Post-traumatic Stress DisorderPhase 4NCT01490697
Developing Memory Reconsolidation Blockers as Novel Posttraumatic Stress Disorder (PTSD) Treatments
A Phase 4 study testing Mifepristone and d-Cycloserine in people with Post-traumatic Stress Disorder, run by Roger K. Pitman, MD at 2 sites in United States.
Trial summary
Despite substantial therapeutic advances, Posttraumatic Stress Disorder (PTSD) remains difficult to treat. One promising new area of research is in post-reactivation pharmacologic intervention, which is based upon the concept of blockade of memory reconsolidation. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Post-traumatic Stress Disorder
- What is being tested?
- Mifepristone and d-Cycloserine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 34 participants
- Where
- 2 sitesUnited States
- Study dates
- Mar 2009to Sep 2015
- Phase
- Phase 4
- 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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Participant has experienced a traumatic event that meets the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)11 A1. and A.2. PTSD criteria
- Participant currently meets DSM-IV criterion B.5, viz., "physiological reactivity on exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event."
Who cannot join
- Medical condition that contraindicates the administration of mifepristone, e.g., history of adrenal failure; concurrent corticosteroid therapy; hemorrhagic disorders; cardiovascular, hypertensive, hepatic, respiratory or renal disease; insulin dependent diabetes mellitus; severe anemia; heavy smoking; porphyria; allergy to mifepristone; concurrent anticoagulant therapy; or medical condition that contraindicates the administration of DCS e.g., hypersensitivity to cycloserine, epilepsy, severe renal insufficiency.
- Pregnant (as determined by mandatory blood pregnancy testing, or currently breast feeding. (Note: Women who have had a hysterectomy or are post-menopausal (defined as over the age of 50 with no menstrual period for at least 12 months) will be exempted from pregnancy testing. Furthermore, women of childbearing potential will only be included if: a) they are using contraception in the form of barrier methods with spermicide, hormonal methods (e.g. birth control pill), or intrauterine devices (IUDs), or b) they have not been sexually active for the preceding 60 days.)
- Contraindicating psychiatric condition, e.g., current psychotic, bipolar, melancholic, or substance dependence or abuse disorder; or currently suicidal.
- Cognitive Impairment or dementia
- Initiation of, or change in, psychotropic medication within one month prior to recruitment
- Current use of medication that may involve potentially dangerous interactions with mifepristone, including certain CYP 3A4 substrates such as calcium channel blockers, azole antifungals, macrolide antibiotics, and tricyclic antidepressants. (Note - we have not included in this list benzodiazepines or selective serotonin reuptake inhibitors, because these drugs are frequently used by PTSD participants, and they have sufficiently wide therapeutic ranges such that any transient increases in blood levels induced by a single dose of mifepristone will not endanger participants); or current use of medication that may involve potentially dangerous interactions with DCS, including ethionamide, isoniazid, and pyridoxine.
- Inability to understand the study's procedures, risks, and side effects, or to otherwise give informed consent for participation;
- Age less than 18.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Massachusetts General Hospital
Boston, Massachusetts, 02114
Dallas VA
Dallas, Texas, 75216
About this study
Official title: Developing Memory Reconsolidation Blockers as Novel PTSD Treatments
Despite substantial therapeutic advances, Posttraumatic Stress Disorder (PTSD) remains difficult to treat. One promising new area of research is in post-reactivation pharmacologic intervention, which is based upon the concept of blockade of memory reconsolidation. Recent animal research suggests that reactivation (retrieval) of a stored memory can return it to a labile (alterable) state from which it must be restabilized in order to persist. This process is called "reconsolidation," and various drugs have been found to block it in animals. This blockade may lead to a weakening of the original memory trace.
The aim of this study is to pilot the effect of mifepristone on physiologic responding during traumatic imagery. Although mifepristone is widely and safely used to cause a medical abortion, it is also a powerful stress hormone receptor blocker. These stress hormones, called glucocorticoids, may enhance memory (re)consolidation. Indeed, a recent study in animals reported that mifepristone blocked reconsolidation of context-conditioned fear in rats.
