Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619000319178
Ethics application status
Approved
Date submitted
20/02/2019
Date registered
1/03/2019
Date last updated
10/06/2021
Date data sharing statement initially provided
1/03/2019
Date results information initially provided
10/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of KER-047 Administered to Healthy Male Volunteers and Postmenopausal Female Volunteers
Scientific title
Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of KER-047 Administered to Healthy Male Volunteers and Postmenopausal Female Volunteers
Secondary ID [1] 297398 0
KER-047-01
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Fibrodysplasia ossificans progressiva 311556 0
Condition category
Condition code
Musculoskeletal 310192 310192 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Investigation product: KER-047 to be administered as an oral capsule or liquid with KER-047 dissolved in SyrSpend. Intervention adherence will be assessed by sponsor representative monitors. The monitors will asses compliance with the study protocol by performing an audit of nurses notes and pharmacy logs.
The study consists of two parts:
1. Single ascending dose (SAD) randomized 3 (study drug): 1 (placebo) in up to 10 cohorts.
Cohort 1: 1mg single oral dose administered on day 1
Cohort 2: 3mg single oral dose administered on day 1
Cohort 3: 10mg single oral dose administered on day 1
Cohort 4: 30mg single oral dose administered on day 1
Cohort 5: 100mg single oral dose administered on day 1
Cohort 6: 300mg single oral dose administered on day 1
Cohort 7: 30mg single oral dose administered on day 1
Cohort 8: 100mg single oral dose administered on day 1
Cohort 9: 300mg single oral dose administered on day 1
Cohort 10: 450mg single oral dose administered on day 1

2. Multiple ascending dose (MAD) The dose of the first MAD cohort will be determined by the Safety Review Committee (SRC), based on the PK and safety results of the SAD study. Dose increases for the MAD will be determined from the SAD. Up to 6 cohorts will be randomized 4 (study drug): 1 (placebo) with once daily, twice daily or every other day dosing for seven (7) or fourteen (14) days.
Intervention code [1] 313652 0
Treatment: Drugs
Comparator / control treatment
The placebo formulation has the same size, shape, color, and qualitative composition as the investigational product (IP), with the exception that the IP drug substance has been replaced with microcrystalline cellulose. For SAD Cohorts 7 and 8 the liquid placebo formulation will be a mixture of SyrSpend and water, and match the KER-047 liquid presentation in volume. For SAD Cohorts 9 and 10 and all MAD Cohorts, a microcrystalline cellulose powder (MCC) will be added to the SyrSpend/Water mixture to mask the opacity of the liquid KER-047, and will match the KER-047 liquid presentation in volume.
Control group
Placebo

Outcomes
Primary outcome [1] 319077 0
To evaluate the safety and tolerability of escalating doses of KER-047 administered as single and multiple oral doses in healthy male volunteers and postmenopausal female volunteers;
Safety will be assessed as follows:
Incidence and severity of adverse events (AEs);
• Incidence of serious adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs);
• Clinically significant changes from baseline in:
- Laboratory evaluations (hematology, coagulation, chemistry, urinalysis);
- Electrocardiograms (ECGs);
- Vital signs;
- Physical examinations.
Timepoint [1] 319077 0
Vitals will be performed daily
Physical exam will be assessed at screening, Day -1, Day 24, and Day 6.
ECG will be performed at screening, pre-dose, 2hours, 4 hours, 8 hours post dose and at day 6.
Blood and urine safety parameters will also be collected at screening, Day -1, Day 2, Day 4 and Day 6
Primary outcome [2] 319078 0
Blood samples will be collected from participants to evaluate the PK parameters following escalating doses of KER-047 administered as single and multiple oral doses.
PK parameters will be calculated at the end of each part of the clinical trial, data presented will include:
Pharmacokinetic Endpoints:
• Area under the plasma KER-047 concentration curve (AUC);
• Peak plasma concentration (Cmax);
• Time to peak plasma concentration (Tmax);
• Elimination half-life (t1/2);
• Elimination rate constant (K);
• Clearance (Cl);
• Volume of distribution (Vz).
Timepoint [2] 319078 0
Part 1 SAD PK collection time points:
Day 1: pre dose, 30 min post dose, 1 hour post dose, 2 hours post dose, 4 hours post dose, 8hrs post dose,
Day 2: 24 hours post dose,
Day 3: 48 hours post dose,
Day 4: 72 hours post dose,
Day 6: 120 hours post dose.

