Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12614000802606
Ethics application status
Approved
Date submitted
17/07/2014
Date registered
29/07/2014
Date last updated
19/10/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1, Adaptive, Single and Multiple Ascending Dose Study of EMA401 Sodium Salt Administered Orally in Healthy, Adult Males to Determine the Maximum Tolerated Dose and Pharmacokinetic Profiles
Scientific title
A Phase 1, Adaptive, Single and Multiple Ascending Dose Study of EMA401 Sodium Salt Administered Orally in Healthy, Adult Males to Determine the Maximum Tolerated Dose and Pharmacokinetic Profiles
Secondary ID [1] 284929 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neuropathic Pain 292403 0
Condition category
Condition code
Neurological 292722 292722 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Single Ascending Dose component: Up to four EMA401 dose levels are planned. The starting dose level will be 800 mg with provision to escalate up to 2,000 mg, subject to Safety Review Committee assessment of the safety, tolerability and EMA401 pharmacokinetic data following completion of each dose level. Final dose levels beyond the starting dose will be selected by the Safety Review Committee. EMA401 capsules will be administered orally as a single dose in the fasted state with at least 250 mL of non-carbonated water.

Multiple Ascending Dose component: EMA401 capsules will be administered orally, twice daily with a 10 hour interval between doses for 7 consecutive days (Days 2-8) with at least 250 mL of non-carbonated water. On Day 1 a single morning dose only will be administered. On Days 2-8 dosing will occur each day at approximately 8am and 6pm in the fasted state and at least 2 hours prior to the evening meal, respectively. On Day 9 a single, final dose will be administered in the morning. Up to three dose levels of EMA401, starting at a dose level of 200 mg twice daily up to a maximum of 1,000 mg twice daily (total 2,000 mg daily dose), will be selected based on the Safety Review Committee review of the safety, tolerability and EMA401 pharmacokinetic data from the Single Ascending Dose and previous dose levels from the Multiple Ascending Dose components of the study. For this adaptive study, the Multiple Ascending Dose component of the study may be permitted to start dosing a cohort at the lowest dose while the Single Ascending Dose component proceeds with dosing at a higher dose level, with such a decision based on the Safety Review Committee review of the safety data from at least the first dose level of the Single Ascending Dose component study.

The patient's ingestion of Investigational Product will be observed in the study clinic by study staff.
Intervention code [1] 289754 0
Treatment: Drugs
Comparator / control treatment
a) Placebo use is a capsule containing Colloidal Silicon Dioxide, Microcrystalline Cellulose, and Magnesium Stearate.

b) During the SAD portion of the study, placebo is administered one time on Day 1.
During the MAD portion of the study, placebo is administered once a day on Days 1 and 9, and twice daily on Days 2 - 8.
Control group
Placebo

Outcomes
Primary outcome [1] 292565 0
Safety and tolerability assessed for each dose level following single and multiple doses of EMA401.
Timepoint [1] 292565 0
Incidence of adverse events for both the Single Ascending Dose and Multiple Ascending Dose components of the study will be recorded between time of consent and the study exit evaluation/follow-up visit [Single Ascending Dose (Day 8), Multiple Ascending Dose (Day 16)].

During both the Single Ascending Dose and Multiple Ascending Dose study components, the EMA401 concentration data determined from analysis of the blood samples collected at specified intervals pre- and post-dose during each component will be reviewed for dose escalation decisions as well as safety.

Single Ascending Dose component:

Physical examination at Screening, Day -1, Day 3 and Day 8.

Twelve lead ECG readings (5 minutes ECG data collection at pre dose and up to 5 minutes ECG data collection at each subsequent time point) will be obtained at Screening, Day -1 and on Day 1 immediately pre-dose and at 0.5, 1, 2, 4, and 8 hours post-dose, Days 2 and 3 (24 and 48 hours post-dose respectively), and on Day 8.

Vital signs will be assessed and recorded at Screening, Day -1, within the hour prior to dose administration on Day 1 and at approximately 1, 2, 4, 8 and 12 hours post-dose and, on Days 2, 3 and 8.

Blood samples for biochemistry, haematology and coagulation will be taken at Screening, Day -1, Day 2 (24 hours post-dose), Day 3 (discharge from unit) and Day 8.

Urine samples for urinalysis will be taken at Screening, Day -1, Day 2 (24 hours post-dose) and Day 8.

Multiple Ascending Dose component:

Physical examination at Screening, Day -1, Day 11 (discharge from unit) and on Day 16.

Twelve lead ECG readings (in triplicate) will be performed atScreening and Day -1; Day 1 at pre-dose and at 0.5, 1, 2, 4 and 8 hours following the single (morning) dose; Days 2 and 8 at pre-dose and at 0.5, 1, 2, 4 and 8 hours following the morning dose and at 0.5, 1, 2, 4 and 6 hours following the evening dose; Days 3-7 at pre-dose and at 1 hour (or at approximately the time considered to be the likely Tmax) following the morning dose; Day 9 at pre-dose and at 0.5, 1, 2, 4 and 8 hours following the single, final (morning) dose; Days 10 and 11 at 24 and 48 hours post the last dose, respectively and Day 16.

