Study to Assess Safety, Tolerability, and Interactions of Cocaine and Oral AFQ056

Study Overview
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Brief Summary
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This is a study to assess safety, tolerability and interactions of AFQ056 and cocaine in patients with cocaine use disorder.

Detailed Description
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This is a randomized, participant- and investigator-blinded, placebo-controlled, parallel group study to assess safety and tolerability and to compare the effects of AFQ056 on IV cocaine's physiological and subjective effects in non-treatment seeking, cocaine-experienced participants who meet American Psychiatric Association Diagnostic and Statistical Manual (DSM-V) criteria for cocaine use disorder. Approximately twenty participants will be randomized to 2 groups (10 in each group), receiving either AFQ056 or placebo treatment for 8 days. Participants will be screened for eligibility as outpatients and inpatients. Outpatient screening will occur between Day -28 and Day -4. On Study Day -3, participants will undergo clinic intake to screen for continued eligibility. On Study Day -2, participants will be screened for eligibility with a participant-blinded screening infusion (Infusion Session 1) of 20 mg cocaine, followed by a saline infusion, followed by a 40 mg cocaine infusion. Each 2 ml infusion of cocaine and saline will be administered by IV over a 60 second time period and approximately 60 minutes apart. Physiological and subjective data (VAS) from these sessions will be part of the eligibility criteria to continue in the study. Once a participant has been determined to be eligible, the participant will be randomized on Day -1 to receive either AFQ056 or placebo in a 1:1: ratio and at the same time, will also be randomized to a specific couple of sequences saline/cocaine or cocaine/saline for Infusion Session 2 and Infusion Session 3 within each treatment group. The order of the saline and cocaine infusions for each participant for Infusion Sessions 4 and 5 will be the same as the randomized order for Infusion Sessions 2 and 3, respectively. Participants will receive baseline infusions determined by the randomized sequences of saline and 20 mg of cocaine on Day 1 (Infusion Session 2) and saline and 40 mg of cocaine on Day 2 (Infusion Session 3). The participants will receive either AFQ056 or matching placebo twice a day from Days 3 to 9. The AFQ056 treatment group will be up titrated to 200 mg according to the following dosing schedule: Day 3: 50 mg twice daily; Day 4: 100 mg twice daily and Days 5-9: 200 mg twice daily. On Day 10, participants will be administered only the morning dose of AFQ056 200 mg or placebo. AFQ056 doses must be taken within 30 minutes of meals. On Day 9 and Day 10, approximately 4 hours after the morning dose of AFQ056 200 mg or placebo, participants will receive treatment infusions determined by the randomized sequence of saline and 20 mg of cocaine on Day 9 (Infusion Session 4) and saline and 40 mg of cocaine on Day 10 (Infusion Session 5). The participants will be discharged from the research clinic on Day 12, two days after the last infusion of cocaine (Infusion Session 5) and will have a Follow-up visit between 7 and 14 days after clinic discharge. A safety follow-up call will be conducted 30 days following the last administration of study treatment on Day 40.

Official Title
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A Randomized, Participant- and Investigator-blinded, Placebo-controlled, Parallel Group Study to Assess Safety, Tolerability, and Potential Interactions of Oral AFQ056 Given Concurrently With Cocaine

Conditions
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Cocaine Use Disorder

