Posttraumatic Stress DisorderPhase 2PTSDNCT02727998
Intensive 7-day Treatment for PTSD Combining Ketamine With Exposure Therapy
A Phase 2 study testing Ketamine and Midazolam in people with Posttraumatic Stress Disorder, run by Yale University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 21 to 75 yearsHealthy volunteers can take part
- Conditions the study is for
- Posttraumatic Stress Disorder
- What is being tested?
- Ketamine and Midazolam
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 28 participants
- Where
- 1 siteUnited States
- Study dates
- Dec 2015to 28 Nov 2021
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 75 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Male or female between the ages of 21-75 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.
Who cannot join
- 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.
Show all 20Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Yale University School of Medicine
New Haven, Connecticut, 06510
About this study
Official title: Combining Neurobiology and New Learning: Ketamine and Prolonged Exposure: A Potential Rapid Treatment for Post Traumatic Stress Disorder (PTSD)
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.
Read the 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 or placebo and will undergo a 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.
- Conditions
- Posttraumatic Stress Disorder
- Keywords
- PTSD
- Medical subject headings
- Stress Disorders, Post-Traumatic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
KetamineDrug
Also called Ketalar
Prolonged exposure therapy combined with a single infusion of 0.50 mg/kg/hour for 40 min on day 2.
MidazolamDrug
Also called Versed
Prolonged exposure therapy combined with a single infusion of 0.045 mg/kg/hour for 40 min on day 2.
| Study group | Role | What they receive |
|---|---|---|
| Single infusion of Ketamine with prolonged exposure | Experimental | 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. Receives: Drug: Ketamine |
| Midazolam with prolonged exposure | Active comparator | 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. Receives: Drug: Midazolam |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in PTSD Symptoms
PTSD symptoms severity will be evaluated overtime using the PTSD Checklist for DSM-5 (PCL-5), a 20 items self-report measure. Items are scored 0-4 (0=not at all to 4=Extremely), thus total PCL-5 score ranges from 0 to 80. Higher scores reflect greater severity of PTSD.
Total PCL-5 scores are reported. PCL score>33 indicates probable PTSD diagnosis. Evidence for the PCL suggested 5 points reduction as a minimum threshold for determining whether an individual has responded to treatment and 10 points reduction in the PCL-5 as a minimum threshold for determining whether the improvement is clinically meaningful.
Measured: Baseline, 7 days, 30 days and 90 days
Secondary outcomes (1)
Change in Beck Depression Inventory (BDI-II)
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
Measured: Baseline, 7 days, 30 days and 90 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Apr 2016 (estimated)
- Study startDec 2015
- Primary completion28 Nov 2021
- Study completion28 Nov 2021
Why it stopped: Study ran out of funding
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Posttraumatic Stress DisorderStudies of the same condition, open and under way.
- More trials run by Yale UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 28 participants (actual)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Ilan Harpaz-Rotem, PhD, Principal investigator, Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02727998
- Sponsor's protocol ID
- 1509016530
- Other IDs
- 23260
- Acronym
- PTSD
- Status last verified
- Oct 2022
- First submitted
- 14 Mar 2016
- Last updated
- 17 Oct 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: Data from the initial stage of the investigation will be used to establish support for a Phase 3 RCT.
Study at a glance
From the registry record, last updated by the sponsor on 17 Oct 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Combining Neurobiology and New Learning: Ketamine and Prolonged Exposure: A Potential Rapid Treatment for Post Traumatic Stress Disorder (PTSD)
- ClinicalTrials.gov ID
- NCT02727998
- Acronym / sponsor ID
- PTSD / 1509016530
- Conditions
- Posttraumatic Stress Disorder
- Keywords
- PTSD
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Study ran out of funding
- Enrolment
- 28 participants (actual)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Study start
- Dec 2015
- Primary completion
- 28 Nov 2021 (actual)
- Study completion
- 28 Nov 2021 (actual)
- First posted
- 5 Apr 2016 (estimated)
- Results
- Posted 17 Oct 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 or placebo and will undergo a 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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Single infusion of Ketamine with prolonged exposure | Experimental | Drug: KetamineAfter 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. |
| Midazolam with prolonged exposure | Active comparator | Drug: MidazolamAfter 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. |
Who may qualify
- Ages
- 21 to 75 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Male or female between the ages of 21-75 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.
Key exclusion criteria (20 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| KetamineAlso: KetalarProlonged exposure therapy combined with a single infusion of 0.50 mg/kg/hour for 40 min on day 2. | Drug | Single infusion of Ketamine with prolonged exposure |
| MidazolamAlso: VersedProlonged exposure therapy combined with a single infusion of 0.045 mg/kg/hour for 40 min on day 2. | Drug | Midazolam with prolonged exposure |
Primary outcome
Change in PTSD Symptoms
Time frame: Baseline, 7 days, 30 days and 90 days
PTSD symptoms severity will be evaluated overtime using the PTSD Checklist for DSM-5 (PCL-5), a 20 items self-report measure. Items are scored 0-4 (0=not at all to 4=Extremely), thus total PCL-5 score ranges from 0 to 80. Higher scores reflect greater severity of PTSD. Total PCL-5 scores are reported. PCL score>33 indicates probable PTSD diagnosis. Evidence for the PCL suggested 5 points reduction as a minimum threshold for determining whether an individual has responded to treatment and 10 points reduction in the PCL-5 as a minimum threshold for determining whether the improvement is clinically meaningful.
1 secondary outcome
Change in Beck Depression Inventory (BDI-II)
Time frame: Baseline, 7 days, 30 days and 90 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Oct 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No. Data from the initial stage of the investigation will be used to establish support for a Phase 3 RCT.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ilan Harpaz-Rotem, PhD principal investigator
Yale University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Ketamine and Midazolam in people with Posttraumatic Stress Disorder, run by Yale University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 17 Oct 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 Oct 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in PTSD Symptoms (time frame: Baseline, 7 days, 30 days and 90 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Oct 2022.