Repurposing Low-Dose Clonidine for PTSD in Veterans

Sponsor
Aurora Health Care (Other)
Overall Status
Not yet recruiting
CT.gov ID
NCT04877093
Collaborator
(none)
32
1
2
24
1.3

Study Details

Study Description

Brief Summary

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

Condition or Disease Intervention/Treatment Phase
  • Drug: Clonidine Pill
  • Other: Placebo
Phase 3

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.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
32 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Intervention Model Description:
Randomized, placebo-controlled, blinded crossoverRandomized, placebo-controlled, blinded crossover
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
The pharmacist will determine the groups for each patient and will not reveal groups to anyone on the study team or the participant until they have finished the trial.
Primary Purpose:
Treatment
Official Title:
Repurposing Low-Dose Clonidine for PTSD in Veterans
Anticipated Study Start Date :
Sep 1, 2022
Anticipated Primary Completion Date :
Dec 1, 2023
Anticipated Study Completion Date :
Sep 1, 2024

Arms and Interventions

Arm Intervention/Treatment
Experimental: Clonidine Phase

Participants will receive clonidine titrations across 6 weeks. Note that this is a crossover design, so patients will move across phases.

Drug: Clonidine Pill
The study will use a flexible-dose adjustment schedule to identify the minimum dose needed to alleviate symptoms while also ensuring acceptable adverse effects. In other words, all subjects will start at the minimum dose (0.1 mg/night). Near the end of every week, each subject will be assessed for symptom alleviation and adverse events by asking the patient two questions from the CAPS-5 (questions B2 and E6. At baseline, each patient will have scored a ≥3 on each of these questions. If one or both scores remain at ≥3 and if any reported adverse events are marked acceptable by both the clinician and subject, then the dosage for the following week will be increased one level according to the titration chart. However, if both scores for these questions are ≤2 and any current adverse events are acceptable, then the dosage will remain the same. Finally, if any adverse events are deemed unacceptable, the clonidine dosage will be reduced to the lowest acceptable daily dosage.

Placebo Comparator: Placebo Phase

Participants will receive placebo titrations across 6 weeks. Note that this is a crossover design, so patients will move across phases.

Other: Placebo
Blinded placebo capsules will be provided to participants.

Outcome Measures

Primary Outcome Measures

  1. Change from Baseline Actigraph measurement of sleep (duration) at 6 weeks into phase [Week 6 of Current Phase]

    Sleep will be measured by the Actigraph, which is a gold standard for measuring sleep outside of a sleep laboratory. Sleep-wake time will be measured in duration.

  2. Change from Baseline Actigraph measurement of sleep (rate of awakenings) at 6 weeks into phase [Week 6 of Current Phase]

    Awakenings will be measured by the Actigraph, which is a gold standard for measuring sleep outside of a sleep laboratory. Sleep-wake time will be measured as number of awakenings.

  3. Change from Baseline in Pittsburgh Sleep Quality Index (PSQI) at 6 weeks into phase [Week 6 of Current Phase]

    Scored 0-21, where higher scores indicate worse sleep quality.

  4. Change from Baseline in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) questions B2 and E6 at 6 weeks into phase [Week 6 of Current Phase]

    Measures PTSD symptoms on sleep, with each question scored 1-4, where higher scores indicate more severe symptoms.

  5. Change from Baseline in PTSD Checklist-Military Version (PCL-5) at 6 weeks into phase [Week 6 of Current Phase]

    Includes 20 items with a severity score range 0-80. Includes the ability to treat each item rated as 2 = "Moderately" or higher as a symptom endorsed, which allows following the DSM-5 diagnostic rule which requires at least: 1 Criterion B item (questions 1-5), 1 Criterion C item (questions 6-7), 2 Criterion D items (questions 8-14), 2 Criterion E items (questions 15-20). In general, use of a cutoff score tends to produce more reliable results than the DSM-5 diagnostic rule.

