Complex Regional Pain SyndromePhase 3NCT03879538

Nitrous Oxide for the Treatment of Complex Regional Pain Syndrome

A Phase 3 study testing Nitrous Oxide and Oxygen in people with Complex Regional Pain Syndrome, run by The Cleveland Clinic at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Patients will then be randomized via a web-based randomization system Redcap Allocation will be stratified based on the presence of a pre-existing spinal cord stimulator to either the nitrous oxide study group or the oxygen control group. Read more about this study

Who is it for?: Ages 18 to 65 years
Conditions the study is for: Complex Regional Pain Syndrome
What is being tested?: Nitrous Oxide and Oxygen
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 44 participants
Where: 1 siteUnited States
Study dates: 2 Jul 2019to 28 Jul 2022
Phase: Phase 3
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 65 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Patients must be diagnosed with CRPS based on the revised International Association for the Study of Pain criteria.
Duration of disease must be at least 6 months.
Written informed consent.

Who cannot join

Patients who had no subjective benefit from ketamine infusions, as determined by interview during the recruitment process.
Patients taking more than 60mg of morphine equivalents or more daily for an alternative chronic pain condition.
Patients with both coronary artery disease (as determined by cardiac catheterization) and a functional status of less than 4 metabolic equivalents. The limited functional status must be secondary to cardiopulmonary symptoms (angina, dyspnea on exertion). Patients with coronary artery disease and a limited functional status (<4 METS) secondary to chronic pain can be included.
Patients with congestive heart failure of any etiology that are NYHA Class III or IV
Patients with moderate or severe pulmonary hypertension as determined by echocardiogram or right heart catheterization.
Patients with intraocular surgery within the past 14 days

Show all 12Show fewer

Patients with worker's compensation claims and active litigation.
Patients who have been diagnosed with COPD.
Patients who use home oxygen therapy for any condition.
Diagnosis of Alcohol Use Disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).
Illicit drug use within the past three months (not including marijuana).
Pregnant patients or patients with upcoming planned pregnancy.

Trial locations and contacts

1 site in 1 country.

United States1 site

Cleveland Clinic Pain Management
Cleveland, Ohio, 44195

Other trials in United States

About this study

Official title: A Prospective Randomized Controlled Pilot Study Nitrous Oxide for the Treatment of Complex Regional Pain Syndrome

The nitrous oxide group will receive 50% nitrous oxide mixed with 50% oxygen, and the control group will receive 50% oxygen (oxygen plus air mixture). Both groups will undergo inhalation therapy for a duration of 2 hours via an FDA-approved mask breathing circuit. Vital signs (blood pressure, respiratory rate, heart rate) will be monitored every 30 minutes. Pulse oximetry monitoring will be continuous. Patients will be monitored for side effects including nausea, vomiting, desaturation, sedation, respiratory depression, and dizziness. Patients and other involved providers will be blinded to the treatment type.

Read the detailed description

Daily opioid consumption data will be collected by having patients record and report their daily opioid use before and after treatment. Oral and transdermal opioids will be converted to standardized morphine equivalents and adjusted for bioavailability.

Patients will present for the first scheduled treatment and they will fill out the PROMIS-29 v2 survey and the SF-MPQ-2 (6 neuropathic pain items). Patients will also turn in their opioid use log.

Vital signs will be obtained. Patients with significantly abnormal vital signs or vital signs that are significantly deviated from baseline will be referred to appropriate medical care.

Patients will then be randomized via a web-based randomization system Redcap. Group allocation will be stratified based on the presence of a pre-existing spinal cord stimulator to either the nitrous oxide study group or the oxygen control group.

The nitrous oxide group will receive 50% nitrous oxide mixed with 50% oxygen, and the control group will receive 50% oxygen. Both groups will undergo inhalation therapy for a duration of 2 hours via an FDA-approved mask breathing circuit. Active Control, because patients may be able to tell if they are receiving nitrous oxide, patient blinding may be compromised. Therefore, we plan to utilize an active control. Both groups will receive 2 mg of intravenous midazolam, to infuse over 5 minutes, at the start of each breathing treatment session. IVs will be removed at the conclusion of each breathing treatment. Vital signs (blood pressure, respiratory rate, heart rate) will be monitored every 30 minutes. Pulse oximetry monitoring will be continuous. Patients will be monitored for side effects including nausea, vomiting, desaturation, sedation, respiratory depression, and dizziness. Patients and other involved providers will be blinded to the treatment type. Research investigators administering the treatments will not be blinded.

