Cariprazine for Cocaine and Opioid Use Disorder

Overseen By Megan Ivey, MS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Kyle Kampman

Must be taking: BUP-NX

Must not be taking: Antidepressants, Benzodiazepines, CYP3A4 drugs

Disqualifiers: Schizophrenia, Bipolar, Severe AUD, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

48 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests if low-dose cariprazine can help reduce cocaine use in patients who are already being treated for opioid addiction. The medication may help balance brain chemicals that make people feel rewarded when they use drugs, potentially reducing their cravings.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you must continue taking BUP-NX (buprenorphine/naloxone) at a stable dose. You cannot take medications that interact with cariprazine or BUP-NX, and you should not be on psychoactive medications, except for occasional Benadryl for sleep.

What data supports the effectiveness of the drug Cariprazine for treating cocaine and opioid use disorder?

Cariprazine, a drug used for bipolar disorder and schizophrenia, was tested in squirrel monkeys for its potential to treat opioid dependence, but it did not show a significant change in drug preference. This suggests it may not be effective in altering opioid reward in non-dependent primates over a short period. ^{1 2 3 4 5}

How is the drug Cariprazine unique for treating cocaine and opioid use disorder?

Cariprazine is unique because it is a dopamine D3-preferring partial agonist, which means it targets specific brain receptors that may help prevent relapse in substance use disorders. This mechanism is different from other treatments that do not specifically target these receptors. ^{6 7 8 9 10}

Eligibility Criteria

Adults aged 18-65 with both cocaine and moderate to severe opioid use disorders, on stable doses of BUP-NX for at least a week, not pregnant or breastfeeding, able to understand English and provide informed consent. Excluded are those with certain mental health conditions, significant medical issues like severe kidney problems or liver damage, current high suicide risk, or taking conflicting medications.

Inclusion Criteria

I am not pregnant or breastfeeding, and I either cannot have children or use effective birth control.

An informed consent document understood, voluntarily signed and dated by the subject

Subject must provide a urine that is cocaine-negative and buprenorphine-positive on the day of enrollment

Exclusion Criteria

Any pending legal action that could prohibit participation and/or compliance in study procedures

My anemia is not severe, staying below grade 2.

Significant medical or psychiatric symptoms or dementia which in the opinion of the investigators would preclude compliance with the protocol, adequate cooperation in the study, or obtaining informed consent

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Baseline

Includes baseline assessments, behavioral tasks/fNIRS session, and randomization

1-2 visits

Outpatient Treatment

Participants receive daily cariprazine (or placebo) and daily BUP-NX, with imaging and behavioral tasks at steady-state

8 weeks

2 visits per week

Follow-up

A follow-up visit to assess medical and psychological status

1 week

Treatment Details

Interventions

• Cariprazine
• Placebo

Trial Overview The study tests if low-dose cariprazine (1.5mg daily) affects cocaine use in patients already on BUP-NX. It's randomized and placebo-controlled; some participants will also undergo brain imaging (fMRI). Over approximately 11 weeks including screening and follow-up phases, urine and blood tests monitor drug compliance.

Participant Groups

Group I: Cariprazine Experimental Treatment 1 Intervention

Group II: Placebo Placebo Group 1 Intervention

Cariprazine is already approved in United States for the following indications:

Approved in United States as Vraylar for:

• Schizophrenia
• Acute manic or mixed episodes associated with bipolar I disorder
• Depressive episodes associated with bipolar I disorder (bipolar depression)
• Adjunctive treatment with an antidepressant therapy (ADT) for major depressive disorder (MDD)

Who Is Running the Clinical Trial?

Kyle Kampman

Lead Sponsor

Trials

4

Recruited

480+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Findings from Research

This review highlights that certain drugs, including L-type calcium channel blockers (isradipine and nifedipine) and serotonin-3 receptor antagonists (MDL72222 and ICS205-930), can effectively block the positive place preference induced by cocaine in rats, suggesting their potential in treating cocaine addiction.

Additionally, the study discusses the blockade of other cocaine-related behaviors by these drugs, indicating their broader implications for understanding cocaine's effects and developing effective treatment strategies for addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blockade of cocaine-induced conditioned place preference: relevance to cocaine abuse therapeutics. Calcagnetti, DJ., Keck, BJ., Quatrella, LA., et al.[2019]

In a 12-week clinical trial involving 94 patients, both amantadine and desipramine showed initial reductions in reported cocaine abuse compared to placebo, but this effect diminished by week 8, indicating limited long-term efficacy.

Despite good treatment retention and compliance, there were no significant differences in cocaine-free urine samples between the medicated groups and placebo, suggesting that these medications may not effectively sustain abstinence in cocaine-abusing methadone-maintained patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy for cocaine-abusing methadone-maintained patients using amantadine or desipramine. Kosten, TR., Morgan, CM., Falcione, J., et al.[2019]

Buprenorphine significantly reduced the preference for remifentanil in squirrel monkeys, indicating its potential effectiveness in decreasing opioid use during the five-day treatment evaluation.

