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.
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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
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
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
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
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)
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 STUDYThis 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 18 and above. 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.
