Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618000996268
Ethics application status
Approved
Date submitted
24/05/2018
Date registered
14/06/2018
Date last updated
26/04/2019
Date data sharing statement initially provided
26/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Multi-Part, Phase 1, Single-Center, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Cyclo-Z When Administered Orally to Healthy Volunteers
Scientific title
A Multi-Part, Phase 1, Single-Center, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Cyclo-Z When Administered Orally to Healthy Volunteers
Secondary ID [1] 294968 0
Nil
Universal Trial Number (UTN)
NMP-CYZ-P1-002
Trial acronym
Nil
Linked study record
Nil

Health condition
Health condition(s) or problem(s) studied:
Type 2 Diabetes 307969 0
Condition category
Condition code
Metabolic and Endocrine 307002 307002 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a Single Dose (Fed and Fasted State) and Multiple Dose Phase trial. Subjects will be randomised to either orally receive with Cyclo-Z or placebo at doses and intervals presented below.

Active treatment will be an oral tablet of Cyclo-Z, a combination of Cyclo (His-pro) (CHP) at doses between 6mg and 60mg and zinc.

In the Singe Ascending Dose (SAD) Phase, there will be up to 5 cohorts with 8 subjects (6 active and 2 placebo). A total of 40 subjects are planned if all 5 dose levels are completed in the fasted state. The same 8 subjects (6 active, 2 placebo) from one dose cohort will be assessed for food effect after an approximately 7-day wash-out or 5 half-lives, whichever comes later.

Cohort 1 will receive 6mg CHP plus 23mg zinc, administered by oral tablet.
Cohort 2 will receive 15mg CHP plus 23 mg zinc, administered by oral tablet.
Cohort 3 will receive 30mg CHP plus 46 mg zinc, administered by oral tablets.
Cohort 4 will receive 45mg CHP plus 69 mg zinc, administered by oral tablets.
Cohort 5 will receive 60mg CHP plus 92 mg zinc, administered by oral tablets.

Dosing will take place in the morning on Day 1 under the supervision of the study staff. Subjects will each receive their first dose of study drug following a 12 hour fast. Water is allowed during the fast. Study drug compliance will be documented in the eCRF by recording: The date and time of the administration and the amount of tablets taken.

Participants will not be allowed to participate in both the SAD and MAD cohorts, however one cohort from the SAD Fasted cohorts will be selected to complete the SAD Fed cohort.

In the Multiple Ascending Dose (MAD) Phase, there will be up to 4 cohorts with 8 subjects (6 active and 2 placebo). A total of 32 subjects are planned if all 4 dose levels are completed.

Cohort 1 will receive 6mg CHP plus 23mg zinc by oral tablet once daily for 10 days.
Cohort 2 will receive 15mg CHP plus 23 mg zinc by oral tablet once daily for 10 days.
Cohort 3 will receive 30mg CHP plus 46 mg zinc by oral tablets once daily for 10 days.
Cohort 4 will receive 45mg CHP plus 69 mg zinc by oral tablets once daily for 10 days.

Dosing will take place in the morning on dosing days under the supervision of the study staff. Subjects will each receive their first dose of study drug following a 12 hour fast. Water is allowed during the fast. Study drug compliance will be documented in the eCRF by recording: The date and time of the administration and the amount of tablets taken.

Following the review of the SAD and MAD cohorts and dependent on the sponsor's review of trial data, the sponsor has allowed for the possibility to run an optional cohort(s). Should the sponsor and site proceed with the optional cohort(s), it will be assessing a Cyclo (his-pro) [CHP] only and/or a zonc only cohort with 8 subjects (6 active and 2 placebo). The dose for this optional cohort(s) will based on the emerging tolerability data from the MAD cohorts. New subjects will be recruited for this cohort.

The optional cohort(s) will follow the same schedule as the MAD cohorts, receiving daily oral tablet(s) dosing for 10 days. Dosing will take place in the morning on dosing days under the supervision of the study staff. Subjects will each receive their first dose of study drug following a 12 hour fast. Water is allowed during the fast. Study drug compliance will be documented in the eCRF by recording: The date and time of the administration and the amount of tablets taken.

