X:BOT:  AN OPEN-LABEL,
HEAD-TO-HEAD STUDY

Open-Label Study on the Treatment of Opioid Dependence1

THE X:BOT STUDY

Extended-Release Naltrexone (XR-NTX) and Buprenorphine-Naloxone (BUP-NX) were equally safe and effective for relapse prevention among participants, once initiated.

The comparative effectiveness of XR-NTX and BUP-NX was assessed in a US-based, 24-week, open-label randomized clinical trial.

  • The primary outcome was the time to a relapse event.* Published secondary outcomes included opioid craving, proportion of participants successfully initiated onto study medication, safety, and frequency of non-study opioid use
    • XR-NTX treatment could be initiated after complete detoxification, whereas BUP-NX could be initiated when withdrawal symptoms emerged. 79 participants could not be initiated on XR-NTX due to unsuccessful detoxification, but only 17 participants could not be initiated onto BUP-NX.

Study Design

X:BOT Study Design Diagram

202 individuals were excluded because they dropped out of treatment, did not meet eligibility criteria, completed screening but were not eligible, or other reasons.

§ 217 randomized early; 353 randomized late.

Participants who were randomized but unable to initiate treatment were considered induction failures and excluded from the per-protocol population.

See full study design and demographics


Primary endpoint

RELAPSE EVENTS: INTENTION-TO-TREAT POPULATION

There were opioid-relapse events in 65% of all participants randomized to XR-NTX and in 57% of all participants randomized to BUP-NX (OR 1.44, 95% CI 1.02-2.01; P=0.036), due in most part to many randomized participants in the ITT population not initiating treatment with XR-NTX.

OPIOID RELAPSE, WEEKS 3-24 – ITT

Opioid relapse, weeks 3-24 - Intention to Treat was 65% for XR-NTX n=283 and 57% for BUP-NX n=287

OR 1.44, 95% CI 1.02-2.01; P=0.036

RELAPSE EVENTS: PER-PROTOCoL POPULATION

Relapse events occurred in 52% of participants inducted to XR-NTX vs 56% of participants inducted to BUP-NX.

  • The median time to relapse was 20.4 weeks in the XR-NTX group and 15.2 weeks in the BUP-NX group (HR 0.92, 95% CI 0.71-1.18; P=0.49)

OPIOID RELAPSE, WEEKS 3-24 – PER-PROTOCOL

Opioid relapse, weeks 3-24 - Per-Protocol was 52% for XR-NTX n=204 and 56% forBUP-NX n=270

OR 0.87, 95% CI 0.60-1.25; P=0.44

Once participants were inducted to either XR-NTX or BUP-NX, they achieved similarly favorable and important clinical outcomes: relapse-free survival, overall relapse, retention in treatment, negative urine samples, days of opioid abstinence, and self-reported cravings.

EARLY TERMINATION

Participants who terminated early from the planned 24-week treatment

53% early termination for XR-NTX 57% early termination for BUP-NX

96 of 204 participants inducted to XR-NTX treatment and 115 of 270 participants inducted to BUP-NX treatment did not end medication early and completed 24 weeks of treatment


SECONDARY ENDPOINTS

OPIOID CRAVING

Subjective opioid craving declined rapidly from baseline in both treatment groups

Average opioid craving was initially less for the XR-NTX group (P=0.0012 at week 7) than for the BUP-NX group, then converged by week 24 (P=0.20)

Graph of opioid craving score over 24 weeks for both per-protocol BUP-NX (n=270) and XR-NTX (n-204)

ADVERSE EVENTS

  Adverse Events and Serious Adverse Events
  XR-NTX group (n=283) BUP-NX group (n=287)
Treatment-emergent adverse events All Serious All Serious
Participants with one or more treatment-emergent adverse eventII 111 (54%) 29 (14%) 141 (52%) 29 (11%)
Number of treatment-emergent adverse events 247 39 334 35
Study medication discontinued due to adverse event 6 8
Type of treatment-emergent adverse event
Injection site reaction, mild or moderate 46 NA
Gastrointestinal 34 59
Psychiatric disorders 30 9 29 11
Injury, poisoning, and procedural complications 23 25
Infections and Infestations 22 5 27 6
Nervous system disorders 22 28
Pregnancy 3 4
Death 3 4
Overdose Events All Per-protocol All Per-protocol
Participants with one or more overdose event 15 9# 8 7#
Number of overdose events 18** 10 10** 9
Fatal overdose events All Per-protocol All Per-protocol
Number 2 2 3 3

II Treatment emergent is defined as any adverse events that occurred after the study day of induction for those participants inducted onto study medication.

P=0.14 (Fisher’s exact).

#P=0.31 (Fisher’s exact).

**Four participants reported more than one overdose event. Three of the four participants were randomly assigned to XR-NTX (two of these were induction failures, one inducted); each reported two overdose events. One of the four was randomly assigned to BUP-NX (inducted) and reported three overdose events. None of these nine overdoses were fatal.

The proportion of participants reporting adverse events and serious adverse events did not differ between groups, with the exception of injection site reactions among the XR-NTX group that were of minor to moderate severity.

