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Trial registered on ANZCTR


Registration number
ACTRN12615000074594
Ethics application status
Approved
Date submitted
10/01/2015
Date registered
28/01/2015
Date last updated
10/08/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1, Randomised, Open-Label, Three-way Crossover Comparative Pharmacokinetic Study of Capsule and Tablet Dosage Forms of EMA401 Sodium Salt When Administered Orally in Healthy Adult Males
Scientific title
A Phase 1, Randomised, Open-Label, Three-way Crossover Comparative Pharmacokinetic Study of Capsule and Tablet Dosage Forms of EMA401 Sodium Salt When Administered Orally in Healthy Adult Males
Secondary ID [1] 285855 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neuropathic Pain 293768 0
Condition category
Condition code
Neurological 294071 294071 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The following formulations and dosage strengths of EMA401 Sodium Salt (EMA401-Na) will be administered orally as a single-dose to each subject in random order across three dosing periods;

300 mg (two 150 mg tablets) EMA401 tablet formulation.
100 mg (two 50 mg tablets) EMA401 tablet formulation.
300 mg (three 100 mg capsules) EMA401 capsule formulation.

On Days 1, 3 and 5, subjects will be randomly assigned in a 1:1:1 ratio to treatment with EMA401 300 mg (two 150 mg tablets), 100 mg (two 50 mg tablets), or 300 mg (three 100 mg capsules) and receive their dose of study medication. All subjects will receive all doses/formulations throughout the study in random order. There will be a minimum 48 hour wash-out between each treatment period. Subjects will be required to be in the fasted state, having no food or drink (apart from water) for the preceding 8 hours on each dosing day. Subjects will be allowed to drink water up to 1 hour prior to study medication administration.

There will be no dosing on Day 2, 4, and 6, however subjects are expected to remain confined to the unit and following procedures will be performed/documented.

Subjects will undergo an exit assessment on Day 7/Early Termination following collection of the 48 hour post-dose pharmacokinetic plasma sample following the last dosing occasion (Day 5).
Intervention code [1] 290836 0
Treatment: Drugs
Comparator / control treatment
To compare the relative exposure of a 300 mg dose in a tablet form to a 300 mg dose in a capsule form. The study design also allows an assessment of exposure and dose proportionality between 100 mg and 300 mg tablet doses.
Control group
Dose comparison

Outcomes
Primary outcome [1] 293856 0
To determine the comparative plasma pharmacokinetics of EMA401 after a single oral dose of capsule and tablet formulations of EMA401-Na.
Timepoint [1] 293856 0
In the first dosing period, blood samples for PK analysis will be taken from each subject at pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 8, 12, 24, 36 and 48 hours post-dose. The 48 hour post Day 1 dose sample will also act as the pre-dose Day 3 sample and then the same post-dose sampling schedule will be followed. The same approach and sampling schedule will be followed for the third and final dose on Day 5. Therefore, 46 blood samples will be collected from each subject; 1 pre-dose sample on Day 1 and 15 post-dose samples in each period.

The following plasma PK parameters will be determined, as data permit: Maximum plasma concentration (Cmax); Time to maximum plasma concentration (Tmax); Area under the plasma concentration curve from time 0 to the last timepoint (AUC0–t); Area under the plasma concentration curve from time 0 extrapolated to infinity (AUC0– ); Half-life (t 1/2).
Secondary outcome [1] 312009 0
Dose proportionality of the 100 mg tablet dose (2 x 50 mg tablets) with the 300 mg tablet dose (2 x 150 mg tablets).
Timepoint [1] 312009 0
In the first dosing period, blood samples for PK analysis will be taken from each subject at pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 8, 12, 24, 36 and 48 hours post-dose. The 48 hour post Day 1 dose sample will also act as the pre-dose Day 3 sample and then the same post-dose sampling schedule will be followed. The same approach and sampling schedule will be followed for the third and final dose on Day 5. Therefore, 46 blood samples will be collected from each subject; 1 pre-dose sample on Day 1 and 15 post-dose samples in each period.

