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Trial registered on ANZCTR


Registration number
ACTRN12618001001280p
Ethics application status
Submitted, not yet approved
Date submitted
8/06/2018
Date registered
14/06/2018
Date last updated
14/06/2019
Date data sharing statement initially provided
14/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A study of different doses of NPI-001 tablets in healthy volunteers compared to a placebo to examine if it is safe and whether it should be taken with food or without food
Scientific title
A Phase I, Placebo-Controlled Dose-Ranging Food Effect and Multiple Dose Study of NPI-001 Tablets in Healthy Subjects
Secondary ID [1] 295149 0
None
Universal Trial Number (UTN)
U1111-1215-3924
Trial acronym
Linked study record
ACTRN12617000911392

Health condition
Health condition(s) or problem(s) studied:
Retinitis pigmentosa 308247 0
Condition category
Condition code
Eye 307270 307270 0 0
Diseases / disorders of the eye

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This randomized, double-blinded, cross-over study will include an evaluation of the Pharmacokinetics of NPI-001 in fed versus fasted healthy volunteers followed by a 5-day dosing period to ascertain if multiple doses of NPI-001 can alter Glutathione and Cysteine levels in plasma.
Potential subjects will be screened to assess their eligibility to enter the study within 28 days prior to first dose administration. Subjects will be resident in the clinical facility at CMAX, Adelaide from the evening prior to first dose (Day -1) until discharge on Day 10. A post-dose follow up visit will occur at Day 15.
On Day 1 and Day 3, each subject will receive a single oral dose of NPI-001 or Placebo. The dose levels of NPI-001 will be 1500 mg for Cohort 1 (6 tablets), and 750 mg for Cohort 2 (3 tablets). Dosing on Days 1 and 3 will be a placebo-controlled, balanced, two-treatment two-sequence randomized fasted/fed crossover design, as follows:
• 8 subjects in each cohort (6 NPI-001, 2 placebo) will be dosed on Day 1 following a 10 hour overnight fast and on Day 3 following a high fat breakfast [Fasted-Fed].
• 8 subjects in each cohort (6 NPI-001, 2 placebo) will be dosed on Day 1 following a high fat breakfast and on Day 3 following a 10 hour overnight fast [Fed-Fasted].
The high fat breakfast will consist of:
2 eggs fried in butter, 2 strips bacon. 2 slices of toast with butter, 4 oz hash brown potatoes fried in butter 8 oz (240 mL) whole milk. This high fat meal contains the equivalent of approximately 150 protein calories, 250 carbohydrate calories, and 500 to 600 fat calories.

For the high fat meal, subjects should commence the recommended meal approximately 30 minutes prior to administration of the study drug. Although study subjects should consume this meal in less than or equal to 30 minutes, the drug product should be administered approximately 30 minutes after starting the meal and at least 80% of the meal should be finished promptly.

The following measures will be employed to ensure treatment and high fat meal compliance:
All study drug doses and high fat meals will be administered under the supervision of suitably qualified study site staff
Immediately after dose administration, visual inspection of the mouth and hands will be performed for each subject
At each dosing occasion, a predose and postdose inventory of IMP and placebo will be performed on the dose containers.

Subjects will be monitored throughout the trial for adherence to the protocol by CMAX staff. All deviations from the protocol will be recorded by staff on duty at the time and logged in the eCRF for the study. Quality control and quality assurance will be performed according to CMAX Clinical Research standard operating procedures (SOPs)