An additional biocomparability cohort will be conducted as an open-label, two-way crossover evaluation to examine the PK and safety of two Cyclo-Z immediate release tablet formulations each containing 15mg CHP and 23mg zinc.

This cohort will consist of a 4-week screening period and two periods (Period 1 and 2) that are separated by an outpatient washout time of 7 (plus or minus 3) days. Subjects will be consented and screened for enrollment up to 4 weeks prior to Day -1 (check-in) and those subjects who meet all of the inclusion criteria and none of the exclusion criteria at Screening and Day -1 will be eligible to participate. During each of the two periods, subjects will remain at the clinical site for a 72 hour inpatient period.

Approximately 8 healthy subjects will be randomized on Day -1/1, in a 1:1 ratio, to receive 1 of 2 Cyclo-Z tablet formulations during Periods 1 and 2 (Tablet A/Tablet B or Tablet B/Tablet A).
Intervention code [1] 301293 0
Treatment: Drugs
Comparator / control treatment
Placebo tablets will be matched for Cyclo-Z tablets in color, shape, and size and will be indistinguishable from Cyclo-Z tablets.

The placebo contains the following ingredients:
MCC, USP
Hydroxypropyl Cellulose
Croscarmellose Sodium
Silicon Dioxide, NF
Magnesium Stearate, NF
Sub-Total (Core)
Opadry II 85F91480 Green
Control group
Placebo

Outcomes
Primary outcome [1] 305990 0
To evaluate the safety and tolerability of single and multiple doses of Cyclo-Z following oral administration in healthy volunteers.
Timepoint [1] 305990 0
Following enrollment into the study and administration of the first dose of study drug the following safety and tolerability assessments will be collected.

For the SAD (fasted and fed):
- Safety laboratory tests (fasting): Day 1 pre-dose and 2, 4, and 8 hours after study drug administration; Day 2 (20-28 hours); and End of Study (68-76 hours, end-of study time point).
- Post prandial blood glucose (2 hours after each meal) from Day -1 to Day 3
- Blood glucose (via glucometer) 4 and 24 hours after study drug administration on Days 1 and 2
- An ECG pre-dose, and 2, 4, 6, 12, 24, 48 hours after the study drug administration.
- Vitals signs: pre-dose, 0.5, 2, 4, 6, 12, 24, 36, and 48 hours after the study drug administration.
- Physical examination, vital signs, and ECG on End of Study (68-76 hours, end-of study time point) after the study drug administration.

Cohort 1 will start and dosing for Cohort 2 can begin after the initial safety review of Cohort 1 following, at a minimum, the discharge of the Cohort 1 from the clinic.

The third and higher dosing cohorts to be selected based on AEs and available PK data.

For the MAD (fasted) subjects:
- Safety laboratory tests (fasting): Day 1 pre-dose and on Days 2, 5, 7, 10, and on End of Study (68-76 hours after the Day 10 dose).
- Post prandial blood glucose (2 hours after each meal) from Day -1 to Day 12
- Blood glucose (via glucometer) 4 and 24 hours after each daily study drug administration from Day 1 to Day 11
- An ECG at the following timepoints:
--Day 1: pre-dose, and 2, 4, 6, 12, 24, 48 hours after the study drug administration
--Days 4, 5, and 7: pre-dose
--Day 10: pre-dose, and 2, 4, 6, 12, 24, 48 hours after the study drug administration
--End of Study: 68-76 hours (end-of study time point) after the Day 10 dose.
- Vital signs will be collected at the following timepoints:
--Day 1: pre-dose, 0.5, 2, 4, 6, 12, 24, and 48 hours after the study drug administration
--Day 4 – 9: pre-dose
--Day 10: pre-dose, 0.5, 2, 4, 6, 12, 24, and 48 hours after the study drug administration
--End of Study: 68-76 hours (end-of study time point) after the Day 10 dose.
-Physical examination on End of Study (68-76 hours after the Day 10 dose).