Secondary Outcome Measures

  1. Change from Baseline in Clinical Global Impressions scale - Improvement (CGI-I)at 6 weeks into phase [Week 6 of Current Phase]

    Provides a subject assessment of the clinician's impression of the general improvement of the patient compared to baseline. Scored 1-7, where lower scores indicate greater improvements. Note that the scale itself does not use outcome-neutral language "(1=very much improved since the initiation of treatment; 2=much improved; 3=minimally improved; 4=no change from baseline (the initiation of treatment); 5=minimally worse; 6= much worse; 7=very much worse since the initiation of treatment)."

  2. Change from Baseline in Actigraph measurement of activity at 6 weeks into phase [Week 6 of Current Phase]

    Will be measured by the Actigraph through step counts and duration activity counts as categorized into sedentary (<100 cpm), light-intensity (100 - 1951 cpm), and moderate-to-vigorous-intensity physical activity (≥ 1952 cpm) using previously validated cutpoints.

  3. Change from Baseline in Heart rate at 6 weeks into phase [Week 6 of Current Phase]

    Measured as beats per minute

  4. Change from Baseline in Blood pressure (Diastolic) at 6 weeks into phase [Week 6 of Current Phase]

    Measured as pressure

  5. Change from Baseline in Blood pressure (Systolic) at 6 weeks into phase [Week 6 of Current Phase]

    Measured as pressure

  6. Change from Baseline in Respiratory rate at 6 weeks into phase [Week 6 of Current Phase]

    Measured as breaths per minute

  7. Change from Baseline in Inventory of Psychosocial Functioning (IPF) for quality of life at 6 weeks into phase [Week 6 of Current Phase]

    Items are scored from 0-6, with higher scores indicating greater functional impairment.

  8. Change from Baseline in Patient Health Questionnaire (PHQ9) (depression) at 6 weeks into phase [Week 6 of Current Phase]

    PHQ9 scores 0-27, with higher scores indicating more severe depression.

  9. Qualitative data on verbal behavior [Week 6 of Current Phase]

    Qualitative data may be collected from the comments made by participants relevant to the study. E.g., "I'm sleeping so much better now compared to where I was four weeks ago."

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • ≥18 years old

  • US military veteran (not necessarily military)

  • Currently has PTSD diagnosis as determined by clinical diagnosing

  • Screening score on CAPS minimum of 30 (per discussions with Dr. Murray Raskind and data from previous studies 32)

  • Has score ≥3 on CAPS nightmare items B2 and E6

  • Speaks and understand English

  • Willing to wear an actigraph and come into the clinic as programmed

Exclusion Criteria:
  • At Moderate or High risk of suicide based on results from the Columbia-Suicide Severity Rating Scale (CSSR-S) screen version - recent.

  • Acute or unstable medical illness

  • 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)

  • Were prescribed clonidine within the last 6 months

  • Blood pressure under 90/50 or symptoms of low blood pressure (light headedness, dizziness, heart palpitations, or other symptoms as determined by clinician).

  • Any contraindications of taking clonidine such as:

  • Known hypersensitivity to clonidine

  • History of 2nd or 3rd 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)

  • 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

  • Current prescriptions for:

  • Prazosin or another α1-adrenergic antagonist

  • Any opiate (e.g., buprenorphine, hydrocodone, oxycodone)

  • Antipsychotic medications

  • Benzodiazepines

  • Cyproheptadine

  • Precluded from taking clonidine for medical or other reasons

  • Based on PI assessment is cognitively unable to engage in the study

Contacts and Locations

Locations

Site City State Country Postal Code
1 Aurora Psychiatric Hospital Wauwatosa Wisconsin United States 53213

Sponsors and Collaborators

  • Aurora Health Care

Investigators

  • Principal Investigator: Gregory Burek, MD, MS, Advocate Aurora Health
  • Principal Investigator: Mindy R Waite, PhD, MS, Advocate Aurora Health

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Aurora Health Care
ClinicalTrials.gov Identifier:
NCT04877093
Other Study ID Numbers:
  • 20-1057
First Posted:
May 7, 2021
Last Update Posted:
Jul 21, 2022
Last Verified:
Jul 1, 2022
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Product Manufactured in and Exported from the U.S.:
Yes
Keywords provided by Aurora Health Care
Additional relevant MeSH terms:

Study Results

No Results Posted as of Jul 21, 2022