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Trial registered on ANZCTR


Registration number
ACTRN12617001375347
Ethics application status
Approved
Date submitted
25/09/2017
Date registered
28/09/2017
Date last updated
5/09/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Safety and tolerability of single and multiple-ascending doses of the study drug ACP-014 in Healthy volunteers.
Scientific title
A Phase 1, Randomized, Placebo controlled, Single and Multiple Ascending Dose Trial to Evaluate the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of ACP-014 in Healthy Adult Subjects (ACP-014 -Phase 1)
Secondary ID [1] 292966 0
ACP-014
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hypoparathyroidism 304865 0
Condition category
Condition code
Metabolic and Endocrine 304178 304178 0 0
Other endocrine disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be enrolled to 1 of the following 3 interventions:

In Part 1 of the trial, comprising up to 8 single ascending dose (SAD) cohorts of 10 subjects each, study drug is administered SC in the abdomen in single doses to ascending dose cohorts [3.5µg, 12 µg, 32 µg, 48 µg, 72 µg, 100 µg, 124 µg, and 152 µg ACP-014 (N=8) or placebo (N=2)] until dose limiting toxicity (DLT) is observed.

Cohort X- After completion of the SAD cohorts, up to 16 subjects will be enrolled in the subsequent 2 by 2 randomized crossover cohort. 8 subjects (optimally 4 males and 4 females) will receive single SC doses of 12 µgACP-014 in either the abdomen/thigh (A/T) or the thigh/abdomen (T/A) in a crossover fashion. The other 8 subjects (optimally 4 males and 4 females) will receive the highest tolerated single dose of ACP-014 in either A/T or T/A in a crossover fashion to obtain initial information on potential PK differences between SC dosing in the abdomen vs. the thigh. All subjects will receive two single doses of ACP-014 at least 7 days apart.

In Part 2, study drug is administered SC in the abdomen daily for 10 days to approximate steady-state to up to 9 multiple ascending dose (MAD) cohorts of 10 subjects each (8 subjects receiving ACP-014 , and 2 subjects receiving placebo). The initial dose cohort of 3.5 µg ACP-014 daily may begin after completion of the 32 µg SAD cohort, based on an expected accumulation ratio of 3 plus an additional 10-fold safety margin. The 2nd MAD dose will be 7.0 µg/day, followed by 12 µg/day, 16 µg/day, 20 µg/day, 24 µg/day, 32 µg/day, 40µg/day and potentially 48 µg/day.


Intervention code [1] 299203 0
Treatment: Drugs
Comparator / control treatment
Placebo
Control group
Placebo

Outcomes
Primary outcome [1] 303484 0
To assess the safety and tolerability of single and multiple daily doses of ACP-014 in healthy adult subjects.
Timepoint [1] 303484 0
SAD Cohorts
AEs, including injection site reactions (Local tolerability): reviewed and recorded just before study drug administration, twice daily during the first 48 hours post-dose, and at each clinic day through Day 5
Physical examination: Day -1 and Day 5
Vital signs: Day -2, Day -1, and Day 1 [ pre-dose and at approximately 15 (±5 min) and 60 minutes (±15 min) and 2 hours (±15 min), 6, and 10 hours (±30 min) post-dose], and daily on Days 2-5
ECG: Pre-dose and at approximately 2 , 4 (±15 min), 12 , 24, and 48 (±30 min) hours post-dose
Safety laboratory tests: in the mornings of Days -1, 1, 2, 3, and 5
Urine or serum pregnancy test (females): Days -2, at discharge
Concomitant medication review and recording of all medications used each day from Day -2 through Day 5

Cohort X

AEs, including injection site reactions: reviewed and recorded just before study drug
administration, twice daily during the first 48 hours post-dose, and at each clinic day
through Day 5
Physical examination: Day -1 and Day 5
Vital signs: Day -2, Day -1, and Day 1 (pre-dose and at approximately 15 (±5 min) and 60 (±15 min) minutes and 2 (±15 min), 6, and 10 (±30 min) hours post-dose), and daily on Days 2-5. Subjects should rest for at least 5 minutes before vital sign assessment.
ECG: Pre-dose and at approximately 2, 4 (±15 min), 12 , 24, and 48 (±30 min) hours
Safety laboratory tests: in the mornings of Days -1, 1, 2, 3, and 5
Urine or serum pregnancy test (females): Period 1 (Days -2 and at discharge), Period 2 (Day -1 and discharge)
Concomitant medication review and recording of all medications used each day from Day -2 through Day 5