On Days 5-9, all subjects will receive NPI-001 or placebo three times per day, at approximately 8am (following a standard breakfast), 2pm and 8pm, with the last dose on the morning of Day 9. The dose levels of NPI-001 will be 500 mg per dose for Cohort 1 (2 tablets), and 250 mg per dose for Cohort 2 (1 tablet).
Safety measures monitored throughout the study will include adverse events and use of concomitant medication, vital signs, and clinical laboratory tests.
Blood samples for assessment of PK will be collected on Days 1, 3 and 9, at pre-dose, then at 0.25, 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10 and 12 hours post-dose, and on Days 2, 4 and 10 at 24 hours post-dose.
Blood samples for assessment of PD will be collected on Days 1 and 3 at pre-dose and 1 hour post-dose, on Day 9 at 1 hour post-dose, and at the follow-up visit.
Intervention code [1] 301484 0
Treatment: Drugs
Comparator / control treatment
NPI-001 Tablets, 250 mg, and matching Placebo for NPI-001 Tablets, will be provided by the Sponsor (along with the lot number, BSE/TSE statement, Microbial Limits Testing, Good Manufacturing Practice (GMP) statement, and Certificate of Analysis) to a licensed, registered pharmacist serving CMAX Clinical Research.
The 250 mg Placebo tablet is identical to the active tablet, but without the active agent, NPI-001. The tablet contains Lactose, NF, Microcrystalline Cellulose, NF, Croscarmellose Sodium, NF and Stearic acid, NF as prepared by Patheon Laboratories.
Florence, South Carolina 29506, USA.
For each dose, IMP will be released by a licensed pharmacist under GCP guidelines as per written instructions prior to administration to subjects. The IMP will be stored at RAH pharmacy in a climate controlled and secure location that is locked with restricted access.
Control group
Placebo

Outcomes
Primary outcome [1] 306225 0
To evaluate the safety and tolerability of multiple oral doses of NPI-001 tablets in healthy adult subjects;

Safety measures monitored throughout the study will include adverse events and use of concomitant medication, vital signs, and clinical laboratory tests.
All AEs will be listed and summarized using descriptive methodology. The incidence of AEs for each treatment will be presented by severity and by association with the study drugs as determined by the Investigator (or designee). Each AE will be coded using the Medical Dictionary for Regulatory Activities. Observed values for 12-lead ECGs will be listed, and observed values for clinical laboratory test data and vital signs will be listed and summarized using descriptive statistics.
Timepoint [1] 306225 0
Adverse event recording will take place on each Day of the study prior to and 1 hour post dose or as reported at any time by the subject for the 10 day study period and again on Day 15 at the follow-up visit.
Prior/concomitant medication monitoring will occur at Screening, Day -1 and each day of the 10 Day study and at the Day 15 follow-up visit.
Blood samples for assessment of safety parameters will be collected at Day -1 (predose) and Days 2, 4 and 10 of the study and at the Day 15 follow-up visit.
Subject vital signs will be taken at Screening, Day -1, each Day of the study following dosing and again at the Day 15 follow-up visit.
A physical examination of each subject will take place at Screening, Day -1, Days 2, 4 and 10 during the study and at the Day 15 follow-up visit.
A 12 lead ECG for each subject will be taken at the screening visit and the Day 15 follow-up visit.

Primary outcome [2] 306226 0
To evaluate the effect of food on the pharmacokinetics (PK) of NPI-001 following single doses, of 1500 mg or 750 mg, in the fed versus fasted state;
PK parameters that will be measured are:
AUC0-6h Area under the plasma concentration-time curve from time 0 to 24 hours
postdose
AUCinf Area under the plasma concentration time curve from time 0 extrapolated
to infinity (single dose only)
AUC0 tlast Area under the plasma concentration time curve from time 0 to the last
measureable concentration (single dose only)
Cmax Maximum observed plasma concentration
CL/F Apparent oral clearance
Lambda(z) Elimination rate constant
RA(AUC) Accumulation ratio
tmax Time to maximum observed plasma concentration
t1/2 Apparent terminal elimination half life
Vz/F Apparent volume of distribution

Each parameter will be measured by blood plasma analysis or urinalysis, as appropriate


Timepoint [2] 306226 0
Blood samples for pharmacokinetics will be drawn predose and at various times through 24 hours postdose based on the published half-lives of N acetyl cysteine and NPI-001.
Pharmacokinetic blood samples will be collected within the following windows

• Days 1, 3 and 9: within 1 hr pre-dose
• Days 1, 3 and 9: at 15 and 30 minutes post-dose ± 2 minutes
• Days 1, 3 and 9: at 1, 1.25, 1.5, 1.75, 2, 2.5, 3, and 4 hours post-dose ± 5 minutes
• Days 1, 3 and 9: at 6, 8, 10 and 12 hours post-dose ± 10 minutes
• Days 2, 4, 10: at 24 hours post-dose ± 0.5 hour
Secondary outcome [1] 347917 0
The composite secondary outcome is to evaluate the effect of NPI-001 on potential biomarkers of the pharmacodynamic (PD) effect (protein carbonyls, GSH/GSSG, cysteine/cystine (Cys/Cys-Cys)).

