Naloxone + Buprenorphine Induction for Opioid Use Disorder

(NBIM Trial)

Recruiting in Palo Alto (17 mi)

Overseen by Cecilia Bergeria, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Johns Hopkins University

Must not be taking: OUD medications

Disqualifiers: Cognitive impairment, Pregnancy, Hypertension, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

The opioid overdose epidemic has persisted for several decades and is now further complicated by the permeation of fentanyl into the illicit opioid supply. While the effectiveness of medications to treat opioid use disorder (MOUD) have been well documented in the literature, the addition of fentanyl to the drug supply has complicated the initiation of MOUD, especially buprenorphine. Naloxone, an opioid antagonist, is currently utilized to reverse opioid overdose by displacing less-competitive ligands which bind at the mu-opioid receptor. Because induction to buprenorphine in the age of fentanyl is uncomfortable and can take several days to stabilize a patient on a therapeutic dose, the use of naloxone prior to buprenorphine can aid in a safe and rapid transition to buprenorphine treatment, without the effect of unintended prolonged precipitated withdrawal which can occur following the displacement of fentanyl by buprenorphine on the mu-opioid receptor. Therefore, this project will assess feasibility and acceptability of naloxone-facilitated buprenorphine initiation using a single-ascending dose design. The investigators will examine whether a single dose of buprenorphine is tolerated following administration of naloxone among a small group of individuals. If the dose is tolerated, the investigators will administer a larger dose among another small group of individuals. The investigators will examine the tolerability of up to 4 doses of buprenorphine following naloxone. This buprenorphine induction method has been characterized in case studies but it has not been evaluated in an empirical, systematic way in a controlled setting. This study will take place within an residential facility at Johns Hopkins Bayview Medical Campus, and will have immediate, real-world applicability in establishing a rapid, safe, and effective option to transition people with chronic fentanyl use to buprenorphine treatment.

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 cannot participate if you are currently taking medications for opioid use disorder or any medication that is contraindicated (not recommended) with the study medication.

What data supports the effectiveness of the drug Naloxone Nasal Spray, Narcan, Evzio for opioid use disorder?

Research shows that naloxone, used in forms like Narcan and Evzio, is effective in reversing opioid overdoses, which can be life-saving in emergency situations. Additionally, buprenorphine, when used in combination with naloxone, has been shown to improve outcomes for individuals with opioid use disorder, although adherence to the medication can be a challenge. ^{1 2 3 4 5}

Is the combination of Naloxone and Buprenorphine safe for humans?

Research shows that the combination of Naloxone and Buprenorphine is generally safe for humans. In clinical trials, it was well tolerated with a good safety profile, and serious adverse events were rare. Compared to other opioid drugs, it has a wider safety margin, meaning it is less likely to cause harmful effects at higher doses. ^{3 6 7 8 9}

How does the drug Naloxone Nasal Spray differ from other treatments for opioid use disorder?

Naloxone Nasal Spray, when used with buprenorphine, offers a unique approach by combining a rapid-acting opioid overdose reversal agent (naloxone) with a medication that reduces cravings and withdrawal symptoms (buprenorphine). This combination can be administered quickly and safely, making it practical for diverse community settings and potentially reducing the risk of misuse compared to buprenorphine alone. ^{5 7 10 11 12}

Research Team

Cecilia Bergeria, PhD

Principal Investigator

Johns Hopkins School of Medicine

Eligibility Criteria

This trial is for adults over 18 who speak English, have a moderate to severe opioid use disorder with fentanyl present in their urine, and are medically cleared to take the study medication. They must be willing to follow the study protocol but not currently on medications for OUD or pregnant/breastfeeding.

Inclusion Criteria

You are currently suffering from a moderate to severe opioid use disorder.

I am 18 years old or older.

My urine test was positive for fentanyl.

Exclusion Criteria

I have not had a serious heart problem in the last 3 years.

Deemed by the principal investigator or medical team to not be a good fit for the study protocol

Unable to read or understand study questions with assistance from the research staff

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (in-person)

Treatment

Participants undergo naloxone-facilitated buprenorphine induction with ascending doses to assess tolerability

2-3 days

Residential stay at clinical research unit

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

1 visit (in-person or virtual)

Extension

Participants are connected to a medical provider for continued buprenorphine prescribing

Treatment Details

Interventions

• Naloxone Nasal Spray (Behavioral Intervention)

Trial Overview The trial tests a new method of starting buprenorphine treatment using naloxone nasal spray among individuals who use fentanyl. It aims to see if this approach can safely and quickly transition patients without prolonged withdrawal by gradually increasing buprenorphine doses.