MAD Cohort

AEs, including injection site reactions: reviewed and recorded just before study drug administration, twice daily during the first 48 hours post-dose, and at each clinic day through Day 14
Physical examination: Day -1 and Day 14 Vital signs: Day -2, Day -1, and Day 1 [Pre-dose and at approximately 15 (±5 min) and
60 (±15 min) minutes and 2 (±15 min), 6 (±30 min), and 10 (±30 min) hours post-dose], and daily on Days 2-14. Subjects should rest for at least 5 minutes before vital signassessment.
ECG: Pre-dose and at approximately 2, 4 (±15 min), 12, 24, and 48 (±30 min) hours post-dose, and in the morning of Days 10 and 13
Safety laboratory tests: in the mornings of Days -1, 1, 2, 3, 5, 8, 10, 12, and 14
Urine or serum pregnancy test (females): Days -2 and 14
Concomitant medication review and recording of all medications used each day from Day -2 through Day 14

No further dose escalation will be allowed when maximum tolerated dose (MTD) is reached. The MTD is the highest dose associated with the occurrence of Dose-Limiting Toxicities( DLT) in <33% of subjects.
Secondary outcome [1] 339051 0
To evaluate the pharmacodynamics (PD) and pharmacokinetics (PK) following single and multiple daily doses of ACP-014
Timepoint [1] 339051 0
SAD

Serum calcium, albumin, phosphorus, and magnesium on Day -1, pre-dose (Day 1) and at 4 hours (±15 minutes), 8 hours (±30 minutes), 12, 16, 24 , 30, 36 hours (±60 minutes), 48, 60, 72, and 96 (±120 minutes) hours post-dose

Parathyroid Hormone (1-84) (PTH) on Day -1, pre-dose (day 1), and at 8 hours (±30 minutes), 12, 16, 24 (±60
minutes), and 48 (±120 minutes) hours post-dose

1,25-dihydroxyvitamin D3 on Day -1, pre-dose (Day 1) and at 12 , 24 (±60 minutes), 48, and 72 (±120 minutes) hours post-dose
25-hydroxyvitamin D on Day -1 and Day 5

Cohort X

Serum calcium, albumin, phosphorus, and magnesium on Day -1; and pre-dose on Day 1 and at 4 (±15 minutes), 8 (±30 minutes), 12, 16, 24, 30, 36 (±60 minutes), 48, 60,72, and 96 (±120 minutes) hours post-dose

PTH(1-84) on Day -1, pre-dose (day 1), and at 8 (±30 minutes), 12, 16, 24 (±60 minutes), and 48 (±120 minutes) hours post dose
1,25-dihydroxyvitamin D3 on Day -1, pre-dose (Day 1) and at 12, 24 (±60 minutes), 48,and 72 (±120 minutes) hours post-dose


MAD

Serum calcium, albumin, phosphorus, and magnesium on Day -1; on Day 1, pre-dose and 4 (±15 minutes), 8 (±30 minutes), 12, and 16 (±60 minutes) hours post-dose ; pre-dose and 4 (±15 minutes), 8 (±30 minutes), 12, and 16 (±60 minutes) hours post-dose on Days
2-5; twice daily (pre-dose and 6 hours (±30 minutes) post-dose) on Days 6-10; and daily in the morning on Days 11-14

PTH(1-84) on Day -1, pre-dose on Day 1, and at 8 (±30 minutes), 12, and 16 (±60 minutes) hours post-dose; pre-dose on Days 2-4, and with each safety sample on Days 5, 10, 12, and 14 (AM)

1,25-dihydroxyvitamin D3 on Day -1; pre-dose on Day 1 and at 12 (±60 minutes) hours post-dose; pre-dose on Days 2-3, and pre-dose on Days 5, 10, 12, and 14

25-hydroxyvitamin D on Day -1, pre-dose on Day 10, and Day 14

Urinary calcium, phosphorus, magnesium, and creatinine in 12 hour collections twice daily on Day -1 and post-dose on Days 10 and 11

3-4 mL for metabolites on Day 11 and for possible further investigation by Ascendis.

Serum BSAP and P1NP, and serum CTx will be collected in fasting AM samples on Day -1 and Days 1, 5, 7, 9, 11 and 14
Secondary outcome [2] 339052 0
To assess whether ACP-014 treatment reduces urine calcium excretion in healthy adult subjects
Timepoint [2] 339052 0
SAD

Urinary calcium, phosphorus, magnesium, and creatinine in 12 hour collections twice daily on Day -1 and post-dose on Days 1 to 4

Cohort X

Urinary calcium, phosphorus, magnesium, and creatinine in 12 hour collections twice daily on Day -1 and post-dose on Days 1 to 4

MAD
Urinary calcium, phosphorus, magnesium, and creatinine in 12 hour collections twice daily on Day -1 and post-dose on Days 10 and 11
Secondary outcome [3] 339053 0
To determine the incidence of antiPTH and antiPEG antibodies
Timepoint [3] 339053 0
SAD

Samples for anti-PTH (may only be analyzed if required) and anti-PEG antibodies collected at screening, Day -1 and Day 5

