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Trial registered on ANZCTR


Registration number
ACTRN12616001351404
Ethics application status
Approved
Date submitted
14/09/2016
Date registered
28/09/2016
Date last updated
28/09/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
A single and multiple dose safety and tolerability study of oral ketamine in healthy volunteer and patients with a history of depression or anxiety.
Scientific title
A single centre, double blind, randomised , parallel group, ascending single and multiple dose, safety and tolerability, pharmacokinetic and pharmacodynamic study of oral ketamine in healthy volunteer and patients with a history of depression or anxiety cohorts.
Secondary ID [1] 290131 0
None
Universal Trial Number (UTN)
U1111-1186-0282
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Depression 300248 0
Anxiety 300284 0
Condition category
Condition code
Mental Health 300112 300112 0 0
Depression
Mental Health 300151 300151 0 0
Anxiety

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be confined at the clinical site for the duration of the dosing and sampling periods.
Cohort 1-3: Study days 0 to 4 and study days 6 to 10
Cohort 4: Study days 0 to 5
Cohort 5: Study days 0 to 2 and study days 6 to 9

Planned doses as follows:
Dose level 1 (Cohort 1 - 8 healthy volunteers): single capsule containing 60 mg oral ketamine or methylcellulose placebo on day 1, then twice daily day 7-9

Dose level 2 (Cohort 2 - 8 healthy volunteers): 2 x capsules containing 60 mg oral ketamine or methylcellulose placebo on day 1, then twice daily day 7-9

Dose level 3 (Cohort 3 - 8 healthy volunteers): 4 x capsules containing 60 mg oral ketamine or methylcellulose placebo on day 1, then twice daily day 7-9

Dose level 4 (Cohort 4 - 6 patients with depression and 6 patients with anxiety): single capsule containing 60 mg oral ketamine once daily in the morning and then 1-2x (dependant on whether or not depression or anxiety has improved along with assessments of safety and tolerability assessed by the Principal Investigator/Head of Department Psychological Medicine) 60 mg oral ketamine once daily 12 hours after the morning dose on day 1 and then 1-4x 60 mg (dependant on whether or not depression or anxiety has improved along with assessments of safety and tolerability assessed by the Principal Investigator/Head of Department Psychological Medicine) twice daily on days 2-4

Dose Level 5 (Cohort 5 - 12 healthy volunteers): Dose will be the highest single dose of oral ketamine from the results of Cohort 1 to 3 in fasted state on day 1 and fed state on day 8.

Volunteers are not required water for 1 hour prior to dosing until 1 hour after dosing (except for the water consumed with each dose).

For cohort 5 volunteers are required not to eat for 10 hours before dosing on day 1 and the a standardised high fat content meal on day 8 and to fast for approximately 4 hours after each dose.
Intervention code [1] 295884 0
Treatment: Drugs
Comparator / control treatment
Identical capsule containing methylcellulose as Placebo
Control group
Placebo

Outcomes
Primary outcome [1] 299596 0
To evaluate the pharmacokinetics (as summarised by Cmax and AUC). All plasma samples will be assayed for ketamine and norketamine using one fully validated LC/MS/MS method. Validation will be conducted to comply with FDA guidelines.
Timepoint [1] 299596 0
Cohort 1, 2,3:
Day 1: Sampling immediately prior to dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 12, 14, 17, 20, 24, 32 & 48 hours after dosing.
Days 7-10: Sampling immediately prior to dosing, then at 12, 24, 36, 48, 48.5, 49, 49.5, 50, 50.5, 51, 51.5, 52, 52.5, 53, 54, 55, 56, 57, 58, 60, 62,65, 68 and 72 hours after the initial dose.

