A Controlled Trial of Losartan in Posttraumatic Stress Disorder

NCT ID: NCT02709018

Last Updated: 2021-03-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 149 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-07-16
• Study Completion Date: 2020-09-29

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.

Conditions

Posttraumatic Stress Disorder

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Losartan

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

Group Type: EXPERIMENTAL

losartan

Intervention Type: DRUG

Angiotensin receptor blocker (ARB)

Placebo

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo

Interventions

losartan

Angiotensin receptor blocker (ARB)

Intervention Type: DRUG

Placebo

Placebo

Intervention Type: DRUG

Other Intervention Names

Cozaar

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Mclean Hospital

OTHER

Sponsor Role: collaborator

Massachusetts General Hospital

OTHER

Sponsor Role: collaborator

Henry M. Jackson Foundation, Walter Reed National Military Medical Center

UNKNOWN

Sponsor Role: collaborator

Foundation for Atlanta Veterans Education and Research, Inc.

OTHER

Sponsor Role: collaborator

NYU Langone Health

OTHER

Sponsor Role: collaborator

George Washington University

OTHER

Sponsor Role: collaborator

University of California, San Diego

OTHER

Sponsor Role: lead

Responsible Party

Murray B. Stein

Professor of Psychiatry, Family Medicine and Public Health

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Murray B Stein, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

University of California, San Diego

Kerry J Ressler, MD, PhD

Role: STUDY_CHAIR

McLean Hospital and Harvard Medical School

Locations

University of California, San Diego

La Jolla, California, United States

George Washington University

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

Walter Reed National Military Medical Center

Bethesda, Maryland, United States

McLean Hospital

Belmont, Massachusetts, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

New York University Langone Health

New York, New York, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 22687631 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22016534 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22580520 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21035950 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25921615 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26257395 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24094510 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34275593 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

W81XWH-15-2-0090

Identifier Type: -

Identifier Source: org_study_id