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Trial registered on ANZCTR


Registration number
ACTRN12613000409774
Ethics application status
Approved
Date submitted
5/04/2013
Date registered
15/04/2013
Date last updated
15/04/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
A trial examining the bioavailability of 4 doses of 3 different formulations of Afuresertib - a Gelatin Formulation and Two Prototype Formulations of Afuresertib, in Normal Healthy Volunteers in both the fasted and non-fasted states .
Scientific title
A Single Center, Randomized, Open-Label, Sequential, Single Dose, 4-Period Crossover Study to Evaluate the Bioavailability and Food Effect of a Gelatin Formulation and Two Prototype Formulations of Afuresertib, an AKT Inhibitor, in Normal Healthy Volunteers.
Secondary ID [1] 282253 0
NIL
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Oncology (general Cancer). Previous research with this agent has been conducted in Multiple Myeloma. Hodgkins Disease, non-Hodgkin's Lymphoma, Chronic Lymphocytic Leukemia and Langerhans Cell Histiocytosis 288777 0
Condition category
Condition code
Cancer 289129 289129 0 0
Leukaemia - Chronic leukaemia
Cancer 289130 289130 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Cancer 289131 289131 0 0
Myeloma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
There are 3 separate drug forumlations in this study:

Afuresertib Forumulation/treatment No1 - Gelatin Capsule - 25mg adminstered per single dose.
Afuresertib Forumulation/treatment No2 - Enteric Coated Tablet - 25mg adminstered per single dose.
Afuresertib Forumulation/treatment No3 - HMPC Capsule (Hydroxypropyl Methylcellulose or 'Hypromellose' capsule)- 25mg adminstered per single dose.

Each of these are further divided into Fasted and Non-Fasted states (providing a total of 6 possible study treatments). The definitions of these states are provided herewith:

Subjects Dosed in the Fasted State:
* Subjects must fast from all food and drink (except water) for at least 10 hours prior to dosing on Day 1 and will continue fasting for at least 4 hours after dosing.
* Each dose of study drug will be administered with 240 mL of water while the subject is standing. All of the water must be completely consumed within 1 minute. Subjects may sit upright, but must not lie down for at least 30 minutes after study drug administration.

Subjects Dosed in the Fed State:
* Subjects must fast from all food and drink (except water) for at least 10 hours prior to breakfast on Day 1 and will continue fasting for at least 4 hours after dosing.
* On Day 1, all breakfast meals will be identical for all Dosing Periods and Subjects and will be served at approximately 30 minutes prior to dosing.
* On Day 1, breakfast must be completely consumed within 20 minutes, and the start and stop time of the meal and any food items not consumed will be recorded.
* Dosing must occur within 10 minutes of completing consumption of the breakfast.
* Each dose of study drug will be administered with 240 mL of water while the subject is standing. All of the water must be completely consumed within 1 minute. Subjects may sit upright, but must not lie down for at least 30 minutes after study drug administration.
* Subjects will receive a high fat (approximately 50% of total caloric content of the meal) and high-calorie (approximately 800 to 1000 calories) meal for breakfast. This meal will derive approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively.

Each participant in the study will receive a total of 4 doses during the treatment period. Each subject will be randomised to 1 of 6 possible treatment arms (also termed 'sequences' within the protocol). Each treatment sequence is a combination of any 4 of the 6 study treatments listed above (known as a 'Dosing Period' in the study protocol). No study treatment will be repeated each each sequence. Each subject will undergo a wash-out period of 10 days between their last dose and their next dose (hence a total of 3 wash-out periods per patient).
Intervention code [1] 286869 0
Treatment: Drugs
Comparator / control treatment
There is one active control arm in the study. The treatment in this arm is Afuresertib (Hard Gelatin capsule) and is orally administrered.

There are two comparator arms in the study both investigating two new formulations of Afuresertib. These are an Enteric Coated Tablet and a HPMC capsule - both are administered Orally.

Subjects will receive a total of 4 single doses from any combination of the 3 listed formulations list above. Since this is a randomised trial, the randomisation schedule will dictate the combination (a maximum of 6 combinations are provided).
Control group
Active

Outcomes
Primary outcome [1] 289246 0
To estimate the relative bioavailability of two new prototype formulations of afuresertib (an HPMC capsule and ECT) in the fasted state, as compared to the hard gelatin capsule (original formulation), following single doses in healthy subjects.
Timepoint [1] 289246 0
Afuresertib area under the plasma concentration-time curve (AUC(0-8)) and AUC(0-t), maximum observed plasma concentration (Cmax)), time to Cmax (tmax), observed plasma concentration at 24 hours (C24), and minimal observed plasma concentration (Ct) following administration of a gelatin capsule, HPMC capsule and ECT administered with and without high fat/calorie meal.
Primary outcome [2] 289247 0
To estimate the relative bioavailability of the hard gelatin capsule (original formulation) and two new prototype formulations of afuresertib, with and without food, following single doses in healthy subjects.
Timepoint [2] 289247 0
Afuresertib area under the plasma concentration-time curve (AUC(0-8)) and AUC(0-t), maximum observed plasma concentration (Cmax)), time to Cmax (tmax), observed plasma concentration at 24 hours (C24), and minimal observed plasma concentration (Ct) following administration of a gelatin capsule, HPMC capsule and ECT administered with and without high fat/calorie meal.
Secondary outcome [1] 302096 0
To assess the safety and tolerability of two new prototype formulations of afuresertib (an HPMC capsule and ECT), with and without food, as compared to the hard gelatin capsule (original formulation), following single doses in healthy subjects.
Timepoint [1] 302096 0
Safety parameters including adverse events (AE), clinical laboratory tests, concomitant medications, electrocardiograms, and vital signs are all assessed at the Screening Visit. The subject will then undergo the sames assessments at Day-1 (pre-dose), Day 1, Day 2 and Day 3 of each treatment period (and there are 4 treatment periods). Following the completion of the 4th treatment period, the subject will undergo one last complete assessment at the Follow-up Visit (which is to be conducted within 14 days after the subject receives their last dose on Day 1 of their last treatment period.
Secondary outcome [2] 302097 0
To evaluate the relationship between the pharmacokinetic and pharmacodynamic characteristics of each formulation, following single doses in healthy subjects. Pharmacodynamic effect will be evaluated by measuring AKT inhibition in peripheral blood samples.
Timepoint [2] 302097 0
Change in phosphoAKT levels in peripheral blood samples following administration of a gelatin capsule, HPMC capsule and ECT.

