Clinical trial NCT02709018: A Controlled Trial of Losartan in Posttraumatic Stress Disorder
Official title: Enhancing Fear Extinction Via Angiotensin Type 1 Receptor Inhibition: A Randomized Controlled Trial in Posttraumatic Stress Disorder
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Posttraumatic Stress Disorder
Keywords: posttraumatic stress disorder
losartan
angiotensin receptor blocker
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
Collaborators: name: Mclean Hospital
name: Massachusetts General Hospital
name: Henry M. Jackson Foundation, Walter Reed National Military Medical Center
name: Foundation for Atlanta Veterans Education and Research, Inc.
name: NYU Langone Health
name: George Washington University
First posted: 2016-03-15
Enrollment: 149
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is being conducted to determine if losartan, an angiotensin receptor blocker (ARB), is safe and effective in the treatment of posttraumatic stress disorder (PTSD) symptoms. The study is also intended to determine if certain genetic markers are useful in predicting PTSD symptom reduction with losartan. Approximately 160 subjects with chronic PTSD ages 18-65 will participate in this study across five sites. Subjects will be assigned by chance to take either flexibly dosed losartan (up to a maximum dosage of 100 mg) or placebo (which resembles the study drug but has no active ingredients), once a day for 10 weeks. Furthermore, it is hypothesized that CC homozygotes for rs4311 SNP in the ACE gene will have a superior response to losartan on PTSD symptoms compared to T carriers.

Detailed description: There are limited current treatments available for PTSD, and the only FDA-approved medications are SSRIs, which were empirically found to be somewhat helpful. Losartan provides a potentially important and exciting development in that it is readily available, safe, inexpensive (available as a generic drug), and has a neurobiological mechanism based on recent exciting discoveries, as outlined below. This proposal is designed to test, in a multisite RCT, this novel, mechanistically-determined, safe and well-tolerated, potentially powerful treatment for PTSD symptoms.

Eligibility criteria: \[Below is a synopsis of relevant eligibility criteria. For details please refer to the protocol by contacting the Principal Investigator\]

Inclusion Criteria

1. Subject must be a man or woman between 18 and 70 years of age, inclusive.
2. Subjects must have a primary DSM-5 diagnosis of Posttraumatic Stress Disorder.
3. Subjects must have a Clinical Administered PTSD Scale for PTSD (CAPS-5) ≥ 25 persistent at Screening for at least 3 months duration.
4. Subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
5. Subject must be willing and able to fill out self-administered questionnaires.
6. Subject must be able to be compliant with self-administration of medication.
7. Subject must be able to swallow the study medication whole with aid of water.
8. Subject must sign an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.

Exclusion Criteria

1. Subjects who have current or imminent risk of suicide as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) at each study visit.
2. Subject with active psychosis.
3. Subject has a history of moderate or severe drug or alcohol use disorder according to DSM-5 criteria within 3 months before screening.
4. Subject has a history of allergy to losartan or other angiotensin receptor blockers (ARBs).
5. Subject has a medical illness likely to result in imminent hospitalization or for which treatments are contraindicated based on lab results, medical history and physical exam.
6. Subject has serious cognitive impairment felt likely to interfere with the ability to participate meaningfully in the study. Participants with mild to moderate traumatic brain injury (TBI) will not be excluded from the study. Only those who evidence significant cognitive impairment at Screening (as evidenced by confusion, inability to track discussion or answer questions, or other clear and significant indicators of cognitive impairment) will be excluded.
7. Concurrent ACE Inhibitors or Angiotensin Receptor Blockers or Prazosin; patients on other antihypertensives may be enrolled if, after consultation with their prescribing physician, it is determined that the addition of losartan would not be contraindicated.
8. Concurrent antidepressants or antipsychotics. Subjects, who have elected, in consultation with their health care provider, to discontinue any antidepressants or antipsychotics, must be off the medications for a minimum of 2 weeks prior to study randomization. Stable bedtime doses of sleep agents (e.g., trazodone ≤ 200mg; eszopiclone; zolpidem; lorazepam) will be allowed as long as the dose has been stable for at least 2 weeks prior to study randomization. Benzodiazepines taken for other than sleep are not permitted.
9. Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant.
10. Subject is unable to comply with the study-specific requirements
11. Subjects with abnormal liver, renal or EKG findings as determined by physician.
12. Subject exhibits clinically-significant hypertension as determined by medical evaluation and/or BP \> 190/100.
13. Systolic Blood Pressure (SBP) \< 90mmHg.
14. Liver function Tests (LFT's) \> 2 times the upper limit of normal.
15. Patients with Chronic Kidney Disease 4, as determined by history, baseline labs (including eGFR \< 45ml/minute) and evaluation by a physician will be excluded