Intervention / Treatment
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* Drug: AFQ056
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Non-treatment seeking participants who meet DSM-V criteria for cocaine use disorder as assessed using the Mini International Neuropsychiatric Interview (MINI) neuropsychiatric interview (version 7.0). Be between 18 and 55 years of age, inclusive Have a body mass index (BMI) within a range of 18.0 to 34.0 kg/m2 and a minimum weight of at least 50.0 kg at screening. Have experience using cocaine by the smoked or IV route at least 6 times in the past 12 months prior to clinic intake (Day -3) and at least one use within the past 30 days. Provide a urine sample positive for cocaine at least once during screening (Days -28 to -4). Key Exclusion Criteria: Have a current or past history of seizure disorder, including alcohol- or stimulant-related seizure, febrile seizure, or significant family history of idiopathic seizure disorder. Have any previous medically adverse reaction to cocaine, including loss of consciousness, chest pain, paranoid reaction or seizure. Have clinically significant findings in the opinion of an investigator based on the MINI (version 7.0) neuropsychiatric interview. Be pregnant or lactating. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception from at least 30 days prior to the first administration of study treatment (Day -2), while taking study treatment, and for at least 30 days after the last dose of the study treatment. Have a systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg and heart rate > 100 beats per minute at screening or clinic intake (Day -3). Have a history of liver or renal disease or current elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT) or creatinine, 1.5 × the upper limit of normal at screening or intake (Day -3).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will undergo a screening infusion session with saline and cocaine on Day -2 as part of the eligibility determination. Once deemed eligible, participants will undergo screening infusion sessions 2 and 3 on Days 1 and 2 respectively. Starting Day 3, participants will receive either AFQ056 or matching placebo twice a day from Day 3 to Day 9. The AFQ056 treatment group will be up titrated to 200 mg according to the following dosing schedule: Day 3: 50 mg twice daily; Day 4: 100 mg twice daily and Days 5-9: 200 mg twice daily. On Day 10, participants will be administered only the morning dose of AFQ056 200 mg or placebo. On Days 9 and 10, participants will have infusion session 4 and 5 respectively. The participants will be discharged from the clinic on Day 12 and return for a follow-up visit between 7 to 14 days after clinic discharge. A safety follow-up call will be conducted on Day 40.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AFQ056<br>Experimental study drug | Drug: AFQ056<br>* oral administration<br>|
| Placebo Comparator: Placebo<br>Matching placebo | Drug: Placebo<br>* matching placebo for oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Treatment Emergent Adverse Events | The distribution of adverse events (AEs) will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. | up to 26 days post-drug administration with a 30-day safety follow-up call | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Observed maximum plasma concentration (Cmax) for cocaine and benzoylecgonine (BE) | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics. | Day 2, Day 10 | 
| Area Under the plasma concentration-time Curve from the time 0 to the last observed quantifiable concentration (AUC(0-t)) for cocaine and benzoylecgonine (BE) | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUC(0-t) will be listed and summarized using descriptive statistics. | Day 2, Day 10 | 
| Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUCinf) for cocaine and benzoylecgonine (BE) | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUC(0-inf) will be listed and summarized using descriptive statistics. | Day 2, Day 10 | 
| Time of maximum observed drug concentration occurrence (Tmax) for cocaine and benzoylecgonine (BE) | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Tmax will be listed and summarized using descriptive statistics. | Day 2, Day 10 | 
| Terminal rate constant (λz) for cocaine and benzoylecgonine (BE) | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. λz will be listed and summarized using descriptive statistics. | Day 2, Day 10 | 
| Terminal elimination half-life (T^1/2) for cocaine and benzoylecgonine (BE) | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. The half-live will be listed and summarized using descriptive statistics. | Day 2, Day 10 | 
| Total systemic clearance for intravenous administration (CL) for cocaine and benzoylecgonine (BE) | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. CL will be listed and summarized using descriptive statistics. | Day 2, Day 10 | 
| Observed maximum plasma concentration (Cmax) for AFQ056 | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics. | Day 10 | 
| Area Under the plasma concentration-time Curve from the time 0 to the last observed quantifiable concentration (AUC(0-t)) for AFQ056 | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUC(0-t) will be listed and summarized using descriptive statistics. | Day 10 | 
| Area Under the plasma concentration-time Curve From 0 To 12 Hours (AUC0-12) for AFQ056 | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUC0-12 will be listed and summarized using descriptive statistics. | Day 10 | 
| Time of maximum observed drug concentration occurrence (Tmax) for AFQ056 | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Tmax will be listed and summarized using descriptive statistics. | Day 10 | 
| Trough plasma concentration (Ctrough) for AFQ056 | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Ctrough will be listed and summarized using descriptive statistics. | Day 10 | 
| Terminal elimination half-life (T^1/2) for AFQ056 | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. The half-live will be listed and summarized using descriptive statistics. | Day 10 | 
| Terminal rate constant (λz) for AFQ056 | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. λz will be listed and summarized using descriptive statistics. | Day 10 | 
| Apparent clearance of the drug from plasma after oral administration (CL/F) for AFQ056 | Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. CL/F will be listed and summarized using descriptive statistics. | Day 10 | 
| Visual Analog Scales (VAS) | The VAS is a self-administered assessment evaluating the subjective effects of cocaine. Participants will use an electronic patient reported outcomes (ePRO) system to answer VAS. | up through day 10 | 
| Brief Substance Craving Scale (BSCS) | The BSCS is a self-administered assessment that asks the participant to rate his or her craving for cocaine. the BSCS used for this study is a modification of the State of Feelings and Cravings Questionnaire. Participants will use an electronic patient reported outcomes (ePRO) system to answer BSCS. | up through Day 10 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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safety, tolerability, interaction, cocaine, cocaine use disorder, AFQ056