Cariprazine and methadone did not show a significant impact on drug preference, suggesting that cariprazine may not alter opioid reward in non-dependent primates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of buprenorphine, methadone, and cariprazine on economic choice between remifentanil and food in squirrel monkeys. Amirali, AS., Hecker, JC., Figueroa, HM., et al.[2023]

Buprenorphine, a mixed opioid agonist/antagonist, shows promise in reducing cocaine abuse among individuals with concurrent opioid and cocaine dependence, although it has not been proven superior to methadone in clinical trials.

The effectiveness of buprenorphine in reducing cocaine use appears to be dose-dependent, with higher doses (6 mg daily) associated with greater reductions in cocaine abuse compared to lower doses (2 mg daily).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine for cocaine and opiate dependence. Kosten, TR., Rosen, MI., Schottenfeld, R., et al.[2013]

A 56 mg/kg dose of naltrexone, administered 4 hours before conditioning, significantly reduced the reinforcing effects of cocaine, suggesting its potential as a treatment for cocaine addiction.

In contrast, an 8 mg/kg dose of methadone given 1 hour prior to conditioning increased cocaine's reinforcing properties, which may explain higher cocaine use among heroin addicts receiving methadone treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Opioidergic modulation of cocaine conditioned place preferences. Bilsky, EJ., Montegut, MJ., Delong, CL., et al.[2019]

Cariprazine (Vraylar) is an atypical antipsychotic that acts as a partial agonist at dopamine D3 and D2 receptors, with a preference for D3, and also affects serotonin 5-HT1A receptors, which contributes to its therapeutic effects.

Approved in the USA in September 2015, cariprazine is used to treat schizophrenia and acute manic or mixed episodes in bipolar I disorder, and is being explored for additional uses in treating negative symptoms of schizophrenia and bipolar depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cariprazine: First Global Approval. McCormack, PL.[2018]

Cariprazine, a D₃-preferring dopamine receptor partial agonist, has shown potential in reducing the rewarding effects of cocaine and preventing relapse in cocaine-seeking behavior in rats, indicating its possible use in treating substance abuse disorders alongside schizophrenia and bipolar mania.

In comparison to aripiprazole and bifeprunox, cariprazine demonstrated effective doses for reducing cocaine's effects and preventing relapse, suggesting it may be a promising candidate for addressing both psychiatric and substance use disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cariprazine (RGH-188), a D₃-preferring dopamine D₃/D₂ receptor partial agonist antipsychotic candidate demonstrates anti-abuse potential in rats. Román, V., Gyertyán, I., Sághy, K., et al.[2021]

Cariprazine, an antipsychotic approved for schizophrenia, has shown significant efficacy in clinical trials, with responder rates of 31% compared to 21% for placebo, and a lower relapse rate in long-term studies (24.8% vs. 47.5% for placebo).

While cariprazine can cause side effects like extrapyramidal symptoms and akathisia, it does not significantly affect metabolic variables or cause major weight gain, making it a relatively safe option for treating schizophrenia and bipolar disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cariprazine for the Treatment of Schizophrenia: A Review of this Dopamine D3-Preferring D3/D2 Receptor Partial Agonist. Citrome, L.[2016]

In clinical trials, cariprazine significantly improved schizophrenia symptoms compared to placebo, as measured by the Positive and Negative Syndrome Scale (PANSS), and showed a longer time to relapse in a long-term study.

Cariprazine was more effective than risperidone in treating negative symptoms of schizophrenia, which are often challenging to address, and it was generally well tolerated with mostly mild to moderate side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cariprazine: A Review in Schizophrenia. Garnock-Jones, KP.[2018]

Cariprazine is a new medication approved by the FDA in 2015 for treating schizophrenia and type I bipolar disorder, showing efficacy in addressing positive, negative, and cognitive symptoms of schizophrenia without causing significant extrapyramidal side effects in animal models.

While cariprazine has a unique mechanism of action as a biased agonist at dopamine receptors, it can still cause mild to moderate side effects in humans, including akathisia, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cariprazine:New dopamine biased agonist for neuropsychiatric disorders. De Deurwaerdère, P.[2017]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Blockade of cocaine-induced conditioned place preference: relevance to cocaine abuse therapeutics. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Pharmacotherapy for cocaine-abusing methadone-maintained patients using amantadine or desipramine. [2019]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Effects of buprenorphine, methadone, and cariprazine on economic choice between remifentanil and food in squirrel monkeys. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Buprenorphine for cocaine and opiate dependence. [2013]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Opioidergic modulation of cocaine conditioned place preferences. [2019]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Cariprazine: First Global Approval. [2018]

7. Germany pubmed.ncbi.nlm.nih.gov

Cariprazine (RGH-188), a D₃-preferring dopamine D₃/D₂ receptor partial agonist antipsychotic candidate demonstrates anti-abuse potential in rats. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Cariprazine for the Treatment of Schizophrenia: A Review of this Dopamine D3-Preferring D3/D2 Receptor Partial Agonist. [2016]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Cariprazine: A Review in Schizophrenia. [2018]

10. Spain pubmed.ncbi.nlm.nih.gov

Cariprazine:New dopamine biased agonist for neuropsychiatric disorders. [2017]