Part 2 MAD
7-Day dosing: PK collection time points:
Day 1: Pre dose,
Day 2: Pre dose,
Day 3: Pre dose,
Day 4: Pre dose,
Day 5: Pre dose,
Day 6: Pre dose,
Day 7: 30min post dose, 1 hour post dose, 2 hour post dose, 4 hour post dose, 8 hour post dose,
Day 8: 24 hour post dose,
Day 11: 96 hour post dose;

14-Day dosing collection time points:
Day 1: Pre dose,
Day 2: Pre dose,
Day 3: Pre dose,
Day 4: Pre dose,
Day 5: Pre dose,
Day 6: Pre dose,
Day 7: Pre dose,
Day 8: Pre dose,
Day 9: Pre dose,
Day 10: Pre dose,
Day 11: Pre dose,
Day 12: Pre dose,
Day 13: Pre dose,
Day 14: Pre dose, 30min post dose, 1 hour post dose, 2 hours post dose, 4 hours post dose, 6 hours post, dose, 8 hours post dose: 12 hours post dose,
Day 15: 24 hour post dose,
Day 18: 96 hour post dose.
Secondary outcome [1] 366916 0
Nil
Timepoint [1] 366916 0
Nil

Eligibility
Key inclusion criteria
Male Subjects:
1. 18 to 60 years old (MAD Cohorts 4, 5 & 6: 50 years) (inclusive) at screening;
2. Good health as determined by review of medical history, physical examination, vital signs, oxygen saturation, clinical laboratory tests, 12-lead ECG, and any abnormal findings are assessed as not clinically significant by the Investigator;
3. Non-smoker or social smokers who agrees to smoke less than or equal to 8 cigarettes per week or willing to abstain from smoking/nicotine products during the study;
4. Body weight between 50 and 110 kg inclusive and body mass index (BMI) between 18 and 32 kg/m2 (inclusive) at screening;

