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Trial registered on ANZCTR


Registration number
ACTRN12619000427178
Ethics application status
Approved
Date submitted
5/12/2018
Date registered
15/03/2019
Date last updated
15/03/2019
Date data sharing statement initially provided
15/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Treatment of alcohol dependence with an mTOR inhibitor: a safety and feasibility pilot study.
Scientific title
Inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) for treatment of alcohol dependence - An open-label early phase safety and feasibility pilot study.
Secondary ID [1] 295468 0
None
Universal Trial Number (UTN)
U1111-1216-9614
Trial acronym
TAMI (Treatment of alcohol dependence with an mTOR inhibitor)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alcohol dependence 308729 0
Condition category
Condition code
Mental Health 307669 307669 0 0
Addiction

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants with moderate to severe alcohol dependence will be allocated to one of two treatment arms:
Arm 1: everolimus 2.5 mg administered orally (tablet) once daily for 14 days
Arm 2: everolimus 5.0 mg administered orally (tablet) once daily for 14 days
The first dose level of everolimus to be tested will be 2.5mg daily. If this dose is found to be safe following analysis performed by the Data Safety Monitoring Board (DSMB), the dose will be increased to 5mg daily for the next group of participants. It is expected that up to 6 participants will be required for each arm.
The study drug will be provided during the early withdrawal phase of treatment, during admission to an inpatient withdrawal clinic. The participant will be admitted as an inpatient for up to 14 days following administration of the study drug. If the participant wishes to discharge after a minimum five day period of treatment after study medication has commenced (i.e. discharge on day 6 or later) they may complete the remainder of the treatment phase as an outpatient. Participants will be monitored daily throughout the treatment period and weekly thereafter for an additional four weeks. Comprehensive medical reviews will be performed on the first day of dosing, after 5-7 days of treatment, and on the final day of treatment (day 14). Participants will also be followed up for four weeks after treatment cessation.
Research interviews will be conducted at day 5, day 8, day 14, and at the 28 day follow up (week 6). Blood samples for safety measures will also be taken at this time. Blood samples for pharmacokinetic analysis will be taken at day 1 and day 14 of treatment, and at the 28 day follow up (day 42 of study). Participants will be asked to complete a daily diary and breathalyser testing throughout the study (weeks 1-6).
Intervention code [1] 312358 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Dose comparison

Outcomes
Primary outcome [1] 318628 0
Safety of everolimus during the withdrawal phase in participants with alcohol dependence as assessed by:
- Complete physical assessments by a physician
- Blood samples for safety analysis (full blood count, liver function, renal function, lipid profile and blood glucose)
- Adverse event log
- Participant diary
Timepoint [1] 318628 0
Day 14 of treatment (end of treatment)
Day 42 post treatment allocation (28 days after end of treatment)
Primary outcome [2] 318630 0
Intervention feasibility, namely administration of everolimus during the withdrawal period, as measured by:
Recruitment rate
Completion rate at end of treatment period
Adherence to everolimus
Timepoint [2] 318630 0
Day 14 of treatment (end of treatment)
Day 42 post treatment allocation (28 days after end of treatment)
Secondary outcome [1] 351840 0
Change in alcohol use as assessed by:
Participant self-report of alcohol use at baseline, and weekly thereafter;
Twice daily breathalyser;
Self report of alcohol use by Time Line Follow Back questionnaire.
Timepoint [1] 351840 0
Day 14 of treatment (end of treatment)
Day 42 post treatment allocation (28 days after end of treatment)
Secondary outcome [2] 351841 0
Changes in craving symptoms as assessed by:
Daily 100 mm Visual Analogue Scale with the question 'how strong is your craving for alcohol at this moment?' (anchored at 'not at all' and 'the most I've ever felt');
Penn Alcohol Craving Scale (PACS);
Cue exposure paradigm (visual and olfactory), with craving/reactivity assessed using the Alcohol Urge Questionnaire and Visual Analogue Scale with the question 'how strong is your craving for alcohol at this moment?' (anchored at 'not at all' and 'the most I've ever felt')
Timepoint [2] 351841 0
Day 14 of treatment (end of treatment)
Day 42 post treatment allocation (28 days after end of treatment)
Secondary outcome [3] 351842 0
Withdrawal symptoms assessed by Alcohol Withdrawal Scale (CIWA-Ar)
Timepoint [3] 351842 0
Day 5 of treatment;
Day 8 of treatment;
Day 14 of treatment (end of treatment)
Secondary outcome [4] 351843 0
Mental health assessed by Depression Anxiety Stress Scale (DASS-21)
Timepoint [4] 351843 0
Day 14 of treatment (end of treatment)
Day 42 post treatment allocation (28 days after end of treatment)
Secondary outcome [5] 366618 0
Social functioning as assessed by the Social Function scale (SF-36)
Timepoint [5] 366618 0
Day 14 of treatment (end of treatment)
Day 42 post treatment allocation (28 days after end of treatment)
Secondary outcome [6] 366619 0
Therapeutic plasma concentrations of everolimus (pharmacokinetic analysis) assessed by peak and trough plasma concentrations
Timepoint [6] 366619 0
Day 1 of treatment
Day 14 of treatment (final day of treatment)
Day 42 post treatment allocation (28 days after end of treatment)