Vital signs to be performed immediately prior to ECG readings on Screening and Day -1; Day 1 within the hour prior to dose administration and at approximately 1, 2, 4, 8 and 12 hours following the single (morning) dose; Days 2 and 8 at pre-dose and at approximately 1, 2, 4 and 8 hours following the morning dose and at pre-dose and approximately 1, 2, 4 and 6 hours following the evening dose; Days 3-7 at pre-dose and at 1 hour (or at approximately the time considered to be the likely Tmax) following the morning dose and pre-dose and at 4 hours following the evening dose; Day 9 at pre-dose and at 1, 2, 4, 8 and 12 hours following the single, final (morning) dose; Days 10 and 11 (at 24 and 48 hours post the last dose respectively) and Day 16.

Blood samples for biochemistry and haematology assessment will be taken at Screening, Day -1, Day 3, Day 6, Day 9, Day 11 (discharge from unit) and Day 16.

Blood samples for coagulation assessment will be taken at Screening, Day -1, Day 3, Day 9, Day 11 (discharge from unit) and Day 16.

Urine samples for urinalysis will be taken at Screening, Day -1, Day 3, Day 9, Day 11 (discharge from unit) and Day 16.
Secondary outcome [1] 309248 0
To determine the plasma pharmacokinetics of EMA401 following single and multiple escalating doses, administered orally (up to 2,000 mg/day) in healthy adult male subjects.
Timepoint [1] 309248 0
Single Ascending Dose component: Plasma pharmacokinetic parameters (Cmax, Tmax, AUC0-t, AUC0–24 and if reliable, kel, t1/2, AUC0-8, CL/F and Vz/F) of EMA401 will be determined following oral administration of a single dose at up to 4 dose levels.

Multiple Ascending Dose component:

Plasma pharmacokinetic parameters (Cmax, Tmax, Cmin, Tmin, AUC0-10, and AUC0-24 for Days 1, 2, 8 and 9 and if reliable, kel and t1/2, plus AUC0-t for Day 9) of EMA401 following oral administration of multiple doses will be determined for each dose level. Time to steady state will also be determined.

Plasma concentrations and pharmacokinetic parameters for EMA401 metabolites will be determined, where possible, following single and multiple doses of EMA401 for each dose level.

Eligibility
Key inclusion criteria
Male and aged between 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; Normotensive blood pressure (systolic blood pressure between 100 mmHg and 160 mmHg inclusive and diastolic blood pressure between 60 mmHg and 95 mmHg inclusive); No clinically relevant abnormality in an ECG; QTcF (QTc Fridericia’s correction) less than or equal to 450 ms, PR interval of 120-220 ms and a QRS duration less than or equal to 120 ms; Resting pulse rate after sitting for 5 minutes greater than 45 bpm (beats per minute) and less than 100 bpm; Individuals who smoked less than 5 cigarettes or tobacco forms (including cigars) 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 two approved methods of contraception from Screening and until 90 days after administration of the study drug. Agreed methods of contraception may include condom, use of 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 and/or surgical sterilization (vasectomy at least six months prior to dosing). If the subject’s partner is pregnant barrier contraception should be used to prevent potential exposure of the foetus to EMA401 in the ejaculate; 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 enrolment, including anaemia (haemoglobin less than 11.0 g/decilitre), neutropenia, thrombocytopenia, elevated liver function test results (AST and ALT) 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/min 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 or Hepatitis C antibody or HIV (human immunodeficiency virus); 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 is equal to 300 mL beer, 1 glass wine, 1 measure spirit); Males who are unwilling to abide by the study restrictions listed in Section 8.3; Any subject who has previously enrolled in this or any clinical trial of EMA401; Any subject that would have difficulty swallowing multiple (up to 20) capsules of the study drug.

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 for the Single Ascending Dose cohorts and E001 for the Multiple Ascending Dose cohorts.

Subjects will be allocated to a sequentially numbered treatment in accordance with the randomisation schedule following confirmation of eligibility on Day 1. The randomisation number for the Single Ascending Dose cohorts will be in the form of a four digit number, Rcrnn, where c is the cohort number, r is a replacement indicator, and nn is the subject-within-cohort randomisation number e.g. for Cohort 1 the subjects would be allocated R1001 – R1012, Cohort 2 would be allocated R2001 – R2012, as so on. If a subject is replaced within a cohort, the second digit is incremented by one, and the same treatment is administered to the replacement subject as was administered to the original subject e.g. R1006 is replaced by R1106, and receives the treatment originally allocated for R1006. Each subject will be assigned to either active EMA401 or placebo. The allocation of active treatment or placebo will be performed using a block randomisation algorithm.

For the Multiple Ascending Dose cohorts, the randomisation will be of a similar form, using M rather than R as the initial character.

The randomisation schedules will be maintained under controlled access. The personnel involved in the dispensing of IP will be accountable for ensuring compliance to randomisation schedules. The analyst concerned will not have access to the randomisation schedules during the course of analysis.

