Clinical trial NCT02583672: Role of Oxidative Stress and Inflammation in Type 1 Gaucher Disease (GD1)
Official title: Role of Oxidative Stress and Inflammation in Type 1 Gaucher Disease (GD1): Potential Use of Antioxidant/Anti-inflammatory Medications
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Gaucher Disease Type 1
Keywords: Gaucher Disease
GD1
N-acetylcysteine
glutathione
GSH
Lead sponsor: University of Minnesota
Sponsor class: OTHER
Collaborators: name: Rare Diseases Clinical Research Network
name: National Center for Advancing Translational Sciences (NCATS)
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: National Institute of Neurological Disorders and Stroke (NINDS)
name: Lysosomal Disease Network
First posted: 2015-10-22
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to measure levels of blood and brain chemicals related to oxidative stress and inflammation in healthy volunteers and individuals with Type 1 Gaucher disease (GD1) to see if these levels are altered by GD1.

Detailed description: The investigators will also examine if there is a change in these blood and brain chemicals in GD1 patients after receiving oral N-acetylcysteine ("NAC"), which is available both as a prescription medication and as a dietary-supplement product, that has antioxidant and anti-inflammatory effects. Any changes the investigators may find in chemical levels may improve our understanding of the disease and could eventually lead to better treatment options. This is a multi-center study of approximately 50 people with Type 1 Gaucher disease (GD1) and healthy volunteers. Healthy volunteers will have 3 study visits over the course of 3 months. Procedures will include review of medical history, blood draws at each visit, and an MRI scan at the third visit. GD1 patients will have 7 study visits over the course of 9 months. Procedures include review of medical history, blood draws at each visit (multiple draws from an IV catheter at Visit 6), neurological exams, pain and fatigue questionnaires, and MRI scans (at Visits 3 and 6). In addition, GD1 patients will be given oral NAC at Visit 3, to begin taking twice a day for 90 days. All MRI scans will be done at the University of Minnesota in Minneapolis.

Eligibility criteria: Inclusion Criteria:

1. All participants must be 18 years or older.
2. All participants must understand and cooperate with requirements of the study in the opinion of the investigators and must be able to provide written informed consent.
3. Individuals with GD1 who are medically stable for participation in the study in the opinion of the investigator.
4. GD1 patients must be on a stable, specific ERT and/or SRT therapy at a specific dose (e.g. on a units/kg basis) for at least 2 years.
5. GD1 patients who have had a change in therapy, i.e. a change in dose or switch from one drug to another, can be enrolled after at least 6 months have elapsed since the change and is considered stable in the opinion of the clinician providing care to the patient.
6. Healthy subjects who will be frequency-matched for age.
7. All participants must not have taken antioxidants coenzyme Q-10, vitamin C, or vitamin E for 3 weeks prior to the study and during the course of the study.

Exclusion Criteria:

1. Medically unstable conditions in any group as determined by the investigators.
2. Concurrent disease; medical condition; or an extenuating circumstance that, in the opinion of the investigator, might compromise subject safety, study compliance, completion of the study, or the integrity of the data collected for the study.
3. Women who are pregnant or lactating or of child-bearing age who are not using acceptable forms of contraception.
4. History of asthma that is presently being treated.
5. Patients enrolled in another interventional study.
6. Allergy to N-acetylcysteine.
7. Patients who cannot or are unwilling to have blood drawn.
8. Inability to undergo MRI scanning, including but not limited to: unable to remain still in an MRI scanner for more than 30 minutes, claustrophobia, presence of paramagnetic substances or pacemakers in body, weight over 300 lbs.
9. Unable to adhere to study protocol for whatever reason.

Primary outcomes:
measure: Change in subjects with Gaucher disease type 1, in concentration of glutathione in brain (μmol/g)
timeFrame: At 90 days and at 180 days
Secondary outcomes:
measure: In healthy volunteers, determination of level of glutathione in brain (μmol/g)
timeFrame: 90 Days After Enrollment
measure: Change in subjects with Gaucher disease type 1, in concentration of glutathione in blood (μmol/g)
timeFrame: Baseline, 45 days, 90 days, 120 days, 150 days, 180 days, and 270 days
measure: Change in healthy volunteers, in concentration of glutathione in blood (μmol/g)
timeFrame: Baseline, 45 days, and 90 days
measure: Change in subjects with Gaucher disease type 1, in concentration of myo-inositol in brain (μmol/g)
timeFrame: At 90 days and at 180 days
measure: In healthy volunteers, determine the concentration of myo-inositol in brain (μmol/g)
timeFrame: 90 Days After Enrollment
measure: Change in subjects with Gaucher disease type 1, in concentration of TNF-alpha in plasma (pg/mL)
timeFrame: Baseline, 45 days, 90 days, 120 days, 150 days, 180 days, and 270 days
measure: Change in healthy volunteers, in concentration of TNF-alpha in plasma (pg/mL)
timeFrame: Baseline, 45 days, and 90 days
measure: Change in subjects with Gaucher disease type 1, in concentration of N-acetylcysteine (NAC) in blood (µg/ml)
timeFrame: 120 days, 150 days, and 180 days
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: New York
country: United States
facility: New York University
state: New York
Study officials:
affiliation: University of Minnesota
name: Reena V. Kartha, PharmD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zhou J, Coles LD, Kartha RV, Nash N, Mishra U, Lund TC, Cloyd JC. Intravenous Administration of Stable-Labeled N-Acetylcysteine Demonstrates an Indirect Mechanism for Boosting Glutathione and Improving Redox Status. J Pharm Sci. 2015 Aug;104(8):2619-26. doi: 10.1002/jps.24482. Epub 2015 Jun 5.
citation: Radtke KK, Coles LD, Mishra U, Orchard PJ, Holmay M, Cloyd JC. Interaction of N-acetylcysteine and cysteine in human plasma. J Pharm Sci. 2012 Dec;101(12):4653-9. doi: 10.1002/jps.23325. Epub 2012 Sep 27.
citation: Coles LD, Tuite PJ, Oz G, Mishra UR, Kartha RV, Sullivan KM, Cloyd JC, Terpstra M. Repeated-Dose Oral N-Acetylcysteine in Parkinson's Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress. J Clin Pharmacol. 2018 Feb;58(2):158-167. doi: 10.1002/jcph.1008. Epub 2017 Sep 22.
citation: Holmay MJ, Terpstra M, Coles LD, Mishra U, Ahlskog M, Oz G, Cloyd JC, Tuite PJ. N-Acetylcysteine boosts brain and blood glutathione in Gaucher and Parkinson diseases. Clin Neuropharmacol. 2013 Jul-Aug;36(4):103-6. doi: 10.1097/WNF.0b013e31829ae713.