A Controlled Trial of Losartan in Posttraumatic Stress Disorder

NCT02709018 | Completed Results DMC

• 1 other identifier: W81XWH-15-2-0090
• Study Type: interventional
• Target: 149
• Locations: 1 country
• Sites: 6

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.

Conditions

Posttraumatic Stress Disorder

Keywords

posttraumatic stress disorder; losartan; angiotensin receptor blocker

Outcome Measures

Primary Outcomes (1)

• 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.

  Clinician-Administered PTSD Scale for DSM-5 also known as CAPS-5 is the gold standard in PTSD assessment. The CAPS-5 is a 30-item structured interview that can be used to, make current (past month) diagnosis of PTSD, make a lifetime diagnosis of PTSD and assess PTSD symptoms over the past week. The CAPS-5 as used here has 20 items, each scored 0-4, to yield a score with a possible range of 0-80. Higher scores mean worse outcome.

  10 weeks

Secondary Outcomes (1)

• 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.

  10 weeks

Study Arms (2)

Losartan

EXPERIMENTAL

Losartan flexibly dosed from 25-100 mg per day over 10 weeks

Drug: losartan

Placebo

PLACEBO COMPARATOR

Placebo flexibly dosed from 25-100 mg per day over 10 weeks

Drug: Placebo

Interventions

losartan DRUG

Angiotensin receptor blocker (ARB)

Also known as: Cozaar

Losartan

Placebo DRUG

Placebo

Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject must be a man or woman between 18 and 70 years of age, inclusive.
• Subjects must have a primary DSM-5 diagnosis of Posttraumatic Stress Disorder.
• Subjects must have a Clinical Administered PTSD Scale for PTSD (CAPS-5) ≥ 25 persistent at Screening for at least 3 months duration.
• Subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
• Subject must be willing and able to fill out self-administered questionnaires.
• Subject must be able to be compliant with self-administration of medication.
• Subject must be able to swallow the study medication whole with aid of water.
• 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.

You may not qualify if:

• Subjects who have current or imminent risk of suicide as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) at each study visit.
• Subject with active psychosis.
• Subject has a history of moderate or severe drug or alcohol use disorder according to DSM-5 criteria within 3 months before screening.
• Subject has a history of allergy to losartan or other angiotensin receptor blockers (ARBs).
• 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.
• 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.
• 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.
• 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.
• Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant.
• Subject is unable to comply with the study-specific requirements
• Subjects with abnormal liver, renal or EKG findings as determined by physician.
• Subject exhibits clinically-significant hypertension as determined by medical evaluation and/or BP \> 190/100.
• Systolic Blood Pressure (SBP) \< 90mmHg.
• Liver function Tests (LFT's) \> 2 times the upper limit of normal.
• Patients with Chronic Kidney Disease 4, as determined by history, baseline labs (including eGFR \< 45ml/minute) and evaluation by a physician will be excluded

Sponsors & Collaborators

• University of California, San Diego: lead
• Mclean Hospital: collaborator
• Massachusetts General Hospital: collaborator
• Henry M. Jackson Foundation, Walter Reed National Military Medical Center: collaborator
• Foundation for Atlanta Veterans Education and Research, Inc.: collaborator
• NYU Langone Health: collaborator
• George Washington University: collaborator

Study Sites (6)

University of California, San Diego

La Jolla, California, 92037, United States

Location

George Washington University

Washington D.C., District of Columbia, 20037, United States

Location

Walter Reed National Military Medical Center

Bethesda, Maryland, 20889, United States

Location

McLean Hospital

Belmont, Massachusetts, 02478, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

New York University Langone Health

New York, New York, 10016, United States

Location

Related Publications (8)

• 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.

  PMID: 22687631 BACKGROUND

• 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.

  PMID: 22016534 BACKGROUND

• 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.

  PMID: 22580520 BACKGROUND

• 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.

  PMID: 21035950 BACKGROUND

• 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.

  PMID: 25921615 BACKGROUND

• 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.

  PMID: 26257395 BACKGROUND

• 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.

  PMID: 24094510 BACKGROUND

• 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.

  PMID: 34275593 DERIVED

MeSH Terms

Conditions

Stress Disorders, Post-Traumatic

Interventions

Losartan

Condition Hierarchy (Ancestors)

Stress Disorders, Traumatic; Trauma and Stressor Related Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Tetrazoles

Results Point of Contact

• Title: Murray B. Stein MD, MPH
• Organization: University of California San Diego

mstein@health.ucsd.edu

858-534-6451

Study Officials

• Murray B Stein, MD, MPH

  University of California, San Diego

  PRINCIPAL INVESTIGATOR

• Kerry J Ressler, MD, PhD

  McLean Hospital and Harvard Medical School

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Psychiatry, Family Medicine and Public Health

Study Record Dates

• First Submitted: March 7, 2016
• First Posted: March 15, 2016
• Study Start: July 16, 2016
• Primary Completion: February 29, 2020
• Study Completion: September 29, 2020
• Last Updated: March 12, 2021
• Results First Posted: March 12, 2021

Record last verified: 2021-02

Locations

US (6)