The following plasma PK parameters will be determined, as data permit: Maximum plasma concentration (Cmax); Time to maximum plasma concentration (Tmax); Area under the plasma concentration curve from time 0 to the last timepoint (AUC0–t); Area under the plasma concentration curve from time 0 extrapolated to infinity (AUC0– ); Half-life (t 1/2).
Secondary outcome [2] 312104 0
The inter-subject variability in plasma pharmacokinetics of EMA401 after a single oral dose of capsule or tablet formulations of EMA401 Na.
Timepoint [2] 312104 0
In the first dosing period, blood samples for PK analysis will be taken from each subject at pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 8, 12, 24, 36 and 48 hours post-dose. The 48 hour post Day 1 dose sample will also act as the pre-dose Day 3 sample and then the same post-dose sampling schedule will be followed. The same approach and sampling schedule will be followed for the third and final dose on Day 5. Therefore, 46 blood samples will be collected from each subject; 1 pre-dose sample on Day 1 and 15 post-dose samples in each period.

The following plasma PK parameters will be determined, as data permit: Maximum plasma concentration (Cmax); Time to maximum plasma concentration (Tmax); Area under the plasma concentration curve from time 0 to the last timepoint (AUC0–t); Area under the plasma concentration curve from time 0 extrapolated to infinity (AUC0– ); Half-life (t 1/2).

Eligibility
Key inclusion criteria
Males between the ages of 18 and 55 years (inclusive); Healthy subjects, healthy subjects are defined as individuals who are free from clinically significant illness or disease as determined by their medical/surgical history, physical examination (including height and weight), 12-lead ECG and clinical laboratory determinations;
Systolic blood pressure between 100 mmHg and 140 mmHg and diastolic blood pressure between 60 mmHg and 90 mmHg (inclusive);
No clinically relevant abnormality in an ECG, QTcF (QTc Fridericia’s correction) 450 ms, PR interval of 120-220 ms and a QRS duration 120 ms (inclusive);
Resting pulse rate after being semi-supine for 5 minutes greater than 55 beats per minute (bpm) and less than 100 bpm;
Individuals who smoked less than 5 cigarettes or tobacco forms (including cigars) or less than the equivalent of 5 cigarettes in terms of nicotine replacement therapy (gum, patches, inhalers, lozenges, etc.) per month in the last 12 months;
Adequate venous access in the left or right arm to allow collection of a number of blood samples;
Body Mass Index (BMI) between 18.5 kg/m2 and 32.0 kg/m2 (inclusive);
Agrees to use approved methods of contraception from Screening and until 90 days after administration of the study drug. Approved methods of contraception for this study are either; subject vasectomy (at least six months prior to dosing), OR the use of a condom in combination with approved birth control pills, patches, implants or injections by the subject’s partner, use of diaphragm by the subject’s partner, use of an IUD (intra uterine device) by the subject’s partner or subject partner’s surgical sterilization. If the subject’s partner is pregnant, barrier contraception should be used to prevent potential exposure of the foetus to EMA401 in the ejaculate for the duration of the pregnancy;
Have given written informed consent to participate in this study in accordance with local regulations.
Minimum age
18 Years
Maximum age
55 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
Have received or is anticipated to receive a new prescription systemic or topical medication within 14 days prior to the start of dosing or an over-the-counter medicine 48 hours prior to the start of dosing;
Subjects receiving medications (within the last 7 days prior to Screening) that have the potential to prolong the QT interval or who may require such medications during the course of the study;
Any condition that would interfere with drug absorption (e.g. chronic diarrhoea);
Subjects with abnormal laboratory test results deemed clinically significant by the Medical Officer (Principal Investigator or medically qualified nominee) within 21 days before enrollment, including anaemia (hemoglobin less than 12.0 g/decilitre), total cholesterol (greater than 5.5 mmol/L which is equivalent to 212 mg/dL), neutropenia, thrombocytopenia, elevated liver function test results [alanine aminotransferase (ALT) and aspartate transaminase (AST)] above the upper limit of normal and, serum potassium or magnesium concentrations outside of the normal range;
Subjects with calcium concentrations greater than 10% outside of the normal range (this variation is to allow for artifactual results due to variations in sampling conditions);
Males known to have experienced elevated liver enzymes or altered white cell counts in any previous clinical study;
Evidence of significant renal insufficiency, as indicated by an estimated creatinine clearance using the Cockcroft-Gault formula of less than 75 mL/minute at Screening;
As a result of medical review, physical examination (including height and weight) or Screening investigations, the Medical Officer considers the subject unfit for the study;
Positive urine drug test or alcohol breath test;
Use of macrolide antibiotics (e.g. erythromycin), azole antifungal agents (e.g. ketoconazole) within 30 days of study dosing;
History or clinical evidence of oral, cardiovascular, cerebrovascular, haematological, gastrointestinal, hepatic, renal, endocrine, pulmonary, neurological, psychiatric or skin disorder;
History of epilepsy;
History or clinical evidence of significant cardiovascular disease including subjects with complete left bundle branch block (LBBB) ischaemic heart disease, peripheral vascular disease, uncontrolled hypertension and history of, or risk factors for, cardiac ventricular arrhythmias (e.g. personal history or family history of syncope, long QT syndrome or sudden death);
Acute therapy for a serious infection within 30 days of study entry;
History of significant drug allergies or significant allergic reaction or currently suffers from clinically significant systemic allergic disease;
Positive Screening test for Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody (HCV) or human immunodeficiency virus (HIV);
Have participated in a clinical trial or have received an experimental therapy within 30 days or 10 half-lives of the drug, whichever is the longer, prior to dosing;
Receipt of blood or blood products, or loss or donation of 450 mL or more of blood within 90 days before the first dose administration;
Males who regularly drink more than four (4) units of alcohol daily (1 unit = 300 mL beer, 1 glass of wine, 1 measure spirit);
Males who are unwilling to abide by study restrictions to be listed in the full protocol. These will include dietary restrictions (certain citrus fruits restriction 14 days prior to admission, caffeine/related products and alcohol restrictions 48 hours prior to admission), willingness to fast for a minimum 8 hours prior to each dose until 2 hours post-dose, fluid restriction (except for water given with dosing, no fluid intake from at least 1 hour prior to each dose until 1 hour post-dose);
Any subject who has previously enrolled in this or any clinical trial of EMA401.