Cohort 4: Sampling immediately before each dose administration and around Tmax (anticipate between 3-5 hours post-dose but timepoints will be finalised based on results of cohorts 1-3)

Cohort 5: D1: Sampling immediately prior to dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 12, 14, 17, 20, 24, 32 & 48 hours after dosing.
D8: Sampling immediately prior to dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 12, 14, 17, 20, 24, 32 & 48 hours after dosing.
Primary outcome [2] 299597 0
To evaluate the pharmadynamics (as summarised by BDNF). All serum samples will be assayed using a fully validated ELISA method. Validation will be conducted to comply with FDA guidelines.
Timepoint [2] 299597 0
Cohort 1, 2,3:
Day 1 at 0 and 24 hours and Days 7-10 at 0, 24 and 72 hours
Days 7 to 10: 0, 3, 12, 24, 36, 48, 72h

Cohort 4:
Days 1-4 at 0, 24, 72 and 96 hours.


Primary outcome [3] 299631 0
To evaluate the safety (as summarised by adverse events, vital signs and ECG).
Timepoint [3] 299631 0
Adverse events will be assessed continuously from dosing until release from confinement period in each cohort.

Vital signs will be:
Cohort 1,2,3, Day 1: 0, 1, 2, 3, 6, 12, 15, 18, 24, 27, 30, 36, 48h and Days 7 to 10: 0, 1, 2, 3, 6, 12, 15, 18, 24, 27, 30, 36, 48, 72h
Cohort 4 has additional time points of 84 and 96 hours
Cohort 5, Day 1 & 8: 0, 1, 2, 3, 6, 12, 15, 18, 24, 27, 30, 36, 48h

12-Lead ECGs:
Cohort 1,2,3, day 1: 0, 3, 12, 24, 36, 48h and days 7 to 10: 0, 3, 12, 24, 36, 48, 72h
Cohort 4 has additional time points of 84 and 96 hours
Cohort 5, Day 1 & 8: 0, 3, 12, 24, 36, 48h

Secondary outcome [1] 327715 0
Time to maximum peak concentration (Tmax) will be determined by plasma sample analysis. Tmax will be the time where the maximum concentration occurred in the sample points.
Timepoint [1] 327715 0
Cohort 1, 2,3:
Day 1: Sampling immediately prior to dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 12, 14, 17, 20, 24, 32 & 48 hours after dosing.
Days 7-10: Sampling immediately prior to dosing, then at 12, 24, 36, 48, 48.5, 49, 49.5, 50, 50.5, 51, 51.5, 52, 52.5, 53, 54, 55, 56, 57, 58, 60, 62,65, 68 and 72 hours after the initial dose.

Cohort 4: Sampling immediately before each dose administration and around Tmax (anticipate between 3-5 hours post-dose but timepoints will be finalised based on results of cohorts 1-3)

Cohort 5: D1: Sampling immediately prior to dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 12, 14, 17, 20, 24, 32 & 48 hours after dosing.
D8: Sampling immediately prior to dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 12, 14, 17, 20, 24, 32 & 48 hours after dosing.
Secondary outcome [2] 327959 0
Additional Primary Outcome: To evaluate efficacy (as summarised by questionnaires and rating scores (CADSS and C-SSRS)).
Timepoint [2] 327959 0
The following Questionnaires and Rating Scales will be used at the times indicated:
CADSS
Cohort 1-3, Day 1: 0, 3, 12, 24, 36, 48h and days 7 to 10: 0, 3, 12, 24, 36, 48, 72h
Cohort 4 has additional time points of 84 and 96 hours
Cohort 5, Day 1 & 8: 0, 3, 12, 24, 36, 48h

C-SSRS
Cohort 1-3, day 1: 0, 24, 48h and days 7 to 10: 0, 24, 48, 72h
Cohort 4 has additional time points of 96 hours
Cohort 5, days 1 and 8: 0, 24, 48h



Eligibility
Key inclusion criteria
Subjects will be eligible for enrolment for Cohorts 1, 2, 3 and 5: on the basis of:
a) Provide written informed consent
b) Male or non-pregnant females
c) Aged 18 to 55 years on the day of consent
d) Body Mass Index greater than 18 and less than 30kg/m2 on day of consent
e) Healthy individuals as determined by medical history, physical examination, ECG, vital signs and laboratory tests
f) HIV and Hepatitis B and C negative
g) Non-smoker (for at least 6 months prior to the date of consent).
h) Drug free as determined by urine drug testing