At the conclusion of inhalation therapy, the gas will be turned off and patients will breathe room air. All patients will be monitored for an additional 30 minutes. This recovery time is more than sufficient to ensure nitrous oxide is completely eliminated in those patients who receive it. Patients will be monitored and asked about side effects.

Patients will receive a total of three treatments (6 total exposure hours) over one week with 2 or 3 days between each session. Possible treatment schedules: Monday-Wednesday-Friday, Wednesday-Friday-Monday, or Friday-Monday-Wednesday. After the conclusion of the third treatment, patients will be followed with phone calls as detailed in the Measurement section below.

Drug Handling Instructions
Nitrous oxide for the study will be stored at room temperature in appropriately labeled E-cylinder tanks.

Conditions: Complex Regional Pain Syndrome
Being tested: Nitrous Oxide, Oxygen
Medical subject headings: Complex Regional Pain Syndromes

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Nitrous OxideDrug
Also called 50 % Nitrous Oxide plus 50% Oxygen
A total of three inhalation treatments with 50% Nitrous Oxide plus 50% oxygen (6 total exposure hours) over one week with 2 or 3 days between each session.
OxygenDrug
Also called 50% Oxygen
A total of three inhalation treatments with 50% oxygen (6 total exposure hours) over one week with 2 or 3 days between each session.

Study groups in NCT03879538
Study group	Role	What they receive
The nitrous oxide group	Active comparator	Nitrous oxide group will receive 50% nitrous oxide mixed with 50% oxygen, inhalation therapy for a duration of 2 hours via an FDA-approved mask breathing circuit. Receives: Drug: Nitrous Oxide
The Control Group	Placebo comparator	Control group will receive 50% oxygen, inhalation therapy for a duration of 2 hours via an FDA-approved mask breathing circuit. Receives: Drug: Oxygen

What is being measured

The primary outcome is the main question the study is designed to answer.

Pain Score
scales ranging from 0 - "no pain" to 10 - "worst pain ever" based on the PROMIS-29 v2.0 questionnaire.
Measured: one-week and one-month follow-up time points

Secondary outcomes (2)

PROMIS-29 Survey Physical Health Z-score, Mental Health Z-score
As intermediate scores, T-scores for each of the 7 domains used in the survey need to be estimated from raw data in order to obtain final summary Z-scores measuring physical and mental health. T-scores were obtained from an on-line service provided by the HealthMeasures Scoring Service (https://www.assessmentcenter.net/ac_scoringservice). Physical and mental summary Z-scores were calculated using the formulas given in the document titled "Calculating physical and mental health summary scores for PROMIS-29 v2.0 and v2.1" (dated on August 8, 2018) by Karen L. Spritzer and Ron D. Hays from the website HealthMeasures.net.
High T-scores indicates more of the concept being measured which can be either desirable or undesirable outcome, e.g., high T-score on fatigue is undesirable whereas desirable for physical function. Z-scores are standard scores with mean of 0 and SD of 1 in reference population. High Z-scores are desirable for either physical or mental health.
Measured: one-week and one-month follow-ups after treatments were ended
PGIC Scale
patient disease perception as measured by the Patient's Global Impression of Change (PGIC) survey (a seven-point scale ranging from 1 - "no change or condition has gotten worse" to 7 - "very much improve").
Measured: one-week and one-month follow-ups.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

2 Jul 201928 Jul 2022

First posted18 Mar 2019
Study start2 Jul 2019
Primary completion28 Jul 2022
Study completion28 Jul 2022