Read more
Reconsolidation blockade is a two-stage process. First, the memory must be destabilized by recalling it. Second, reconsolidation of the memory must be blocked by a drug. Memory traces formed under stressful conditions may resist destabilization and thus are inaccessible to reconsolidation blockers. However, when a reconsolidation blocker was paired with d-cycloserine (DCS) in animals that had been trained under stressful conditions, reconsolidation blockade became successful. These results suggest that DCS promotes the destabilization of resistant memory traces. The traumatic memories of individuals with PTSD may be particularly resistant to destabilization. Therefore, this study will compare mifepristone paired with DCS to placebo controls.
The same script-driven traumatic imagery method validated in previous studies of propranolol in this lab will be used. Briefly, subjects with PTSD will describe their traumatic event during a script preparation session, which will reactivate the memory. They will then receive a) mifepristone and DCS or b) placebo. A week later, they will engage in script-driven mental imagery of their traumatic event while physiologic responses (heart rate, sweating, etc) are measured. This is a pilot study so there are no formal hypotheses. The aim is to estimate effect sizes for mifepristone and to compare them with effect sizes for propranolol from this lab's previous work.
- Conditions
- Post-traumatic Stress Disorder
- Being tested
- Mifepristone, d-Cycloserine, Placebo-matching Mifepristone, Placebo-matching d-Cycloserine (DCS)
- Keywords
- stress disorders, posttraumatic, memory, mifepristone, d-cycloserine, psychophysiology
- Medical subject headings
- Stress Disorders, Post-Traumatic, Stress Disorders, Traumatic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MifepristoneDrug
Also called RU-486, Mifeprex
1800 mg tablet, single dose 90 minutes prior to script preparation on Day 7.
d-CycloserineDrug
Also called Seromycin
100 mg capsule, single dose, taken 4 hours prior to to mifepristone on Day 7.
Placebo-matching MifepristoneDrug
Placebo-matching mifepristone tablets
Placebo-matching d-Cycloserine (DCS)Drug
Placebo-matching DCS capsules
| Study group | Role | What they receive |
|---|---|---|
| Mifepristone plus d-Cycloserine (DCS) | Experimental | DCS 100 mg capsule orally followed by mifepristone1800 mg tablet orally 4 hours later and 90 minutes prior to traumatic memory retrieval via the traumatic event script preparation procedure, all on Day 7. Receives: Drug: Mifepristone; Drug: d-Cycloserine |
| Placebo plus Placebo | Placebo comparator | Placebo-matching DCS 100 mg capsule orally followed by placebo-matching mifepristone1800 mg tablet orally 4 hours later and 90 minutes prior to traumatic memory retrieval via the traumatic event script preparation procedure, all on Day 7. Receives: Drug: Placebo-matching Mifepristone; Drug: Placebo-matching d-Cycloserine (DCS) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Physiological Posttraumatic Stress Disorder (PTSD) Probability as Determined From Psychophysiologic Responses to Traumatic Recollection
The posterior probability of developing PTSD was determined for each participant from a composite of psychophysiological responses to script-driven imagery of traumatic events that included assessments of heart rate response in beats per minute, skin conductance response in microSiemens, and corrugator electromyogram (EMG) responses of the left lateral frontalis facial muscle in microVolts. Responses for the traumatic scripts were averaged and square-root transformed for analysis. Responses during personal traumatic imagery of previously studied individuals with and without current PTSD was used to calculate each participant's posterior probability of being classified as PTSD.
Measured: 1 week following treatment (Day 14)
Secondary outcomes (1)
Change From Baseline in the Impact of Event Scale-Revised (IES-R) Total Score
IES-R is a 22-item patient reported measure of PTSD symptoms. Each question is answered using a 5-point scale where 0=not at all to 4=extremely for a total possible score of 0 to 88. Lower scores represent less severe symptoms and higher scores representing more severe symptoms. IES-R change scores were calculated by subtracting the Day 14 IES-R total score from the Day 7 IES-R total score. A negative change from Baseline indicates improvement of symptoms and a positive change from Baseline indicates a worsening of symptoms.
Measured: Day 7 (Baseline) and Day 14
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Dec 2011 (estimated)
- Study startMar 2009
- Primary completionSep 2015
- Study completionSep 2015
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.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Post-traumatic Stress DisorderStudies of the same condition, open and under way.