Participant Groups

Group I: 8mg buprenorphine Experimental Treatment 1 Intervention

8mg of buprenorphine will be given to a subset of participants immediately after naloxone administration.

Group II: 4mg buprenorphine Experimental Treatment 1 Intervention

4mg of buprenorphine will be given to a subset of participants immediately after naloxone administration.

Group III: 24mg buprenorphine Experimental Treatment 1 Intervention

24mg of buprenorphine will be given to a subset of participants immediately after naloxone administration.

Group IV: 16mg buprenorphine Experimental Treatment 1 Intervention

16mg of buprenorphine will be given to a subset of participants immediately after naloxone administration.

Naloxone Nasal Spray is already approved in Canada for the following indications:

Approved in Canada as Naloxone for:

• Reversal of opioid overdose

Who Is Running the Clinical Trial?

Johns Hopkins University

Lead Sponsor

Trials

2,366

Recruited

15,160,000+

Theodore DeWeese

Johns Hopkins University

Chief Executive Officer since 2023

MD from an unspecified institution

Allen Kachalia

Johns Hopkins University

Chief Medical Officer since 2023

MD from an unspecified institution

Cure Addiction Now

Collaborator

Trials

1

Recruited

30+

Findings from Research

Initiating buprenorphine treatment for Opioid Use Disorder (OUD) by paramedics in the prehospital setting shows promise as a potential intervention for patients at high risk of overdose, especially those who refuse transport to medical facilities.

The preliminary cases suggest that starting buprenorphine during emergency medical services (EMS) responses can help engage patients in long-term treatment services, contributing to a broader strategy to address the opioid epidemic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prehospital Initiation of Buprenorphine Treatment for Opioid Use Disorder by Paramedics. Hern, HG., Goldstein, D., Kalmin, M., et al.[2022]

In a study involving 42 healthy participants, the naloxone auto-injector (NAI) was significantly more effective than the intranasal delivery system (NXN) for administering naloxone during a simulated opioid overdose, with 90.5% success for NAI compared to 0% for NXN before training.

After training, 100% of participants successfully used NAI, while only 57.1% could use NXN, highlighting that NAI is easier to use and requires less training for effective administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Usability Study of a Novel Auto-Injector and an Intranasal System for Naloxone Delivery. Edwards, ET., Edwards, ES., Davis, E., et al.[2020]

NARCAN® Nasal Spray is easier to use than a naloxone prefilled syringe with nasal atomizer (PFS-NA), requiring fewer steps for administration, which is crucial in high-stress opioid overdose situations.

Inexperienced users, such as bystanders or nonmedical first responders, are more likely to make mistakes with the more complex PFS-NA, highlighting the importance of using NARCAN® Nasal Spray to improve the chances of timely and correct naloxone delivery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Human Factors Evaluation of Two Nasal Naloxone Administration Devices: NARCAN® Nasal Spray and Naloxone Prefilled Syringe with Nasal Atomizer. Tippey, KG., Yovanoff, M., McGrath, LS., et al.[2020]

The study will involve 280 adults with opioid use disorder and aims to improve adherence to buprenorphine-naloxone treatment through two psychological interventions: contingency management (CM) and brief motivational interviewing plus substance-free activities and mindfulness (BSM).

The primary goal is to assess which intervention is more effective in promoting medication adherence, measured by attendance at physician appointments and the presence of buprenorphine in urine toxicology, with follow-up occurring 8 months after randomization.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of a sequential multiple assignment randomized trial to test contingency management and an integrated behavioral economic and mindfulness intervention for buprenorphine-naloxone medication adherence for opioid use disorder. Peter, SC., Murphy, JG., Witkiewitz, K., et al.[2023]

The use of the naloxone autoinjector (NAI) Evzio significantly increased from 218 prescriptions in Year 1 to 2,527 in Year 3, leading to a reduction in fatal opioid overdoses, with 2.5 deaths avoided in Year 3 compared to matched controls.

Despite rising acquisition costs of the NAI, which reached nearly $1.5 million in Year 3, the medical resource savings associated with its use offset these costs, resulting in a net cost of $481,000, demonstrating the economic benefit of timely access to naloxone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Economic impact of a novel naloxone autoinjector on third-party payers. Weiss, RC., Bazalo, GR., Thomson, H., et al.[2015]

Buprenorphine-naloxone (Suboxone) was found to be safe and well tolerated for short-term opioid detoxification in a study involving 234 opioid-dependent patients across twelve community-based treatment programs.