Cohort X

Samples for anti-PTH and anti-PEG antibodies collected at screening, Day -1 and the Day of discharge after the 2nd dose

MAD

Samples for anti-PTH and anti-PEG antibodies collected at screening, Day -2 or Day -1 and Day 14
Secondary outcome [4] 339054 0
Cohort X only: To compare PK between subcutaneous (SC) injection of ACP-014 in the abdomen vs. the thigh
Timepoint [4] 339054 0
The following assessments and collections will be made in temporal relationship to the administration of study drug, which will be considered Day 1, Time 0, unless otherwise specified:

Collection of PK samples for Total PTH, Total PTH(1-34) and Free PTH at pre-dose (Day1), and at 4 (±15 minutes), 8(±30 minutes), 12 , 16, 24, 30, 36 (±60 minutes), 48, 60, 72, and 96 (±120 minutes) hours post-dose

Eligibility
Key inclusion criteria
1) Healthy adult males and females aged 18-60 years
2) Body mass index (BMI) 18.5 – 27 kg/m2
3) Able to provide informed consent
4) All male and females of childbearing potential must agree to
use a barrier method of contraception from the time of
signing informed consent until 30 days after study
completion if engaging in sexual activity, unless a female of
childbearing potential has been using a non-barrier highly
effective forms of contraception including oral contraceptive
pills, long-acting implantable hormones, injectable
hormones, a vaginal ring or an intrauterine device and
agrees to continue this form of contraception until 30 days
after study completion, or has had a tubal ligation, or their
male partner has had a vasectomy. Subjects with same sex
partners (abstinence from penile-vaginal intercourse) are
eligible when this is their preferred and usual lifestyle. Male
subjects must use contraception (ie, male condom) or
practice complete abstinence for 30 days after study
completion and must not donate sperm during this time.

5) Any subjects using calcium/minerals and/or vitamin D
supplements at screening must continue the same doses of
these supplements throughout the study.
Minimum age
18 Years
Maximum age
60 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1) History or presence of malignant disease, other than basal
cell epithelioma/carcinoma or completely resected
squamous skin cancer with no recurrence for 12 months
2) Any history of hyperparathyroidism, hypoparathyroidism,
hypercalcemia, hypercalciuria, kidney stones, Familial Benign Hypocalciuric Hypercalcemia, osteomalacia, Paget’s disease, osteoporosis, or any type of metabolic bone disease or radiation therapy to the skeleton
3) Pregnant or lactating females
4) History of diabetes mellitus
5) Use of any prescription drug other than hormonal contraception [(oral contraceptives pills (OCP’s), longacting implantable hormones, injectable hormones, a vaginal ring or an intrauterine device (IUD)] within 7 days prior admission without approval of the medical monitor/expert
6) Screening level 25-hydroxyvitamin D3 of < 25 ng/mL
7) History of drug abuse
8) Known or suspected HIV-positive status
9) Known or suspected infection with hepatitis B or C
10) Known hypersensitivity to the components of the trial medication
11) The subject is likely to be non-compliant with respect to trial conduct
12) Participation in any other trial of an investigational agent within 30 days prior to entry
13) 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)
Unblinded pharmacist
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation tables
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Other
Other design features
This is a single center, phase 1, randomized, first in human, double-blind, placebo-controlled SAD/MAD trial of ACP-014 given by SC injection to adult male and female healthy subjects. There is also a single-blind, crossover cohort comparing single doses of two different dose levels administered by SC injection to the abdomen and thigh.
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
Descriptive statistics will be provided for each dose cohort of SAD and MAD. Within subject comparisons will be conducted for subjects in the crossover cohort of the study.

Pharmacokinetic analysis

All subjects who will have received the study drug and for whom the primary pharmacokinetic data are considered sufficient and interpretable will be analyzed in the pharmacokinetic analyses. Given the exploratory nature of this study, and the relatively low number of subjects per dose level, pharmacokinetic parameters will generally be estimated with summary statistics. The pharmacokinetic parameters and their statistical evaluation will be included in the clinical study report. Based on the well-understood PK/PD relationship of PTH in general, and PTH(1-34) in particular, and the data showing that continuous infusion of PTH(1-34) provides optimal treatment of both adults and children with hypoparathyroidism, PK data will not be used for dose advancement, nor will the PK data for a given cohort be available at the time of the safety teleconference for that cohort. Instead, dose advancement will be based on the totality of the safety data available, including primarily the serum calcium response.