The dosing for first MAD Cohort can start after the initial safety review of the first SAD Cohort following, at a minimum, the discharge of the Cohort 1 from the clinic. The dosing for the second MAD dosing cohort can start at the same time as SAD Cohort 2.
The third and higher dosing cohorts to be selected based on AEs and available PK data.


Monitoring for adverse events and concomitant medications will be conducted at frequent intervals when housed in the clinic from the time of the signed consent to the EoS visit.

AEs, vital signs, ECGs, clinical laboratory test results, and available PK data will be reviewed for the entire cohort of all subjects who have completed all of the study procedures by a dose group that includes the Principal Investigator, Medical Monitor, and other representatives of the Sponsor. Any other safety data available up to discharge such as clinically significant AEs may also be reviewed to add to the consideration for dose escalation in the SAD and the MAD phases.
Primary outcome [2] 305991 0
To assess the plasma pharmacokinetics (PK) of Cyclo-Z after single and multiple oral doses to healthy volunteers. The following parameters will be computed from plasma concentration data for Cyclo (his-pro) and zinc, if deemed appropriate: Cmax, tmax, t1/2, lambda z, AUC(0-t), AUC(0-24), AUCinf, MRT, CL/F, and Vz/F
Timepoint [2] 305991 0
Blood samples for the assay of Cyclo (his-pro) and zinc will be collected at the following timepoints:

Single and Multiple Dose Phases:
- Day 1: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours and,
- 24, 36, 48, 60 and 72 hours after Day 1 study drug administration.

Multiple Dose Phase (in addition)
- Days 5 and 7 (pre-dose)
- Day 10: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours, and
- 24, 36, 48, 60 and 72 hours after last study drug administration
Primary outcome [3] 305992 0
To assess the relative bioavailability of CHP and zinc in the fed and fasted state following a single oral dose of Cyclo-Z in healthy volunteers.
Timepoint [3] 305992 0
Blood samples for the assay of Cyclo (his-pro) and zinc will be collected at the following timepoints:

Single Dose Phases:
- Day 1: 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours and,
- 24, 36, 48, 60 and 72 hours after Day 1 study drug administration.
Secondary outcome [1] 347228 0
To evaluate the concentration-response modelling of the relationship between Cyclo-Z plasma levels and cardiodynamic markers in healthy volunteers
Timepoint [1] 347228 0
Serial ECGs will be collected in parallel with serial pharmacokinetic sampling.

For the Single Dose Phase, ECGs will be collected at the following timepoints:

Pre-dose, and 2, 4, 6, 12, 24, 48 hours after the study drug administration, and End of Study (68-76 hours, end-of study time point).

For the Multiple Dose Phase, ECGs will be collected at the following timepoints:
- Day 1: pre-dose, and 2, 4, 6, 12, 24, 48 hours after the study drug administration
- Days 4, 5, and 7: pre-dose
- Day 10: pre-dose, and 2, 4, 6, 12, 24, 48 hours after the study drug administration
- End of Study: 72 ± 4 hours (end-of study time point) after the Day 10 dose.
Secondary outcome [2] 369750 0
Additional primary outcome for the biocomparibility cohort is to assess the biocomparibility (Pharmacokinetics) of two tablets formulations of Cyclo-Z (Tablet A and B) after a single dose in healthy volunteers.

The following parameters will be computed from plasma concentration data for Cyclo (his-pro) and zinc, if deemed appropriate: Cmax, tmax, t1/2, lambda z, AUC(0-t), AUC(0-24), AUCinf, MRT, CL/F, and Vz/F
Timepoint [2] 369750 0
The primary objectives will be evaluated by:
Pharmacokinetics: Concentrations of Cyclo (his-pro) and zinc in plasma samples will be determined by using validated analytical methods.

