Multicenter Trial of Combined Pharmacotherapy to Treat Cocaine Dependence

Study Overview
=================
Brief Summary
-----------------
The proposed protocol is a multi-site double-blind, placebo-controlled outpatient study of the safety and efficacy of Adderall-XR (MAS-ER) and topiramate in the treatment of cocaine dependence. 198 patients will be enrolled and 176 patients randomized in a 14-week trial. The proportion of participants achieving sustained cocaine abstinence for three consecutive weeks at the end of the study will be significantly greater for the combined pharmacotherapies group compared to the placebo group.

Detailed Description
-----------------
The investigators hypothesize that the combination of an agent that increased baseline dopamine signaling (amphetamine) with one that reduced cocaine-induced dopamine release (topiramate) will improve dopamine regulation and be associated with improved cocaine use outcomes. 99 subjects at each of the two sites whom meet criteria for cocaine dependence, and all other study inclusion and exclusion criteria will be assigned to the 14-week double-blind, placebo-controlled treatment trial. Subjects will be randomized to receive either placebo or MAS-ER and topiramate. This proposal will test the hypothesis that MAS-ER and topiramate will promote cocaine abstinence. Participants who are randomized to the combination medication arm will have their dose titrated to 60 mg MAS-ER daily (over 2 weeks) and 200 mg topiramate a day (over 6 weeks) and maintained on this dose through week 13 of the trial. During week 14, participants will be tapered off both medications. All participants will receive a supportive behavioral treatment that emphasizes study procedure adherence. Starting in week one, all patients will receive incentives for compliance with study procedures on an escalating reinforcement schedule similar to that developed previously and not contingent on urine results. The purpose of the lead-out is to blind patients to the exact point of medication discontinuation and to provide naturalistic data on the effects of medication discontinuation. Moreover, a 3 month follow-up will be conducted to determine what happens to cocaine use after treatment discontinuation.

Official Title
-----------------
Multicenter Trial of Combined Pharmacotherapy to Treat Cocaine Dependence

Conditions
-----------------
Cocaine Dependence

Intervention / Treatment
-----------------
* Drug: Adderall-ER
* Drug: Topiramate
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men and women between the ages of 18-60 who meet DSM-IV criteria for cocaine dependence. Used cocaine at least 9 days in the past 28 days with at least weekly cocaine use. Able of giving informed consent and capable of complying with study procedures. Exclusion Criteria: Meets DSM-IV-TR criteria for bipolar disorder, schizophrenia or any psychotic disorder other than transient psychosis due to drug abuse. Individuals with any current Axis I psychiatric disorder as defined by DSM-IV-TR supported by the SCID-I/P that in the investigator's judgment are unstable, would be disrupted by study medication, or are likely to require pharmacotherapy or psychotherapy during the study period. Individuals who are currently stable on a psychotropic medication for at least 3 months may be included if in the investigator's opinion the psychotropic medication the patient is taking is compatible with the study medication (mixed amphetamine salts plus topiramate) and does not entail serious risk of adverse effects from the drug interactions. Individuals cannot be on any psychostimulants or other contraindicated medications. Individuals with a history of seizures or unexplained loss of consciousness History of allergic reaction to candidate medications (amphetamine or topiramate). Individuals with significant current suicidal risk. Women who are pregnant, nursing, or failure in sexually active female patients to use adequate contraceptive methods. Unstable physical disorders which might make participation hazardous such as uncontrolled hypertension (SBP > 140, DBP> 90,or HR > 100 when sitting quietly), acute hepatitis(patients with chronic mildly elevated transaminases < 3x upper limit of normal are acceptable), or uncontrolled diabetes. Individuals with coronary vascular disease as indicated by history or suspected by abnormal ECG, cardiac symptoms, fainting, open-heart surgery and/or arrhythmia, and family history of ventricular tachycardia/sudden death. Individuals with use of carbonic anhydrase inhibitors History of glaucoma History of kidney stones Use of drugs that may be additive to the bicarbonate lowering effects of topiramate Body Mass Index (BMI) < 18kg/m2 History of failure to respond to a previous adequate trial of either of the candidate medications for cocaine dependence Individuals physiologically dependent on any other drugs (excluding nicotine or cannabis) which require medical intervention Individuals who are legally mandated (e.g., to avoid incarceration, monetary or other penalties,etc.) to participate in substance abuse treatment program Individuals with a current history (within the past 6 months) of amphetamine abuse or dependence including amphetamines such as methamphetamine and MDMA.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Adderall-ER and Topiramate<br>Adderall-ER will be taken once per day in the morning or early afternoon since it may be activating. The dose is titrated to 60 mg per day or the maximum tolerated dose over two weeks and maintained for the duration of the study. Topiramate will be taken twice per day in the morning and the evening and titrated to 200mg/day or the maximum tolerated dose over the course of 6 weeks and maintained for the duration of the study. | Drug: Adderall-ER<br>* MAS-ER 60mg/day<br>* Other names: Adderall extended release (MAS-ER);Drug: Topiramate<br>* Topiramate 100 mg bid.<br>* Other names: Topamax;|
| Placebo Comparator: Placebo<br>Placebo will be packaged in matching gelatin capsules similar to the pills in the active arm. Placebo will be taken as frequently and for the same duration as those taken in the active arm. | Other: Placebo<br>* Placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Three Weeks of Cocaine Abstinence at End of Study | The number of participants in each study arm achieving sustained cocaine abstinence for three consecutive weeks at the end of the study. This will be measured by self reported cocaine use on the daily Time line Follow Back (TLFB) and corroborated by the urine toxicology samples collected 3 times per week. | assessed during 14 weeks of trial, presented for last 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Any Three Consecutive Weeks of Abstinence During Study | The proportion of participants in each study arm achieving sustained cocaine abstinence for three consecutive weeks at any time during the 14 week trial. This will be measured by self reported cocaine use on the daily Time line Follow Back (TLFB)and corroborated by the urine toxicology samples collected 3 times per week. | 14 weeks of study or length of study participation | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
cocaine dependence, adderall, topiramate