Intensive 7-day Treatment for PTSD Combining Ketamine With Exposure Therapy (PTSD)

• ClinicalTrials.gov Identifier: NCT02727998
• Recruitment Status: Recruiting
• First Posted: April 5, 2016
• Last Update Posted: March 24, 2021
• Sponsor: Yale University
• Information provided by (Responsible Party): Yale University

Tracking Information

• First Submitted Date: March 14, 2016
• First Posted Date: April 5, 2016
• Last Update Posted Date: March 24, 2021
• Study Start Date: December 2015
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 19, 2021)

Change from baseline to 90 days post treatment in PTSD symptoms [ Time Frame: Baseline, 7 days, 30 days and 90 days ]

PTSD Symptoms severity will be evaluated overtime using PTSD Check List (PCL-5). Evidence for the PCL suggested 5 points as a minimum threshold for determining whether an individual has responded to treatment and 10 points as a minimum threshold for determining whether the improvement is clinically meaningful. PCL Score > 33 indicates probable PTSD.

Original Primary Outcome Measures (submitted: March 30, 2016)

Change from baseline to 90 days post treatment in Clinician-Administered PTSD Scale scores [ Time Frame: Baseline, 7 days, 30 days and 90 days ]

Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). A higher score is associated with higher severity of PTSD. The score is interpreted as follows: 0-19=Asymptomatic/few symptoms 20-39=Sub-threshold/mild PTSD 40-59=Threshold PTSD/moderate 60-79=Severe PTSD >80=Extreme PTSD

Current Secondary Outcome Measures (submitted: March 30, 2016)

Change from baseline to 90 days post treatment in Beck Depression Inventory (BDI-II) [ Time Frame: Baseline, 7 days, 30 days and 90 days ]

The self-report BDI-II will be used to assess severity of depressive symptoms. A higher score is associated with higher severity of depression. The score is interpreted as follows: 0-13 indicates minimal depression, 14-19 indicates mild depression, 20-28 indicates moderate depression and 29-63 indicates severe depression

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Intensive 7-day Treatment for PTSD Combining Ketamine With Exposure Therapy
• Official Title: Combining Neurobiology and New Learning: Ketamine and Prolonged Exposure: A Potential Rapid Treatment for Post Traumatic Stress Disorder (PTSD)
• Brief Summary: The purpose of this study is to combine a single infusion of Ketamine with 7-days of trauma focus psychotherapy to relieve post traumatic stress disorder (PTSD) symptoms more effectively. This treatment has the potential to produce a significant therapeutic effect that otherwise would take months to occur.

Detailed Description

Based on the current research findings on the therapeutic effectiveness of trauma focus psychotherapy and of ketamine, combining the two treatments may yield a promising new rapid 7-day treatment for PTSD. As PTSD symptoms' structure is comprised of several unique clusters which include re-experiencing, avoidance, numbing/depression and hypervigilance the investigators hypothesize that by combining Ketamine with prolonged exposure (PE) the investigators can address these symptoms clusters more effectively. This treatment has the potential to produce a significant therapeutic effect that otherwise would take months to occur by tapping on the enhanced neuroplasticity and the antidepressant effect of ketamine (which lasts between 24hrs to 7 days), to promote rapid changes in learning and memory using prolonged exposure therapy within this unique "window of opportunity".

During the first visit participants will undergo a clinical interview to establish a PTSD diagnosis and other eligibility criteria. If found eligible participants will be invited to take part in this 7-day rapid treatment trial for PTSD.

On the first therapy visits, participants will be educated about the psychological treatment that will be provided and the potential benefit of ketamine to enhance the psychotherapy outcomes.

On the second day of the study, participants will receive an infusion of ketamine and will undergo an magnetic resonance imaging (MRI) scan and will receive the second psychotherapy session.

On days 3-6 participants will attend a 60-90 minutes psychotherapy session to address their PTSD symptoms.

Day 7 will include another MRI scan and the last psychotherapy session.

Participants will be asked to come back for a follow up evaluation of their PTSD symptoms 30 and 90 days post discharge.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Posttraumatic Stress Disorder

Intervention

• Drug: Ketamine
  Prolonged exposure therapy combined with a single infusion of 0.50 mg/kg/hour for 40 min on day 2.
  Other Name: Ketalar
• Drug: Midazolam
  Prolonged exposure therapy combined with a single infusion of 0.045 mg/kg/hour for 40 min on day 2.
  Other Name: Versed

Study Arms

• Experimental: Single infusion of Ketamine with prolonged exposure
  After the reactivation of the scripted memories during PE on day 2, the ketamine infusion procedure will begin inside the MRI. A physician will oversee and administer the ketamine infusions. A nurse will accompany the subject throughout the study sessions, from the insertion of bilateral cannula for drug infusion and blood sampling, to the recovery following ketamine infusion. Whilst subjects undergo the infusion, their heart rate and blood pressure will be constantly monitored. The participant will receive a steady state ketamine infusion of 0.50 mg/kg/hour. The infusion will continue for 40 minutes.
  Intervention: Drug: Ketamine
• Experimental: Two infusion of Ketamine with prolonged exposure
  After the reactivation of the scripted memories during PE on day 4, the ketamine infusion procedure will begin inside the MRI. A physician will oversee and administer the ketamine infusions. A nurse will accompany the subject throughout the study sessions, from the insertion of bilateral cannula for drug infusion and blood sampling, to the recovery following ketamine infusion. Whilst subjects undergo the infusion, their heart rate and blood pressure will be constantly monitored. The participant will receive a steady state ketamine infusion of 0.50 mg/kg/hour. The infusion will continue for 40 minutes.
  Intervention: Drug: Ketamine
• Active Comparator: Midazolam with prolonged exposure
  After the reactivation of the scripted memories during PE on day 2, the midazolam infusion procedure will begin inside the MRI. A physician will oversee and administer the Midazolam infusions. A nurse will accompany the subject throughout the study sessions, from the insertion of bilateral cannula for drug infusion and blood sampling, to the recovery following midazolam infusion. Whilst subjects undergo the infusion, their heart rate and blood pressure will be constantly monitored. The participant will receive a steady midazolam infusions at a rate 0.045 mg/kg for 40 minutes.
  Intervention: Drug: Midazolam

