Clinical trial NCT04378426
Conditions: PTSD
Keywords: PTSD Nitrous Oxide
Sponsor: VA Office of Research and Development
Start date: 2021-10-07; Completion date: 2022-08-31
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Post-traumatic stress disorder (PTSD) seriously disrupts the lives of many Veterans. Current first-line treatments, serotonin reuptake inhibitors or prolonged exposure therapy, take weeks to months to bring meaningful improvement, leaving Veterans experiencing prolonged suffering. A promising new treatment approach for rapidly reducing PTSD symptoms is nitrous oxide, an inhalation anesthetic and putative glutamate modulator that diminishes depression symptoms within 1 day and has limited side effects. If shown to be similarly effective in PTSD, nitrous oxide may add dramatically to the treatment armamentarium by bringing rapid symptom decrease before longer-term therapies take hold. The proposed projects test the efficacy of nitrous oxide in relieving Veteran's PTSD symptoms and, in parallel, explore how nitrous oxide may modify cognitive and pain outcomes.

Detailed description:
The proposed projects will examine the efficacy of nitrous oxide in relieving Veteran's PTSD symptoms and in parallel, explore whether nitrous oxide improves cognitive and pain outcomes. Specifically, the investigators will first assess whether nitrous oxide treatment improves PTSD symptoms within 1 week. In parallel, the investigators will explore whether the treatment improves co-existing depression and pain. In addition, the investigators will explore nitrous oxide's effects on a PTSD-associated impairment that is often overlooked - disruption in cognitive control, a core neurobiological process critical for regulating thoughts and for successful daily functioning.

Arms: arm 1: PTSD participants in this arm will receive and admixture of up to 50%nitrous oxide and 50% oxygen plus intravenous saline arm 2: PTSD participants in this arm will receive and admixture of up to 50%nitrogen and 50% oxygen plus intravenous 0.045mg/kg midazolam
Interventions: intervention 1: Nitrous Oxide intervention 2: Midazolam intervention 3: Nitrogen intervention 4: Oxygen intervention 5: Saline
Intervention descriptions: intervention 1: PTSD participants in this arm will receive and admixture of up to 50% nitrous oxide and 50% oxygen plus intravenous saline intervention 2: PTSD participants in this arm will receive and admixture of up to 50%nitrogen and 50% oxygen plus intravenous 0.045mg/kg midazolam intervention 3: PTSD participants in this arm will receive and admixture of up to 50%nitrogen and 50% oxygen plus intravenous 0.045mg/kg midazolam intervention 4: inhaled gas intervention 5: Placebo infusion

Protocol documents:
Prot_002.pdf: 
Title: Nitrous Oxide for 
Posttraumatic Stress Disorder 
(PTSD):  A Phase IIa Trial
Protocol ID # 53017 
PD: Carolyn Rodriguez, MD, PhD 
Approval Period: 06/21/2022 - 02/01/2023 
NCT04378426
Date: 01/18/2023
PROTOCOL APPLICATION FORM 
Human Subjects Research Stanford 
University


Clinical Study
Purpose: 
PTSD seriously disrupts the lives of many Veterans. Current first-line pharmacological treatments 
often fail to bring meaningful improvement, leaving these Veterans with distressing and impairing 
symptoms. Developing more effective and more rapidly effective therapeutic options is critical. The 
purpose of the study is to assess efficacy of nitrous oxide in PTSD and the duration of its short-term 
therapeutic effects.
Objectives:
1. To determine the efficacy of nitrous oxide in PTSD 
2. To examine the safety of nitrous oxide administration in PTSD
Design: 
The clinical study design is a randomized placebo-controlled clinical trial including two groups: 
Group 1) “Active Treatment” Nitrous oxide group, and, Group 2) “Active Comparator/Placebo 
group.”
Methods:
The study’s first phase is the Screening phase, to assess eligibility via inclusion and exclusion criteria. 
During the Baseline phase, participants will be rated for PTSD. Participants will then enter the 
Randomization phase and be randomized (1:1) to receive either an admixture of up to 50% nitrous 
oxide and 50% oxygen plus IV saline ("active treatment") plus IV saline or 50% nitrogen and 50% 
oxygen plus 0.045mg/kg midazolam ("active comparator") for 1 hour. During the Treatment phase, 
the gas mixture will be administered via facemask connected to a standard anesthesia machine at 4-8 
L/min. Participants will be continuously monitored (EKG, BP, O2) during treatment per the 
American Society of Anesthesiologists standard and observed for an additional four hours of 
recovery supervised by an attending-level anesthesiologist. To examine changes in PTSD, symptoms 
will be reassessed 7 days (1 week) post-administration. Unexpected adverse effects of nitrous oxide 
will be recorded at each time point.

SAP_003.pdf: 
Title: Nitrous Oxide for 
Posttraumatic Stress Disorder 
(PTSD):  A Phase IIa Trial
Protocol ID # 53017 
PD: Carolyn Rodriguez, MD, PhD 
NCT04378426
Date: 01/18/2023
Statistical Methods: Hypothesis Test/Power Analysis


Primary Hypothesis: A one-hour nitrous oxide inhalation session will reduce PTSD within 1 week 
compared to placebo.  
To test the primary hypothesis that nitrous oxide will show efficacy for PTSD, we will regress the 1 week 
CAPS-5 score on treatment, adjusted for CAPS-5 baseline score. We will incorporate a Kaplan-Meier 
approach with log-rank test comparing time to drop-out in the two treatment groups as a preliminary 
analysis.
Power analysis/sample size: Assuming that a change in the CAPS-5 of 12 points represents 
meaningful improvement in clinical symptoms, using STATA 14 (StataCorp., 2017), we calculate that an 
expected sample size of 78 completers (39 per group) will provide 80% power to detect a moderate 
effect size of a difference of 0.6 standard deviations in the change score, allowing a definitive go/no 
decision. At least 104 participants will be randomized over the 4 years to achieve 78 total sample, 
accounting for 25% attrition. We note that this estimate is conservative as it does not take into account 
partial data from non-completers and uses the unrealistic, mathematically worst-case, scenario for mixed 
effects models in which the intra-individual correlation structure is such that the mixed effects model 
provides no added information. If the drug does not meet this threshold, it would not be pursued further. 
On the other hand, if nitrous oxide yields a clinically meaningful change, we would have important data 
(e.g., an estimated effect size in nitrous oxide vs midazolam and an estimated correlation structure) for a 
future multi-site Phase 3 confirmatory clinical trial.