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Trial registered on ANZCTR


Registration number
ACTRN12624000895583
Ethics application status
Approved
Date submitted
5/07/2024
Date registered
22/07/2024
Date last updated
8/09/2024
Date data sharing statement initially provided
22/07/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Ketamine-assisted psychotherapy for methamphetamine use disorder
Scientific title
An open-label safety and feasibility pilot trial of ketamine-assisted psychotherapy for methamphetamine use disorder in adults
Secondary ID [1] 312469 0
None
Universal Trial Number (UTN)
U1111-1312-8045
Trial acronym
KAPPA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Addiction 334307 0
Methamphetamine use disorder 334308 0
Condition category
Condition code
Mental Health 330963 330963 0 0
Addiction

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention consists of four sessions (1:1, face-to-face) of psychotherapy (cognitive behavioural therapy; CBT) over four weeks with adjuvant ketamine in the 24 to 48 hours prior to the second, third and fourth sessions.

1. CBT
The routine 4-session manualised Cognitive Behavioural Therapy (CBT) program developed by Baker et al (2003) will be provided by trained therapists to all participants in the trial. The broad content and aims of each session are outlined below, with sessions lasting approximately 1.5 hours each:

Session 1 - Motivational interviewing. Key aims of this session: engagement and building motivation for change in relation to methamphetamine (MA) use, preparing to reduce MA use, and introduction to behavioural self-monitoring.

Session 2 - Coping with cravings and lapses. Key aims of this session: reinforcing motivation to maintain abstinence/reduced level of use, coping with cravings to use, preparing for a lapse.

Session 3 - Controlling thoughts about amphetamine use and pleasurable activities. Key aims of this session: introduction to the concept that thoughts influence behaviour, developing a plan of achievement and pleasurable tasks to carry out through the week, and continuing to cut down/maintain abstinence.

Session 4 - Amphetamine refusal skills and preparation for future high-risk situations. Key aims of this session: learning and practicing MA refusal skills, identifying potential high-risk situations that may occur in the future, developing a specific relapse prevention/relapse management plan for anticipated high-risk situation, encouraging use of relapse prevention/relapse management plan to prevent use of MA, learning how to deal with a lapse.

Therapists are defined as staff with graduate qualifications in a relevant health discipline (such as counselling, nursing, social work, psychology, psychiatry), including trainees with adequate skills, that have undergone training on the use of the manual. Therapists will be trained by a senior psychologist with expertise in CBT for MAUD. Training will be face-to-face, delivered during a workshop, at least 1 week prior to the first participant enrolment. Session checklists will be completed post-session by the therapist to assess treatment fidelity and discussed during group supervision with a senior psychologist. As per Baker et al (2003), study participants will be encouraged to complete homework tasks in-between sessions. Therapists will also be certified in ICH-GCP.

The initial assessment will take place as part of CBT session 1, covering: (1) alcohol and other drug use history, (2) mental health assessment, (3) client’s readiness to change MA use. Information about what will happen during the first ketamine dose session will be provided.

One week later, a preparation session will be undertaken immediately prior to ketamine dose 1. Psychological preparation and pre-infusion relaxation exercises will be given, and participants be briefed on what to expect during the ketamine dose along with a discharge information sheet.

Within 24-48 hours of ketamine dose 1, CBT session 2 will be undertaken, guided initially by an integration session where experiences of the ketamine session will be briefly explored. This approach will be used for the remaining sessions.

Therapists will coordinate the four sessions to occur at least one week apart. Session 1 will occur during week 1; Sessions 2, 3 and 4 will occur during weeks 2,3 and 4 respectively within 24-48 hours of participants receiving study medication. An optional one-hour 'booster’ session with the therapist will be offered at week 6. CBT session attendance will be used to monitor adherence to the intervention.

2. Medication
The medication under investigation is the TGA approved ketamine hydrochloride 200mg/ml, commercially available and branded in Australia formulated in liquid solution for intravenous and intramuscular injection as an anaesthetic agent. It has also been administered subcutaneously in the sub-anaesthetic doses used in study trials for TRD (Loo et al., 2016, 2023). A total of three subcutaneous doses, at least 7 days apart, will be administered by a registered nurse, once weekly during Weeks 2, 3 and 4. An increasing dose regimen will be used as follows:
- Dose 1: 0.75mg/kg
- Dose 2: if dose 1 well tolerated, increase to 0.9mg/kg. If dose 1 moderately tolerated, reduce to 0.75mg mg/kg. If dose 1 poorly tolerated, reduce to 0.6mg/kg.
- Dose 3: dose range 0.5mg/kg to 0.9mg/kg depending on tolerability of dose 2.