Pharmacodynamic samples will be collected on Day 1 (pre-dose) and then at 2, 12 and 24 hours following treatment administration, and for each dosing period.

Pharmacokinetic samples will be collected on Day 1 (pre-dose) and then at 0.5, 1,2,3,4,6,8,10,12,24,48 and 72 hours following treatment administration, and for each dosing period.

Eligibility
Key inclusion criteria
1. Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.

2. Male or female between 18 and 40 years of age inclusive, at the time of signing the informed consent.

3. Body weight greater than or equal to 50 kg and BMI less than or equal to 32 kg/m2.

4. A female subject is eligible to participate if she is of:

*Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy [for this definition, “documented” refers to the outcome of the Investigator's/designee’s review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject’s medical records]; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<147 pmol/L) is confirmatory]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods permitted as per protocol if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.

* Child-bearing potential with negative pregnancy test as determined by serum hCG test at Screening and prior to dosing, AND;

a. Agrees to use one of the contraception methods listed in the protocol for an appropriate period of time (as determined by the product label or Investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until 14 days (2 weeks) post last dose.

b. OR has only same-sex partners, when this is her preferred and usual lifestyle.

5. Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods as listed in the protocol. This criterion must be followed from the time of the first dose of study drug until 14 days (2 weeks) post last dose.

6. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

7. ALT, alkaline phosphatase and bilirubin equal to or less than 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

8. Based on single or averaged QTc values of triplicate ECGs obtained over a brief recording period:
*QTc < 450 msec; or
*QTc < 480 msec in subjects with Bundle Branch Block.
Minimum age
18 Years
Maximum age
40 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).

2. History of GERD, dyspepsia, GI bleeding, GI surgery that could affect motility.

3. History of atrial arrhythmias

4. History of regular alcohol consumption within 6 months of the study defined as:

'an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 ml) of wine or 1 (25 ml) measure of spirits'.

5. History of sensitivity to heparin or heparin-induced thrombocytopenia.

6. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or GSK Medical Monitor, contraindicates their participation.

7. Use of prescription or non-prescription medications, vitamins, and dietary or herbal supplements (including St John’s Wort) within 7 days (or 14 days if the drug/supplement is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study drug until completion of the Follow-up Period, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study.

8. Unable to abstain from smoking tobacco or the use of nicotine-containing products while admitted to the clinic.

9. Consumption of red wine, seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of Study Drug on Day 1 of Dosing Period 1, until completion of the Follow-up Period.

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)
Successfully screened subjects will be sequentially allocated a treatment sequence (consisting of a combination of the 4 formulations) by a trial pharmacist at the centre, the trial pharmacist will be provided by the sponsor with a treatment 'Randomisation Schedule' from which the treatment sequence will be allocated.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Bio-availability
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
22/05/2013
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
36
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 287019 0
Commercial sector/Industry
Name [1] 287019 0
GlaxoSmithKline
Country [1] 287019 0
United Kingdom
Primary sponsor type
Commercial sector/Industry
Name
GlaxoSmithKline
Address
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex,
TW8 9GS
Country
United Kingdom
Secondary sponsor category [1] 285802 0
Commercial sector/Industry
Name [1] 285802 0
INC Research Australia
Address [1] 285802 0
124 Lipson Street,
Port Adelaide
SA 5015
Country [1] 285802 0
Australia

Ethics approval
Ethics application status
Approved

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

Contacts
Principal investigator
Name 39018 0
Dr Jason Lickliter
Address 39018 0
Nucleus Network Limited
AMREP Office: Level 5
89 Commercial Road
AMREP
Melbourne
Victoria 3004
Country 39018 0
Australia
Phone 39018 0
+61 (03) 9076 8906
Fax 39018 0
Email 39018 0
[email protected]
Contact person for public queries
Name 39019 0
Alex Seta
Address 39019 0
INCResearch Australia Pty Ltd
Level 1, 20 Atherton Road
Oakleigh (Melbourne),
VIC 3166
Country 39019 0
Australia
Phone 39019 0
+61 (03) 8533 6804
Fax 39019 0
Email 39019 0
[email protected]
Contact person for scientific queries
Name 39020 0
Jason Lickliter
Address 39020 0
Nucleus Network Limited
AMREP Office: Level 5
89 Commercial Road
AMREP
Melbourne
Victoria 3004
Country 39020 0
Australia
Phone 39020 0
+61 (03) 9076 8906
Fax 39020 0
Email 39020 0
[email protected]

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No Supporting Document Provided



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