LOSe-PTSD: A Controlled Trial of Losartan in Posttraumatic Stress Disorder

• Sponsor: University of California, San Diego (Other)
• Overall Status: Completed
• CT.gov ID: NCT02709018
• Collaborator: Mclean Hospital (Other), Massachusetts General Hospital (Other), Henry M. Jackson Foundation, Walter Reed National Military Medical Center (Other), Foundation for Atlanta Veterans Education and Research, Inc. (Other), NYU Langone Health (Other), George Washington University (Other)
• Enrollment: 149
• Locations: 6
• Arms: 2
• Actual Duration (Months): 50.5
• Patients Per Site: 24.8
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Posttraumatic Stress Disorder	Drug: losartan; Drug: Placebo	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 149 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Enhancing Fear Extinction Via Angiotensin Type 1 Receptor Inhibition: A Randomized Controlled Trial in Posttraumatic Stress Disorder
• Actual Study Start Date: Jul 16, 2016
• Actual Primary Completion Date: Feb 29, 2020
• Actual Study Completion Date: Sep 29, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Losartan Losartan flexibly dosed from 25-100 mg per day over 10 weeks	Drug: losartan; Angiotensin receptor blocker (ARB); Other Names: Cozaar
Placebo Comparator: Placebo Placebo flexibly dosed from 25-100 mg per day over 10 weeks	Drug: Placebo; Placebo

Outcome Measures

Primary Outcome Measures

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. [10 weeks]

   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.

Secondary Outcome Measures

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]

   The Clinician-Administered PTSD Scale for DSM-5 (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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

[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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Diego	La Jolla	California	United States	92037
2	George Washington University	Washington	District of Columbia	United States	20037
3	Walter Reed National Military Medical Center	Bethesda	Maryland	United States	20889
4	McLean Hospital	Belmont	Massachusetts	United States	02478
5	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
6	New York University Langone Health	New York	New York	United States	10016

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Murray B Stein, MD, MPH, University of California, San Diego
• Study Chair: Kerry J Ressler, MD, PhD, McLean Hospital and Harvard Medical School

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 2, 2021

More Information

Publications

• 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.
• 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.
• 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.
• Llano López LH, Caif F, García 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.
• 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.
• 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.
• Saavedra JM, Sánchez-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. Review.

• Responsible Party: Murray B. Stein, Professor of Psychiatry, Family Medicine and Public Health, University of California, San Diego
• ClinicalTrials.gov Identifier: NCT02709018
• Other Study ID Numbers: W81XWH-15-2-0090
• First Posted: Mar 15, 2016
• Last Update Posted: Mar 12, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Murray B. Stein, Professor of Psychiatry, Family Medicine and Public Health, University of California, San Diego: posttraumatic stress disorder; losartan; angiotensin receptor blocker
• Additional relevant MeSH terms: Disease; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Losartan

Study Results

Participant Flow

Arm/Group Title	Losartan	Placebo
Arm/Group Description	Losartan flexibly dosed from 25-100 mg per day over 10 weeks losartan: Angiotensin receptor blocker (ARB)	Placebo flexibly dosed from 25-100 mg per day over 10 weeks Placebo: Placebo
Period Title: Overall Study
STARTED	75	74
COMPLETED	59	58
NOT COMPLETED	16	16

Baseline Characteristics

Arm/Group Title	Losartan	Placebo	Total
Arm/Group Description	Losartan flexibly dosed from 25-100 mg per day over 10 weeks losartan: Angiotensin receptor blocker (ARB)	Placebo flexibly dosed from 25-100 mg per day over 10 weeks Placebo: Placebo	Total of all reporting groups
Overall Participants	75	74	149
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.4 (12.3)	35.5 (12.6)	36.0 (12.4)
Sex: Female, Male (Count of Participants)
Female	43 57.3%	54 73%	97 65.1%
Male	32 42.7%	20 27%	52 34.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 4%	1 1.4%	4 2.7%
Asian	7 9.3%	2 2.7%	9 6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	8 10.7%	14 18.9%	22 14.8%
White	50 66.7%	44 59.5%	94 63.1%
More than one race	6 8%	11 14.9%	17 11.4%
Unknown or Not Reported	1 1.3%	2 2.7%	3 2%
CAPS-5 Total (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	33.5 (10.3)	34.2 (10.0)	33.8 (10.2)

Outcome Measures

1. Primary Outcome

Title	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.
Description	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.
Time Frame	10 weeks

Outcome Measure Data

Analysis Population Description

Modified Intent to Treat (mITT) Population

Arm/Group Title	Losartan	Placebo
Arm/Group Description	Losartan flexibly dosed from 25-100 mg per day over 10 weeks losartan: Angiotensin receptor blocker (ARB)	Placebo flexibly dosed from 25-100 mg per day over 10 weeks Placebo: Placebo
Measure Participants	58	58
Mean (95% Confidence Interval) [score on a scale]	-15.96	-16.89

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Losartan, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.66
	Comments
	Method	Mixed Models Analysis
	Comments

2. Secondary Outcome

Title	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.
Description	The Clinician-Administered PTSD Scale for DSM-5 (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.
Time Frame	10 weeks

Outcome Measure Data

Analysis Population Description

Subjects on Losartan Arm

Arm/Group Title	CC Homozygotes on Losartan	T Carriers on Losartan
Arm/Group Description	CC Homozygotes on Losartan	T Carriers on Losartan
Measure Participants	11	40
Mean (Standard Deviation) [score on a scale]	16.7 (10.1)	15.8 (13.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Losartan, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.57
	Comments
	Method	Mixed Models Analysis
	Comments

Adverse Events

Time Frame	10 Weeks (Study Duration)
Arm/Group Title	Losartan		Placebo
Arm/Group Description	Losartan flexibly dosed from 25-100 mg per day over 10 weeks losartan: Angiotensin receptor blocker (ARB)		Placebo flexibly dosed from 25-100 mg per day over 10 weeks Placebo: Placebo
All Cause Mortality
	Losartan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/75 (0%)		0/74 (0%)
Serious Adverse Events
	Losartan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/75 (2.7%)		1/74 (1.4%)
Gastrointestinal disorders
Gallbladder Pain	1/75 (1.3%)	1	0/74 (0%)	0
Nervous system disorders
Neurosyphilis	0/75 (0%)	0	1/74 (1.4%)	1
Cataplexy	1/75 (1.3%)	1	0/74 (0%)	0
Other (Not Including Serious) Adverse Events
	Losartan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/75 (26.7%)		18/74 (24.3%)
Nervous system disorders
Lightheadedness	8/75 (10.7%)	13	7/74 (9.5%)	9
Insomnia	4/75 (5.3%)	4	5/74 (6.8%)	5
headache	16/75 (21.3%)	24	14/74 (18.9%)	21

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.