- 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 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 34 participants (actual)
Sponsor and investigators
- Lead sponsor
- Roger K. Pitman, MD
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Roger K. Pitman, MD, Massachusetts General Hospital
- Investigators
- Roger K Pitman, MD, Principal investigator, Massachusetts General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01490697
- Sponsor's protocol ID
- 2009P000647
- Status last verified
- May 2017
- First submitted
- 9 Dec 2011
- Last updated
- 29 Jun 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Wood NE, Rosasco ML, Suris AM, Spring JD, Marin MF, Lasko NB, Goetz JM, Fischer AM, Orr SP, Pitman RK. Pharmacological blockade of memory reconsolidation in posttraumatic stress disorder: three negative psychophysiological studies. Psychiatry Res. 2015 Jan 30;225(1-2):31-39. doi: 10.1016/j.psychres.2014.09.005. Epub 2014 Sep 16.
PubMed 25441015
Study at a glance
From the registry record, last updated by the sponsor on 29 Jun 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Developing Memory Reconsolidation Blockers as Novel PTSD Treatments
- ClinicalTrials.gov ID
- NCT01490697
- Acronym / sponsor ID
- 2009P000647
- Conditions
- Post-traumatic Stress Disorder
- Keywords
- stress disorders, posttraumatic, memory, mifepristone, d-cycloserine, psychophysiology
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 34 participants (actual)
- Lead sponsor
- Roger K. Pitman, MDUniversity, hospital or other
- Study start
- Mar 2009 (actual)
- Primary completion
- Sep 2015 (actual)
- Study completion
- Sep 2015 (actual)
- First posted
- 13 Dec 2011 (estimated)
- Results
- Posted 29 Jun 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Despite substantial therapeutic advances, Posttraumatic Stress Disorder (PTSD) remains difficult to treat. One promising new area of research is in post-reactivation pharmacologic intervention, which is based upon the concept of blockade of memory reconsolidation. Recent animal research suggests that reactivation (retrieval) of a stored memory can return it to a labile (alterable) state from which it must be restabilized in order to persist. This process is called "reconsolidation," and various drugs have been found to block it in animals. This blockade may lead to a weakening of the original memory trace.
The aim of this study is to pilot the effect of mifepristone on physiologic responding during traumatic imagery. Although mifepristone is widely and safely used to cause a medical abortion, it is also a powerful stress hormone receptor blocker. These stress hormones, called glucocorticoids, may enhance memory (re)consolidation. Indeed, a recent study in animals reported that mifepristone blocked reconsolidation of context-conditioned fear in rats.
Reconsolidation blockade is a two-stage process. First, the memory must be destabilized by recalling it. Second, reconsolidation of the memory must be blocked by a drug. Memory traces formed under stressful conditions may resist destabilization and thus are inaccessible to reconsolidation blockers. However, when a reconsolidation blocker was paired with d-cycloserine (DCS) in animals that had been trained under stressful conditions, reconsolidation blockade became successful. These results suggest that DCS promotes the destabilization of resistant memory traces. The traumatic memories of individuals with PTSD may be particularly resistant to destabilization. Therefore, this study will compare mifepristone paired with DCS to placebo controls.
The same script-driven traumatic imagery method validated in previous studies of propranolol in this lab will be used. Briefly, subjects with PTSD will describe their traumatic event during a script preparation session, which will reactivate the memory. They will then receive a) mifepristone and DCS or b) placebo. A week later, they will engage in script-driven mental imagery of their traumatic event while physiologic responses (heart rate, sweating, etc) are measured. This is a pilot study so there are no formal hypotheses. The aim is to estimate effect sizes for mifepristone and to compare them with effect sizes for propranolol from this lab's previous work.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Mifepristone plus d-Cycloserine (DCS) | Experimental | Drug: Mifepristone, Drug: d-CycloserineDCS 100 mg capsule orally followed by mifepristone1800 mg tablet orally 4 hours later and 90 minutes prior to traumatic memory retrieval via the traumatic event script preparation procedure, all on Day 7. |
| Placebo plus Placebo | Placebo comparator | Drug: Placebo-matching Mifepristone, Drug: Placebo-matching d-Cycloserine (DCS)Placebo-matching DCS 100 mg capsule orally followed by placebo-matching mifepristone1800 mg tablet orally 4 hours later and 90 minutes prior to traumatic memory retrieval via the traumatic event script preparation procedure, all on Day 7. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Participant has experienced a traumatic event that meets the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)11 A1. and A.2. PTSD criteria
- Participant currently meets DSM-IV criterion B.5, viz., "physiological reactivity on exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event."
