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A Pilot Study of N-acetylcysteine in Thrombotic Thrombocytopenia Purpura (NACinTTP)

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ClinicalTrials.gov Identifier: NCT01808521
Recruitment Status : Completed
First Posted : March 11, 2013
Last Update Posted : September 20, 2017
Sponsor:
Collaborator:
University of Washington
Information provided by (Responsible Party):
Bloodworks

Brief Summary:
In this study, the investigators want to determine if N-acetylcysteine(NAC), given intravenously, will decrease complications in patients with Thrombotic Thrombocytopenia Purpura (TTP) who are receiving treatment with therapeutic plasma exchange (TPE). The investigators want to determine, through anti-oxidant activity, if NAC will have additional efficacy in TTP by improving cleavage of the patients' VWF by ADAMTS13, and preventing propagation of platelet/VWF strings. This will be manifest by a more rapid improvement in the patient's platelet count, decrease in number of days requiring TPE, and decrease in microvascular thrombotic complications. The investigators will additionally: 1) Assess safety of NAC by evaluating subjects for adverse events and significant adverse events 2) Determine effects on TTP by measuring clinical and research laboratory values 3) Determine drug effects by measuring clinical and research laboratory values.

Condition or disease Intervention/treatment Phase
Purpura, Thrombotic Thrombocytopenic TTP Drug: N-Acetylcysteine Early Phase 1

Detailed Description:
Thrombotic thrombocytopenic purpura (TTP) is a rare hemostatic disorder with life threatening consequences secondary to microvascular thrombosis. While the use of therapeutic plasma exchange (TPE) has greatly improved survival, end organ damage, resistance to therapy, and relapses occur in many patients. Ultra-large von Willebrand factor multimers (ULVWF) are pathogenic in TTP. The investigators have found that N-acetylcysteine (NAC) cleaves ULVWF in vitro and in vivo in the ADAMTS13 deficient mice that are at increased risk of TTP. NAC is well tolerated in humans at intravenous doses used for treatment of acetaminophen overdose. This dosage correlates with that producing an effect in the murine studies noted above, and thus is an attractive treatment for patients with TTP. By cleaving VWF and preventing propagation of platelet/VWF strings, the investigators hypothesize that NAC treatment will decrease complications in patients with TTP receiving treatment with TPE. This will be manifest by a more rapid improvement in platelet count, decrease in number of days requiring plasma exchange, and decrease in microvascular thrombotic complications. To prepare for a larger trial the investigators propose a pilot study in 3 patients with suspected TTP at the University of Washington (UW) Medical Center. The study will be approved by the UW IRB prior to study initiation. Patients who consent to the study will receive daily NAC infusions beginning after the first TPE, in doses used for acetaminophen overdose. Blood samples will be collected for laboratory assays to determine optimal timing for sample collection in the larger multicenter trial, and to pilot the data collection forms. The investigators will also evaluate safety and patient tolerability.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 3 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Study of N-acetylcysteine in Suspected Thrombotic Thrombocytopenia Purpura
Study Start Date : May 2013
Actual Primary Completion Date : July 2017
Actual Study Completion Date : July 2017


Arm Intervention/treatment
Experimental: N-acetylcysteine
IV administration of N-acetylcysteine (Acetadote) at 150mg/Kg loading bolus over 60 minutes followed by 150mg/Kg over 17 hours if loading dose was well tolerated.
Drug: N-Acetylcysteine
IV administration of N-Acetylcysteine at 150mg/kg over 60 min first, then if well tolerated, 150mb/kg over 17 hours
Other Name: Acetadote




Primary Outcome Measures :
  1. Changes in platelet count [ Time Frame: Daily for 7 days and at hospital discharge, expected to be at 1-2 weeks post infusion. ]
    The platelet count will be measured before, daily during 4 days of NAC infusion, the subsequent 3 days and on the day of hospital discharge which is estimated to be at 1-2 weeks post infusion. Changes in platelet count over time will be reported.


Secondary Outcome Measures :
  1. Laboratory measures of VWF activity [ Time Frame: Daily for 7 days and at hospital dischargewhich is estimated to be at 1-2 weeks post-infusion ]
    VWF levels, oxidation and activity will be measured before, each day of NAC infusion, the subsequent 3 days and at hospital discharge, expected to be at 1-2 weeks post-infusion. Changes in values over time will be reported.

  2. Laboratory measures of ADAMTS13 activity [ Time Frame: Daily for 7 days and at hospital discharge which is estimated to be at 1-2 weeks post-infusion ]
    ADAMTS13 level, oxidation and activity will be measured before, daily during the NAC infusion, for the 3 subsequent days and at hospital discharge, expected to be at 1-2 weeks post-infusion. Changes over time will be reported.

  3. Laboratory measures of red blood cell (RBC) hemolysis and oxidation [ Time Frame: Daily for 7 days and at hospital discharge which is estimated to be at 1-2 weeks post-infusion ]
    Laboratory markers of RBC hemolysis and oxidation will be measured before, daily during the NAC infusion, for 3 subsequent days and at hospital discharge, expected to be at 1-2 weeks post-infusion. Changes in values over time will be reported.

  4. Safety of NAC infusion [ Time Frame: Over the study period ]
    Adverse events will be collected daily during the hospitalization, at 2 weeks and 8 weeks following infusion.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age >= 18 years of age
  2. Diagnosis of suspected TTP (lab evidence of hemolysis, platelet count <120,000, schistocytes on peripheral smear)
  3. Plans for or just initiated therapeutic plasma exchange (TPE), and before 3rd TPE
  4. Normal baseline prothrombin time (PT) and activated partial thromboplastin time (aPTT)
  5. Anticipated TPE for > 5 days

Exclusion Criteria:

  1. Asthma
  2. Life expectancy < 1 week
  3. Liver function tests abnormal- (ALT, direct bilirubin > three times upper normal limit)
  4. Known underlying bleeding disorder
  5. Pregnancy or nursing
  6. Known allergy to NAC
  7. Phosphodiesterase Type 5 inhibitors, nitroglycerin, or carbamazepine current use

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01808521


Locations
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United States, Washington
Puget Sound Blood Center
Seattle, Washington, United States, 98104
Sponsors and Collaborators
Bloodworks
University of Washington
Investigators
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Principal Investigator: Barbara A Konkle, MD Bloodworks

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Responsible Party: Bloodworks
ClinicalTrials.gov Identifier: NCT01808521     History of Changes
Other Study ID Numbers: N-Acetylcysteine in TTP
First Posted: March 11, 2013    Key Record Dates
Last Update Posted: September 20, 2017
Last Verified: September 2017

Keywords provided by Bloodworks:
Purpura, Thrombotic Thrombocytopenic
TTP

Additional relevant MeSH terms:
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Thrombocytopenia
Purpura
Purpura, Thrombocytopenic
Purpura, Thrombotic Thrombocytopenic
Blood Platelet Disorders
Hematologic Diseases
Blood Coagulation Disorders
Hemorrhage
Pathologic Processes
Skin Manifestations
Signs and Symptoms
Thrombotic Microangiopathies
Immune System Diseases
Thrombophilia
Acetylcysteine
N-monoacetylcystine
Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes