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Trial registered on ANZCTR


Registration number
ACTRN12617000911392
Ethics application status
Approved
Date submitted
16/06/2017
Date registered
21/06/2017
Date last updated
9/04/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A study of a new drug, NPI-001 in healthy volunteers to test its safety and tolerability
Scientific title
A Phase I, Randomized, Double blinded, Adaptive, Single and Multiple Ascending Dose Study of the Safety and Tolerability of NPI 001 Solution in Healthy Subjects
Secondary ID [1] 292211 0
Nacuity Pharmaceuticals Pty Ltd: CL-17-01
Secondary ID [2] 292212 0
CMAX: 6517
Universal Trial Number (UTN)
U1111-1198-0239
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Retinitis pigmentosa (RP) 303702 0
Condition category
Condition code
Eye 303074 303074 0 0
Diseases / disorders of the eye

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This randomized, double blinded study will be comprised of Part A, a single ascending dose evaluation, and Part B, a multiple ascending dose evaluation, in healthy volunteers. In each cohort of Part A, 4 subjects will receive a single oral dose of NPI-001 (250, 750, 1500, 3000 or 4000 mg) and 2 subjects will receive the vehicle placebo in the fasting state. Subjects will be evaluated in the clinic overnight and will have a follow up visit at Day 7. One cohort in Part A, Cohort A3 (1500 mg NPI-001), will also receive the same dose after a high fat meal to evaluate the effect of food. Subjects in Cohort A3 (food-effect evaluation) will participate in 2 treatment periods separated by a 7-day (minimum) wash-out period, and will receive 2 single doses of NPI-001 or placebo. The wash-out period may be extended following review of the PK data to ensure that at least 7 half-lives have elapsed.
The high fat meal will be given as a high fat breakfast: 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. The drug product will be administered approximately 30 minutes after starting the meal and at least 80% of the meal should be finished promptly.
In Part B, 6 subjects will receive oral doses of NPI-001, and 2 subjects will receive the vehicle placebo, for 14 days while in the clinic. A postdose follow up visit will occur at Day 21. The doses and dose regimen will be determined based on the data obtained during Part A, but doses will not exceed a total daily dose of 4000 mg. Blood samples for pharmacokinetic and pharmacodynamic measurements will be collected at various time points in both parts of the study.
Intervention code [1] 298367 0
Treatment: Drugs
Comparator / control treatment
OraSweet® vehicle placebo. (Ora-Sweet is a commercially available syrup vehicle containing water, sucrose, glycerin, sorbitol, flavoring, buffering agents (citric acid and/or sodium phosphate), methyl paraben and potassium sorbate, pH 4.2 manufactured by Paddock Laboratories, Inc., Minneapolis, Minnesota) USA.
Control group
Placebo

Outcomes
Primary outcome [1] 302454 0
Safety: Adverse events. Adverse events are expected to be similar to those of the approved drug N acetylcysteine (NAC). These are: listed as: stomatitis, nausea, vomiting, rhinorrhea, drowsiness, clamminess, chest tightness and bronchoconstriction. Rare hypersensitivity reactions have been reported, including urticaria, dyspnea, bronchospasm and anaphylactic/anaphylactoid reactions, fever, headache, drowsiness, low blood pressure, and liver function changes. In a recent high dose study of NAC diarrhea, flatulence, nausea, upper abdominal pain, abdominal discomfort, vomiting, dysgeusia, dizziness, headache, convulsion, and syncope were reported.