PK samples will be drawn at 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, and 16 hours and, 24, 36, 48, 60 and 72 hours after study drug administration

Eligibility
Key inclusion criteria
All subjects are required to meet the following criteria in order to be included in the study:
1. Male or female between 18 and 55 years of age.
2. Female subjects must be either:
a. Surgically sterile (i.e., have had bilateral tubal ligation, hysterectomy, or bilateral oophorectomy) at least 6 months before randomization, or
b. Post-menopausal for at least 12 months prior to screening, or
c. If of childbearing potential and sexually active, must agree to use a highly effective contraceptive method from screening to 30 days after the end of dosing. Females who are abstinent will not be required to use a contraceptive method unless they become sexually active. Females who are sexually active with partners of same gender will not be required to use a contraceptive method.
3. Sexually active male subjects with female partners of childbearing potential must use two reliable forms of contraception from screening to 30 days after the end of dosing. Note: The female partners of male subjects must agree to use double barrier method, which includes using highly reliable forms of contraception, and male partner must agree to use condom. Male subjects who are sexually active with partners of same gender must use a condom from screening to 30 days after end of dosing. Male subjects who are abstinent will not be required to use contraception unless they become sexually active.
4. Estimated creatinine clearance greater than 60 mL/min based on the Cockcroft-Gault calculation or serum creatinine value less then 1.5 times the upper limit of normal (ULN), unless deemed not clinically significant by the Investigator.
5. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) values less than 1.5 times the upper limit of normal, unless deemed not clinically significant by the Investigator.
6. Be current non-smokers and also may not have used tobacco products (e.g., cigarettes, e-cigarettes, cigars, pipe tobacco) within the year prior to screening.
7. Good general health as determined by medical history, and by results of physical examination, vital signs, ECG, and clinical laboratory tests obtained within 14 days (2 weeks) prior to study drug administration.
8. Able to provide written informed consent and understand and comply with the requirements of the study.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
All subjects with the following characteristics will be excluded from the study:
1. Subject participation in more than one cohort.
2. History or presence of any clinically significant organ system disease that could interfere with the objectives of the study or the safety of the subjects.
3. Blood pressure and/or heart rate at outside the ranges 90-140 mmHg systolic, 40-90 mmHg diastolic, heart rate 40-100 beats/min.
4. 12-lead ECG with any abnormality judged by the Investigator to be clinically significant, QT >500 milliseconds (msec), or QTcF interval of greater than 450 msec for men or greater than 470 msec for women.
5. Presence or history of any abnormality or illness, which in the opinion of the Investigator may affect absorption, distribution, metabolism or elimination of the study drug.
6. Any other clinically significant laboratory abnormality at the screening visit or prior to the administration of the first dose of study drug. In general, each laboratory value from screening and baseline chemistry and hematology panels should fall within the limits of the normal laboratory reference range, unless deemed not clinically significant by the Investigator.
7. History of or current active tuberculosis (TB) infection; history of latent TB that has not been fully treated or current latent TB infection.
8. Positive serum test for HIV, hepatitis C or hepatitis B virus infection.
9. History of significant allergy to any medication.
10. History of clinically significant alcohol or drug abuse within the past 24 months.
11. Use of any tobacco or nicotine containing product within the previous 12 months. Note: Subjects who are social/occasional smokers may be eligible with Sponsor approval.
12. Administration of any prescription drug (oral contraceptives permitted) within 21 days of study drug administration; or over-the-counter drug (paracetamol and ibuprofen less than or equal to 1 g/day permitted) or herbal, nutritional or vitamin supplement within 7 days of study drug administration, unless Sponsor approval granted.
13. Evidence of drug abuse on urine testing, or a positive test for alcohol.
14. Administration or use of any investigational drug or device within 30 days of study drug administration.
15. Blood or plasma donation within 60 days 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)
Copies of the randomization sequence and treatment codes will be kept in the pharmacy at the Clinical Research Unit. Unblinded pharmacy (or other qualified site) personnel will be utilized to prepare the study drug for this trial.

