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Trial registered on ANZCTR


Registration number
ACTRN12621001077853p
Ethics application status
Submitted, not yet approved
Date submitted
29/06/2021
Date registered
16/08/2021
Date last updated
16/08/2021
Date data sharing statement initially provided
16/08/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A Study to Evaluate the Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Effects of KER-012 Administered to Healthy, Postmenopausal Women
Scientific title
A Randomized, Double-Blind, Placebo Controlled, Two-Part, Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Effects of KER-012 Administered to Healthy, Postmenopausal Women
Secondary ID [1] 304510 0
KER012-HV-101
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Healthy Postmenopausal Women 322395 0
Condition category
Condition code
Musculoskeletal 320054 320054 0 0
Osteoporosis
Cardiovascular 320197 320197 0 0
Hypertension
Musculoskeletal 320198 320198 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
KER-012 will be administered subcutaneously. Intervention adherence will be assessed by study monitors, this will be done by audit of nurses notes and pharmacy logs
The study consists of two parts:
Single Ascending Dose: 4 cohorts of 10 participants randomized 4 (study drug): 1 (placebo)
Cohort 1: 0.75 mg/kg single subcutaneous on day 1
Cohort 2: TBD* mg/kg on single subcutaneous on day 1
Cohort 3: TBD* mg/kg on single subcutaneous on day 1
Cohort 4: TBD* mg/kg on single subcutaneous on day 1
(*the doses for subsequent cohorts will be based on the Safety Review Committee (SRC) recommendation after review of pharmacokinetic and safety data from cohort 1)

Multiple Ascending Dose: 4 cohorts of 10 participants randomized 4 (study drug): 1 (placebo)
Cohort 1: TBD* mg/kg subcutaneous on every 4 weeks (Q4W) on Days 1, 29, and 57 or dosing every 2 weeks (Q2W) on Days 1, 15, 29, 43, and 57
Cohort 2: TBD* mg/kg subcutaneous on every 4 weeks (Q4W) on Days 1, 29, and 57 or dosing every 2 weeks (Q2W) on Days 1, 15, 29, 43, and 57
Cohort 3: TBD* mg/kg subcutaneous on every 4 weeks (Q4W) on Days 1, 29, and 57 or dosing every 2 weeks (Q2W) on Days 1, 15, 29, 43, and 57
Cohort 4: TBD* mg/kg subcutaneous on every 4 weeks (Q4W) on Days 1, 29, and 57 or dosing every 2 weeks (Q2W) on Days 1, 15, 29, 43, and 57
(*specified dose levels and frequency to be confirmed following review of safety and pharmacokinetics data from part 1(SAD) and based on data it is anticipated that three cohorts will receive every 4-week (Q4W) dosing and one cohort will explore every 2-week dosing (Q2)
Intervention code [1] 320868 0
Treatment: Drugs
Comparator / control treatment
The placebo will be sterile saline and will be administered subcutaneously
Control group
Placebo

