Using lofexidine with buprenorphine to help veterans with PTSD and opioid addiction

Lofexidine Combined With Buprenorphine for Reducing Symptoms of Post-Traumatic Stress Disorder (PTSD) and Opioid Use Relapse in Veterans

This study is testing if adding lofexidine to buprenorphine can help veterans with both PTSD and opioid addiction feel better and reduce their chances of relapse.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 120 (estimated)
• Ages: 18 Years to 70 Years
• Sex: All
• Sponsor: Pharmacotherapies for Alcohol and Substance Use Disorders Alliance (Academic / other)
• Drugs / interventions: crizotinib, imatinib
• Locations: 2 sites (Houston, Texas and 1 other locations)
• Trial ID: NCT04360681 on ClinicalTrials.gov

What this trial studies

This clinical trial aims to evaluate the effectiveness of lofexidine (LFX) as an adjunct treatment to buprenorphine (BUP) for veterans suffering from both opioid use disorder (OUD) and post-traumatic stress disorder (PTSD). The study will measure the impact of this combination therapy on reducing opioid relapse and alleviating PTSD symptoms. Primary endpoints include monitoring drug-taking behavior and changes in PTSD symptom scores over a specified treatment period. The trial will also assess the safety and tolerability of the combined treatment compared to BUP alone.

Who should consider this trial

Good fit: Ideal candidates for this study are veterans aged 18 to 70 who are currently on a stable dose of buprenorphine and have a documented diagnosis of PTSD.

Not a fit: Patients who are not veterans, those with terminal illnesses, or individuals who cannot provide informed consent may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could significantly improve treatment outcomes for veterans struggling with both PTSD and opioid addiction.

How similar studies have performed: Other studies have explored similar combinations of treatments for PTSD and opioid use disorder, showing promising results, but this specific approach is relatively novel.

Eligibility criteria

Inclusion Criteria:

1. Male or female, 18 to 70 years of age, capable of reading and understanding English, and able to provide written informed consent (i.e. no persons who are imprisoned, of minor age, diagnosed with dementia, diagnosed with a terminal illness, or who otherwise require a surrogate to provide informed consent).
2. Be on a stable dose of BUP maintenance therapy for at least 7 days at the same maintenance dose. Veterans or non-Veterans who are not currently on a stable dose of BUP maintenance therapy will be referred to the Substance Dependence Treatment Program at the MEDVAMC or the Addiction Clinic at BTGH and invited to screen for this study once BUP treatment is stable.
3. Have a positive urine toxicology screen for BUP.
4. Has a previous diagnosis of PTSD documented in CPRS or meets criteria for current PTSD as assessed by the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5).
5. Have hematology and chemistry laboratory tests within 3 months of study entry that are within normal (± 15%) limits, except liver function test results, which can be 5X the upper limit of normal.
6. Have a medical history and physical examination demonstrating no clinically significant contraindications for study participation within 3 months of study entry.

Exclusion Criteria:

1. DSM-5 criteria for substance use disorders (SUDs) other than OUD, nicotine, or cannabis, or stimulants \[assessed by UDS and the Mini-International Neuropsychiatric Interview (MINI)\].

   \*Note that because the MINI assesses for SUDs over the past 12 months, potential participants will only be excluded if they both meet DSM-5 criteria for a SUD and have a positive UDS for that substance on study day 1. If a participant both meets DSM-5 criteria for a SUD and has a positive UDS at the screening visit, they will be informed that to be enrolled in the study they must have a negative UDS at their first study visit (i.e., prior to being enrolled).
2. Self-reported use of methadone in the last 14 days.
3. Be undergoing significant opioid withdrawal, as assessed by the COWS (defined as \>12 on the COWS).
4. Increased risk of suicide that necessitates inpatient treatment or warrants therapy excluded by the protocol, and/or current suicidal plan, per investigator clinical judgement, based on interview and defined on the Columbia Suicidality Severity Rating Scale (C-SSRS).
5. Females of child-bearing potential must be using medically acceptable birth control (e.g. oral, implantable, injectable, or transdermal contraceptives; intrauterine device; double-barrier method) AND not be pregnant OR have plans for pregnancy or breastfeeding during the study.
6. Use of any of the following medications within 30 days prior to enrollment (self-report on Prior/Concomitant Medications (Meds) form):