Female Subjects:
1. Postmenopausal female aged 45 to 60 years (MAD Cohorts 4, 5 & 6: 50 years) (inclusive) at screening;
2. Good health as determined by review of medical history, physical examination, vital signs, oxygen saturation, clinical laboratory tests, 12-lead ECG, and any abnormal findings are assessed as not clinically significant by the Investigator;
3. Non-smoker or social smokers who agrees to smoke less than or equal to 8 cigarettes per week or willing to abstain from smoking/nicotine products during the study;
4. Body weight between 50 and 100 kg (inclusive) and BMI between 18.5 and 32 kg/m2 (inclusive) at screening.
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. History of or current malignancy (excluding non-melanoma skin cancer that has been resected with no evidence of metastatic disease for 3 years);
2. Use of any prescription or over-the-counter medications taken within 7 days prior to dosing should be discussed with Investigator and Sponsor Medical Monitor (if deemed necessary). Use of medication should be ceased prior to dosing. Subject may be enrolled if the medication taken is not expected to interfere either with safety or study results;
3. Clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other major disease;
4. Chronic stable diseases including migraines, hypertension, hyperthyroid disorder, hypothyroid disorder, gastroesophageal reflux disease, or mild depression/anxiety ;
5. History of opportunistic infection (e.g. invasive candidiasis or pneumocystis pneumonia);
6. Serious local infection (e.g., cellulitis, abscess) or systemic infection (e.g., septicemia) within the 3 months prior to screening;
7. History of severe allergic or anaphylactic reactions;
8. Surgery within the previous 3 months to screening (other than minor cosmetic surgery or minor dental procedures);
9. Fever (body temperature > 38°C) or symptomatic viral or bacterial infection within 2 weeks prior to screening that has not resolved prior to dosing;
10. Clinically relevant/significant laboratory findings (up to 2 repeats permitted) at screening including, but not limited to:
• Alanine transaminase and Aspartate transaminase > 1.0 x upper limit of normal (ULN), isolated and mainly unconjugated hyperbilirubinemia consistent with Gilbert's should not be excluded;
• Creatinine outside normal laboratory range;
• Serum creatine kinase > 1.5 x ULN;
11. Treatment with another investigational drug, investigational device, or approved therapy for investigational use within 1 month or 7 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 at the investigational product manufacturing facility as such that 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
SAD cohorts: Subjects in each SAD cohort will be randomized in a ratio of 3:1 to KER-047 or placebo. Subjects will be screened and report to the study site over a 5 week period.
MAD cohorts: Subjects in each MAD cohort will be randomized in a ratio of 4:1 to KER-047 or placebo. Subjects will be screened and report to the study site over an 8 week period.
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
The sample size is customary for Phase 1 studies evaluating safety, and PK parameters; it is not based on statistical hypothesis testing.
In general, 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.
Only data from protocol scheduled visits/time points will be included in the summary tables. Data from unscheduled visits/time points will not be included in the summary tables but will be included in the figures and listings.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
30/04/2019
Actual
30/04/2019
Date of last participant enrolment
Anticipated
1/12/2020
Actual
7/09/2020
Date of last data collection
Anticipated
28/02/2021
Actual
6/10/2020
Sample size
Target
141
Accrual to date
Final
131
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 13135 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 25676 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 301971 0
Commercial sector/Industry
Name [1] 301971 0
Keros Therapeutics, Australia Pty Ltd
Country [1] 301971 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Keros Therapeutics, Australia Pty Ltd
Address
Floor 19, HWT Tower,
40 City Road
Southbank, VIC, 3006
Country
Australia
Secondary sponsor category [1] 301745 0
None
Name [1] 301745 0
Address [1] 301745 0
Country [1] 301745 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302651 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 302651 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 302651 0
Australia
Date submitted for ethics approval [1] 302651 0
27/02/2019
Approval date [1] 302651 0
02/04/2019
Ethics approval number [1] 302651 0

Summary
Brief summary
KER-047 is being developed by Keros Therapeutics Australia Pty Ltd as a potential treatment for Fibrodysplasia ossificans progressive (FOP). FOP is a rare genetic condition where the muscles, tendons and ligaments of the body slowly turn into bone. There are no approved treatments for FOP; This study aims to recruit healthy volunteers to determine the safety and pharmacokinetics of single and multiple dose of KER-047.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 90934 0
Dr Ben Snyder
Address 90934 0
Nucleus Network
Level 1/484 St Kilda Road, Melbourne Victoria 3004
Country 90934 0
Australia
Phone 90934 0
+61 3 8593 9835
Fax 90934 0
Email 90934 0
[email protected]
Contact person for public queries
Name 90935 0
Dr Ben Snyder
Address 90935 0
Nucleus Network
Level 1/484 St Kilda Road, Melbourne Victoria 3004
Country 90935 0
Australia
Phone 90935 0
+61 3 8593 9835
Fax 90935 0
Email 90935 0
[email protected]
Contact person for scientific queries
Name 90936 0
Dr Ben Snyder
Address 90936 0
Nucleus Network
Level 1/484 St Kilda Road, Melbourne Victoria 3004
Country 90936 0
Australia
Phone 90936 0
+61 3 8593 9835
Fax 90936 0
Email 90936 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual participant data will not be available, data will be analyzed by group and descriptive statistics will be generated.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseZebrafish disease models in drug discovery: from preclinical modelling to clinical trials.2021https://dx.doi.org/10.1038/s41573-021-00210-8
EmbaseBMP receptor blockade overcomes extrinsic inhibition of remyelination and restores neurovascular homeostasis.2021https://dx.doi.org/10.1093/brain/awab106
N.B. These documents automatically identified may not have been verified by the study sponsor.