Safety analysis

The reporting of the safety data is descriptive, and will include all subjects receiving at least one dose of ACP-014 or placebo. Descriptive analysis will include the incidence and type of AEs, changes in laboratory, vital signs, and 12-lead ECG parameters from pre-dosing to all post dosing time points. Listings of abnormal laboratory data by treatment group will be presented. Treatment-emergent abnormal ECGs will be summarized. Incidence of abnormal vital signs and ECG observations over time will be summarized by treatment/dose group. All AEs will be coded using MedDRA and tabulated by System Organ Class. Individual events within eachSystem will be presented in descending frequency. AEs will also be tabulated by severity and relationship to the study drug and will be presented by dosage. SAEs will be summarized separately from non-serious AEs. Important safety findings will be listed and summarized as appropriate.

Interim analysis:
The safety data from each cohort will be analyzed at the completion of each
cohort.

Pharmacodynamic analysis

The absolute and percent change from baseline will be summarized for each PD parameter. All subjects who have received ACP-014 or placebo, and for whom the primary PD data are considered to be sufficient and interpret-able, will be included in the PD analyses. Data from all clinical assessments will be listed where appropriate, and summarized by cohort using descriptive statistics.

Interim analysis:
The PD data from each cohort will be analyzed at the completion of each
cohort.

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] 9100 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 17599 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 297592 0
Commercial sector/Industry
Name [1] 297592 0
Ascendis Pharma Bone Diseases A/S
Address [1] 297592 0
Tuborg Boulevard 5,
DK-2900
Hellerup,
Denmark
Country [1] 297592 0
Denmark
Primary sponsor type
Commercial sector/Industry
Name
Ascendis Pharma Bone Diseases A/S
Address
Tuborg Boulevard 5,
DK-2900
Hellerup,
Denmark
Country
Denmark
Secondary sponsor category [1] 296606 0
Commercial sector/Industry
Name [1] 296606 0
Pharmaceutical Solutions Australia Pty Ltd
Address [1] 296606 0
Level 9
Avaya House
123 Epping Road North
North Ryde
NSW 2113
Country [1] 296606 0
Australia
Other collaborator category [1] 279750 0
Commercial sector/Industry
Name [1] 279750 0
Nucleus Network
Address [1] 279750 0
Level 5
89 Commercial Road
Melbourne
Victoria 3004
Country [1] 279750 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298683 0
The Alfred Hospital Ethics Committee
Ethics committee address [1] 298683 0
The Alfred
55 Commercial Rd,
Melbourne
VIC 3004
Ethics committee country [1] 298683 0
Australia
Date submitted for ethics approval [1] 298683 0
27/07/2017
Approval date [1] 298683 0
08/09/2017
Ethics approval number [1] 298683 0
282/17

Summary
Brief summary
This research project is testing the safety, tolerability, immunology (how the study drug affects the immune system), pharmacokinetics (how the body effects the study drug) and pharmacodynamics (how the study drug effects the body) of single and multiple doses of a new drug called ACP-014 when given as a subcutaneous (into the skin) injection. Ascendis Pharma is developing the drug ACP-014 for the potential his study will run in 3 Parts:

• Single Ascending Dose (SAD) Phase: will assess the effect of a single ascending dose of ACP-014 or
placebo when administered as a subcutaneous (under the skin) injection abdomen.

• Cross Over (Cohort X) Phase: will assess the effect of a single subcutaneous dose of ACP-014 in their
abdomen and thigh. This phase of the study involves all participants receiving both study treatments in a particular
sequence.

• Multiple Ascending Dose (MAD) Phase: will assess the effect of multiple ascending daily doses of ACP-014
when administered as subcutaneous injections into the abdomen.

Up to 80 participants will be enrolled in up to 8 cohorts (groups) with up to 10 participants in each cohort. In each cohort, 8 participants will receive the active drug (ACP-014) and 2 will receive the placebo. This study is a dose escalation study and total participation consists of 35 days.
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 77882 0
Dr Jason Lickliter
Address 77882 0
Nucleus Network
Level 5
89 Commercial Road
Melbourne
Victoria 3005
Country 77882 0
Australia
Phone 77882 0
+61390768900
Fax 77882 0
+61390768911
Email 77882 0
J.Lickliter@nucleusnetwork.com.au
Contact person for public queries
Name 77883 0
Ms Jessica Faggian
Address 77883 0
Nucleus Network
Level 5
89 Commercial Road
Melbourne
Victoria 3005
Country 77883 0
Australia
Phone 77883 0
+61385939860
Fax 77883 0
+61390768911
Email 77883 0
J.Smyrnis@nucleusnetwork.com.au
Contact person for scientific queries
Name 77884 0
Dr Jason Lickliter
Address 77884 0
Nucleus Network
Level 5
89 Commercial Road
Melbourne
Victoria 3005
Country 77884 0
Australia
Phone 77884 0
+61 3 8593 9805
Fax 77884 0
+61390768911
Email 77884 0
J.Smyrnis@nucleusnetwork.com.au

No data has been provided for results reporting
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary