Safety Study of MP4CO in Adult Sickle Cell Patients

• ClinicalTrials.gov Identifier: NCT01356485
• Recruitment Status: Completed
• First Posted: May 19, 2011
• Last Update Posted: August 19, 2013
• Sponsor: Sangart
• Information provided by (Responsible Party): Sangart

Tracking Information

• First Submitted Date: May 17, 2011
• First Posted Date: May 19, 2011
• Last Update Posted Date: August 19, 2013
• Study Start Date: January 2012
• Actual Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: May 17, 2011): No efficacy evaluations will be made in this safety study [ Time Frame: 28 days ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: May 23, 2011)

• Adverse events [ Time Frame: From 0 hrs after dosing through 28 Day Follow-up visit ]
• Vital signs [ Time Frame: Baseline, Hourly from 0 - 8 hours, 24, 48, and 72 hours, and at 7 days ]
  Blood pressure, heart rate, respiration, temperature
• Laboratory assessments [ Time Frame: Baseline, 24, 48, and 72 hours, and at 7 days ]
  Hematology, serum chemistry, urinalysis, renal function and biomarkers
• Pain levels [ Time Frame: Baseline, Hourly from 0 - 8 hours, 24, 48, and 72 hours, and at 7 days ]
  Patient self-assessment of pain levels using Visual Analogue Scale
• Pulmonary artery pressure assessment [ Time Frame: Baseline, Pre-infusion, 1 hour post-infusion ]
  Trans-thoracic Echocardiography (TTE)

Original Secondary Outcome Measures (submitted: May 17, 2011)

• Adverse events [ Time Frame: From 0 hrs after dosing through 28 Day Follow-up visit ]
• Vital signs [ Time Frame: Baseline, Hourly from 0 - 8 hours, 24, 48, and 72 hours, and at 7 days ]
  Blood pressure, heart rate, respiration, temperature
• Laboratory assessments [ Time Frame: Baseline, 24, 48, and 72 hours, and at 7 days ]
  Hematology, serum chemistry, urinalysis, renal function and biomarkers
• Pain levels [ Time Frame: Baseline, Hourly from 0 - 8 hours, 24, 48, and 72 hours, and at 7 days ]
  Patient self-assessment of pain levels using Visual Analogue Scale

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety Study of MP4CO in Adult Sickle Cell Patients
• Official Title: A Multi-center, Randomized, Double Blind, Dose Escalation Safety Study of MP4CO in Clinically Stable Adult Sickle Cell Patients

Brief Summary

Sickle Cell Anemia 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 in the circulatory system, the deoxygenated abnormal hemoglobin S can begin to polymerize. When this occurs, the red blood cells can become sticky and elongated. These sickled red blood cells are less flexible and will obstruct small blood vessels and block normal red blood cells from traveling through the circulatory system, which limits oxygen delivery to tissues and organs. This is known as a "sickle crisis".

Patients suffering from a sickle crisis experience severe pain and are at risk of stroke, heart attack or even death. By lowering the level of oxygen pressure at which sickling occurs and opening the vasculature and rapidly delivering oxygen directly to ischemic tissues, the addition of MP4CO to existing treatment protocols may alleviate pain associated with a sickle cell crisis, abort a crisis and/or potentially reduce the duration of a crisis. This could mean less time in the hospital and an improved quality of life for patients with sickle cell anemia.

Detailed Description

To date, no specific agent has been approved to treat sickle cell crisis, to reduce the severity of a sickling crisis, or to shorten the duration of admission. Current therapy for a sickling 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. Carbon monoxide (CO) binds to Hb S and, while attached, prevents and reverses polymerization of Hb S chains and consequent distortion of the red blood cell. Carbon monoxide at very low doses also acts as a messenger to cells, reducing inflammation, reducing oxygen requirements, and preventing programmed cell death (apoptosis).

The MP4 molecule can be modified to carry CO and other gases to enhance therapeutic benefit for certain patients. MP4CO is therefore designed to deliver therapeutic, non-toxic levels of CO, to provide an immediate metabolic signal to cells and to reduce inflammation. Once the CO is released from the compound, the MP4 molecule gets oxygenated in the lung and then delivers oxygen to ischemic tissues.

Previously published studies provide a good foundation to postulate that a chemically modified hemoglobin such as MP4CO might have the ideal properties as an oxygen therapeutic agent for treatment or reversal of a sickling crisis. The initial release of CO from MP4CO is predicted to have a therapeutic effect including immediate stabilization of Hb S to prevent further polymerization and reverse existing sickling, vasodilation of capillaries, and anti-inflammatory properties. The subsequent circulation of the MP4 molecule as an oxygen therapeutic agent (after converting to MP4OX following oxygenation in the lungs) will help to 1) preferentially oxygenate ischemic cells, 2) reverse partially sickled red cells, and 3) improve oxygenation of local tissues, thereby potentially ameliorating the painful VOC caused by red blood cell sickling. In addition, MP4CO has enhanced chemical stability, which enables storage at room temperature while minimizing methemoglobin formation.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Condition

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

Intervention

• Drug: MP4CO
  43 mg/mL pegylated carboxyhemoglobin [≥ 90% CO hemoglobin saturation] in physiological acetate electrolyte solution
  Other Names:

  • Pegylated carboxyhemoglobin
  • PEG carboxyhemoglobin
• Drug: Sodium chloride solution
  Normal saline (0.9% sodium chloride solution)
  Other Names:

  • Normal saline
  • Sodium chloride
  • 0.9% NaCL solution

Study Arms

• Experimental: MP4CO
  Escalating doses of MP4CO, administered intravenously
  Intervention: Drug: MP4CO
• Placebo Comparator: Saline
  Normal saline (0.9% sodium chloride solution)
  Intervention: Drug: Sodium chloride solution

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 17, 2011): 32
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: December 2012
• Actual Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Adult male or female patients (18 years of age or older) with diagnosed sickle cell disease based on Hb SS, or S/β0 Thalassemia genotype, who are clinically stable and not experiencing an acute episode of pain

Exclusion Criteria:

• At least 4 painful VOCs within the preceding year requiring hospital treatment
• Urgent care facility, hospital treatment or admission for treatment of a painful VOC within the previous 2 months
• History of a painful VOC lasting longer than 2 weeks or > 12 pain episodes requiring intervention in a medical facility (emergency room, urgent care or clinic) in preceding year
• Baseline VAS pain score ≥ 4 cm
• Hemoglobin < 6 g/dL
• Transfusion of packed red blood cells within previous 4 weeks
• Currently on iron chelation therapy
• History of sickle cell disease-attributed CNS disease (including a) recent or past history of stroke; b) ongoing treatment with chronic transfusion therapy to prevent stroke; c. history of seizures or epilepsy; and d. evidence of or known overt cerebral vasculopathy or known cerebral vessel narrowing
• Evidence of pulmonary hypertension, based on an estimated systolic pulmonary artery pressure > 25 mmHg calculated from TRJ velocity from a transthoracic echocardiography (TTE) assessment at Screening visit or from a previous TTE assessment if it was done within 1 year prior to randomization
• Baseline oxygen saturation by pulse oximetry ≤ 90%
• History of a priapism within the last year
• History of hypertension requiring anti-hypertensive therapy
• Baseline bradycardia (heart rate < 60/min)
• History of myocardial infarction, myocardial ischemia, or angina
• Renal dysfunction or creatinine level within past 6 weeks of ≥ 1.2 mg/dL (≥ 106 µmol/L) or a urine protein/creatinine ratio (PCR) > 50 mg/mmol
• Hepatic dysfunction (AST or GGT > 3x ULN, or ALT >2x ULN, or conjugated bilirubin > 2x patient's baseline within the last 6 weeks)
• Positive pregnancy test
• Any acute or chronic condition which would limit the patient's ability to complete the study
• Evidence of, or known to be chronically abusing illegal drugs or excessive quantities of alcohol
• Known to have HIV, or active Hepatitis B or C infection, or tuberculosis
• Received any other investigational drug(s) within 30 days prior to randomization
• Professional or ancillary personnel involved with this study or in the employment of the investigator

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France, Jamaica, Lebanon, United Kingdom

Administrative Information

• NCT Number: NCT01356485
• Other Study ID Numbers: SCD-105
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Sangart
• Original Responsible Party: Howard Levy, MD, PhD, Chief Medical Officer, Sangart, Inc.
• Current Study Sponsor: Sangart
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Tania Small, MD; Sangart, Inc.

• PRS Account: Sangart
• Verification Date: August 2013