None listed
Conditions
Brief summary
Alcohol use disorders are a leading cause of morbidity and mortality. Existing pharmacological treatments for alcohol use disorders have limited success rates. New research is expanding the focus of development for the treatment of substance use disorders, attempting to identify the underlying neurobiological mechanisms that maintain addiction, rather than more traditional approaches of agonist based treatments or management of acute withdrawal symptoms. Recently, a series of animal studies have shown that rapamycin, an mTORC1 inhibitor, may provide ongoing protection against the expression of addiction and relapse behaviours. The aim of this study is to examine the safety and feasibility of everolimus, an mTORC1 inhibitor, in the treatment of alcohol dependence, whilst also looking for any change in alcohol use whilst taking the study drug and during a four week follow up period.
Interventions
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 parti
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).
Sponsors
Hunter New England Health Drug and Alcohol Clinical Services
Study design
Allocation
Non-randomised trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to 65 Years
Healthy volunteers
No
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
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)
Outcome results
None listed