD availability
Summary results
No Results