Subjects will be eligible for enrolment for Cohort 4 on the basis of:
a) Provide written informed consent
b) Male or non-pregnant females
c) Aged 18 to 60 years on the day of consent
d) Body Mass Index greater than 18 and less than 35 kg/m2 on day of consent
e) Healthy individuals as determined by medical history, physical examination, ECG, vital signs and laboratory tests
f) HIV and Hepatitis B and C negative
g) Previously Diagnosed DSM-5 Major Depressive Disorder (MDD) (n=6) or Generalized Anxiety Disorder (GAD) /Social Anxiety Disorder (SAD) (n=6)
h) An inadequate response, ie treatment was not successful, treatment with at least 2 prescribed antidepressants
i) MADRS score of at least 20 (MDD) or HAM-A score of 18 (GAD/SAD)
j) Psychotropic medication and/or psychotherapy regime is stable i.e no change to drugs or dose or visit schedule within previous four weeks
k) Previous positive response to off label SC injection ketamine use as determined by documentation of a 50% change in previous Hamilton Anxiety Scale (HAM-A) for MDD, Spielberger State Anxiety inventory (SSAI) plus Fear Questionnaire (FQ) for SAD
l) Drug free as determined by urine drug testing
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 for Cohorts 1, 2, 3 and 5: on the basis of:
a) Evidence from medical history, physical or laboratory examinations of clinically significant neurologic, psychiatric, cardiac, respiratory, renal, hepatic, endocrine, gastrointestinal, immunological condition or any other diagnosed conditions that might interfere with the absorption, distribution, metabolism or excretion of the drug, interfere with the ability to accurately record study measurements or which may potentiate or predispose to undesired effects.
b) Participants receiving treatment with monoamine oxidase inhibitors, vasoconstriction agents, thyroxine or benzodiazepines.
c) Any clinically significant history of alcohol or drug abuse or dependency including ketamine or its excipients.
d) Any clinically significant illness in the 30 days prior to dosing day 1.
e) Any clinically significant infection or febrile illness in the five days prior to dosing day 1.
f) Clinically significant Abnormal ECG at the screening visit
g) Females who are pregnant or breastfeeding
h) Females who are not using effective contraception for the prevention of pregnancy ie prescribed hormonal contraceptives or other reliable methods
i) Participation in any drug study in the 60 days preceding dosing day 1
j) Participants who do not consent to their GP being contacted prior to the commencement of the study, if necessary, about their medical history or after the study about any adverse results or reactions
k) Participants who, in the opinion of the Investigator, do not understand the information and procedures of the study, or would not be compliant with them (in particular the study restrictions and risks involved).
l) Any participation for whom the Investigator believes, for any reason, inclusion would not be an acceptable risk
m) Subject with any clinically significant abnormality or abnormal laboratory test results found during medical screening
n) History of mental illness requiring medication or treatment by a physician

