SepsisPhase 1MB-NONCT00159510
Studies of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome
A Phase 1 study testing Methylene blue, Nitric oxide and Methylene blue & nitric oxide in people with Sepsis, run by Northern State Medical University at 1 site in Russia.
Trial summary
Nitric oxide (NO) plays a pivotal role in maintenance of normal vascular tone. However, in sepsis the excessive production of NO results in myocardial depression, vasoplegia, and cytotoxic effects, thus promoting shock and multiple organ dysfunction. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Sepsis
- What is being tested?
- Methylene blue, Nitric oxide and Methylene blue & nitric oxide
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 28 participants
- Where
- 1 siteRussia
- Study dates
- Apr 2004to Sep 2014
- Phase
- Phase 1
- Are there results?
- None posted in the registry
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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Informed written consent from the patient, or a written consent from a relative together with a the doctor responsible for the treatment of the patient
- Aged 18 years or above.
- Severe sepsis diagnosed less than 72 h prior to randomization.
- Septic shock defined as a syndrome characterized by severe sepsis in association with either:
- a MAP <70 mm Hg for at least 30 consecutive minutes despite fluid resuscitation or,
- a requirement for vasopressor support with a constant dose rate of either epinephrine >0,05 mcg/kg/min and/or norepinephrine >0.05 mcg/kg/min and/or dopamine >5 mcg/kg/min and/or phenylephrine >0.5 mcg/kg/min for at least 30 consecutive minutes to maintain a MAP >90 mm Hg
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- Cardiac index (CI) must be >3.5 l/min/m2, pulmonary artery occlusion pressure (PAOP) must be between 8 and 18 mm Hg, and in the opinion of the investigator the patient must be adequately fluid resuscitated
- A 4 French Pulsiocath thermodilution catheter (Pulsion Medical Systems, München, Germany) in place in one of the femoral arteries and a 7 French thermistor-tipped balloon floatation catheter (Swan Ganz) in the pulmonary artery for determination of hemodynamics, including extravascular lung water index (EVLWI).
- A dedicated intravenous line for infusion of MB
- A respirator with a device for delivery of gaseous NO to the inspiration gas and equipped with analysis tools for lung mechanics
- The patients will be treated in intensive care units with the possibility to provide full life support for the whole duration of the study
- In female patients a negative pregnancy test will be requires before inclusion unless the patient is either in the post-partum period or known to have undergone prior tubal ligation or hysterectomy, or be postmenopausal
Who cannot join
- 1) Patients who have received vasopressor infusion therapy as described in the definition of septic shock either intermittently or continuously for a period of more than 24 h prior to randomization 2) The use of any vasoactive drug infusion other than epinephrine, norepinephrine, dopamine, phenylephrine and dobutamine, at the time of study entry 3) Patients in whom either vasodilators or dobutamine are contraindicated 4) Patients who cannot have their MAP managed safely within the range of 70-90 mm Hg (e.g. patients with raised intracranial pressure) 5) Shock due to any cause other than severe sepsis (e.g. drug reaction or drug overdose, adrenal insufficiency, pulmonary embolus, burn injury etc.) 6) Patients that are immunocompromised due to any of the following:
- known corticosteroid therapy either greater than or equal to a total daily dose equivalent to 1 mg/kg or greater than 70 mg/day of oral prednisolone for at least 7 consecutive days within one month prior to study entry,
- clinically suspected or known to have Acquired Immunodeficiency Syndrome (AIDS),
- granulocyte count less than 1000/mm3 due to a cause other than severe sepsis (e.g. metastatic or hematological malignancies or chemotherapy),
- immunosuppressant therapy (e.g. due to an organ or bone marrow transplant), 7) Underlying disease, exclusive of septic shock, which is expected to cause death within 1 month from study entry 8) Within 30 days prior to this study, the patient should not have been included in any other randomized therapeutic study of an agent not licensed, or administration of any other investigational agent for the treatment of sepsis and/or septic shock. Patients must not participate in such studies for at least 30 days after enrolment into this study.
- 9) Pregnant women, pregnancy test required of any fertile women.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Controlled Prospective Randomized Open-Label Study of Methylene Blue and Inhaled Nitric Oxide in Patients With Septic Shock and Acute Lung Injury
Nitric oxide (NO) plays a pivotal role in maintenance of normal vascular tone. However, in sepsis the excessive production of NO results in myocardial depression, vasoplegia, and cytotoxic effects, thus promoting shock and multiple organ dysfunction. A recently completed study from our group showed advantageous cardiovascular effects of continuously infused methylene blue (MB), an inhibitor of NO pathway, in human septic shock. In another investigation, we have found that the combination of inhaled NO and continuously infused MB attenuates endotoxin-induced acute lung injury (ALI) in sheep. Our intention is, in a new study, to test the hypothesis that the combination of MB and NO (MB+NO) improves both cardiovascular and pulmonary functions as well as clinical outcome in patients with septic shock and ALI. Forty mechanically ventilated patients diagnosed with hyperdynamic septic shock and ALI, will be randomized to groups receiving
- Conventional treatment (control group)(n =10);
- MB infusion in addition to conventional treatment (n=10);
- Inhaled NO in addition to conventional treatment (n=10);
- MB infusion combined with inhaled NO (MB+NO) in addition to conventional treatment (n=10).
Read the detailed description
The therapy with either MB+NO or NO or MB alone will be prolonged for up to 24 h or until resolution of septic shock, whichever occurs first. MB will be injected as a bolus of 2 mg/kg subsequently followed by dose-titrated infusion. The latter beginning with 0.25 mg/kg/h continuing within the range of from 0.05 to 0.5 mg/kg/h. The goal is to maintain mean arterial pressure within the range of 70-90 mm Hg, with the purpose of reducing any concurrent vasopressor therapy. The NO therapy will be started from 10 ppm and aimed at maintaining the mean pulmonary artery pressure at the lowest possible levels by inhaling NO in concentrations from 1 to 20 ppm.
- Conditions
- Sepsis
- Being tested
- Methylene blue, Nitric oxide, Methylene blue & nitric oxide
- Keywords
- sepsis, methylene blue, nitric oxide, acute lung injury
- Medical subject headings
- Sepsis, Acute Lung Injury
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Methylene blueDrug
Injection bolus of 2 mg/kg PBW and infusion of 0.2 mg/kg/hr
Nitric oxideDrug
Also called Not actual
An inhalation of NO via ETT at 10 ppm, partially weaned by 72 hrs of therapy
Methylene blue & nitric oxideDrug
Also called Not actual
See the dosage in the previous arms
| Study group | Role | What they receive |
|---|---|---|
| Control | No intervention | The control group with neither nitric oxide nor methylene blue used |
| MB alone | Active comparator | Single methylene blue used Receives: Drug: Methylene blue |
| NO alone | Active comparator | Nitric oxide alone used Receives: Drug: Nitric oxide |
| MB+NO | Active comparator | Both nitric oxide and methylene blue used Receives: Drug: Methylene blue & nitric oxide |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mortality
Mortality rate by Day 28
Measured: 28
Secondary outcomes (2)
Duration of inotropic and vasopressor support
Duration of vasopressor and/or inotrope suppor
Measured: 7 Days
Severity of organ dysfunction
Number of organ-specific dysfunctions
Measured: 7 Days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Sep 2005 (estimated)
- Study startApr 2004
- Primary completionSep 2014
- Study completionSep 2014
Why it stopped: Inability to recruit the patients due to the short supply and changed local hospital protocol
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for SepsisStudies of the same condition, open and under way.
- 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 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 28 participants (actual)
Sponsor and investigators
- Lead sponsor
- Northern State Medical University
- Sponsor type
- University, hospital or other
- Collaborators
- Helse Nord
- Responsible party
- Principal investigator, Mikhail Y. Kirov, Northern State Medical University
- Investigators
- Mikhail Y Kirov, MD, PhD, Principal investigator, Northern State Medical University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00159510
- Sponsor's protocol ID
- 4001.721.132
- Other IDs
- Helse Nord (Norway), project, number 4001.721.132
- Acronym
- MB-NO
- Status last verified
- Oct 2015
- First submitted
- 8 Sep 2005
- Last updated
- 6 Oct 2015
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 6 Oct 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Controlled Prospective Randomized Open-Label Study of Methylene Blue and Inhaled Nitric Oxide in Patients With Septic Shock and Acute Lung Injury
- ClinicalTrials.gov ID
- NCT00159510
- Acronym / sponsor ID
- MB-NO / 4001.721.132
- Conditions
- Sepsis
- Keywords
- sepsis, methylene blue, nitric oxide, acute lung injury
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Inability to recruit the patients due to the short supply and changed local hospital protocol
- Enrolment
- 28 participants (actual)
- Lead sponsor
- Northern State Medical UniversityUniversity, hospital or other
- Collaborators
- Helse Nord
- Study start
- Apr 2004
- Primary completion
- Sep 2014 (actual)
- Study completion
- Sep 2014 (actual)
- First posted
- 12 Sep 2005 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Nitric oxide (NO) plays a pivotal role in maintenance of normal vascular tone. However, in sepsis the excessive production of NO results in myocardial depression, vasoplegia, and cytotoxic effects, thus promoting shock and multiple organ dysfunction. A recently completed study from our group showed advantageous cardiovascular effects of continuously infused methylene blue (MB), an inhibitor of NO pathway, in human septic shock. In another investigation, we have found that the combination of inhaled NO and continuously infused MB attenuates endotoxin-induced acute lung injury (ALI) in sheep. Our intention is, in a new study, to test the hypothesis that the combination of MB and NO (MB+NO) improves both cardiovascular and pulmonary functions as well as clinical outcome in patients with septic shock and ALI. Forty mechanically ventilated patients diagnosed with hyperdynamic septic shock and ALI, will be randomized to groups receiving
- Conventional treatment (control group)(n =10);
- MB infusion in addition to conventional treatment (n=10);
- Inhaled NO in addition to conventional treatment (n=10);
- MB infusion combined with inhaled NO (MB+NO) in addition to conventional treatment (n=10).