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 30, 2016): 40
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2025
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Male or female between the ages of 21-55 years. This age range was chosen to fit with prior samples in which no adverse effects of ketamine have been observed. Adults in the 18-20 ranges have been eliminated because previous experience indicates that they often lack the maturity to participate effectively in similar protocols. Females will be included if they are not pregnant and agreed to utilize a medically accepted birth control method (to include oral, injectable, or implant birth control, condom, diaphragm with spermicide, intrauterine device, tubal ligation, abstinence, or partner with vasectomy) or if post-menopausal for at least 1 year, or surgically sterile.
• Able to provide written informed consent according to Yale HIC guidelines.
• Able to read and write English as a primary language.
• Diagnosis of PTSD, as determined by the Clinician Administered PTSD Scale (CAPS-5) (Weathers et al., 2013).
• Must have a score of 50 or higher on the Clinician-Administered PTSD Scale (CAPS-5) at screening.
• No more than mild Traumatic Brain Injury (TBI) according to a modified version of the Brief TBI Screen (Schwab, et al., 2006).
• Must not have a medical/neurological problem or use medication that would render ketamine unsafe by history or medical evaluation.

Exclusion Criteria:

• Patients with a diagnostic history of bipolar disorder, schizophrenia or schizoaffective disorder or currently exhibiting psychotic features as determined by the Structured Clinical Interview for DSM (SCID) (First, et al. 2010); dementia or suspicion thereof, are excluded. Other DSM Axis I disorders are permitted as long as they are not considered primary disorders.
• Patients with a history of antidepressant-induced hypomania or mania as determined by open-ended psychiatric interview.
• Serious suicide or homicide risk, as assessed by evaluating clinician; A serious suicide risk will be considered an inability to control suicide attempts, imminent risk of suicide in the investigator's judgment, or a history of serious suicidal behavior, which is defined using the Columbia-Suicide Severity Rating Scale (C-SSRS) (Posner et al., 2011) as either (1) one or more actual suicide attempts in the 3 years before study entry with the lethality rated at 3 or higher, or (2) one or more interrupted suicide attempts with a potential lethality judged to result in serious injury or death.
• Substance abuse or dependence during the 6 months prior to screening as determined by the Structured Clinical Interview for DSM (SCID).
• Any significant history of serious medical or neurological illness.
• Any signs of major medical or neurological illness on examination or as a result of electrocardiogram (ECG) screening or laboratory studies.
• Lifetime history of psychoactive substance or alcohol dependence or substance or alcohol abuse (other than nicotine or caffeine abuse), or drinking more than 5 drinks/week during the last year.
• Abnormality on physical examination. A subject with a clinical abnormality may be included only if the study physician considers the abnormality will not introduce additional risk factors and will not interfere with the study procedure.
• A positive pre-study (screening) urine drug screen or, at the study physician's discretion on any drug screens given before the scans.
• Pregnant or lactating women or a positive urine pregnancy test for women of child-bearing potential at screening or prior to any imaging day.
• Positive HIV or Hepatitis B tests. This test will take place at the screening visit. Subjects will be invited back to the Yale Depression Research Program either for their next study visit or for a HIV/Hep debriefing session. A study physician will inform them in person of the results. They will be given access to counselling and advised of the appropriate next steps.
• Has received either prescribed or over-the-counter (OTC) centrally active medicine or herbal supplements within 60 days of enrollment into the study. Subjects who have taken OTC medication or herbal supplements may still be entered into the study, if, in the opinion of the principal/co-investigator, the medication received will not interfere with the study procedures or compromise safety.
• Any history indicating learning disability, mental retardation, or attention deficit disorder.
• Known sensitivity to ketamine.
• Body circumference of 52 inches or greater.
• Body weight of 250 pounds or greater.
• History of claustrophobia.
• Presence of cardiac pacemaker or other electronic device or ferromagnetic metal foreign bodies in vulnerable positions as assessed by a standard pre-MRI screening questionnaire.
• Donation of blood in excess of 500 mL within 56 days prior to dosing.
• History of sensitivity to heparin or heparin-induced thrombocytopenia.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 21 Years to 55 Years (Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Ilan Harps-Rotem, PhD; 203-937-4760; ilan.harpaz-rotem@yale.edu

Contact: Charles Gordon, MA; 203-932-5711 ext 4326; charles.gordon@yale.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02727998
• Other Study ID Numbers: 1509016530; 23260 ( Other Grant/Funding Number: NARSAD )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: Data from the initial stage of the investigation will be used to establish support for a Phase 3 RCT.

• Responsible Party: Yale University
• Study Sponsor: Yale University
• Collaborators: Not Provided

Investigators

• Principal Investigator: Ilan Harpaz-Rotem, PhD; Yale University

• PRS Account: Yale University
• Verification Date: March 2021