Phase 2 Study of MP4CO to Treat Vaso-occlusive Sickle Crisis

Study Overview
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Brief Summary
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Sickle Cell disease is caused by an inherited hemoglobin disorder. Healthy red blood cells are discoid and can deform and move through small blood vessels to carry oxygen to all parts of the body. In Sickle Cell disease, as red blood cells circulate and oxygen is released, the deoxygenated abnormal Hemoglobin S can begin to polymerize and cause red cells to become sticky and elongated. These sickled red cells are less flexible and will obstruct small blood vessels and prevent normal red cells from circulating freely, which limits oxygen delivery to tissues and organs. This is known as a sickling crisis or vaso-occlusive crisis and is the leading cause of hospitalization in patients with Sickle Cell disease. Patients suffering from a sickle crisis experience severe pain and are at risk of stroke, heart attack or even death. Current therapy is limited to hydration and symptomatic pain relief. The administration of MP4CO as an adjunct treatment to standard therapy may alleviate pain associated with a sickling crisis and potentially reduce the severity and duration of a crisis. This may shorten the time in hospital and potentially improve the quality of life for patients with sickle cell anemia.

Detailed Description
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Sickle cell disease (SCD) is an autosomal recessive disorder of the β globin gene of the hemoglobin molecule. To date, no specific agent has been approved to treat a sickle cell crisis, to reduce the severity of a sickling crisis, or to shorten the duration of admission. Current therapy for a crisis is limited to hydration and symptomatic pain relief with opiates when pain is severe enough to cause admission to hospital. Administration of oxygen by inhalation alone has not proven effective. The carbon monoxide (CO) molecule binds to Hb S and, while attached, prevents and reverses polymerization of Hb S chains and the distortion of the red cell. CO at very low doses also acts as a cell-signaling molecule, and may reduce inflammation, decrease oxygen requirements, and prevent programmed cell death (apoptosis). MP4CO is designed as an ischemic rescue therapy to deliver non-toxic levels of CO, to provide an immediate metabolic signal to cells to help reverse red cell sickling, and to reduce inflammation. Previously published studies provide a foundation to postulate that MP4CO might have the appropriate properties for treatment or reversal of an acute sickling crisis. The initial release of CO from MP4CO is predicted to have a beneficial effect including immediate stabilization of Hb S to prevent further red cell polymerization and reverse existing sickling, dilation of capillaries to enhance tissue perfusion, and anti-inflammatory cell-signalling properties. The subsequent circulation of the MP4 molecule as an oxygen therapeutic (after converting to MP4OX following oxygenation in the lungs) will help to 1) preferentially oxygenate ischemic tissue, 2) reverse partially sickled red cells, and 3) improve perfusion and oxygenation of local tissues to potentially ameliorate the painful crisis caused by sickling of red cells. In addition, MP4CO has enhanced chemical stability, which enables storage at room temperature.

Official Title
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A Phase 2 Multi-center, Randomized, Double-blind, Comparator-Controlled Dose Finding Study to Evaluate MP4CO for the Acute Treatment of Vaso-occlusive Crises in Subjects With Sickle Cell Disease

Conditions
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Anemia, Sickle Cell, Sickle Cell Anemia, Sickle Cell Disease, Sickle Cell Disorders, Hemoglobin SC Disease, Sickle Cell Hemoglobin C Disease

Intervention / Treatment
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* Drug: MP4CO
* Drug: Sodium chloride solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed Informed Consent (and assent as required for minors) Diagnosis of SCD (known HbSS or HbSß0) Sixteen years of age or older Prior history of at least one VOC requiring hospitalization within the last 24 months Exclusion Criteria: ≥ 5 VOCs within the preceding 6 months requiring Emergency Room (ER) visits or hospital admissions History of overt stroke or cerebral vascular accident within the previous 12 months Remained in the hospital for ≥2 weeks (14 days) for VOC management within the previous 6 months Known pulmonary hypertension based on an estimated tricuspid regurgitant jet velocity (TRJV) >2.90 m/s or definitive diagnosis by prior right heart catheterization Baseline SaO2 level by pulse oximetry <92% on room air Systemic hypertension (baseline systolic pressure ≥ 160 mmHg or diastolic pressure ≥ 90 mmHg) History of myocardial infarction, myocardial ischemia, or angina On a chronic red blood cell transfusion therapy program (simple or exchange) Renal dysfunction presenting with a GFR<60 mL/min/1.73m Any diagnosis of a concurrent chronic debilitating disease that may affect the completion of the study or results of the study as determined by the investigator Currently enrolled in any other investigational treatment study Significant substance abuse. Known to have HIV, active hepatitis B, or C infection, or active tuberculosis

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MP4CO<br>Escalating doses of MP4CO, administered intravenously | Drug: MP4CO<br>* 43 mg/mL pegylated carboxyhemoglobin [≥ 90% CO hemoglobin saturation] in physiological acetate electrolyte solution<br>* Other names: PEG carboxyhemoglobin;|
| Active Comparator: Sodium chloride solution<br>Normal saline (0.9% Sodium Chloride Injection USP)administered intravenously | Drug: Sodium chloride solution<br>* Normal saline solution (0.9% Sodium Chloride Injection USP)<br>* Other names: 0.9% NaCl solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of hospitalization for treatment of painful vaso-occlusive crisis (VOC) | Time from randomization to resolution of the vaso-occlusive crisis, assessed by evaluation of cessation of opioid analgesia, recovery of ambulation, and/or ready for hospital discharge. | Up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain levels | Proportion of subjects with a pre-defined reduction in pain levels assessed using a visual analogue scale (VAS) | Up to 7 days | 
| Readmission to emergency room (ER) | Proportion of subjects with at least one return visit to ER after hospital discharge | Up to 28 days | 
| Re-admission to hospital for treatment of VOC | Proportion of subjects re-admitted to hospital for VOC treatment within 7 days after discharge | Up to 28 days | 
| Acute Chest Syndrome (ACS) complications | Proportion of subjects with ACS complications | Up to 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sickle cell anemia, Sickle cell disease, Sickling crisis, Vaso-occlusive crisis, Carboxyhemoglobin, Oxygen therapeutic, Ischemic rescue therapy, Hemoglobin solution, Pegylated hemoglobin