Conditions: Posttraumatic Stress Disorder
Keywords: posttraumatic stress disorder losartan angiotensin receptor blocker
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 149
Healthy volunteers: no

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.

Arms:
arm 1: Losartan flexibly dosed from 25-100 mg per day over 10 weeks arm 2: Placebo flexibly dosed from 25-100 mg per day over 10 weeks

Interventions: intervention 1: losartan intervention 2: Placebo
Intervention descriptions: intervention 1: Angiotensin receptor blocker (ARB) intervention 2: Placebo

Protocol document:
Prot_SAP_000.pdf: 
  
A Controlled Trial of Losartan in Posttraumatic Stress Disorder 
 
NCT02709018  
 
February 2, 2021 
 
 
 


STUDY PROTOCOL 
 
Study Design 
The trial was conducted between 01AUG 2016 and 25FEB 2020 at 6 clinical sites: five 
University academic medical sites and one University active-duty military hospital. The trial 
consisted of ten-week, randomized, double-blind, placebo-controlled administration of losartan 
or placebo. Eligible participants were randomized in a 1:1 ratio based on a randomly permuted 
block design stratified by site. Participants were prescribed 25 mg of active drug or placebo at 
Week 0 and then flexibly uptitrated (as tolerated) to 50 mg by Week 2, 75 mg by Week 4, and 
then 100 mg at Week 6. If significant side effects were encountered, the dosage could be held 
or reduced to a minimum of 25 mg and held stable at Week 6. Participants unable to tolerate the 
25 mg dose were withdrawn from the study. 
 
Losartan and placebo were prescribed as identical capsules, with the losartan 
overencapsulated. Randomization lists were prepared by the biostatistics analytical team (led by 
SJ) and distributed to research pharmacies at the sites who dispensed the drug. Only the 
biostatistics team had access to the treatment assignment codes.  
 
Study Participants 
Potential subjects participated in informed consent procedures approved by Institutional Review 
Boards for each performance site and the Department of Defense Human Research Protection 
Office (HRPO). A Data Safety Monitoring Board (DSMB) oversaw safety and progress of the 
study. To be included in the trial, veteran or civilian women and men, aged 18-70 years were 
required to meet past-month criteria for posttraumatic stress disorder (PTSD) according to 
DSM-5. Participants were required to have a CAPS-5 score of > 25 at screening in order to 
enter the trial.  
 
Exclusion criteria were: 1) current, imminent risk of suicide (as assessed by the C-SSRS (23)), 
2) active psychosis, 3) moderate or severe DSM-5 alcohol or other substance use disorder in 
the past 3 months, 4) unable to attend regular appointments, 5) prior intolerance of or allergy to 
losartan or other ARBs, 6) medical illness likely to result in imminent hospitalization or for which 
treatments are contraindicated (based on lab results, medical history and physical exam) (e.g., 
systolic blood pressure < 90 mm Hg), 7) serious cognitive impairment (as evidenced by 
cognitive impairment felt likely to interfere with the ability to participate meaningfully in the 


study); traumatic brain injury was not excluded unless there was serious cognitive impairment, 
8) concurrent ACE Inhibitors or ARBs, 9) concurrent antidepressants or antipsychotics, and 10) 
currently pregnant or trying to become pregnant, or of childbearing potential and unwilling to use 
a proven method of birth control. Potential participants were required to be off of all 
antidepressants for a minimum of 2 weeks (6 weeks for fluoxetine) prior to randomization; only 2 
participants had been on SSRIs prior to entering the study. Sleep agents (e.g., trazodone < 200 
mg; eszopiclone; zolpidem) were allowed as long as the dose had been stable for at least 2 
weeks; 14 patients used p.r.n. sleep aids during the study. Participation in a trauma-focused 
psychotherapy during the trial was prohibited. Participation in other psychotherapeutic 
modalities maintained for 3 months before and during the trial was permitted; 2 patients were on 
long-term supportive therapy during the study. 
 