The treatment showed high medication compliance (81% of doses ingested) and successful induction, with 90% of patients reaching the target dose within three days, indicating its efficacy and practicality in diverse settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bringing buprenorphine-naloxone detoxification to community treatment providers: the NIDA Clinical Trials Network field experience. Amass, L., Ling, W., Freese, TE., et al.[2022]

Buprenorphine/naloxone has a unique pharmacology that provides a ceiling effect on its cardio-respiratory depressant properties, making it potentially safer than other opioids, especially at higher doses.

Data from various safety monitoring systems indicate that buprenorphine/naloxone has a favorable safety profile compared to other opioids and psychotropic drugs, suggesting it may reduce the risk of overdose-related morbidity and mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Question About the Safety of Buprenorphine/Naloxone and Benzodiazepine Drugs. Howland, RH.[2015]

Narcan, a nasal-spray form of naloxone, is FDA-approved and provides an easy-to-use method for reversing opioid overdoses, making it a critical tool for saving lives.

As overdose deaths rise in hospitals, health systems are considering equipping police and security officers with naloxone and training them in its use to enhance emergency response capabilities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Equipping an urban hospital police and security team with Narcan. Driscoli, J., Michelman, B.[2018]

In a case series of three patients from a Vancouver addiction clinic, unexpected precipitated withdrawal occurred during the initiation of buprenorphine/naloxone (BUP/NX) after periods of fentanyl abstention, highlighting a challenge in treating opioid use disorder.

The findings suggest that fentanyl may have a longer-lasting effect in the body than previously thought, complicating the BUP/NX induction process and indicating a need for revised strategies when treating individuals with a history of fentanyl use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Challenges with buprenorphine inductions in the context of the fentanyl overdose crisis: A case series. Shearer, D., Young, S., Fairbairn, N., et al.[2023]

This study is the first randomized controlled trial comparing rapid micro-induction to standard induction of buprenorphine/naloxone in treating opioid use disorder, involving 50 participants to assess safety and effectiveness.

Rapid micro-induction could potentially eliminate the need for patients to experience withdrawal symptoms before starting treatment, addressing a significant barrier to accessing care for opioid use disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing rapid micro-induction and standard induction of buprenorphine/naloxone for treatment of opioid use disorder: protocol for an open-label, parallel-group, superiority, randomized controlled trial. Wong, JSH., Nikoo, M., Westenberg, JN., et al.[2023]

A survey of intravenous drug users in Helsinki revealed that 73% used buprenorphine as their primary drug, primarily for self-treating addiction or withdrawal symptoms.

The combination of buprenorphine and naloxone (Suboxone) was tried by 68% of respondents, but 80% reported negative experiences, suggesting that while it may help reduce buprenorphine abuse, its acceptance among users is low.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abuse liability of buprenorphine-naloxone tablets in untreated IV drug users. Alho, H., Sinclair, D., Vuori, E., et al.[2015]

References

1. England pubmed.ncbi.nlm.nih.gov

Prehospital Initiation of Buprenorphine Treatment for Opioid Use Disorder by Paramedics. [2022]

2. England pubmed.ncbi.nlm.nih.gov

The feasibility of employing a home healthcare model for education and treatment of opioid overdose using a naloxone auto-injector in a private practice pain medicine clinic. [2019]

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

Comparative Usability Study of a Novel Auto-Injector and an Intranasal System for Naloxone Delivery. [2020]

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

Comparative Human Factors Evaluation of Two Nasal Naloxone Administration Devices: NARCAN® Nasal Spray and Naloxone Prefilled Syringe with Nasal Atomizer. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Use of a sequential multiple assignment randomized trial to test contingency management and an integrated behavioral economic and mindfulness intervention for buprenorphine-naloxone medication adherence for opioid use disorder. [2023]

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

Economic impact of a novel naloxone autoinjector on third-party payers. [2015]

7. England pubmed.ncbi.nlm.nih.gov

Bringing buprenorphine-naloxone detoxification to community treatment providers: the NIDA Clinical Trials Network field experience. [2022]

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

A Question About the Safety of Buprenorphine/Naloxone and Benzodiazepine Drugs. [2015]

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

Equipping an urban hospital police and security team with Narcan. [2018]

10. Australia pubmed.ncbi.nlm.nih.gov

Challenges with buprenorphine inductions in the context of the fentanyl overdose crisis: A case series. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Comparing rapid micro-induction and standard induction of buprenorphine/naloxone for treatment of opioid use disorder: protocol for an open-label, parallel-group, superiority, randomized controlled trial. [2023]

12. Ireland pubmed.ncbi.nlm.nih.gov

Abuse liability of buprenorphine-naloxone tablets in untreated IV drug users. [2015]