All AEs, whether volunteered, elicited, or noted on physical examination, will be recorded from the first dose of study drug until study completion. AE information will also be collected from the start of the wash-out period between fasting and fed dosing for Cohort A3 and will be recorded as interim medical history for the second period. The nature, time of onset, duration, and severity will be documented, together with an Investigator’s (or designee’s) opinion of the relationship to drug administration.
Adverse events will be assessed by a range of tools and tests. These include:
a) Vital signs:
Semi-supine blood pressure, pulse rate, and tympanic body temperature will be assessed regularly throughout the study period. Vital signs may also be performed at other times if judged to be clinically appropriate or if the ongoing review of the data suggests a more detailed assessment of vital signs is required. All measurements will be performed singly, and repeated once if outside the relevant clinical reference range.
b) Clinical Laboratory Evaluations: Blood and urine samples will be collected for clinical laboratory evaluations (including clinical chemistry, hematology, urinalysis, and serology) at regular intervals throughout the study. Subjects will also be asked to provide urine samples for a drugs of abuse screen and cotinine tests, and take an alcohol breath test at nominated study times. For all female subjects, a serum pregnancy test will be performed at nominated times. Additionally, for women considered to be postmenopausal, FSH will be analyzed at Screening. An Investigator (or designee) will perform a clinical assessment of all clinical laboratory data.
c) 12 Lead Electrocardiogram:
Resting 12 lead ECGs will be recorded after the subject has been semi-supine and at rest for at least 5 minutes at nominated times.
Single 12 lead ECGs will be repeated once if either of the following criteria apply:
• QT interval corrected for heart rate using Fridericia’s method (QTcF) >450 msec
• QTcF change from the baseline (predose) is >60 msec.
Additional 12 lead ECGs may be performed at other times if judged to be clinically appropriate or if the ongoing review of the data suggests a more detailed assessment of ECGs is required. The Investigator (or designee) will perform a clinical assessment of each 12 lead ECG.
d) Physical Examination: A full physical examination will be performed at Screening, Day -1 and at other time points where indicated by symptoms.
The date of the physical examination will be recorded and any clinically significant findings will be recorded as AEs.



Timepoint [1] 302454 0
7 days after dose for Part A subjects and 21 days after first dose for Part B subjects
Primary outcome [2] 302456 0
Clinical laboratory findings: A full range of standard tests for clinical chemistry, haematology, urinalysis, serology and urinary drug screens will be conducted In addition a urine test for cotinine and an alcohol breath test will be conducted. Female subjects only will have Follicle stimulating hormone (postmenopausal females only) and a
Serum pregnancy test (human chorionic gonadotropin)
Timepoint [2] 302456 0
At screening and 7 days post dose for Part A subjects and 21 days post first dose for Part B subjects.
Primary outcome [3] 302457 0
Vital signs: blood pressure, pulse rate, body temperature, 12- lead ECG and physical examination, This a composite primary outcome.
Timepoint [3] 302457 0
Screening, nominated times during the study and 7 days post dose for Part A subjects and 21 days post first dose for Part B subjects
Secondary outcome [1] 336066 0
Pharmacokinetics: Standard pharmacokinetic parameters will be calculated for NPI-001-treated subjects. (Levels of a metabolite of NPI 001 will be determined for NPI-001- and placebo-treated subjects.) The parameters to be measured are: AUC0-24 Area under the plasma concentration-time curve from time 0 to 24 hours postdose AUC0 8 Area under the plasma concentration time curve from time 0 extrapolated to infinity AUC0 t last Area under the plasma concentration time curve from time 0 to the last measurable concentration AUC0 t Area under the plasma concentration time curve during 1 dosing interval (Part B only) Cavg Average plasma concentration (Part B only) Cmax Maximum observed plasma concentration Ctrough Trough concentration CL/F Apparent oral clearance (Lambda) z Elimination rate constant MRT Mean residence time RAAUC Accumulation ratio (Part B only) tmax Time to maximum observed plasma concentration t1/2 Apparent terminal elimination half life Vz/F Apparent volume of distribution
Timepoint [1] 336066 0
Blood sampling for pharmacokinetic analysis:
For part A subjects: Day 1: predose , 15 minutes and 30 minutes, and 1, 1.5, 2, 3, 4, 5, 6, 8, 12 hours postdose
Day 2: 24 hours postdose
For Part B subjects: Day 1: predose, 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 5, 6, 8, 12 hours postdose
Day 2 and Day 15: 24 hours postdose