Study Procedures 
All intakes and interview measures were completed by trained study personnel qualified to 
conduct the intake assessment. CAPS-5  training and certification was conducted (by Frank 
Weathers PhD) at the start of the study and yearly recalibration assessment reviews took place 
at each site.  At intake, a standardized past and current medical history with review of 
symptoms (including allergies to losartan, other ARBs, or any other medications) was obtained. 
The study physician also conducted a screening medical examination that included 
determination of standing and sitting blood pressure. Blood was drawn for renal and liver 
function tests, urine for drug screen, and a baseline EKG. If the patient was a woman of 
childbearing potential a urine pregnancy test was also done.  
 
Study Assessments 
Study assessments occured at baseline week (week 0) and weeks 1, 2, 4, 6, 8 and 10.  These 
assessments included interview and self report measures of symptoms and function, as well as 
evaluation of adverse events and assessment of standing and sitting blood pressure. The 
primary endpoint was at 10 weeks and the primary outcome measure was the Clinician 
Administered PTSD Scale for DSM-5 (CAPS-5; (24)), the gold standard in PTSD assessment. 
The CAPS-5 past-month was administered at intake and the past-week version re-administered 
at Weeks 0 (baseline), 4, 8 and 10 week endpoint (or earlier endpoint if the subject discontinued 
early from the study). Key secondary measures were the PTSD Checklist for DSM-5 (PCL-5; 
(25)) and the Clinical Global Impressions of Improvement Scale (CGI-I; (26)), and the Patient 
Health Questionnaire-9 (PHQ-9; (27)) for depressive symptoms. 


 
Genotyping and Genetic Analysis 
DNA was collected from salivary samples using the Oragene OG-500 salivary DNA collection 
Kit.  DNA from all participants was extracted using Qiagen extraction kits, and quantifed by gel 
electrophoresis using Quantity One (BioRad, Hercules, CA) and then normalized.  Taqman 
reactions were performed using Taqman SNP Genotyping Assays along with Taqman 
Genotyping Master Mix (Applied Biosystems Inc., Foster City, CA). rs4311 alleles were 
discerned using the 7900HT Fast Real-Time PCR system. 
 
 
STATISTICAL ANALYSIS PLAN 
Statistical Methods 
The primary outcome (CAPS-5) was analyzed using an MMRM (mixed model repeated 
measures) approach based on a modified intent-to-treat (mITT) population, defined as 
randomized subjects who initiated treatment and had both a baseline and at least one post-
baseline outcome score during the blinded phase of the study (Week 10). Participants from the 
mITT population who were included in the MMRM model also required both a baseline and at 
least one post-baseline CAPS-5 score. The model included as the dependent variable change 
from baseline in CAPS-5 total score at each post-baseline visit (Weeks 4, 8 and 10).  
Independent variables in the MMRM model included treatment, visit, treatment-by-visit 
interaction, and baseline CAPS-5 total.  Visit was treated as a categorical variable. Unstructured 
variance-covariance structure was used. This same analysis was also repeated on the per 
protocol population, defined as as all eligible subjects for whom the 10-week assessments for 
the primary analysis were available and who were dispensed at least 50mg of the protocol 
prescribed medication at the 6-week time point. Descriptive analyses were performed to 
compare baseline data between treatment groups. Categorical variables were evaluated using 
Fisher’s exact test. Continuous variables were analyzed with Wilcoxon’s rank sum test.  Safety 
data were summarized overall and by treatment groups for the blinded and extended phases of 
the study. Fisher’s exact test was used to compare the number of subjects between groups who 
experienced any adverse events.  
 
The study was a priori powered assuming 10% attrition and an alpha set to 0.05 using a two-
sided, two-sample t-test.  Based on a sample size of 160 subjects to have an evaluable sample 
size of 144 (72 per arm), we could detect with 80% power a standardized change score 


between the groups of 47%. All analyses are based on the modified intent-to-treat (mITT) 
sample unless otherwise specified. 
 
Analogous methods to the primary analysis were used for the other continuous secondary 
outcomes. The categorical secondary outcome, treatment response status, (response defined 
as a score of 1 [“Much Improved”] or 2 [“Improved”] on the CGI-I) was analyzed using a 
generalized estimating equation (GEE) model for binary  data.  The  model  included  the binary 
responder status at Weeks 1, 2, 4, 6, 8 and 10 as the dependent variable; treatment, visit and 
the treatment-by-visit interaction as independent variables. Statistical analyses were performed 
using R version 3.5.2 (http://www.r-project.org).