Subjects will receive a 3-digit screening number at the Screening Visit, following informed consent and if deemed eligible, a randomization number will be allocated (based on the randomization schedule at any time from Day -1 to prior to Dosing on Day 1. The assignment of number and code for subject identification is based on the obligation for anonymity.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
This is a single center Phase 1 study; the study site's pharmacists (or qualified designee) will obtain the study drug assignment from a computer based randomization code list, by cohort, using a validated random generator software. The randomization scheme and codes will be generated by an unblinded statistician and provided to the site prior to study commencement.
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
Intervention assignment
Other
Other design features
Assignment is ascending dose escalation by cohort.
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Determination of Sample Size: The number of subjects for this study is not based on any formal sample size calculation. A total of 40 subjects for SAD and 32 subjects for MAD have been determined adequate to meet the study objectives, which are to establish the PK and safety profiles of escalating doses of Cyclo-Z doses administered as a single dose or multiple doses for 10 days.

Statistical Methods: The disposition, demographics, baseline characteristics, medical history, safety and PK variables will be summarized using descriptive statistics by treatment group and visit, as appropriate. For continuous variables, the descriptive statistics include: the number of observations (n), means, standard deviation (SD), median, minimum and maximum. For categorical variables, the summaries will contain the number and percentage of subjects falling into each category.

All demographic and baseline characteristics will be summarized by descriptive statistics utilizing the Safety, PK, and FAS analysis sets.

All pharmacokinetic variables will be summarized by descriptive statistics utilizing PAS.

All estimates for statistical modelling will be reported with SD and 95% confidence interval.

All analyses, summaries, and listings will be performed and will be generated using SAS software version 9.4 or higher.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
29/07/2018
Actual
30/07/2018
Date of last participant enrolment
Anticipated
13/10/2018
Actual
11/12/2018
Date of last data collection
Anticipated
26/10/2018
Actual
22/12/2018
Sample size
Target
96
Accrual to date
Final
90
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 10967 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 22755 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 299557 0
Commercial sector/Industry
Name [1] 299557 0
NovMetaPharma Co., Ltd.
Country [1] 299557 0
Korea, Republic Of
Primary sponsor type
Commercial sector/Industry
Name
NovMetaPharma Co., Ltd.
Address
13th Floor, Trees Building
727, Eonju-ro, Gangnam-gu, Seoul, Korea
Country
Korea, Republic Of
Secondary sponsor category [1] 298863 0
Commercial sector/Industry
Name [1] 298863 0
InClin Pty Ltd
Address [1] 298863 0
210 / 25 Berry Street
North Sydney, NSW
Australia, 2060
Country [1] 298863 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300454 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 300454 0
Ethics committee country [1] 300454 0
Australia
Date submitted for ethics approval [1] 300454 0
28/05/2018
Approval date [1] 300454 0
04/07/2018
Ethics approval number [1] 300454 0
295/18

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 83714 0
Dr Jason Lickliter
Address 83714 0
The Nucleus Network
Burnet Tower AMREP Precinct
89 Commercial Road
Melbourne, VIC 3001
Country 83714 0
Australia
Phone 83714 0
+61 3 9076 8960
Fax 83714 0
Email 83714 0
[email protected]
Contact person for public queries
Name 83715 0
Taylor Kilfoil
Address 83715 0
InClin PTY LTD
210/25 Berry Street
North Sydney, NSW
Australia, 2060
Country 83715 0
Australia
Phone 83715 0
+61 408 880 403
Fax 83715 0
Email 83715 0
[email protected]
Contact person for scientific queries
Name 83716 0
Peter Lee
Address 83716 0
NovMetaPharma Co., Ltd.
13th Floor, Trees Bldg.
727, Eonju-ro, Gangnam-gu, Seoul, Korea
Phone: +82-2-538-1893
Country 83716 0
Korea, Republic Of
Phone 83716 0
+82-2-538-1893
Fax 83716 0
Email 83716 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
Data to remain confidential


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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