Subjects will be excluded for Cohort 4: on the basis of:
a) Evidence from medical history, physical or laboratory examinations of clinically significant neurologic, cardiac, respiratory, renal, hepatic, endocrine, gastrointestinal, immunological condition or any other diagnosed conditions that might interfere with the absorption, distribution, metabolism or excretion of the drug, interfere with the ability to accurately record study measurements or which may potentiate or predispose to undesired effects.
b) Participants receiving treatment with monoamine oxidase inhibitors, vasoconstriction agents, thyroxine or benzodiazepines.
c) Any clinically significant history of alcohol or drug abuse or dependency.
d) Any clinically significant illness in the 30 days prior to dosing day 1.
e) Any clinically significant infection or febrile illness in the five days prior to dosing day 1.
f) Clinically significant Abnormal ECG at the screening visit
g) Females who are pregnant or breastfeeding
h) Females who are not using effective contraception for the prevention of pregnancy ie prescribed hormonal contraceptives or other reliable methods
i) Participation in any drug study in the 60 days preceding dosing day 1
j) Participants who do not consent to their GP being contacted prior to the commencement of the study, if necessary, about their medical history or after the study about any adverse results or reactions
k) Participants who, in the opinion of the Investigator, do not understand the information and procedures of the study, or would not be compliant with them (in particular the study restrictions and risks involved).
l) Any participation for whom the Investigator believes, for any reason, inclusion would not be an acceptable risk
m) Subject with any clinically significant abnormality or abnormal laboratory test results found during medical screening
n) Past or current history of schizophrenia, bipolar disorder, or other psychotic disorder
o) History of abuse of ketamine or phencyclidine
p) Significant current risk of suicide as assessed by C-SSRS
q) Contraindication to the use of ketamine, e.g., any condition in which a significant elevation of blood pressure would be hazardous, such as decompensated heart failure, severe or poorly controlled hypertension (blood pressure systolic less than or equal to 160 or diastolic less than or equal to 90, tested on 2 or more occasions); within last 3 months, recent myocardial infarction, stroke, cerebral haemorrhage; myasthenia gravis.
r) History of neurogenerative disorder eg Alzheimers disease, vascular dementia, Parkinson's disease or evidence of mild cognitive impairment

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)
After obtaining consent and confirming eligibility,the participant will be randomised in the study. Study drug will be prepared for each participant by pharmacy staff, according to the randomisation code. All clinical staff will remain blinded. Individual randomisation envelopes will be provided in case the identity of study drug administered to a participant needs to be known.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomization by computer
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/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
29/09/2016
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
48
Accrual to date
Final
Recruitment outside Australia
Country [1] 8224 0
New Zealand
State/province [1] 8224 0
Otago

Funding & Sponsors
Funding source category [1] 294506 0
Commercial sector/Industry
Name [1] 294506 0
Douglas Pharmaceuticals Limited
Country [1] 294506 0
New Zealand
Primary sponsor type
Commercial sector/Industry
Name
Zenith Technology Corp Ltd
Address
PO Box 1777
156 Frederick St
Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 293371 0
None
Name [1] 293371 0
Address [1] 293371 0
Country [1] 293371 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295939 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 295939 0
Freyberg Building
20 Aitken Street
PO Box 5013
Wellington 6011
Ethics committee country [1] 295939 0
New Zealand
Date submitted for ethics approval [1] 295939 0
04/08/2016
Approval date [1] 295939 0
13/09/2016
Ethics approval number [1] 295939 0
16/STH/121

Summary
Brief summary
This study will investigate the safety and tolerability of ketamine given to
healthy volunteers and patients with a history of depression and anxiety. It will examine how the drug is absorbed and excreted from the body. The study will also examine what effects ketamine has on specific functions of the body.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 68974 0
Dr Paul W Glue
Address 68974 0
Department of Psychologist Medicine
University of Otago
PO Box 913
Dunedin 9054
Country 68974 0
New Zealand
Phone 68974 0
+64 3 470 3867
Fax 68974 0
+6434779605
Email 68974 0
paul.glue@otago.ac.nz
Contact person for public queries
Name 68975 0
Mrs Linda Folland
Address 68975 0
Zenith Technology Corp Ltd
PO Box 1777
156 Frederick St
Dunedin 9054
Country 68975 0
New Zealand
Phone 68975 0
+6434779669
Fax 68975 0
+6434779605
Email 68975 0
linda.folland@zenithtechnology.co.nz
Contact person for scientific queries
Name 68976 0
Dr Tak Hung
Address 68976 0
Zenith Technology Corp Ltd
PO Box 1777
156 Frederick St
Dunedin 9054
Country 68976 0
New Zealand
Phone 68976 0
+6434779669
Fax 68976 0
+6434779605
Email 68976 0
tak.hung@zenithtechnology.co.nz

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

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseSafety and efficacy of extended release ketamine tablets in patients with treatment-resistant depression and anxiety: open label pilot study.2020https://dx.doi.org/10.1177/2045125320922474
N.B. These documents automatically identified may not have been verified by the study sponsor.