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)
Potential subjects will be assigned a unique identification number (Screening Number) as they are screened for the study. All volunteers who sign an informed consent at Screening will receive a three-digit sequential number starting at S001.

As this is an open-label study, allocation is not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Subjects will be allocated to a sequentially numbered treatment in accordance with the randomization schedule following confirmation of eligibility on Day 1. The randomization number will be in the form of a three digit number, R0XX, where XX is a sequential number 01-15, i.e. R001 – R015.

Randomization is produced by computer software.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
None
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Pharmacokinetic Analyses
Individual plasma concentrations and blood collection times will be listed by subject. Summaries of concentration data by treatment will include mean, standard deviation and coefficient of variation at each scheduled collection time.

Noncompartmental pharmacokinetic parameters for each subject will be calculated using Phoenix WinNonlin 6.3 or later. Values reported as below the limit of quantitation will be assumed to be 0 ng/mL for the calculations. The following parameters will be calculated; Maximum observed concentration (Cmax), time of maximum observed concentration (Tmax), area under plasma concentration time curve from 0 hours to the time of the last measurable concentration above the lower limit of quantitation (AUC0–t), area under plasma concentration time curve from 0 hours to infinity (AUC0-8), the percent of the AUC0-8 value that was extrapolated from AUC0-t (%AUCextrap), the terminal elimination rate constant (kel; also termed lambda-z by WinNonlin),
the terminal elimination half-life (t 1/2), dose-normalised Cmax (NCmax), dose-normalised AUC0-t (NAUC0-t), dose-normalised AUC0-8 (NAUC0-8).