Outcomes
Primary outcome [1] 327909 0
Part 1/ Part 2: To evaluate the safety and tolerability of escalating doses of KER-012 administered as single and multiple SC doses in healthy postmenopausal women.
To be assessed by monitoring
• Incidence and severity of adverse events (AE);
• Incidence of serious adverse events (SAE) and suspected unexpected serious adverse reactions;
• Clinically significant changes from baseline in:
- Laboratory evaluations (hematology, chemistry, urinalysis, function tests);
- Electrocardiograms (ECG);
- Vital signs;
- Physical examinations;
- Anti-drug antibodies
Timepoint [1] 327909 0
Part 1/ Part 2: From baseline to Day 1, Day 2, Day 3, Day 4, Day 5, Day 7, Day 11, Day 15, Day 22, Day 29, Day 43, Day 57
Part 2 (every four weeks; Q4W): From baseline to Day 1, Day 2, Day 3, Day 4, Day 5, Day 7, Day 11, Day 15, Day 22, Day 28, Day 29, Day 36, Day 43, Day 50, Day 56, Day 57, Day 58, Day 59, Day 61, Day 63, Day 67, Day 71, Day 78, Day 85, Day 99, Day 113
Part 2 (every two weeks; Q2W): From baseline to Day 1, Day 2, Day 3, Day 4, Day 5, Day 7, Day 11, Day 14, Day 15, Day 22, Day 28, Day 29, Day 36, Day 42, Day 43, Day 50, Day 56, Day 57, Day 58, Day 59, Day 61, Day 63, Day 67, Day 71, Day 78, Day 85, Day 99, Day 113
Secondary outcome [1] 396981 0
Part 1/ Part 2: To evaluate the pharmacokinetic profile following escalating doses of KER-012 administered as single and multiple SC doses
The following parameters will be used for pharmacokinetic assessment: Maximum concentration (Cmax), Time to maximum concentration (tmax), Area under the concentration-time curve from time 0 to last (AUC0-last), Area under the concentration-time curve from time 0 to infinity (AUC0-inf), Terminal elimination half-life (t1/2), Apparent clearance (CL/F), Apparent volume of distribution (Vz/F), Minimum concentration (Ctrough), Area under the concentration-time curve over the dosing interval AUC (0-tau), Accumulation ratio (Rac).
Timepoint [1] 396981 0
Part 1: From baseline to Day 1, Day 2, Day 3, Day 4, Day 5, Day 7, Day 11, Day 15, Day 22, Day 29, Day 43, Day 57 post intervention administration
Part 2 (every four weeks; Q4W): From baseline to Day 1, Day 2, Day 3, Day 5, Day 7, Day 11, Day 15, Day 22, Day 29, Day 36, Day 43, Day 50, Day 57, Day 58, Day 59, Day 61, Day 63, Day 67, Day 71, Day 78, Day 85, Day 99, Day 113 post intervention administration
Part 2 (every two weeks; Q2W): From baseline to Day 1, Day 2, Day 3, Day 5, Day 7, Day 11, Day 15, Day 22, Day 29, Day 36, Day 43, Day 50, Day 57, Day 58, Day 59, Day 61, Day 63, Day 67, Day 71, Day 78, Day 85, Day 99, Day 113 post intervention administration
Secondary outcome [2] 396982 0
Part 1/ Part 2: To assess the pharmacodynamic effect on follicle-stimulating hormone (FSH) following escalating doses of KER-012 administered as single and multiple SC doses as assessed in change from baseline
Timepoint [2] 396982 0
Part 1: From baseline to Day 1, Day 2, Day 3, Day 4, Day 5, Day 7, Day 11, Day 15, Day 22, Day 29, Day 43, Day 57 post intervention administration
Part 2 (every four weeks or every two weeks): From baseline to Day 1, Day 2, Day 3, Day 5, Day 7, Day 11, Day 15, Day 22, Day 29, Day 36, Day 43, Day 50, Day 57, Day 58, Day 59, Day 61, Day 63, Day 67, Day 71, Day 78, Day 85, Day 99, Day 113 post intervention administration

Secondary outcome [3] 396983 0
Part 1/ Part 2: To assess the pharmacodynamic effect on bone tissue following escalating doses of KER-012 administered as single and multiple SC doses
In Part 1 and Part 2 of this study, the pharmacodynamic effect will be assessed based on change from baseline in biomarkers of bone growth and resorption