Eligibility
Key inclusion criteria
1. Provide written, informed consent to participate in the study
2. Aged 18 to 65 years
3. Be treatment seeking for alcohol dependence
4. Meet DSM-5 criteria for moderate to severe alcohol use disorder (alcohol dependence) for at least twelve months
5. Self-report alcohol use of greater than or equal to 21 days out of the previous 28
6. Adequate liver function as shown by normal total bilirubin and albumin, ALT and AST less than or equal to 2.5 X upper limit of normal, INR less than or equal to 2
7. Adequate renal function, serum creatinine less than or equal to 1.5 X ULN
8. Patient must have adequate lipid profile, including fasting serum cholesterol, fasting glucose or fasting triglycerides
9. Full blood count and WBC differential within normal ranges
10. Adequate bone marrow function, including ANC and platelets
11. Females of child bearing potential must not be pregnant as confirmed by a negative pregnancy test (serum confirmed beta-hCG) or breastfeeding prior to study enrolment. Women of childbearing potential must agree to use adequate high-effective contraception for the duration of study participation and at least four months after the last dose of everolimus (e.g. oral contraception, intrauterine device, implant, combination of barrier methods, abstinence). Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception for the duration of study participation, and 4 months after completion of everolimus administration.
12. Be willing and able to comply with requirements of study
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Plans for immediate residential treatment/rehabilitation post withdrawal
2. Antidypsotropic (acamprosate, naltrexone, disulfiram) pharmacological treatment for alcohol dependence for more than 7 days in the previous month
3. Plans to commence antidypsotropic pharmacological treatment (acamprosate, naltrexone, disulfiram) for alcohol dependence during the study (inclusive of treatment and follow-up period)
4. History of complicated/severe alcohol withdrawal (e.g. alcohol withdrawal seizures, delirium).
5. Patients with a known hypersensitivity to everolimus or other rapalogues (sirolimus, temsirolimus)
6. Contraindication to study drug (everolimus): Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients
7. High or increasing C-reactive Protein, CRP levels =10mg/L
8. Systemic infection requiring therapy at study entry
9. Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4. As lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx or medical reference text.
10. HIV-positive patients on combination antiretroviral therapy. These therapies have potential pharmacokinetic interactions with everolimus. Patients are also at increased risk of lethal infections when treated with marrow suppressive therapy.
11. Presence of another moderate-severe substance use disorder (other illicit or prescription drug dependence) with the exception of nicotine dependence, diagnosed by specialist clinical assessment against DSM-5 criteria, including urine drug screen. Already receiving study drug for any reason (e.g. kidney or cardiac allograft)
12. Patients who have had major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anaesthesia), or patients who may require major surgery during the course of the study.
13. Prior treatment with any investigational drug within the preceding 4 weeks.
14. Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent, except corticosteroids with a daily dosage equivalent to prednisone = 20 mg. Patients receiving these corticosteroids must have been on a stable dosage regimen for a minimum of 4 weeks prior to the first treatment with Everolimus. Topical or inhaled corticosteroids are allowed.
15. Patients who have received immunization with attenuated live vaccines within one week of study entry or during study period.
16. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
a. Symptomatic congestive heart failure of New York Heart Association Class III or IV.
b. Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease.
c. Severely impaired lung function as evidenced by:
(TLC) <50% predicted, OR (FVC) <50% predicted OR, (DLCO) <40% predicted
d. Uncontrolled diabetes/pre-diabetes as defined by fasting serum glucose >5.5mmol/L.
e. Active (acute or chronic) or uncontrolled severe infections.
f. Liver disease such as cirrhosis, chronic active hepatitis B and C, or chronic persistent hepatitis.
g. HIV seropositivity.
17. Current, severe unstable mental health problem (e.g. acute psychosis, severe anxiety and/or mood disorder, intent to harm self or others assessed by study medical officer and/or psychiatrist)
18. Not available for follow-up (e.g. likely travel or imprisonment)