In the event that the Investigator considers an AE to be of such severity as to require specific knowledge of the identity and dose of the relevant product, the Investigator may break the study code for that subject only. A record of breaking the blind will be recorded in the eCRF. The study medical monitor should be informed promptly.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A statistician not involved in the conduct of the study will generate a randomization code list for each cohort and supply this to the pharmacy who will prepare doses for each individual subject.
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
Demographics and baseline characteristics will be tabulated and summarised by dose. Physical examination and medical/surgical history data will be listed.
All clinical safety and tolerability data will be listed for each subject and, tabulated and summarised by dose. Vital signs and ECG parameters will be listed and, tabulated and summarised by dose. Laboratory values will be listed, along with comments as to clinical significance for values outside the laboratory’s normal ranges and, tabulated and summarised by dose level.

Treatment-emergent adverse events, following the investigational product dosing, will be listed and, tabulated and summarised by dose. All adverse events reported in this study will be coded using the latest version of MedDRA (Medical Dictionary for Regulatory Activities).

Individual plasma concentrations and blood collection times will be listed by subject. Summaries of concentration data will include mean, standard deviation and coefficient of variation by dose level and dose day at each scheduled collection time.

Pharmacokinetic parameters (Single Ascending Dose component): At a minimum, Cmax, Tmax, AUC0-t and AUC0–24 will be calculated. If reliable, values for kel, t1/2, AUC0-8, CL/F and Vz/F would be calculated.

Pharmacokinetic parameters (Multiple Ascending Dose component): Cmax, Tmax, Cmin, Tmin, AUC0-10, and AUC0-24 would be calculated for Days 1, 2, 8 and 9. If reliable, kel, t1/2, and AUC0-t would be calculated for Day 9.

Summaries of pharmacokinetic parameters will include mean, standard deviation and coefficient of variation, median, minimum and maximum by dose level and dose day.

No sample size calculation has been conducted for this study.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
17/07/2014
Actual
31/07/2014
Date of last participant enrolment
Anticipated
23/12/2014
Actual
9/10/2014
Date of last data collection
Anticipated
Actual
Sample size
Target
84
Accrual to date
Final
84
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 2707 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 8419 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 289558 0
Commercial sector/Industry
Name [1] 289558 0
Spinifex Pharmaceuticals Pty Ltd
Country [1] 289558 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Spinifex Pharmaceuticals Pty Ltd
Address
Corporate One, Suite G5, 84 Hotham St, Preston, VIC, 3072
Spinifex Pharmaceuticals Pty Ltd

Tom McCarthy, PhD, CEO
Country
Australia
Secondary sponsor category [1] 288240 0
Commercial sector/Industry
Name [1] 288240 0
Spinifex Pharmaceuticals, Inc
Address [1] 288240 0
100 First Stamford Place
6th Floor, Suite 606
Stamford
Connecticut, 06902

Ronald Marcus, MD, Chief Medical Officer
Country [1] 288240 0
United States of America
Secondary sponsor category [2] 289649 0
Commercial sector/Industry
Name [2] 289649 0
Spinifex Pharmaceuticals, Inc.
Address [2] 289649 0
100 First Stamford Place 6th Floor, Suite 606 Stamford Connecticut, 06902 Geoff Kitson, MD, Medical Monitor (Consultant)
Country [2] 289649 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291297 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 291297 0
129 Glen Osmond Rd, Eastwood, SA, 5063
Ethics committee country [1] 291297 0
Australia
Date submitted for ethics approval [1] 291297 0
14/07/2014
Approval date [1] 291297 0
16/07/2014
Ethics approval number [1] 291297 0
2014-05-288-A-1

Summary
Brief summary
This integrated, adaptive, single and multiple dose study is designed to determine the maximum tolerated dose as assessed by safety and tolerability and to determine the plasma pharmacokinetics of EMA401 following single and multiple escalating doses, administered orally (up to 2,000 mg/day) in healthy adult male subjects.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 49742 0
Dr Sepehr Shakib
Address 49742 0
Department of Clinical Pharmacology, Mail Delivery Point 22, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, 5000
Country 49742 0
Australia
Phone 49742 0
+61 8 8222 2763
Fax 49742 0
Email 49742 0
[email protected]
Contact person for public queries
Name 49743 0
Dr Tom McCarthy
Address 49743 0
Spinifex Pharmaceuticals Pty Ltd
Corporate One, Suite G5, 84 Hotham St, Preston, Victoria, 3072
Country 49743 0
Australia
Phone 49743 0
+61 3 9863 6820
Fax 49743 0
Email 49743 0
[email protected]
Contact person for scientific queries
Name 49744 0
Dr Geoff Kitson
Address 49744 0
Spinifex Pharmaceuticals, Inc.
100 First Stamford Place, 6th Floor, Suite 606, Stamford, Connecticut, 06902
Country 49744 0
United States of America
Phone 49744 0
+1 903 989 2100
Fax 49744 0
Email 49744 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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