Clinical trial NCT01808521: A Pilot Study of N-acetylcysteine in Thrombotic Thrombocytopenia Purpura
Official title: A Pilot Study of N-acetylcysteine in Suspected Thrombotic Thrombocytopenia Purpura
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Purpura, Thrombotic Thrombocytopenic
TTP
Keywords: Purpura, Thrombotic Thrombocytopenic
TTP
Lead sponsor: Bloodworks
Sponsor class: OTHER
Collaborators: name: University of Washington
First posted: 2013-03-11
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Changes in platelet count
timeFrame: Daily for 7 days and at hospital discharge, expected to be at 1-2 weeks post infusion.
Secondary outcomes:
measure: Laboratory measures of VWF activity
timeFrame: Daily for 7 days and at hospital dischargewhich is estimated to be at 1-2 weeks post-infusion
measure: Laboratory measures of ADAMTS13 activity
timeFrame: Daily for 7 days and at hospital discharge which is estimated to be at 1-2 weeks post-infusion
measure: Laboratory measures of red blood cell (RBC) hemolysis and oxidation
timeFrame: Daily for 7 days and at hospital discharge which is estimated to be at 1-2 weeks post-infusion
measure: Safety of NAC infusion
timeFrame: Over the study period
Other outcomes:
Locations:
city: Seattle
country: United States
facility: Puget Sound Blood Center
state: Washington
Study officials:
affiliation: Bloodworks
name: Barbara A Konkle, MD
role: PRINCIPAL_INVESTIGATOR
References: