Acquired Methaemoglobinaemia
Conditions
Keywords
Acquired Methaemoglobinemia, Methylene Blue
Brief summary
This is an open label, uncontrolled, Phase 4 study including 10 patients who present in hospital/urgent care setting with acquired methemoglobinemia. The population may include pediatric and adult patients (males and females of all ages are included). The study will run in both the EU and the US. The aim of the study is to confirm safety and efficacy of ProvayBlueTM for the treatment of acquired methemoglobinemia and has been requested by the US-FDA as a Post-Marketing requirements.
Interventions
DRUGMethylene Blue
Administration of Methylene Blue to treat acquired methaemoglobinaemia
Sponsors
Provepharm SAS
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Pediatric or adult patients (males and females of all ages are included) diagnosed with acquired methemoglobinemia and receiving treatment with ProvayBlue™ as per the treating physician's diagnosis and hospital standard of care. Acquired methemoglobinemia is defined as a level of methemoglobinemia \>30% or ≤30% in case of clinical symptoms (e.g. sleepiness, cyanosis, dizziness, etc.). * Written informed consent obtained prior to any data collection (retrospective and prospective) for this study and study specific assessments.
Exclusion criteria
* Known severe hypersensitivity reactions to methylene blue or any other thiazine dye; * Known deficiency in glucose-6-phosphate dehydrogenase (G6PD) due to the risk of hemolytic anemia as well as lack of therapeutic effect; * Known deficiency in Nicotinamide Adenine Dinucleotide Phosphate Hydrogen (NADPH) reductase. * Known use of selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), MonoAmine Oxidase (MAO) inhibitors or drugs metabolised via CYP isoenzymes anticipated during the treatment phase of the study. * Women who refuse to stop breastfeeding for up to 8 days after receiving the last dose of ProvayBlueTM.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Efficacy Endpoint: Number of Participants With and Without 50% Reduction in metHb Level | 1 hour | A 50% reduction in metHb level within 1 hour of the first dose of ProvayBlue for treatment of acquired methemoglobinemia. The timing of postdosing metHb level assays is inconsistent in clinical practice, for that reason metHb level at 1-hour postdosing was derived using linear interpolation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With and Without Concomitant Normalization of Heart Rate | 2 hours | Normalization of the heart rate within 2 hours of the first dose of ProvayBlue. The normal range used for heart rate was 50-100 beats per minute. |
| Number of Participants With and Without Concomitant Normalization of Blood Pressure | 2 hours | Normalization of blood pressure standard values within 2 hours of the first dose of ProvayBlue. The normal range used for systolic blood pressure was was 90-140 mm HG and the normal range used for diastolic blood pressure was 60-90 mm HG. |
| Second Dose | 1 hour | Evaluation of the patients who achieve a 50% reduction in metHb level after a second dose of ProvayBlue |
| Number of Participants With and Without Concomitant Normalization of Respiratory Rate | 2 hours | Normalization of the respiratory rate within 2 hours of the first dose of ProvayBlue. The normal range used for respiratory rate was 12-20 breaths per minute. |
| Methylene Blue Content in Blood Samples | 24 hours | Blood samples will be analyzed for methylene blue content |
| Azure B Content in Blood Samples | 24 hours | Blood samples will be analyzed for Azure B content |
| Number of Participants With Treatment-related Adverse Events | 24 hours | Number of participants who experience a treatment emergent adverse event assessed by the investigator as being related to study drug.. |
Countries
France
Participant flow
Recruitment details
Recruitment period was from July 2018- August 2020. There were 13 hospital/urgent care sites initiated in France, the United Kingdom (UK), and the United States (US).
Participants by arm
| Arm | Count |
|---|---|
| ProvayBlue (Methylene Blue) Arm Methylene Blue 0.5% will be administered.
1 mg/kg will be administered intravenously over 5-30 minutes. If methemoglobin level remains above 30% or if clinical symptoms persist, give a repeat dose of up to 1 mg/kg one hour after the first dose.
Methylene Blue: Administration of Methylene Blue to treat acquired methaemoglobinaemia | 7 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Other | 1 |
Baseline characteristics
| Characteristic | ProvayBlue (Methylene Blue) Arm |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants |
| Age, Continuous | 44.3 years STANDARD_DEVIATION 17.2 |
| Baseline methemoglobin | 40.7 percentage of methemoglobin in blood STANDARD_DEVIATION 21.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Region of Enrollment France | 6 participants |
| Region of Enrollment United States | 1 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 7 |
| other Total, other adverse events | 0 / 7 |
| serious Total, serious adverse events | 2 / 7 |
Outcome results
Primary
Primary Efficacy Endpoint: Number of Participants With and Without 50% Reduction in metHb Level
A 50% reduction in metHb level within 1 hour of the first dose of ProvayBlue for treatment of acquired methemoglobinemia. The timing of postdosing metHb level assays is inconsistent in clinical practice, for that reason metHb level at 1-hour postdosing was derived using linear interpolation.
Time frame: 1 hour
Population: The efficacy analysis set includes all safety analysis set patients who have at least 1 metHb assessment before and after ProvayBlue infusion
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ProvayBlue (Methylene Blue) Arm | Primary Efficacy Endpoint: Number of Participants With and Without 50% Reduction in metHb Level | 50% reduction in metHb level within 1 hour of the first dose: Yes | 3 Participants |
| ProvayBlue (Methylene Blue) Arm | Primary Efficacy Endpoint: Number of Participants With and Without 50% Reduction in metHb Level | 50% reduction in metHb level within 1 hour of the first dose: No | 3 Participants |
Secondary
Azure B Content in Blood Samples
Blood samples will be analyzed for Azure B content
Time frame: 24 hours
Population: Due to the nature of the disease, treatment with ProvayBlue was per the investigator's standard care and may have occurred prior to the informed consent document (PICD) being signed. However, data collection and study-specific assessments were to take place only after ICD signature. This often prevented collection of pharmacokinetic (PK) blood draws as informed consent was often given after the blood draws were to have been completed. As a result there were no patients with evaluable PK data.
Secondary
Methylene Blue Content in Blood Samples
Blood samples will be analyzed for methylene blue content
Time frame: 24 hours
Population: Due to the nature of the disease, treatment with ProvayBlue was per the investigator's standard care and may have occurred prior to the informed consent document (PICD) being signed. However, data collection and study-specific assessments were to take place only after ICD signature. This often prevented collection of pharmacokinetic (PK) blood draws as informed consent was often given after the blood draws were to have been completed. As a result there were no patients with evaluable PK data.
Secondary
Number of Participants With and Without Concomitant Normalization of Blood Pressure
Normalization of blood pressure standard values within 2 hours of the first dose of ProvayBlue. The normal range used for systolic blood pressure was was 90-140 mm HG and the normal range used for diastolic blood pressure was 60-90 mm HG.
Time frame: 2 hours
Population: All participants who received a dose of study drug
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| ProvayBlue (Methylene Blue) Arm | Number of Participants With and Without Concomitant Normalization of Blood Pressure | Systolic BP | normalized within 2 hours of the first dose of ProvayBlue: Yes | 2 Participants |
| ProvayBlue (Methylene Blue) Arm | Number of Participants With and Without Concomitant Normalization of Blood Pressure | Systolic BP | normalized within 2 hours of the first dose of ProvayBlue: No | 0 Participants |
| ProvayBlue (Methylene Blue) Arm | Number of Participants With and Without Concomitant Normalization of Blood Pressure | Systolic BP | N/A (Normal at baseline or no measurement within 2 hours of the first dose) | 5 Participants |
| ProvayBlue (Methylene Blue) Arm | Number of Participants With and Without Concomitant Normalization of Blood Pressure | Diastolic BP | normalized within 2 hours of the first dose of ProvayBlue: Yes | 0 Participants |
| ProvayBlue (Methylene Blue) Arm | Number of Participants With and Without Concomitant Normalization of Blood Pressure | Diastolic BP | normalized within 2 hours of the first dose of ProvayBlue: No | 1 Participants |
| ProvayBlue (Methylene Blue) Arm | Number of Participants With and Without Concomitant Normalization of Blood Pressure | Diastolic BP | N/A (Normal at baseline or no measurement within 2 hours of the first dose) | 6 Participants |
Secondary
Number of Participants With and Without Concomitant Normalization of Heart Rate
Normalization of the heart rate within 2 hours of the first dose of ProvayBlue. The normal range used for heart rate was 50-100 beats per minute.
Time frame: 2 hours
Population: All participants who received study drug
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ProvayBlue (Methylene Blue) Arm | Number of Participants With and Without Concomitant Normalization of Heart Rate | Heart rate normalized within 2 hours of first dose: Yes | 2 Participants |
| ProvayBlue (Methylene Blue) Arm | Number of Participants With and Without Concomitant Normalization of Heart Rate | Heart rate normalized within 2 hours of first dose: No | 1 Participants |
| ProvayBlue (Methylene Blue) Arm | Number of Participants With and Without Concomitant Normalization of Heart Rate | N/A (normal at baseline or no measurement within 2 hours post first dose) | 4 Participants |
Secondary
Number of Participants With and Without Concomitant Normalization of Respiratory Rate
Normalization of the respiratory rate within 2 hours of the first dose of ProvayBlue. The normal range used for respiratory rate was 12-20 breaths per minute.
Time frame: 2 hours
Population: All Patients who received study drug
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ProvayBlue (Methylene Blue) Arm | Number of Participants With and Without Concomitant Normalization of Respiratory Rate | Respiratory rate normalized within 2 hours: Yes | 2 Participants |
| ProvayBlue (Methylene Blue) Arm | Number of Participants With and Without Concomitant Normalization of Respiratory Rate | Respiratory rate normalized within 2 hours: No | 2 Participants |
| ProvayBlue (Methylene Blue) Arm | Number of Participants With and Without Concomitant Normalization of Respiratory Rate | N/A (normal at baseline or no measurement within 2 hours of first dose) | 3 Participants |
Secondary
Number of Participants With Treatment-related Adverse Events
Number of participants who experience a treatment emergent adverse event assessed by the investigator as being related to study drug..
Time frame: 24 hours
Population: All participants who received at least one dose of study drug
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ProvayBlue (Methylene Blue) Arm | Number of Participants With Treatment-related Adverse Events | Related treatment emergent adverse event: yes | 0 Participants |
| ProvayBlue (Methylene Blue) Arm | Number of Participants With Treatment-related Adverse Events | Related treatment emergent adverse event: No | 7 Participants |
Secondary
Second Dose
Evaluation of the patients who achieve a 50% reduction in metHb level after a second dose of ProvayBlue
Time frame: 1 hour
Population: Only 1 patient received a second dose of ProvayBlue and they did not have a metHb measurement within 1 hour of that second dose