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

A Pilot Study of N-acetylcysteine in Suspected Thrombotic Thrombocytopenia Purpura

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.

Study Overview

• Status: Completed
• Conditions: Purpura, Thrombotic Thrombocytopenic; TTP
• Intervention / Treatment: Drug: N-Acetylcysteine

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.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98104
      • Puget Sound Blood Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: Acetadote

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in platelet count	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.	Daily for 7 days and at hospital discharge, expected to be at 1-2 weeks post infusion.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Laboratory measures of VWF activity	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.	Daily for 7 days and at hospital dischargewhich is estimated to be at 1-2 weeks post-infusion
Laboratory measures of ADAMTS13 activity	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.	Daily for 7 days and at hospital discharge which is estimated to be at 1-2 weeks post-infusion
Laboratory measures of red blood cell (RBC) hemolysis and oxidation	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.	Daily for 7 days and at hospital discharge which is estimated to be at 1-2 weeks post-infusion
Safety of NAC infusion	Adverse events will be collected daily during the hospitalization, at 2 weeks and 8 weeks following infusion.	Over the study period

Collaborators and Investigators

• Sponsor: Bloodworks
• Collaborators: University of Washington
• Investigators: Principal Investigator: Barbara A Konkle, MD, Bloodworks

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): July 1, 2017
• Study Completion (Actual): July 1, 2017

Study Registration Dates

• First Submitted: February 22, 2013
• First Submitted That Met QC Criteria: March 7, 2013
• First Posted (Estimate): March 11, 2013

Study Record Updates

• Last Update Posted (Actual): September 20, 2017
• Last Update Submitted That Met QC Criteria: September 18, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: TTP; Purpura, Thrombotic Thrombocytopenic
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Hematologic Diseases; Hemorrhage; Blood Coagulation Disorders; Skin Manifestations; Blood Platelet Disorders; Thrombophilia; Thrombotic Microangiopathies; Purpura; Purpura, Thrombocytopenic; Purpura, Thrombotic Thrombocytopenic; Thrombocytopenia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: N-Acetylcysteine in TTP