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Other trials for Complex Regional Pain SyndromeStudies of the same condition, open and under way.
More trials run by The Cleveland ClinicThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Model description: The nitrous oxide group will receive 50% nitrous oxide mixed with 50% oxygen, and the control group will receive 50% oxygen (oxygen plus air mixture). Both groups will undergo inhalation therapy for a duration of 2 hours via an FDA-approved mask breathing circuit. Vital signs (blood pressure, respiratory rate, heart rate) will be monitored every 30 minutes.
Masking: Double blind
Who is masked: Participant, Outcomes assessor
Enrolment: 44 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03879538
Sponsor's protocol ID: 19-150
Status last verified: Feb 2024
First submitted: 31 Jan 2019
Last updated: 9 Feb 2024
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

Enrolling by invitationPhase 4
Low Dose Naltrexone Therapy for Complex Regional Pain Syndrome
Complex Regional Pain Syndrome, Chronic Pain
RecruitingPhase 3
Evaluation of IV AMBTX-01 (Neridronate) for Treatment of CRPS Type 1 (CRPS-RISE)
Complex Regional Pain Syndrome Type I
Recruiting
The Effectiveness of Conservative Treatment in Patients With Complex Regional Pain Syndrome.
CRPS (Complex Regional Pain Syndromes)
RecruitingPhase 3
Phase 3, Open-Label Extension Study of AMBTX-01 (Neridronate) for Complex Regional Pain Syndrome Type 1
Complex Regional Pain Syndrome Type I
Active, not recruiting
Transcranial Magnetic Stimulation for Chronic Neuropathic Pain
Chronic Neuropathic Pain, Post-Stroke Pain

All Complex Regional Pain Syndrome trials

Study at a glance

From the registry record, last updated by the sponsor on 9 Feb 2024. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Prospective Randomized Controlled Pilot Study Nitrous Oxide for the Treatment of Complex Regional Pain Syndrome
ClinicalTrials.gov ID: NCT03879538
Acronym / sponsor ID: 19-150
Conditions: Complex Regional Pain Syndrome
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 44 participants (actual)
Lead sponsor: The Cleveland ClinicUniversity, hospital or other
Study start: 2 Jul 2019 (actual)
Primary completion: 28 Jul 2022 (actual)
Study completion: 28 Jul 2022 (actual)
First posted: 18 Mar 2019 (actual)
Results: Posted 9 Feb 2024

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Patients will present for the first scheduled treatment and they will fill out the PROMIS-29 v2 survey and the SF-MPQ-2 (6 neuropathic pain items). Patients will also turn in their opioid use log.

Vital signs will be obtained. Patients with significantly abnormal vital signs or vital signs that are significantly deviated from baseline will be referred to appropriate medical care.

Drug Handling Instructions
Nitrous oxide for the study will be stored at room temperature in appropriately labeled E-cylinder tanks.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Double blind (participant, outcomes assessor)
Number of arms: 2
Model description: The nitrous oxide group will receive 50% nitrous oxide mixed with 50% oxygen, and the control group will receive 50% oxygen (oxygen plus air mixture). Both groups will undergo inhalation therapy for a duration of 2 hours via an FDA-approved mask breathing circuit. Vital signs (blood pressure, respiratory rate, heart rate) will be monitored every 30 minutes.

Arm	Type	Receives
The nitrous oxide group	Active comparator	Drug: Nitrous OxideNitrous oxide group will receive 50% nitrous oxide mixed with 50% oxygen, inhalation therapy for a duration of 2 hours via an FDA-approved mask breathing circuit.
The Control Group	Placebo comparator	Drug: OxygenControl group will receive 50% oxygen, inhalation therapy for a duration of 2 hours via an FDA-approved mask breathing circuit.

Who may qualify

Ages: 18 to 65 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (3 listed)

Patients must be diagnosed with CRPS based on the revised International Association for the Study of Pain criteria.
Duration of disease must be at least 6 months.
Written informed consent.

