Opioid Withdrawal
Conditions
Brief summary
A phase II double-blind placebo-controlled parallel group clinical trial that will randomize 90 subjects to investigate whether pregabalin (PGB) combined with Lofexidine (LFX) can reduce opioid withdrawal-related subjective effects, and investigate, whether the PGB/LFX combination can increase the proportion of patients with an opioid use disorder (OUD) who complete detoxification and transition to antagonist treatment with extended-release injectable naltrexone (XR-NTX).
Detailed description
An inpatient detoxification study where pregabalin (PBG) will be given orally at a starting dose of up to 600 mg daily (group 1) tapered to 100 mg daily over 7 days; given with lofexidine (LFX) starting at 2.16 mg daily and declining to 0.72 mg over 7 days. On day 8, subjects are offered an injection of XR-NTX if they provide a urine sample that is negative for opioids and buprenorphine and pass a naloxone challenge. All subjects, regardless of whether or not they receive XR-NTX, will be given a referral and appointment for follow-up treatment when they leave the inpatient detoxification program.
Interventions
DRUGPregabalin 200 MG capsules
oral pregabalin 200 mg capsules given with a taper on day 5
DRUGPlacebo oral tablet
oral Placebo
DRUGLofexidine 0.18Mg Tab
lofexidine 0.18 tab given with a taper starting on day 5
Sponsors
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
The Penn Investigational Drug Service (IDS) will prepare blinded pregabalin capsules by over encapsulation of the drug into capsules shells matching the placebo capsules. Blinded pregabalin capsules will be packaged into blister packs along with lofexidine tablets, in separate compartments that are labeled for dosing times on days 1-7 and ship them to the research sites.
Intervention model description
for the primary comparison of longitudinal subjective withdrawal measures, comparing the groups on rate of decrease across detox days, using a linear group by time effect for the mixed effects models described above. We have one primary outcome, so use an alpha level of 0.05, and we use two-sided tests. 90 subjects, 30 from each of three sites, who will be randomized into two groups, with 30 assigned to Lofexidine plus Placebo, and 60 to Lofexidine plus a starting daily dose of 400 mg of pregabalin and increasing to 600mg Pregabalin on day 2.
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Male and/or female subjects ≥ 18 years of age 2. Meet DSM-5 criteria for an Opioid Use Disorder with physiologic features. Have 2 or more of the 11 DSM 5 criteria for opioid disorder including tolerance and withdrawal features in the last 12 months 3. Interested in opioid antagonist treatment 4. Have used opioids in 20 or more of the last 30 days 5. Have a stable address in the local area; not planning to move; have documents for ID check 6. Absence of medical or psychiatric conditions that are likely to interfere with study participation 7. Have a 12 lead ECG demonstrating a QTc ≤450 msec and a QRS interval ≤120 msec. The site PI has the final determination for inclusion into the study for ECGs unless there is a question of QT prolongation or other factors (QTc/Fre uses the Frederica formula (QTc = QT/RR(1/3)). If consultation is needed, the PENN cardiologists and the medical monitor should be contacted 8. If female, have a negative pregnancy test and uses adequate contraception if of childbearing potential
Exclusion criteria
1. Current psychotic disorder (bipolar I, schizophrenia, major depression with psychotic features,) as defined by the MINI 2. An alcohol, benzodiazepine, or other sedative use disorder with physiological features that require medication for detoxification 3. History of allergy or other serious adverse event due to treatment with pregabalin, XR-NTX, or lofexidine 4. Pending incarceration in the next 30 days 5. Homicidal or otherwise behaviorally disturbed requiring immediate attention. 6. High Risk for suicide as determined by answering 'yes' to questions 4 and/or 5 on C-SSRS at screening 7. Blood pressure \<90 mm Hg (systolic) or \<60 mm Hg (diastolic). If this value is out of normal range, the investigator and a study clinician will decide subject inclusion or exclusion on a case-by-case basis 8. Heart rate and/or pulse\<50 bpm at screening-sitting 9. An Estimated Glomerular Filtration Rate eGFR\<90 mL/min/1.73m2 10. A History of, or current Seizure disorder (excluding childhood febrile seizures) 11. Inability to read and/or understand English. For example, unable to understand the informed consent as demonstrated by failing to answer 9/10 questions correctly on the quiz 12. Pregnant or breastfeeding 13. Currently taking sympathomimetic drugs, or a thiazolidinedione antidiabetic 14. An ALT and/or AST test that is at \>4X the top limit of normal 15. A Child-Pugh score \>7 16. Currently receiving opioids for pain management 17. In a treatment study where medication was administered in the last 30 days 18. Currently using medications that are known to be strong or moderate inhibitors of CYP2D6 such as fluoxetine, paroxetine, mirabegron, bupropion, quinidine, terbinafine, cimetidine, cinacalcet, duloxetine, or fluvoxamine 19. In a methadone maintenance or buprenorphine treatment program within the last 30 days
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Subjective Opioid Withdrawal Scale-Gossop (SOWS) Scale Score | 7 days | mild = 1-10 moderate=11-20 severe=21-30 higher number equals worse score |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Completion of Withdrawal Management | 7 days | proportion of participants who completed the 7-day detoxification |
Countries
United States
Participant flow
Recruitment details
Participants were recruited based on media advertising from 3 treatment programs between December 2020 and March 2023. The first participant was enrolled on December 17, 2020 and the last participant was enrolled on 3/1/2023.
