Clinical trial NCT04877093: Repurposing Low-Dose Clonidine for PTSD in Veterans
Official title: Repurposing Low-Dose Clonidine for PTSD in Veterans
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: PTSD
Posttraumatic Stress Disorder
Sleep
Keywords: PTSD
veterans
military
sleep
adrenergic receptor
Lead sponsor: Wake Forest University Health Sciences
Sponsor class: OTHER
First posted: 2021-05-07
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Randomized, placebo-controlled, blinded crossover
Primary purpose: TREATMENT

Brief summary: Hypothesis: Veterans with PTSD prescribed clonidine will demonstrate improvements in PTSD symptoms, including daytime, nighttime, and sleep-related behaviors.

Detailed description: Military veterans with Posttraumatic Stress Disorder (PTSD) suffer emotionally, physically, and socially. They have higher rates of suicide,1 issues with anger/aggression,2 substance use disorder,3 or other life difficulties (e.g., mental health disorders, marriage instability, unemployment).4 However, current first-line treatments are only effective for around half of patients receiving treatment.5,6 This is problematic given that PTSD is relatively common with a lifetime prevalence in US veterans of 10 - 31%3,7 meaning that many military veterans and their families are suffering for lack of effective treatments.

PTSD symptoms can be categorized into four clusters: re-experiencing, avoidance, cognitive or mood disturbances, and hyperarousal/reactivity.8 Symptoms may occur during the day or at night, thus disrupting sleep. Many symptoms are thought to be mediated through noradrenergic pathways. Specifically, noradrenergic overactivity may directly or indirectly affect irritability/aggression, hypervigilance, ability to concentrate, startle reactions, and sleep or other nighttime symptoms.9 These nighttime disruptions are especially problematic given that lack of sleep can exacerbate other PTSD symptoms directly or through associations with increased depression, heightened anxiety, and unstable mood/affect.10-12 Selective serotonin reuptake inhibitors (SSRI) are a first-line pharmacotherapy for PTSD, yet SSRIs do not target noradrenergic pathways, have reduced efficacy in veterans,13 and only weakly impact nighttime symptoms.11,14,15

To directly address hyperarousal and sleep, previous studies have tested medications targeting the noradrenergic pathway or sleep interventions, resulting in promising outcomes for a subpopulation of veterans with PTSD.16-27 Studies on prazosin, an antagonist of post-synaptic α1 noradrenergic receptors, have shown promise for veterans with PTSD.16,18 Clonidine is similar to prazosin and is proposed to have similar effects on PTSD; however, whereas prazosin and blocks the effects of norepinephrine, clonidine decreases norepinephrine release 28 and could therefore have greater effects on hyperarousal. Retrospective, open-label studies have suggested that clonidine use is associated with improvement in PTSD.16,17 However, no prospective studies have been published testing the effects of clonidine on PTSD, either in veterans or any other population.

Hypothesis: Veterans prescribed clonidine will demonstrate improvements in PTSD symptoms, including daytime, nighttime, and sleep-related behaviors.

Eligibility criteria: Inclusion Criteria:

* ≥18 years old
* US military veteran
* Currently has PTSD diagnosis as determined by clinical diagnosing or by the PI
* Screening score on PCL5 minimum of 40 (per data from previous studies36-38, a PCL5 score of 40 is roughly equivalent to a CAPS score of 30)
* Scores ≥10 on PCL5 items 1-5 (intrusion) or scores ≥10 on PCL5 items 15-20
* From PCL5 questionnaire, must score the following minimum in each of the following categories:

  * 1x score of 2 on Questions 1-5
  * 1x score of 2 on Questions 6-7
  * 2x score of 2 on Questions 8-14
  * 2x score of 2 on Questions 15-20
* Has score ≥3 on CAPS nightmare items B2 and E6
* Speaks and understands English
* Willing to come into the clinic as programmed

Exclusion Criteria:

* Pregnant or breastfeeding
* At Moderate or High risk of suicide based on "past month" column of the Columbia-Suicide Severity Rating Scale (CSSR-S) screen version - recent.
* Has acute or unstable mental illness or any cognitive issues which the PI determines would interfere with engagement in the study (e.g., active schizophrenia, uncontrolled bipolar, history of neurocognitive impairment, history of moderate-severe traumatic brain injury)
* Currently receiving exposure therapy
* Recently enrolled (\<1 month) in other behavioral health therapies (exclusions made at the PI's discretion depending on therapy type and length since admission)
* Urgent hypertension (BP above 160/100) or symptomatic of hypertension (having a hypertensive emergency)
* Blood pressure under 100/60 or symptoms of low blood pressure (light headedness, dizziness, heart palpitations, or other symptoms as determined by clinician).
* Any contraindications to taking clonidine such as:

  * Known hypersensitivity to clonidine
  * History of 2nd or 3rd degree atrioventricular block
  * History of sinus bradycardia
  * History of pheochromocytoma
  * History of Raynaud's phenomenon
  * Stage 5 Kidney disease
  * Recent myocardial infarction (\<6 months)
  * History of cerebrovascular disease or recent stoke (\<6 months)
* Have used any of the following drugs in the past 30 days, unprescribed or not used as prescribed:

  * Heroin
  * Other opiates/analgesics
  * Barbiturates
  * Other sedatives/, hypnotics, or tranquilizers
  * Cocaine
  * Amphetamines
  * Cannabis
  * Hallucinogens
  * Inhalants
* Currently have any of the following diagnoses:

  * Opioid use disorder
  * Cocaine use disorder
  * Alcohol use disorder
  * Cannabis use disorder
  * Sleep apnea diagnosis with verbal indication of non-adherence to treatment
* Were prescribed clonidine within the last 6 months

  * Any α2 agonist

    * Catapres/Kapvay (clonidine)
    * Aldomet (Methyldopa)
    * Zanaflex (Tizanidine)
    * Intuniv (Guanfacine)
    * Lucemyra (Lofexidine)
  * Any α1-adrenergic antagonist

    * Prazosin
    * Terazosin
    * Doxazosin
    * Silodosin
    * Alfuzosin
    * Tamsulosin
  * Any opiate (e.g., buprenorphine, hydrocodone, oxycodone)
  * Any antipsychotic medication

    * Haldol (haloperidol)
    * Loxitane (loxapine)
    * Mellaril (thioridazine)
    * Moban (molindone)
    * Navane (thiothixene)
    * Prolixin (fluphenazine)
    * Serentil (mesoridazine)
    * Stelazine (trifluoperazine)
    * Trilafon (perphenazine)
    * Thorazine (chlorpromazine)
    * Abilify (aripiprazole)
    * Clozaril (clozapine)
    * Geodon (ziprasidone)
    * Risperdal (risperidone)
    * Seroquel (quetiapine)
    * Zyprexa (olanzapine)
  * Benzodiazepines
  * Cyproheptadine
* Based on PI or study team assessment is cognitively unable to engage in the study
* Has a legal guardian

Primary outcomes:
measure: Change from Baseline in Pittsburgh Sleep Quality Index (PSQI) at 6 weeks into phase
timeFrame: Week 6 of Current Phase
measure: Change from Baseline in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) questions B2 and E6 at 6 weeks into phase
timeFrame: Week 6 of Current Phase
measure: Change from Baseline in PTSD Checklist-Military Version (PCL-5) at 6 weeks into phase
timeFrame: Week 6 of Current Phase
Secondary outcomes:
measure: Change from Baseline in Patient Health Questionnaire (PHQ9) at 6 weeks into phase
timeFrame: Week 6 of Current Phase
measure: Change from Baseline in Sleep Diary at 6 weeks into phase
timeFrame: Week 6 of Current Phase
measure: Change from Baseline in quality of life scale (Q-LES-Q-SF) at 6 weeks into phase
timeFrame: Week 6 of Current Phase
Other outcomes:
Locations:
city: Wauwatosa
country: United States
facility: Aurora Psychiatric Hospital
state: Wisconsin
Study officials:
affiliation: Wake Forest University Health Sciences
name: Gregory Burek, MD, MS
role: PRINCIPAL_INVESTIGATOR
affiliation: Wake Forest University Health Sciences
name: Michael Fendrich, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kang HK, Bullman TA. Risk of suicide among US veterans after returning from the Iraq or Afghanistan war zones. JAMA. 2008 Aug 13;300(6):652-3. doi: 10.1001/jama.300.6.652. No abstract available.
citation: Buchholz KR, Bohnert KM, Sripada RK, Rauch SA, Epstein-Ngo QM, Chermack ST. Associations between PTSD and intimate partner and non-partner aggression among substance using veterans in specialty mental health. Addict Behav. 2017 Jan;64:194-199. doi: 10.1016/j.addbeh.2016.08.039. Epub 2016 Aug 31.
citation: Norman SB, Haller M, Hamblen JL, Southwick SM, Pietrzak RH. The burden of co-occurring alcohol use disorder and PTSD in U.S. Military veterans: Comorbidities, functioning, and suicidality. Psychol Addict Behav. 2018 Mar;32(2):224-229. doi: 10.1037/adb0000348.