Evaluation of ProvayBlue safety/efficacy in acquired methemoglobinemia
Research type
Research Study
Full title
Open label clinical study to evaluate the safety and efficacy of ProvayBlueTM (methylene blue injection USP) for the treatment of acquired methemoglobinemia
IRAS ID
229635
Contact name
Samuel Ackroyd
Contact email
Sponsor organisation
Provepharm SAS
Eudract number
2017-000290-37
Duration of Study in the UK
1 years, 0 months, 0 days
Research summary
Research Summary:
This is an open-label, multinational phase IV study to study the safety and efficacy of ProvayBlue (methylene blue injection) in 10 patients, with acquired methemoglobinemia , in attendance at hospital/urgent care settings. The study drug will be administered as per the hospital’s standard of care, therefore treatment can take place prior to and after the Informed consent form is signed. Blood samples will be taken from patient’s participating in the trial, in order to determine the fate of ProvayBlue inside the body. Data collection and assessments will however only take place after the Informed consent form is signed. Trial participants will range from infants to adults.\n\nThis study has been requested by the US Regulatory Authority (FDA) as a post-marketing requirement, and its main purpose is to confirm that a single administration of ProvayBlue is effective in patients with acquired methemoglobinemia. In addition to sites in the US, this trial will be conducted in France, Germany and the UK.\n\nStudy duration will vary for each patient, depending upon the clinical situation and outcome of treatment. After receiving the study drug, a follow-up visit will take place in 5-10 days, followed by a follow-up telephone call 10-15 days later.Summary of Results:
The Clinical Study report that has been prepared is a combination of the data collected from this study and the data collected from an observational study conducted in the USA (study number HQF-METHB-2018001).A total of 31 subjects were enrolled in the interventional study (7 subjects) and the observational study (24 subjects) and were included in the database for this report. All 31 enrolled subjects received at least 1 ProvayBlue infusion and were included in the Safety Analysis Set. The Efficacy Analysis Set included a total of
20 Primary Cases who had at least 1 methemagloboinemia (metHb) assessment before and after ProvayBlue infusion (2 Primary Cases did not have either a baseline [1 subject)] or posttreatment [1 subject] metHb level in the database).Among the 22 Primary Cases, median age was 49.5 years and age ranged from 19 to 72 years. Females comprised 54.5% of Primary Cases, and almost all Primary Cases were white (95.5%). Results were similar for All Subjects.
The majority (59.1%) of Primary Cases came from home, were diagnosed in an emergency or urgent care setting (53.3%; 8/15 with available data), and exposure to a causative agent was prescribed (63.6%), with the suspected causative agent being dapsone in 50.0% of subjects and benzocaine in 13.6% of subjects. Among Primary Cases, almost one-third (31.8%) were exposed to the causative agent as a result of abuse, with 27.3% reporting use of poppers (amyl nitrate) and 4.5% reporting use of contaminated cannabis. All Primary Cases and 74.2% of All Subjects had signs or symptoms of methemoglobinemia; all of the subjects were administered ProvayBlue before enrollment in the studies. As would be expected, mean and median metHb levels at baseline were higher among the Primary Cases than among All Subjects; the highest mean and median baseline metHb levels were among subjects with non-dapsone causes of methemoglobinemia, typically resulting from inhalational abuse of amyl nitrate.Efficacy Results:
Twenty subjects (10 dapsone-treated and 10 non-dapsone treated) comprised the Efficacy Analysis Set. Nine (45.0%) subjects, including 5 (50.0%) dapsone-treated subjects and 4 (40.0%) non-dapsone-treated subjects, had metHb assessed within 2 hours of the end of the first ProvayBlue treatment. At 1-hour postdosing, 8 (88.9%) of these subjects had at least a 50% reduction in metHb, with an overall median predicted metHb of 3.2% (2.2% among dapsone-treated subjects and 11.4% among non-dapsone-treated subjects). In this analysis group, the overall median predicted time when metHb 50% reduction would be achieved was 0.7 hours (42 minutes).
Among all subjects in the Efficacy Analysis Set, regardless of timing of the first follow-up metHb measurement, median time from the end of the first infusion to the first metHb follow-up was 2.6 hours, with an overall median metHb of 2.0% (2.1% among dapsone-treated subjects and 1.5% among non-dapsone-treated subjects).
Among the 13 subjects in the Efficacy Analysis Set who had vital sign measurements at baseline, median values for systolic blood pressure, diastolic blood pressure, and heart rate were within normal range; median value for respiratory rate was above the ULN. Following administration of ProvayBlue, most subjects had vital sign values that were unchanged from the baseline category (low, normal, high). Shifts from normal to high were observed in systolic and diastolic blood pressure in 1 subject and in respiratory rate in 1 subject. Shifts from high to normal were observed in systolic pressure in 1 subject, in heart rate in 1 subject, and in respiratory rate in 4 subjects. Shift from low to normal in systolic blood pressure was observed in 1 subject. Oxygen saturation (SpO2) increased in 10 (76.9%) subjects and was unchanged in 2 (15.4%) subjects.Among subjects in the Efficacy Analysis Set, the most common prespecified signs and symptoms of methemoglobinemia (reported by ≥2 subjects overall) at baseline were cyanosis (45.0%), dyspnoea (35.0%), fatigue (35.0%), depressed central nervous system (CNS) (15.0%), headache (10.0%), weakness (10.0%), and dizziness (10.0%). No subjects experienced syncope, seizures, arrhythmias, or metabolic acidosis. Following administration of ProvayBlue, signs and symptoms of methemoglobinemia improved rapidly; 24 hours after treatment, no prespecified signs and symptoms were reported.
For all Primary Cases, results were also presented as a series of individual subject narratives, befitting the observational nature of most of the data. The narratives describing the clinical course of methemoglobinemia were prepared from review of medical records and identify issues in individual subjects’ past medical history, exposures, and comorbidities that may impact the consideration and interpretation of “normal” vital signs and related parameters. Contextualization of care in the narratives at times included complementary data derived from source material review that was not necessarily entered onto the study data collection form (DCF). These individual narratives demonstrated that response to treatment with ProvayBlue was rapid, with reduction of metHb levels, resolution of signs and symptoms, and normalization of vital signs.Safety Results:
One to 3 administrations of IV ProvayBlue were safe and well tolerated in subjects treated for methemoglobinemia.
Overall, 5 (16.1%) subjects experienced at least 1 TEAE, 4 of whom were Primary Cases (2 dapsone-treated, 2 non-dapsone-treated). A total of 2 (6.5%) subjects had severe TEAEs (methemoglobinemia [a second event following discharge] and headache). One subject (Primary Case) had a TEAE considered possibly related to ProvayBlue (seizure-like phenomena in a subject who had an ongoing history of drug-induced seizure); all other TEAEs were considered not related. Three subjects had serious TEAEs (seizure-like phenomena, thrombosis, methemoglobinemia), all of whom were Primary Cases.MetHb levels, evaluated as part of the efficacy analysis, improved; changes in other laboratory parameters, including haematology and serum chemistry testing, were either unremarkable or followed an expected course (eg, serum lactate decreased as sepsis was treated). Vital signs, which were evaluated as part of the efficacy analysis, normalized (within clinical context) following administration of ProvayBlue.
REC name
Yorkshire & The Humber - Leeds West Research Ethics Committee
REC reference
18/YH/0009
Date of REC Opinion
22 Mar 2018
REC opinion
Further Information Favourable Opinion