Blood plasma samples for assessment of PD will be collected at appropriate time points during the study
Timepoint [1] 347917 0
Plasma samples for assessment of PD will be collected on Days 1 and 3 prior to dosing and 1 hour post-dose, and on Day 9 at 1 hour post-dose, and at the follow-up visit on Day 15

Eligibility
Key inclusion criteria
Subjects must satisfy all of the following criteria at the Screening Visit unless otherwise stated:
1. Males or females, of any race, between 18 and 60 years of age, inclusive.
2. Body mass index between 18.0 and 32.0 kg/m2, inclusive.
3. In good health, determined by no clinically significant findings from medical history, physical examination, 12-lead ECG, vital sign measurements, and clinical laboratory evaluations at Screening or Check-in as assessed by the Investigator (or designee).
4. Females will be nonpregnant and nonlactating, and females of childbearing potential and males will agree to use contraception.
5. Able to comprehend and willing to sign an informed consent form (ICF) and to abide by the study restrictions.
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Subjects will be excluded from the study if they satisfy any of the following criteria at the Screening visit, unless otherwise stated:
1. Significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as determined by the Investigator (or designee).
2. History of significant hypersensitivity to any drug compound, food, or other substance, unless approved by the Investigator (or designee).
3. History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs, including cholecystectomy (uncomplicated appendectomy and hernia repair will be allowed).
4. History of alcohol abuse or drug/chemical abuse per the Diagnostic and Statistical Manual of Mental Disorders-IV criteria within 2 years prior to Check in.
5. Alcohol consumption of >21 units per week for males and >14 units for females.
6. Positive urinary drug screen (confirmed by repeat, if necessary) at Screening (does not include alcohol) or Check in (does include alcohol breath test).
7. Liver function test values >1.5 upper limit of normal (ULN) (excluding isolated hyperbilirubinemia) or QTcF >450 milliseconds.
8. Positive hepatitis panel and/or positive human immunodeficiency test. Subjects whose results are compatible with prior immunization and not infection may be included at the discretion of the Investigator.
9. Participation in a clinical study involving administration of an investigational drug (new chemical entity) in the past 30 days or 5 half lives, whichever is longer, prior to Check in.
10. Use or intend to use any medications/products known to alter drug absorption, metabolism, or elimination processes, including St. John’s Wort, within 30 days or 5 half-lives (whichever is longer) prior to Check in, unless deemed acceptable by the Investigator (or designee).
11. Use or intend to use any prescription medications/products other than oral, implantable, transdermal, injectable, or intrauterine contraceptives, or hormone replacement therapy, within 14 days prior to Check in, unless deemed acceptable by the Investigator (or designee).
12. Use or intend to use any nonprescription medications/products (excluding paracetamol, which is allowed), vitamins, minerals, antioxidant supplements (e.g., acetylecysteine-related, cysteine-related or glutathione-related substances, etc.) and phytotherapeutic/herbal/plant derived preparations within 7 days prior to Check in, unless deemed acceptable by the Investigator (or designee).
13. Use of tobacco or nicotine containing products within 3 months prior to Check in and positive urine cotinine test at screening or check-in.
14. Receipt of blood products within 2 months prior to Check in.
15. Donation of blood from 30 days prior to Screening, plasma from 2 weeks prior to Screening, or platelets from 6 weeks prior to Screening.
16. Poor peripheral venous access.
17. Have previously completed or withdrawn from this study or any other study investigating NPI 001 or NACA, and have previously received the investigational product.
18. Subjects who, in the opinion of the Investigator and/or Sponsor (or designee), should not participate in this study.
19. An employee of the sponsor or research site personnel directly affiliated with this study or their immediate family members defined as a spouse, parent, sibling, or child, whether biological or legally adopted.