Key exclusion criteria (8 listed)
- Medical condition that contraindicates the administration of mifepristone, e.g., history of adrenal failure; concurrent corticosteroid therapy; hemorrhagic disorders; cardiovascular, hypertensive, hepatic, respiratory or renal disease; insulin dependent diabetes mellitus; severe anemia; heavy smoking; porphyria; allergy to mifepristone; concurrent anticoagulant therapy; or medical condition that contraindicates the administration of DCS e.g., hypersensitivity to cycloserine, epilepsy, severe renal insufficiency.
- Pregnant (as determined by mandatory blood pregnancy testing, or currently breast feeding. (Note: Women who have had a hysterectomy or are post-menopausal (defined as over the age of 50 with no menstrual period for at least 12 months) will be exempted from pregnancy testing. Furthermore, women of childbearing potential will only be included if: a) they are using contraception in the form of barrier methods with spermicide, hormonal methods (e.g. birth control pill), or intrauterine devices (IUDs), or b) they have not been sexually active for the preceding 60 days.)
- Contraindicating psychiatric condition, e.g., current psychotic, bipolar, melancholic, or substance dependence or abuse disorder; or currently suicidal.
- Cognitive Impairment or dementia
- Initiation of, or change in, psychotropic medication within one month prior to recruitment
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 |
|---|---|---|
| MifepristoneAlso: RU-486, Mifeprex1800 mg tablet, single dose 90 minutes prior to script preparation on Day 7. | Drug | Mifepristone plus d-Cycloserine (DCS) |
| d-CycloserineAlso: Seromycin100 mg capsule, single dose, taken 4 hours prior to to mifepristone on Day 7. | Drug | Mifepristone plus d-Cycloserine (DCS) |
| Placebo-matching MifepristonePlacebo-matching mifepristone tablets | Drug | Placebo plus Placebo |
| Placebo-matching d-Cycloserine (DCS)Placebo-matching DCS capsules | Drug | Placebo plus Placebo |
Primary outcome
Physiological Posttraumatic Stress Disorder (PTSD) Probability as Determined From Psychophysiologic Responses to Traumatic Recollection
Time frame: 1 week following treatment (Day 14)
The posterior probability of developing PTSD was determined for each participant from a composite of psychophysiological responses to script-driven imagery of traumatic events that included assessments of heart rate response in beats per minute, skin conductance response in microSiemens, and corrugator electromyogram (EMG) responses of the left lateral frontalis facial muscle in microVolts. Responses for the traumatic scripts were averaged and square-root transformed for analysis. Responses during personal traumatic imagery of previously studied individuals with and without current PTSD was used to calculate each participant's posterior probability of being classified as PTSD.
1 secondary outcome
Change From Baseline in the Impact of Event Scale-Revised (IES-R) Total Score
Time frame: Day 7 (Baseline) and Day 14
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Jun 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 25441015Wood NE, Rosasco ML, Suris AM, Spring JD, Marin MF, Lasko NB, Goetz JM, Fischer AM, Orr SP, Pitman RK. Pharmacological blockade of memory reconsolidation in posttraumatic stress disorder: three negative psychophysiological studies. Psychiatry Res. 2015 Jan 30;225(1-2):31-39. doi: 10.1016/j.psychres.2014.09.005. Epub 2014 Sep 16.
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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.
Roger K Pitman, MD principal investigator
Massachusetts General Hospital
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Mifepristone and d-Cycloserine in people with Post-traumatic Stress Disorder, run by Roger K. Pitman, MD at 2 sites 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 2 inclusion and 8 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: finished, as of the sponsor's last update on 29 Jun 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites 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. Some participants in this study may receive a placebo. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
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 29 Jun 2017). 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?
Physiological Posttraumatic Stress Disorder (PTSD) Probability as Determined From Psychophysiologic Responses to Traumatic Recollection (time frame: 1 week following treatment (Day 14)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01490697, which also lists 1 linked publication.
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 29 Jun 2017.