   1. Benzodiazepines, barbiturates, or other CNS depressants
   2. Methadone or any other prescription analgesics, except BUP or BUP/naloxone
   3. Opioid antagonists such as naltrexone, except naloxone in combination with BUP
   4. Tricyclic antidepressants, which may reduce the efficacy of imidazoline derivatives
   5. Drugs that have been associated with QT prolongation, including:

   i. Antiarrhythmics: amiodarone, ajmaline, quinidine, disopyramide, procainamide, sotalol, ibutilide, dofetilide, etc.

ii. Antimicrobials

1. Fluoroquinolones: ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, etc.
2. Macrolides: erythromycin, roxithromycin, azithromycin, clarithromycin, etc.
3. Antifungals: ketoconazole, itraconazole, etc. iii. Antipsychotics: haloperidol, thioridazine, ziprasidone, clozapine, quetiapine\*, risperidone\*, olanzapine, etc.

   f. Any other medications that might seriously and adversely interact with either LFX or BUP or have contraindication(s) to these medications
   * The following medications will be permissible at the discretion of the study physician:

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1. Bupropion a. Allowable dosage of up to 150mg daily (this is well below the therapeutic dose for depression, but is given for smoking cessation)
2. Quetiapine

   a. Allowable dosage 25mg -150 mg daily (typically given at night for sleep and well below the antipsychotic dosage of 400 mg or more)
3. Risperidone

   1. Allowable dosage 0.25mg- 1mg daily (below the antipsychotic dose of 2-8 mg daily) Prospective participants must be on a steady dose of the medication to be considered.

7. Prescription of any of the following medications within 30 days prior to enrollment (review of EDC patient chart):

a. Inducers or inhibitors of cytochrome P-450 3A4 (CYP3A4), the main metabolic enzyme of BUP: i. Antiretrovirals or other strong CYP3A4 inhibitors: boceprevir, cobicistat, conivaptan, danoprevir and ritonavir, elvitegravir and ritonavir, grapefruit juice, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, paritaprevir and ritonavir and ombitasvir and/or dasabuvir, posaconazole, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, troleandomycin, voriconazole, clarithromycin, diltiazem, idelalisib, nefazodone, nelfinavir, etc.

ii. Moderate CYP3A4 inhibitors: aprepitant, cimetidine, ciprofloxacin, clotrimazole, crizotinib, cyclosporine, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, tofisopam, verapamil, etc.

iii. Anticonvulsants or other strong CYP3A4 inducers: carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's wort, etc.

8. Clinically significant abnormal ECG (such as second- or third-degree heart block, QTc interval ≥500 msec, uncontrolled arrhythmia), and/or history of a myocardial infarction.

9. Heart rate \< 55 bpm or symptomatic bradycardia.

10. Systolic blood pressure \< 90 mmHg, and/or diastolic blood pressure \< 60 mmHg, and/or symptomatic hypotension.

11. Have a history of seizure disorder or severe traumatic brain injury (TBI); per the Ohio State TBI assessment.

12. Self-reported HIV/AIDS, active tuberculosis, and/or active syphilis.

13. Have significant hepatic, pancreatic (e.g., Type I diabetes), gastrointestinal or renal (that would affect absorption, metabolism or excretion of the study drug), endocrine, cardiac, neurological, psychiatric, pulmonary, hematologic, or other disorders (self-reported during Medical History assessment) that a study clinician believes would make study participation unsafe, treatment compliance difficult, or otherwise be determined by the PI to not be a good study candidate.

* The following conditions will be permissible at the discretion of the study physician:

  i. Type I \&II diabetes- participants must meet the following criteria:

  1. Participants must be receiving MAT for at least 6 months 2. Hemoglobin A1c levels must be stable and relatively low 3 months prior to study entry and at the time of screening ii. Pancreatitis

  1. There must be 12 months between enrollment and last pancreatitis episode iii. Hepatitis

  1. Lab work submitted 3 months prior to study entry and at the time of screening should exhibit no elevations in liver functioning tests beyond 3X the upper limit of normal

Where this trial is running

Houston, Texas and 1 other locations

• Michael E. DeBakey Veterans Affairs Medical Center — Houston, Texas, United States (Recruiting)
• South Texas Veterans Health Care System — San Antonio, Texas, United States (Recruiting)

Study contacts

• Principal investigator: Christopher D. Verrico, PhD — Baylor College of Medicine
• Study coordinator: Adetola Vaughan

Conditions Post Traumatic Stress Disorder; Opioid-use Disorder; Opioid Use Disorder; Opioid; Opioid Use; Veteran