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)
Each patient dose will be prepared according to the schedule generated by CPR Pharma Services Pty Ltd and provided to a registered pharmacist from the Royal Adelaide Hospital, who does not otherwise participate in the collection of study data. Each dose container will be appropriately labeled with cohort and subject number. Doses will be administered by study staff at CMAX Clinical Research who are blinded to the treatment assignment of the subject.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomization schedule will be produced by CPR using a computer generated pseudo random permutation procedure provided to the registered pharmacist. Within each cohort, 6 subjects will be randomized to receive NPI 001, and 2 subjects will be randomized to receive placebo.
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
This will be a double-blind, placebo-controlled, crossover study.
The double-blind status of the study will be maintained by ensuring that:
• Placebo Tablets are identical in appearance to NPI-001 tablets, 250 mg
• Pharmacist (unblinded) will prepare doses in opaque, capped plastic bottles that are dispensed for dosing to blinded Study Staff and subjects.
• Investigator and other members of staff involved in the study will remain blinded to the randomized treatment.
• All doses will be administered under the supervision of suitably qualified study site staff
• Immediately after dose administration, visual inspection of the mouth and hands will be performed for each subject
• At each dosing occasion, a predose and postdose inventory of IMP and placebo will be performed on the dose containers.

The crossover component of the study will measure food effects on the PK of NPI-001 by having half the subjects receive first dose after fasting followed by second dose after a high fat meal and the other half of the subjects receiving first dose after a high fat meal and second dose after fasting.
On Day 1 and Day 3, each subject will receive a single oral dose of NPI-001 or Placebo. The dose levels of NPI-001 will be 1500 mg for Cohort 1 (6 tablets), and 750 mg for Cohort 2 (3 tablets). Dosing on Days 1 and 3 will be a placebo-controlled, balanced, two-treatment two-sequence randomized fasted/fed crossover design, as follows:
• 8 subjects in each cohort (6 NPI-001, 2 placebo) will be dosed on Day 1 following a 10 hour overnight fast and on Day 3 following a high fat breakfast [Fasted-Fed].
• 8 subjects in each cohort (6 NPI-001, 2 placebo) will be dosed on Day 1 following a high fat breakfast and on Day 3 following a 10 hour overnight fast [Fed-Fasted].
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
This study is not powered to test a statistical hypothesis. The goal is to have a minimum of 12 subjects complete the food-effect BA study as per U.S. FDA Guidance (Guidance for Industry, 2002).
Incidences of adverse events, mean changes in clinical laboratory tests and vital signs for NPI-001-treated subjects and placebo-treated subjects will be compared qualitatively.
Plasma concentrations and PK parameters of NPI-001 and NAC will be summarized using descriptive statistics. Pharmacokinetic parameters will be analysed using a general linear model to evaluate the food effect for each dose level.
Change from baseline in PD measures will be summarized using descriptive statistics.
The PK parameters of NPI-001 and NAC will be determined from plasma concentrations obtained on Days 1, 3 and 9. Pharmacokinetic calculations will be performed using standard noncompartmental methods, and commercial software such as Phoenix™ WinNonlin® Version 8.0 or higher (Certara USA, Inc.).

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
A business decision on where to formulate the tablet for human consumption is pending. . .
Date of first participant enrolment
Anticipated
16/07/2018
Actual
Date of last participant enrolment
Anticipated
20/08/2018
Actual
Date of last data collection
Anticipated
4/09/2018
Actual
Sample size
Target
32
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 11114 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 22927 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 299727 0
Commercial sector/Industry
Name [1] 299727 0
Nacuity Pharmaceuticals Inc
Country [1] 299727 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Nacuity Pharmaceuticals Pty Ltd
Address
58 Gipps Street, Collingwood,
VIC, 3066
AUSTRALIA
Country
Australia
Secondary sponsor category [1] 299075 0
None
Name [1] 299075 0
Address [1] 299075 0
Country [1] 299075 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 300617 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 300617 0
129 Glen Osmond Road Eastwood South Australia 5063
Ethics committee country [1] 300617 0
Australia
Date submitted for ethics approval [1] 300617 0
15/06/2018
Approval date [1] 300617 0
Ethics approval number [1] 300617 0