Detailed description
The therapy with either MB+NO or NO or MB alone will be prolonged for up to 24 h or until resolution of septic shock, whichever occurs first. MB will be injected as a bolus of 2 mg/kg subsequently followed by dose-titrated infusion. The latter beginning with 0.25 mg/kg/h continuing within the range of from 0.05 to 0.5 mg/kg/h. The goal is to maintain mean arterial pressure within the range of 70-90 mm Hg, with the purpose of reducing any concurrent vasopressor therapy. The NO therapy will be started from 10 ppm and aimed at maintaining the mean pulmonary artery pressure at the lowest possible levels by inhaling NO in concentrations from 1 to 20 ppm.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Control | No intervention | –The control group with neither nitric oxide nor methylene blue used |
| MB alone | Active comparator | Drug: Methylene blueSingle methylene blue used |
| NO alone | Active comparator | Drug: Nitric oxideNitric oxide alone used |
| MB+NO | Active comparator | Drug: Methylene blue & nitric oxideBoth nitric oxide and methylene blue used |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- Informed written consent from the patient, or a written consent from a relative together with a the doctor responsible for the treatment of the patient
- Aged 18 years or above.
- Severe sepsis diagnosed less than 72 h prior to randomization.
- Septic shock defined as a syndrome characterized by severe sepsis in association with either:
- Cardiac index (CI) must be >3.5 l/min/m2, pulmonary artery occlusion pressure (PAOP) must be between 8 and 18 mm Hg, and in the opinion of the investigator the patient must be adequately fluid resuscitated
Key exclusion criteria (6 listed)
- 1) Patients who have received vasopressor infusion therapy as described in the definition of septic shock either intermittently or continuously for a period of more than 24 h prior to randomization 2) The use of any vasoactive drug infusion other than epinephrine, norepinephrine, dopamine, phenylephrine and dobutamine, at the time of study entry 3) Patients in whom either vasodilators or dobutamine are contraindicated 4) Patients who cannot have their MAP managed safely within the range of 70-90 mm Hg (e.g. patients with raised intracranial pressure) 5) Shock due to any cause other than severe sepsis (e.g. drug reaction or drug overdose, adrenal insufficiency, pulmonary embolus, burn injury etc.) 6) Patients that are immunocompromised due to any of the following:
- known corticosteroid therapy either greater than or equal to a total daily dose equivalent to 1 mg/kg or greater than 70 mg/day of oral prednisolone for at least 7 consecutive days within one month prior to study entry,
- clinically suspected or known to have Acquired Immunodeficiency Syndrome (AIDS),
- granulocyte count less than 1000/mm3 due to a cause other than severe sepsis (e.g. metastatic or hematological malignancies or chemotherapy),
- immunosuppressant therapy (e.g. due to an organ or bone marrow transplant), 7) Underlying disease, exclusive of septic shock, which is expected to cause death within 1 month from study entry 8) Within 30 days prior to this study, the patient should not have been included in any other randomized therapeutic study of an agent not licensed, or administration of any other investigational agent for the treatment of sepsis and/or septic shock. Patients must not participate in such studies for at least 30 days after enrolment into this study.
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 |
|---|---|---|
| Methylene blueInjection bolus of 2 mg/kg PBW and infusion of 0.2 mg/kg/hr | Drug | MB alone |
| Nitric oxideAlso: Not actualAn inhalation of NO via ETT at 10 ppm, partially weaned by 72 hrs of therapy | Drug | NO alone |
| Methylene blue & nitric oxideAlso: Not actualSee the dosage in the previous arms | Drug | MB+NO |
Primary outcome
Mortality
Time frame: 28
Mortality rate by Day 28
2 secondary outcomes
Duration of inotropic and vasopressor support
Time frame: 7 Days
Severity of organ dysfunction
Time frame: 7 Days
Results and safety
The study was stopped early (reason given: Inability to recruit the patients due to the short supply and changed local hospital protocol). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Oct 2015.
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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.
Mikhail Y Kirov, MD, PhD principal investigator
Northern State Medical University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Methylene blue, Nitric oxide and Methylene blue & nitric oxide in people with Sepsis, run by Northern State Medical University at 1 site in Russia.
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 12 inclusion and 6 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: stopped early, as of the sponsor's last update on 6 Oct 2015. 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 Russia. 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. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Inability to recruit the patients due to the short supply and changed local hospital protocol). Results are not available in the source record.
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?
Mortality (time frame: 28). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 6 Oct 2015.