Direct observation will be used to monitor adherence to the intervention.
Intervention code [1] 328986 0
Treatment: Other
Intervention code [2] 329057 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 338731 0
Safety will be monitored by study staff conducting weekly clinic visits, with oversight from the site Principal Investigator. All safety measures will be assessed as a primary composite outcome. Safety data will be collected through Adverse Event and Serious Adverse Event reporting, and a Data Safety and Monitoring Board (DSMB) will be convened to review accumulating data. The incidence of adverse events (AEs) will be recorded across the duration of the study, by system organ class (SOC), including the number of participants with AEs of vital signs recorded outside expected limits. The primary safety measure is the number of treatment-emergent AEs by SOC, described by seriousness, severity, causality and expectedness (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Annotated with TGA Comments, 2016; National Health and Medical Research Council, 2016). Adverse events will be documented at each clinic visit. Subjective descriptions of AEs provided by participants will be transcribed verbatim and reported in accordance with the Medical Dictionary for Regulatory Activities (MedDRA) terminology, developed under the auspices of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Severity will be graded from Grade 1 (mild) to Grade 5 (death) by the site Principal Investigator (U.S. Department of Health and Human Services, 2017). Causality will be determined by the site Principal Investigator, and expectedness in accordance with international guidelines and Australian product labels for ketamine hydrochloride 200mg/ml for injection (Baxter, 2020; Pfizer, 2021). Any known reaction listed on the product label will be considered potentially causally related. Adverse events will be elicited through structured assessment with the Ketamine Side-Effects Tool (KSET) (Bayes et al, 2022). Additional safety measures will be reported descriptively including:
- Blood pressure and heart rate trends
- Dissociative effects
- Suicidality
- Non-medical use liability
- Changes in other drug use (including ketamine)
Timepoint [1] 338731 0
Assessments will be conducted weekly during Weeks 1-4, post-treatment (Week 5), primary endpoint (end of Week 8), and two follow-up points (Week 12, Week 24).
Primary outcome [2] 338732 0
Feasibility. All feasibility measures will be assessed as a primary composite outcome.
Timepoint [2] 338732 0
All feasibility outcomes will be assessed upon conclusion of the study (i.e. the end of Week 24). Qualitative interviews will be conducted during Weeks 5 - 8.
Secondary outcome [1] 437223 0
Self-reported change in past 28-days of methamphetamine use
Timepoint [1] 437223 0
Weekly from baseline to Week 5 (post treatment), then at Week 8, Week 12 and Week 24 post intervention commencement,
Secondary outcome [2] 437226 0
Presence of methamphetamine in urine
Timepoint [2] 437226 0
Weekly from baseline to Week 5, then at Week 8, Week 12 and Week 24 post intervention commencement.
Secondary outcome [3] 437227 0
Changes in methamphetamine craving
Timepoint [3] 437227 0
Weekly from baseline to Week 5, then at Week 8, Week 12 and Week 24 post intervention commencement
Secondary outcome [4] 437228 0
Changes in methamphetamine withdrawal symptoms
Timepoint [4] 437228 0
At baseline, then at Week 5, Week 8, Week 12 and Week 24 post intervention commencement
Secondary outcome [5] 437229 0
Changes in quality of life
Timepoint [5] 437229 0
At baseline, then at Week 5, Week 8, Week 12 and Week 24 post intervention commencement
Secondary outcome [6] 437230 0
Treatment satisfaction
Timepoint [6] 437230 0
Week 5, Week 8 post intervention commencement
Secondary outcome [7] 437231 0
Changes in self-reported scores for depression
Timepoint [7] 437231 0
At baseline, then at Week 5, Week 8, Week 12 and Week 24 post intervention commencement
Secondary outcome [8] 437232 0
Changes in self-reported scores for anxiety
Timepoint [8] 437232 0
At baseline, then at Week 5, Week 8, Week 12 and Week 24 post intervention commencement
Secondary outcome [9] 437233 0
Changes in emotion regulation
Timepoint [9] 437233 0
At baseline, then at Week 5, Week 8, Week 12 and Week 24 post intervention commencement
Secondary outcome [10] 437234 0
Changes in sleep quality
Timepoint [10] 437234 0
At baseline, then at Week 5, Week 8, Week 12 and Week 24 post intervention commencement
Secondary outcome [11] 437235 0
Changes in HIV and other sexually transmitted infection risk behaviours
Timepoint [11] 437235 0
At baseline, then at Week 5, Week 8, Week 12 and Week 24 post intervention commencement
Secondary outcome [12] 437236 0
Subjective medication effects
Timepoint [12] 437236 0
120 minutes post each ketamine administration
Secondary outcome [13] 437237 0
Changes in cognitive control and flexibility
Timepoint [13] 437237 0
Baseline and 24 hours post third ketamine administration.
Secondary outcome [14] 437238 0
Changes in cognitive control
Timepoint [14] 437238 0
Baseline and 24 hours post third ketamine administration.