Summary
Brief summary
This study has its objectives:
To evaluate the safety and tolerability of multiple oral doses of NPI-001 Tablets in healthy adult subjects;
To evaluate the effect of food on the pharmacokinetics (PK) of NPI-001 following single doses, 1500 mg and 750 mg, in the fed versus fasted state;
To characterize the pharmacokinetics of NPI-001 following multiple doses over 5 days, fed;
To evaluate the effect of NPI-001 on potential biomarkers of the pharmacodynamic effect (protein carbonyls, GSH/GSSG, cysteine/cystine (Cys/Cys-Cys)).
Study design:
This randomized, double-blinded, cross-over study will include an evaluation of PK of NPI-001 in fed versus fasted healthy volunteers followed by a 5-day dosing period to ascertain if multiple doses of NPI-001 can alter GSH and CYS levels in plasma.
Potential subjects will be screened to assess their eligibility to enter the study within 28 days prior to first dose administration. Subjects will be resident in the clinical facility from the evening prior to first dose (Day -1) until discharge on Day 10. A post-dose follow up visit will occur at Day 15.
On Day 1 and Day 3, each subject will receive a single oral dose of NPI-001 or Placebo. The dose levels of NPI-001 will be 1500 mg for Cohort 1 (6 tablets), and 750 mg for Cohort 2 (3 tablets). Dosing on Days 1 and 3 will be a placebo-controlled, balanced, two-treatment two-sequence randomized fasted/fed crossover design, as follows:
• 8 subjects in each cohort (6 NPI-001, 2 placebo) will be dosed on Day 1 following a 10 hour overnight fast and on Day 3 following a high fat breakfast [Fasted-Fed].
• 8 subjects in each cohort (6 NPI-001, 2 placebo) will be dosed on Day 1 following a high fat breakfast and on Day 3 following a 10 hour overnight fast [Fed-Fasted].
On Days 5-9, all subjects will receive NPI-001 or placebo three times per day, at approximately 8am (following a standard breakfast), 2pm and 8pm, with the last dose on the morning of Day 9. The dose levels of NPI-001 will be 500 mg per dose for Cohort 1 (2 tablets), and 250 mg per dose for Cohort 2 (1 tablet).
Safety measures monitored throughout the study will include adverse events and use of concomitant medication, vital signs, and clinical laboratory tests.
Blood samples for assessment of PK will be collected on Days 1, 3 and 9, at pre-dose, then at 0.25, 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10 and 12 hours post-dose, and on Days 2, 4 and 10 at 24 hours post-dose.
Blood samples for assessment of PD will be collected on Days 1 and 3 at pre-dose and 1 hour post-dose, on Day 9 at 1 hour post-dose, and at the follow-up visit.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 84226 0
Prof Sepehr Shakib, MBBS, PhD FRACP
Address 84226 0
CMAX Clinical Research Pty Ltd
Level 5
18a North Terrace, Adelaide
South Australia 5000
Country 84226 0
Australia
Phone 84226 0
+61 8 8222 2763
Fax 84226 0
Email 84226 0
[email protected]
Contact person for public queries
Name 84227 0
Haydn Scott
Address 84227 0
Nacuity Pharmaceuticals, Pty Ltd
58 Gipps Street,
Collingwood, VIC, 3066
AUSTRALIA
Country 84227 0
Australia
Phone 84227 0
+61428904485
Fax 84227 0
Email 84227 0
[email protected]
Contact person for scientific queries
Name 84228 0
Haydn Scott
Address 84228 0
Nacuity Pharmaceuticals, Pty Ltd
58 Gipps Street,
Collingwood, VIC, 3066
AUSTRALIA
Country 84228 0
Australia
Phone 84228 0
+61428904485
Fax 84228 0
Email 84228 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
The clinical trial did not proceed.


What supporting documents are/will be available?

No Supporting Document Provided



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