Secondary outcome [2] 336067 0
Pharmacodynamics: The effect of NPI-001 on the mean changes in levels of protein carbonyls and the GSH/GSSG ratio will be determined.
Timepoint [2] 336067 0
Blood sampling for analysis of protein carbonyl content and GSH:GSSH ratio
Part A subjects:
Day 1: predose and 4 hours postdose
Part B Subjects:
Day 1: predose (within 1 hour of dosing) and 4 hours (±5 minutes) postdose
Day 15: 24 hours post dose ± 30 minutes

Eligibility
Key inclusion criteria
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
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
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 immediate 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 (uncomplicated appendectomy and hernia repair will be allowed).
4. History of alcohol abuse or drug/chemical abuse 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, 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, 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)
Numbered containers will be prepared by the Royal Adelaide Hospital Pharmacy as assigned by a computer generated randomization list.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software i.e. computerised sequence generation.
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
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
This study is not powered to test a statistical hypothesis.
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.

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)
SA
Recruitment hospital [1] 8382 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 16451 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 296752 0
Commercial sector/Industry
Name [1] 296752 0
Nacuity Pharmaceuticals Inc
Address [1] 296752 0
Nacuity Pharmaceuticals Inc
Fort Worth Club Building
306 W. 7th Street, Suite 310
Fort Worth,
Texas 76102

Country [1] 296752 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Nacuity Pharmaceuticals Pty Ltd
Address
Nacuity Pharmaceuticals, Pty Ltd
58 Gipps Street,
Collingwood, VIC, 3066
AUSTRALIA
ABN - 63 619 122 744
Country
Australia
Secondary sponsor category [1] 295726 0
None
Name [1] 295726 0
Address [1] 295726 0
Country [1] 295726 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297976 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 297976 0
Bellberry Ltd
129 Glen Osmond Road,
Eastwood,
South Australia, 5063
Ethics committee country [1] 297976 0
Australia
Date submitted for ethics approval [1] 297976 0
07/06/2017
Approval date [1] 297976 0
24/07/2017
Ethics approval number [1] 297976 0
Bellberry Application No: 2017-05-368

Summary
Brief summary
This trial is being undertaken to evaluate the safety and tolerability of oral doses of a new drug NPI-001 in healthy volunteer subjects. It will determine the effect of NPI-001 on their vital signs, and they will undergo physical examinations and clinical laboratory tests. Blood samples will be taken to determine where the drug goes in the body and how long it stays in the body following single and multiple doses.
The study is randomized, and double blinded. In each group of subjects some will receive the new drug in a sugar solution and 2 will receive just the sugar solution - a placebo.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 75642 0
Prof Sepehr Shakib, MBBS, PhD
Address 75642 0
CMAX Clinical Research Pty Ltd
Level 5, 18a North Terrace,
Adelaide SA 5000
Country 75642 0
Australia
Phone 75642 0
+61411100278
Fax 75642 0
Email 75642 0
sepehr.shakib@sa.gov.au
Contact person for public queries
Name 75643 0
Ms Sheryl Harradine
Address 75643 0
CMAX Clinical Research Pty Ltd
Level 5, 18a North Terrace,
Adelaide SA 5000
Country 75643 0
Australia
Phone 75643 0
+61870887940
Fax 75643 0
Email 75643 0
Sheryl.Harradine@cmax.com.au
Contact person for scientific queries
Name 75644 0
Dr Haydn Scott
Address 75644 0
Nacuity Pharmaceuticals Pty Ltd
58 Gipps St
Collingwood
Vic 3066
Country 75644 0
Australia
Phone 75644 0
+61428904485
Fax 75644 0
Email 75644 0
hvs195@gmail.com

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