Five fatal overdoses occurred: two participants treated with XR-NTX and three participants treated with BUP-NX.

This is not a complete list of adverse events for VIVITROL. Please see Important Safety Information and full Prescribing Information for additional safety information.


STUDY LIMITATIONS

  • Study sites varied in detoxification protocols and length of inpatient stay
  • Ease of induction is a well-known limitation of XR-NTX compared to BUP-NX
  • A real-world effectiveness study such as this includes more sources of bias than a tightly managed efficacy study, but has potentially higher generalizability

DOWNLOAD THE FULL STUDY

View the complete open-label, head-to-head study in the treatment of opioid dependence.

DOWNLOAD X:BOT STUDY

This study was done in parallel with Tanum: An Open-Label Study, a randomized trial also evaluating XR-NTX versus BUP-NX.2 The authors of the X:BOT study reported that the findings of the two studies were consistent. Both studies found that for participants who were able to begin treatment, XR-NTX and BUP-NX were equally safe and effective in preventing relapse. Both products have important clinical utility and should be available to appropriate patients.


FULL STUDY DESIGN

Data from a US-based 24-week, multicenter, open-label, randomized clinical trial of opioid use disorder (DSM-5 criteria) outpatients, age above 18 years. 772 participants were recruited and screened during voluntary, usual care, inpatient detoxification admissions. Participants had used non-prescribed opioids in the previous 30 days. Of these, 570 participants were randomized to receive either daily sublingual self-administered BUP-NX, 8 to 24 mg/day (n=287), or XR-NTX, 380 mg, administered intramuscularly every fourth week (n=283). XR-NTX treatment could be initiated after ≥3 days from last opioid use, opioid-negative urine drug test, and a negative naloxone challenge; criteria were not met by 79 participants. BUP-NX treatment could be initiated once withdrawal symptoms emerged; criteria were not met by 17 participants. Exclusion criteria included the presence of serious medical, psychiatric, or substance use disorders; liver function tests greater than 5 times the upper limit of normal; suicidal or homicidal; had allergy or sensitivity to XR-NTX or BUP-NX; were not able to have safe intramuscular XR-NTX treatment; or women who were or could become pregnant, or were breastfeeding.

DEMOGRAPHICS and CLINICAL BASELINE CHARACTERISTICS

  Intention to Treat
(N=570)
  Extended-release Naltrexone
(n=283)
Buprenorphine-Naloxone
(n=287)
Age, years 34.0 (9.5) 33.7 (9.8)
Male 69% 72%
Female 31% 28%
White 73% 75%)
Opioid use, years 12.8 (9.0) 12.2 (9.0)
Opioid used in the 7 days before detox admission
Heroin 81% 81%
Opioid analgesic 15% 16%
Buprenorphine 2% 1%
Methodone 1% 1%

Data are mean (SD).

*Relapse was defined as opioid use after day 20, either 4 consecutive weeks with at least one day of non-study opioid use as measured by a weekly urine drug test or 7 consecutive days with self-reported opioid use.

Craving was self-reported with an opioid-craving visual analog scale (VAS), range 0-100.

Before XR-NTX induction, participants had to complete detoxification (≥3 days from last opioid use), have opioid-negative urine, and a negative naloxone challenge (no or minimal opioid withdrawal symptoms following intramuscular, subcutaneous, or intravenous administration of ≥0.4 mg dose of naloxone, a short-acting opioid antagonist).

VIVITROL is not right for everyone. There are significant risks from VIVITROL treatment, including risk of opioid overdose, injection site reactions and sudden opioid withdrawal.
See Important Safety Information below. Discuss all benefits and risks with your patients. See Prescribing Information and Medication Guide with your patients.

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REQUEST A REPRESENTATIVE

Request a visit from a VIVITROL representative to learn more about how VIVITROL may help your opioid- and alcohol-dependent patients.

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VIVITROL® Co-pay Savings Program

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Learn how the VIVITROL® Co-pay Savings Program may assist eligible* patients with out-of-pocket expenses for their VIVITROL prescriptions.

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References:

  1. Lee JD, Nunes EV Jr, Novo P, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomized controlled trial. Lancet. 2018;391(10119):309-318.
  2. Tanum L, Solli KK, Latif ZE, et al. Effectiveness of injectable extended-release naltrexone vs daily buprenorphine-naloxone for opioid dependence: a randomized clinical non-inferiority trial. JAMA Psychiatry. 2017;74(12):1197-1205.
*Eligibility for Alkermes-Sponsored Co-pay Assistance: Offer valid only for prescriptions for FDA-approved indications. You must be at least 18 years old. If you are purchasing your VIVITROL prescriptions with benefits from Medicare, including Medicare Part D or Medicare Advantage plans; Medicaid, including Medicaid Managed Care or Alternative Benefit Plans (“ABPs”) under the Affordable Care Act; Medigap; Veterans Administration (“VA”); Department of Defense (“DoD”); TriCare®; or any similar state funded programs such as medical or pharmaceutical assistance programs, you are not eligible for this offer. Void where prohibited by law, taxed or restricted. Alkermes, Inc. reserves the right to rescind, revoke, or amend these offers without notice.