Primary outcomes:
measure: The Primary Outcome for This Study is Mean Change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) Over the Treatment Period of 10 Weeks Between the Losartan Arm and the Placebo Arm.
timeFrame: 10 weeks
Secondary outcomes:
measure: Change in CAPS-5 Associated With CC Homozygosity for rs4311 SNP in the Angiotensin Converting Enzyme Gene (ACE) Compared to T Carriers, Among Subjects Randomized to Losartan.
timeFrame: 10 weeks
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California, San Diego
state: California
city: Washington
country: United States
facility: George Washington University
state: District of Columbia
city: Bethesda
country: United States
facility: Walter Reed National Military Medical Center
state: Maryland
city: Belmont
country: United States
facility: McLean Hospital
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: New York
country: United States
facility: New York University Langone Health
state: New York
Study officials:
affiliation: University of California, San Diego
name: Murray B Stein, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: McLean Hospital and Harvard Medical School
name: Kerry J Ressler, MD, PhD
role: STUDY_CHAIR
References:
citation: Khoury NM, Marvar PJ, Gillespie CF, Wingo A, Schwartz A, Bradley B, Kramer M, Ressler KJ. The renin-angiotensin pathway in posttraumatic stress disorder: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are associated with fewer traumatic stress symptoms. J Clin Psychiatry. 2012 Jun;73(6):849-55. doi: 10.4088/JCP.11m07316. Epub 2012 May 1.
citation: Krause EG, de Kloet AD, Scott KA, Flak JN, Jones K, Smeltzer MD, Ulrich-Lai YM, Woods SC, Wilson SP, Reagan LP, Herman JP, Sakai RR. Blood-borne angiotensin II acts in the brain to influence behavioral and endocrine responses to psychogenic stress. J Neurosci. 2011 Oct 19;31(42):15009-15. doi: 10.1523/JNEUROSCI.0892-11.2011.
citation: Llano Lopez LH, Caif F, Garcia S, Fraile M, Landa AI, Baiardi G, Lafuente JV, Braszko JJ, Bregonzio C, Gargiulo PA. Anxiolytic-like effect of losartan injected into amygdala of the acutely stressed rats. Pharmacol Rep. 2012;64(1):54-63. doi: 10.1016/s1734-1140(12)70730-2.
citation: Saavedra JM, Sanchez-Lemus E, Benicky J. Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: Therapeutic implications. Psychoneuroendocrinology. 2011 Jan;36(1):1-18. doi: 10.1016/j.psyneuen.2010.10.001. Epub 2010 Oct 29.
citation: Nylocks KM, Michopoulos V, Rothbaum AO, Almli L, Gillespie CF, Wingo A, Schwartz AC, Habib L, Gamwell KL, Marvar PJ, Bradley B, Ressler KJ. An angiotensin-converting enzyme (ACE) polymorphism may mitigate the effects of angiotensin-pathway medications on posttraumatic stress symptoms. Am J Med Genet B Neuropsychiatr Genet. 2015 Jun;168B(4):307-15. doi: 10.1002/ajmg.b.32313. Epub 2015 Apr 29.
citation: Hurt RC, Garrett JC, Keifer OP Jr, Linares A, Couling L, Speth RC, Ressler KJ, Marvar PJ. Angiotensin type 1a receptors on corticotropin-releasing factor neurons contribute to the expression of conditioned fear. Genes Brain Behav. 2015 Sep;14(7):526-33. doi: 10.1111/gbb.12235. Epub 2015 Aug 25.
citation: Marvar PJ, Goodman J, Fuchs S, Choi DC, Banerjee S, Ressler KJ. Angiotensin type 1 receptor inhibition enhances the extinction of fear memory. Biol Psychiatry. 2014 Jun 1;75(11):864-72. doi: 10.1016/j.biopsych.2013.08.024. Epub 2013 Oct 4.
citation: Stein MB, Jain S, Simon NM, West JC, Marvar PJ, Bui E, He F, Benedek DM, Cassano P, Griffith JL, Howlett J, Malgaroli M, Melaragno A, Seligowski AV, Shu IW, Song S, Szuhany K, Taylor CT, Ressler KJ; LOSe-PTSD Investigators. Randomized, Placebo-Controlled Trial of the Angiotensin Receptor Antagonist Losartan for Posttraumatic Stress Disorder. Biol Psychiatry. 2021 Oct 1;90(7):473-481. doi: 10.1016/j.biopsych.2021.05.012. Epub 2021 May 21.