Timepoint [3] 396983 0
Part 1: Day 1, Day 5, Day 7, Day 15, Day 22, Day 29, Day 43, Day 57 post intervention administration
Part 2 (every four weeks; Q4W): Day 1, Day 7, Day 15, Day 22, Day 29, Day 36, Day 43, Day 50, Day 57, Day 63, Day 71, Day 78, Day 85, Day 99, Day 113 post intervention administration
Part 2 (every two weeks; Q2W): Day 1, Day 7, Day 15, Day 22, Day 29, Day 36, Day 43, Day 50, Day 57, Day 63, Day 71, Day 78, Day 85, Day 99, Day 113 post intervention administration
The dual-energy X-ray absorptiometry (DXA) assessment is to be conducted within 7 days of dosing (not as part of the initial Screening visit)
Secondary outcome [4] 397208 0
Part 2: To assess the pharmacodynamic effect on bone tissue following escalating doses of KER-012 administered as single and multiple SC doses
The pharmacodynamic effect will be assessed based on change from baseline in lean body mass, fat mass, and bone mineral density (BMD) using total body scan by dual-energy X-ray absorptiometry (DXA).
Timepoint [4] 397208 0
Part 2 (every four weeks; Q4W or every two weeks; Q2W): From baseline to Day 56, Day 113 post intervention administration
The dual-energy X-ray absorptiometry (DXA) assessment is to be conducted within 7 days of dosing (not as part of the initial Screening visit)

Eligibility
Key inclusion criteria
For part 1 and part 2:
1. Postmenopausal female, aged 45 to 70 years (inclusive) at Screening.
NOTE: Postmenopausal is defined as: 12 months of spontaneous amenorrhea, OR 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels >40 IU/L or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.
2. Non-smoker or social smoker who agrees to smoke <=8 cigarettes per week or is willing to abstain from smoking/nicotine products during the study including the follow-up period.
3. Body mass index of >18.5 kg/m2 to <32 kg/m2 at Screening.
4. In good health as determined by review of medical history, physical examination, vital signs, oxygen saturation, clinical laboratory tests, 12-lead electrocardiogram (ECG), and any abnormal findings that are assessed as not clinically significant by the Investigator.

Minimum age
45 Years
Maximum age
70 Years
Gender
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
For part 1 and part 2:
1. Clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other major disease.
2. History of or current malignancy (excluding basal cell carcinoma that has been resected with no evidence of metastatic disease for 3 years, or cervical intraepithelial neoplasia >5 years ago that was treated and not known to have recurred).
3. Current opportunistic infection (e.g., invasive candidiasis or pneumocystis pneumonia).
4. Serious local infections (e.g., cellulitis, abscess) or systemic infection (eg, septicemia) within the 3 months prior to Screening.
5. History of severe allergic or anaphylactic reaction(s) or hypersensitivity to recombinant proteins or excipients in the investigational drug
6. Surgery within 3 months prior to Screening (exception is various minor procedures [e.g., mole removal, minor cosmetic procedures, or minor dental procedures]).
7. Clinically relevant/significant laboratory findings at Screening (up to 2 repeats permitted) or on Day -1 (repeats not permitted) including, but not limited to: Alanine transaminase (ALT) and aspartate transaminase (AST) >1.2 × upper limit of normal (ULN); isolated and mainly unconjugated hyperbilirubinemia consistent with Gilbert's should not be excluded.
8. Fever (body temperature >38°C) or symptomatic viral or bacterial infection within 2 weeks prior to Screening that has not resolved prior to dosing.
9. Donated blood (1 unit or more) within 1 month prior to dosing or plans to donate blood during the study.
10. Hormone replacement therapy within 3 months prior to dosing or plans to begin hormone replacement therapy at any time during the study. Estrogen replacement is permitted.
11. Systemic glucocorticoid therapy for more than 1 month within 6 months before Screening.
12. Changes in medications that may affect muscle function (e.g., high intensity statins, beta-blockers) within 3 months prior to dosing. Dose to remain stable while on study.
13. History of alcohol or drug abuse or drug addiction (including cannabis products) within the last 12 months prior to Screening.
14. Treatment with another investigational drug, investigational device, or approved therapy for investigational use within 1 month or 5 half-lives prior to dosing.