Key exclusion criteria (12 listed)

Patients who had no subjective benefit from ketamine infusions, as determined by interview during the recruitment process.
Patients taking more than 60mg of morphine equivalents or more daily for an alternative chronic pain condition.
Patients with both coronary artery disease (as determined by cardiac catheterization) and a functional status of less than 4 metabolic equivalents. The limited functional status must be secondary to cardiopulmonary symptoms (angina, dyspnea on exertion). Patients with coronary artery disease and a limited functional status (<4 METS) secondary to chronic pain can be included.
Patients with congestive heart failure of any etiology that are NYHA Class III or IV
Patients with moderate or severe pulmonary hypertension as determined by echocardiogram or right heart catheterization.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Nitrous OxideAlso: 50 % Nitrous Oxide plus 50% OxygenA total of three inhalation treatments with 50% Nitrous Oxide plus 50% oxygen (6 total exposure hours) over one week with 2 or 3 days between each session.	Drug	The nitrous oxide group
OxygenAlso: 50% OxygenA total of three inhalation treatments with 50% oxygen (6 total exposure hours) over one week with 2 or 3 days between each session.	Drug	The Control Group

Primary outcome

Pain Score
Time frame: one-week and one-month follow-up time points
scales ranging from 0 - "no pain" to 10 - "worst pain ever" based on the PROMIS-29 v2.0 questionnaire.

2 secondary outcomes

PROMIS-29 Survey Physical Health Z-score, Mental Health Z-score
Time frame: one-week and one-month follow-ups after treatments were ended
PGIC Scale
Time frame: one-week and one-month follow-ups.

Results and safety

Results posted to the registry on 9 Feb 2024, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
The Nitrous Oxide Group	20	20
The Control Group	24	24

Primary outcome: Pain Score

Time frame: one-week and one-month follow-up time points. Mean (Standard Deviation). Unit: score on a scale

Measure	The Nitrous Oxide Group n = 20	The Control Group n = 24
one-week follow-up	5.9 (1.5)	6.0 (2.5)
one-month follow-up	6.5 (2.0)	6.8 (2.2)

The Nitrous Oxide Group vs The Control Group: Mean Difference (Net): -0.57 (95% CI -1.42 to 0.28), p = 0.19, Mixed Models Analysis

Population analysed: A few patients had missing primary outcome measurements. The Mean (SD) values presented here was based on available raw data. In our formal analysis of treatment effect on primary outcome, we used multiple imputation procedures to impute missing primary outcome values.

2 secondary outcomes are reported in the full results.

Adverse events

Time frame: 1 month. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
The Nitrous Oxide Group	0 of 20 (0%)	0 of 20 (0%)	0 of 20
The Control Group	0 of 24 (0%)	0 of 24 (0%)	0 of 24

Limitations and caveats (from the sponsor): limitations include the purely subjective nature of pain which was our primary outcome. Validity of the trial thus depends critically on adequacy of blinding. Because many patients can detect inhaled nitrous oxide, we gave all participants midazolam which has similar effects. But it remains possible that some patients could distinguish nitrous oxide from air, and were thus biased.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 9 Feb 2024.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.

Related trials for Complex Regional Pain Syndrome

Enrolling by invitationPhase 4
Low Dose Naltrexone Therapy for Complex Regional Pain Syndrome
Complex Regional Pain Syndrome, Chronic Pain
RecruitingPhase 3
Evaluation of IV AMBTX-01 (Neridronate) for Treatment of CRPS Type 1 (CRPS-RISE)
Complex Regional Pain Syndrome Type I
Recruiting
The Effectiveness of Conservative Treatment in Patients With Complex Regional Pain Syndrome.
CRPS (Complex Regional Pain Syndromes)
RecruitingPhase 3
Phase 3, Open-Label Extension Study of AMBTX-01 (Neridronate) for Complex Regional Pain Syndrome Type 1
Complex Regional Pain Syndrome Type I
Active, not recruiting
Transcranial Magnetic Stimulation for Chronic Neuropathic Pain
Chronic Neuropathic Pain, Post-Stroke Pain

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Jason Hale, MD principal investigator

Anesthesiologist

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Nitrous Oxide and Oxygen in people with Complex Regional Pain Syndrome, run by The Cleveland Clinic at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 9 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 9 Feb 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Pain Score (time frame: one-week and one-month follow-up time points). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03879538.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Feb 2024.