For each drug treatment, descriptive statistics will be calculated for each parameter except %AUCextrap. The statistics will include mean, standard deviation, coefficient of variation, geometric mean (except for Tmax), median, minimum, maximum, and number of observations.
Log-transformed Cmax, AUC0–t, and AUC0–8 will each be fit by a mixed model ANOVA with factors for treatment sequence, period, and treatment (fixed effects) and subject within treatment sequence (random effect). The treatment contrast of 300 mg dose tablet versus 300 mg dose capsule will be evaluated. Treatment mean differences and 90% confidence intervals for each difference will be estimated. Treatment mean differences and confidence intervals of the log transformed PK parameters will be back-transformed and expressed as percent relative bioavailability ratios. A similar approach for a treatment contrast of 100 mg dose tablet versus 300 mg dose tablet will be conducted using NCmax, NAUC0–t, and NAUC0–8.

Safety Analyses
All clinical safety and tolerability data will be listed for each subject. Treatment-emergent adverse events, following the first investigational product dosing, will be listed and summarised by treatment. All AEs reported in this study will be coded using MedDRA (Medical Dictionary for Regulatory Activities). Relationship to study medication will be classified as related (probably related’ and ‘possibly related’) and unrelated (‘not related’). Severity will be classified as ‘mild’, ‘moderate’ and ‘severe’. Serious AEs and AEs leading to discontinuation will be summarised by body system and preferred term.

Vital sign and ECG parameters will be summarised by treatment. Laboratory values will be listed, along with comments as to clinical significance for values outside the laboratory’s normal ranges.

A sample size of 15 healthy male subjects has been chosen as a reasonable sample size for an estimate of the relative bioavailability of EMA401 when 3 different dosage forms of EMA401-Na are each given orally as a single oral dose in a fasted state.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
16/02/2015
Actual
15/02/2015
Date of last participant enrolment
Anticipated
16/02/2015
Actual
23/02/2015
Date of last data collection
Anticipated
Actual
Sample size
Target
15
Accrual to date
Final
15
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 3270 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 9059 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 290428 0
Commercial sector/Industry
Name [1] 290428 0
Spinifex Pharmaceuticals Pty Ltd
Country [1] 290428 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Spinifex Pharmaceuticals Pty Ltd
Address
Corporate One, Suite G5, 84 Hotham St, Preston, VIC, 3072
Country
Australia
Secondary sponsor category [1] 289140 0
Commercial sector/Industry
Name [1] 289140 0
Spinifex Pharmaceuticals, Inc
Address [1] 289140 0
100 First Stamford Place, 6th Floor, Suite 606, Stamford, Connecticut, 06902
Country [1] 289140 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292110 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 292110 0
Ethics committee country [1] 292110 0
Australia
Date submitted for ethics approval [1] 292110 0
Approval date [1] 292110 0
08/01/2015
Ethics approval number [1] 292110 0

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

Contacts
Principal investigator
Name 53570 0
Dr Sepehr Shakib
Address 53570 0
Department of Clinical Pharmacology, Mail Delivery Point 22, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, 5000
Country 53570 0
Australia
Phone 53570 0
+61 8 8222 2763
Fax 53570 0
Email 53570 0
sepehr.shakib@health.sa.gov.au
Contact person for public queries
Name 53571 0
Tom McCarthy
Address 53571 0
Spinifex Pharmaceuticals Pty Ltd, Corporate One, Suite G5, 84 Hotham St, Preston, VIC, 3072
Country 53571 0
Australia
Phone 53571 0
+61 3 9863 6820
Fax 53571 0
Email 53571 0
tom.mccarthy@spinifexpharma.com
Contact person for scientific queries
Name 53572 0
Geoff Kitson
Address 53572 0
Spinifex Pharmaceuticals, Inc., 100 First Stamford Place, 6th Floor, Suite 606, Stamford, Connecticut, 06902
Country 53572 0
United States of America
Phone 53572 0
+1 203 989 2100
Fax 53572 0
Email 53572 0
gkitson@propharmapartners.uk.com

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