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)
Allocation is concealed. The allocation will occur via numbered containers at the investigational product manufacturing facility as such they will be the holder of the allocation schedule
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A computer-generated randomization schedule will be prepared by an unblinded statistician prior to the start of the study. Investigational product will be prepared in accordance with the randomization list
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other
Other design features
Single-ascending dose (SAD) cohorts: participants in each cohort will be randomized in a ratio of 4:1 to KER-012 or placebo
Participants will be screened within 28 days prior to dosing and will report to the study site over a 12 week period
Multiple-ascending dose (MAD) cohorts: participants in each cohort will be randomized in a ratio of 4:1 to KER-012 or placebo
Participants will be screened within 28 days prior to dosing and will report to the study site over a 20 week period
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
Part 1 (single-ascending dose) and Part 2 (multiple-ascending dose) data will be analysed separately. In general, data will be summarized by dose group, with participants receiving placebo pooled across cohorts. Data will be summarized using descriptive statistics (mean, median, standard deviation, minimum, and maximum) or frequency counts and percentages, as appropriate to the type of data. Baseline will be defined as the last available, valid, non-missing assessment prior to dosing.

Recruitment
Recruitment status
Not yet 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)
QLD,VIC
Recruitment hospital [1] 19846 0
Q-Pharm Pty - Clive Berghofer Research Centre (CBCRC) - Herston
Recruitment hospital [2] 19847 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 34536 0
4007 - Herston
Recruitment postcode(s) [2] 34537 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 308875 0
Commercial sector/Industry
Name [1] 308875 0
Keros Therapeutics
Address [1] 308875 0
99 Hayden Avenue, Suite 120, Building E, Lexington, MA 02421, USA
Country [1] 308875 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Keros Therapeutics
Address
99 Hayden Avenue, Suite 120, Building E, Lexington, MA 02421, USA
Country
United States of America
Secondary sponsor category [1] 309794 0
None
Name [1] 309794 0
Address [1] 309794 0
Country [1] 309794 0
Other collaborator category [1] 281864 0
Commercial sector/Industry
Name [1] 281864 0
Novotech (Australia) Pty Limited
Address [1] 281864 0
Level 3, 235 Pyrmont street, Pyrmont NSW 2009
Country [1] 281864 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 308780 0
Alfred Hospital HREC
Ethics committee address [1] 308780 0
55 Commercial Road, Melbourne VIC 3004
Ethics committee country [1] 308780 0
Australia
Date submitted for ethics approval [1] 308780 0
30/06/2021
Approval date [1] 308780 0
Ethics approval number [1] 308780 0

Summary
Brief summary
This is a randomized, double-blind, placebo-controlled, single-ascending dose (SAD, Part 1) and multiple-ascending dose study (MAD, Part 2) of KER-012 in healthy postmenopausal women. The study will evaluate the safety, tolerability and PK of KER-012. In addition, this study will explore the effects of KER-012 on muscle, bone, and adipose tissues, and determine the pharmacokinetic/pharmacodynamic (PD) relationship of those effects.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 111858 0
Dr Richard Friend
Address 111858 0
Nucleus Network – Brisbane, 300c Herston Road, Herston, Queensland, 4006
Country 111858 0
Australia
Phone 111858 0
+61 403 415 925
Fax 111858 0
Email 111858 0
r.Friend@nucleusnetwork.com.au
Contact person for public queries
Name 111859 0
Dr Richard Friend
Address 111859 0
Nucleus Network – Brisbane, 300c Herston Road, Herston, Queensland, 4006
Country 111859 0
Australia
Phone 111859 0
+61 403 415 925
Fax 111859 0
Email 111859 0
r.Friend@nucleusnetwork.com.au
Contact person for scientific queries
Name 111860 0
Mr Howard Wraight
Address 111860 0
Novotech (Australia) Pty Limited, Level 3, 235 Pyrmont street, Pyrmont NSW 2009
Country 111860 0
Australia
Phone 111860 0
+61393411928
Fax 111860 0
Email 111860 0
Howard.Wraight@novotech-cro.com

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
No Results