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)
Allocation is not concealed
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
Parallel
Other design features
The first dose level of everolimus to be tested will be 2.5mg daily. If this dose is found to be safe following analysis performed by the Data Safety Monitoring Board the dose will be increased to 5mg daily for the next group of participants.
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Descriptive analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
13/05/2019
Actual
Date of last participant enrolment
Anticipated
31/08/2020
Actual
Date of last data collection
Anticipated
5/10/2020
Actual
Sample size
Target
12
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 12181 0
Belmont Hospital - Belmont
Recruitment hospital [2] 13085 0
Drug and Alcohol Clinical Services, Hunter New England Local Health District - Newcastle
Recruitment postcode(s) [1] 24350 0
2280 - Belmont
Recruitment postcode(s) [2] 25594 0
2300 - Newcastle

Funding & Sponsors
Funding source category [1] 300058 0
Government body
Name [1] 300058 0
Hunter New England Local Health District
Country [1] 300058 0
Australia
Funding source category [2] 300939 0
University
Name [2] 300939 0
The University of Newcastle
Country [2] 300939 0
Australia
Primary sponsor type
Government body
Name
Hunter New England Health Drug and Alcohol Clinical Services
Address
Newcastle Community Health Centre
Level 3, 670 Hunter Street
Newcastle NSW 2300
Country
Australia
Secondary sponsor category [1] 299454 0
None
Name [1] 299454 0
Address [1] 299454 0
Country [1] 299454 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300905 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 300905 0
Ethics committee country [1] 300905 0
Australia
Date submitted for ethics approval [1] 300905 0
27/02/2018
Approval date [1] 300905 0
05/07/2018
Ethics approval number [1] 300905 0
18/03/21/3.02

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

Contacts
Principal investigator
Name 85226 0
Prof Adrian Dunlop
Address 85226 0
Drug and Alcohol Clinical Services
Newcastle Community Health Centre
Level 3, 670 Hunter Street
Newcastle NSW 2290
Country 85226 0
Australia
Phone 85226 0
+61 2 4016 4664
Fax 85226 0
Email 85226 0
Adrian.Dunlop@hnehealth.nsw.gov.au
Contact person for public queries
Name 85227 0
Adrian Dunlop
Address 85227 0
Drug and Alcohol Clinical Services Research
Newcastle Community Health Centre
Level 3, 670 Hunter Street
Newcastle NSW 2290
Country 85227 0
Australia
Phone 85227 0
+61 2 4016 4664
Fax 85227 0
Email 85227 0
Adrian.Dunlop@hnehealth.nsw.gov.au
Contact person for scientific queries
Name 85228 0
Adrian Dunlop
Address 85228 0
Drug and Alcohol Clinical Services Research
Newcastle Community Health Centre
Level 3, 670 Hunter Street
Newcastle NSW 2290
Country 85228 0
Australia
Phone 85228 0
+61 2 4016 4664
Fax 85228 0
Email 85228 0
Adrian.Dunlop@hnehealth.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This is an early phase pilot study with a small sample size. Individual patient data will not be released for privacy reasons.


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
No additional documents have been identified.