Eligibility
Key inclusion criteria
Adults presenting to outpatient drug treatment services seeking treatment for methamphetamine use disorder (MAUD) satisfying all of the following criteria:

Greater than or equal to 18 years of age

Able to provide informed consent

Willing and able to comply with all study requirements, as determined by the Principal Investigator

Meets DSM-5-TR diagnostic criteria for Current Stimulant Use Disorder – Amphetamine-Type Substance – as determined by the Principal Investigator and confirmed with Mini International Neuropsychiatric Interview (MINI)

Urine drug screen (UDS) point of care (POC) test positive for methamphetamine

Seeking treatment to cease or reduce methamphetamine use

If person of childbearing potential, willing to avoid pregnancy for study duration

Willing to register as a client of the St Vincent’s Hospital Sydney (SVHS) Stimulant Treatment Program (STP)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
DSM-5-TR diagnosis of current or past use disorder for ketamine or ketamine analogues as assessed by Mini International Neuropsychiatric Interview (MINI)

Prescribed or non-prescribed use of ketamine in the previous four weeks

Currently enrolled in another treatment trial of MAUD or clinical trial, which is likely to affect safety, data quality or may interfere with participation in this study, as determined by the Principal Investigator

Currently pregnant or breastfeeding, or planning on becoming pregnant during the course of the study

DSM-5-TR diagnosis of current psychotic disorder as assessed by the Principal Investigator including review of MINI

Current acute suicidality defined as ‘high risk’ using the C-SSRS-6 screener or as determined by the Principal Investigator

DSM-5-TR diagnosis of bipolar disorder as assessed by the Principal Investigator including review of MINI

Current DSM-5-TR diagnosis with other substance use disorders, moderate or severe, except tobacco, caffeine, or cannabis as assessed by the Principal Investigator including review of MINI. Opioid use disorder permitted if stable on opioid agonist treatment; OAT) (i.e. no dose changes for six weeks if on oral OAT and maximum of one missed dose/week. At least three months with no missed doses if on long-acting injectable)

History of sensitivity to ketamine or any other components of this product

If prescribed antidepressants, the participant must have been on a stable dose for four or more weeks

Contraindications to ketamine according to Australian Product Information:

Severe cardiovascular disease

Heart failure

Severe or poorly controlled hypertension

Recent myocardial infarction

History of stroke

Cerebral Trauma

Intracerebral mass or haemorrhage

Any other medical or psychiatric condition which in the opinion of the Principal Investigator would make participation hazardous. In particular, caution if severe liver, kidney or bladder disease, and also caution if elevated cerebrospinal fluid pressure, increased intraocular pressure, acute intermittent porphyria, seizures, hyperthyroidism, pulmonary or upper respiratory infection, intracranial mass lesions, a presence of head injury, globe injuries, or hydrocephalus.

Likely or planned surgery, travel, incarceration or other engagement during the study that may interfere with study participation

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
7/10/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
20
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 26761 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 42810 0
2010 - Darlinghurst

Funding & Sponsors
Funding source category [1] 316884 0
Government body
Name [1] 316884 0
Australian Government Department of Health and Aged Care
Country [1] 316884 0
Australia
Primary sponsor type
Hospital
Name
St Vincent's Hospital Sydney
Address
Country
Australia
Secondary sponsor category [1] 319132 0
None
Name [1] 319132 0
Address [1] 319132 0
Country [1] 319132 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315649 0
St Vincent’s Hospital Human Research Ethics Committee
Ethics committee address [1] 315649 0
https://svhs.org.au/home/research-education/research-office
Ethics committee country [1] 315649 0
Australia
Date submitted for ethics approval [1] 315649 0
19/04/2024
Approval date [1] 315649 0
24/06/2024
Ethics approval number [1] 315649 0
2024/ETH00530

Summary
Brief summary
This study aims to determine the safety and feasibility of a combination of ketamine and cognitive behavioural therapy (ketamine-assisted therapy) for people with methamphetamine use disorder in an outpatient drug and alcohol treatment setting. There are currently no approved medications in Australia to help people manage, reduce, or stop their methamphetamine use; and psychotherapy is moderately effective. It is hoped that this study will help find out if ketamine-assisted psychotherapy (four sessions of cognitive behavioural therapy with three doses of ketamine, over a four-week period) is a safe and feasible treatment approach for methamphetamine use disorder.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 135366 0
Prof Nadine Ezard
Address 135366 0
St Vincent’s Hospital Sydney Alcohol and Drug Service 390 Victoria Street Darlinghurst NSW 2010
Country 135366 0
Australia
Phone 135366 0
+61 2 8382 1014
Fax 135366 0
Email 135366 0
[email protected]
Contact person for public queries
Name 135367 0
Kathryn Fletcher
Address 135367 0
Centre for Clinical Research on Emerging Drugs, University of New South Wales
Country 135367 0
Australia
Phone 135367 0
+61 02 93850333
Fax 135367 0
Email 135367 0
[email protected]
Contact person for scientific queries
Name 135368 0
Brendan Clifford
Address 135368 0
St Vincent’s Hospital Sydney Alcohol and Drug Service 390 Victoria Street Darlinghurst NSW 2010
Country 135368 0
Australia
Phone 135368 0
+61 457 474 854
Fax 135368 0
Email 135368 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
23958Study protocol  [email protected]
23959Informed consent form  [email protected]
23960Ethical approval  [email protected]



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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