Pre-assignment details
90 consented and enrolled participants who met inclusion criteria and were randomized 1:1 ratio of either active pregabalin + lofexidine, or placebo pregabalin + lofexidine.
Participants by arm
| Arm | Count |
|---|---|
| PGB/LFX; 0.54 mg lofexidine and 200 mg Pregabalin on days 1 -7 with taper for pregabalin and lofexidine starting on day 5
Pregabalin 200 MG capsules: oral pregabalin 200 mg capsules given with a taper on day 5
Lofexidine 0.18Mg Tab: lofexidine 0.18 tab given with a taper starting on day 5 | 58 |
| Lofexidine and PLACEBO 0.54 mg lofexidine and Placebo (PLB) on days 1-7 with taper for lofexidine starting on day 5
Placebo oral tablet: oral Placebo
Lofexidine 0.18Mg Tab: lofexidine 0.18 tab given with a taper starting on day 5 | 32 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 24 | 19 |
| Overall Study | Not Dosed Never met WD criteria | 4 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 0 |
Baseline characteristics
| Characteristic | PGB/LFX; | Lofexidine and PLACEBO | Total |
|---|---|---|---|
| Age, Continuous | 39.4138 years STANDARD_DEVIATION 10.40417 | 37.6563 years STANDARD_DEVIATION 10.2189 | 38.7889 years STANDARD_DEVIATION 10.3157 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 0 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 54 Participants | 32 Participants | 86 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Fentanyl Use | 53 Participants | 30 Participants | 83 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 6 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 10 Participants | 2 Participants | 12 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 32 Participants | 23 Participants | 55 Participants |
| Region of Enrollment United States | 58 participants | 32 participants | 90 participants |
| Sex: Female, Male Female | 13 Participants | 8 Participants | 21 Participants |
| Sex: Female, Male Male | 45 Participants | 24 Participants | 69 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 58 | 0 / 32 |
| other Total, other adverse events | 36 / 58 | 26 / 32 |
| serious Total, serious adverse events | 0 / 58 | 1 / 32 |
Outcome results
Primary
Subjective Opioid Withdrawal Scale-Gossop (SOWS) Scale Score
mild = 1-10 moderate=11-20 severe=21-30 higher number equals worse score
Time frame: 7 days
Population: males, females 18+ years of age, opioid use disorder
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PGB/LFX; | Subjective Opioid Withdrawal Scale-Gossop (SOWS) Scale Score | 7.0 score on a scale | Standard Deviation 4.6 |
| Lofexidine and PLACEBO | Subjective Opioid Withdrawal Scale-Gossop (SOWS) Scale Score | 9.1 score on a scale | Standard Deviation 5.1 |
Comparison: A nonparametric (Kruskal-Wallis) comparison of the two groups (p=0.049)p-value: 0.05Chi-squared
Secondary
Completion of Withdrawal Management
proportion of participants who completed the 7-day detoxification
Time frame: 7 days
Population: male, females 18+ years of age, opioid Use diagnosis
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PGB/LFX; | Completion of Withdrawal Management | completed detox | 23 Participants |
| PGB/LFX; | Completion of Withdrawal Management | did not complete detox | 35 Participants |
| Lofexidine and PLACEBO | Completion of Withdrawal Management | completed detox | 9 Participants |
| Lofexidine and PLACEBO | Completion of Withdrawal Management | did not complete detox | 23 Participants |
Comparison: hypothesis: more people in active PGB/LFX will complete withdrawal CI = 95% P = 0.5p-value: 0.27Chi-squared