Safety Study of High Doses of Zinc in ALS Patients

Phase 1 Open Label Study of Zinc Therapy in ALS Patients

The purpose of this study is to determine the safety of Zinc given at 90mg/d in conjunction with 2mg/d of copper in ALS patients.

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: Zinc and Copper

Detailed Description

Physicians at Phoenix Neurological Associates (PNA) are looking for individuals diagnosed with ALS to participate in an open label phase II safety trial with zinc in conjunction with copper, used in combination with Riluzole for treating ALS. This investigator initiated trial conducted by Drs. Todd Levine and David Saperstein will help determine if zinc given at high doses is safe and tolerated and could possibly slow the progression of ALS.

Over fifty years ago an epidemic of ALS was discovered on the Island of Guam where a disease complex of ALS was found to be one hundred times more prevalent than in the rest of the world. Research on ALS in Guam linked ALS, along with Parkinson's Disease and Dementia, with a neurotoxin, β-methylamino-L-alanine (BMAA). BMAA is a non-essential amino acid and is produced by a cyanobacterium found in large concentrations in the food consumed by the people on Guam. Subsequently several groups have identified high concentrations of BMAA in brain tissues of patients from North America and Europe with several neurodegenerative diseases including ALS, Parkinson's Disease and Alzheimer's Diseases.

A small proportion of ALS, (about 2%), is associated with a mutation in the superoxide dismutase (SOD1) gene. Mice who express this mutant gene exhibit a progressive, ALS-like neurodegenerative disease.Since it is known that SOD1 binds zinc, and many of the mutant forms of this enzyme associated with ALS show altered zinc binding, zinc may play a key role in all pathological processes associated with ALS. Previous studies have shown that in ALS mutant G93A SOD transgenic mice, actual zinc supplementation delayed death. Zinc has also been thought to serve as an endogenous antioxidant in the central nervous system and help protect the BBB against oxidative stress and prevent BMAA from crossing into the brain.

It has been demonstrated that BMAA binds exceptionally strongly to transition metal ions such as zinc, copper, and nitrogen. If BMAA crossed over the permeable BBB, and enters a compartment in which glutamate was bound to zinc, then the glutamate/zinc complex would dissociate in favor of zinc having a stronger affinity to BMAA. This could lead to higher levels of unbound glutamate which is believed to be highly neurotoxic in ALS patients. We hypothesize by exposing patients to high levels of zinc, both BMAA and glutamate would be kept in a bound complex with zinc, i.e. eliminating competitive binding for zinc, which lead to less excitotoxic free glutamate and glutamate toxicity would be reduced.

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85018
      • Phoenix Neurological Associates

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18-85
2. Male or Female
3. Clinically definite or probable ALS by El Escorial criteria
4. ALS-FRS > 25
5. If on Riluzole they must be on a stable dose for at least 30 days prior to screening
6. Capable of providing informed consent and complying with trial procedures

Exclusion Criteria:

1. Patients with FVC below 50%
2. History of liver disease
3. Severe renal failure
4. Creatinine greater than or equal to 1.5 mg/dL
5. History of intolerance to zinc or copper
6. Evidence of motor neuron disease for greater than 5 years
7. Any other co-morbid condition which would make completion of the trial unlikely
8. If female, pregnant or breast-feeding; or, if of childbearing age, an unwillingness to use birth control.
9. Any other trial medications. Non-trial medications are not cause for exclusion
10. Patient with history of significant anemia
11. Elevated levels of zinc at baseline
12. Patients with copper levels below normal at baseline

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Zinc and Copper	Drug: Zinc and Copper; Optizinc 90 mg/d Copper 1 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To evaluate the safety of high doses of zinc in patients with ALS	1 year

Secondary Outcome Measures

Outcome Measure	Time Frame
Measure levels of BMAA in blood and urine to determine if there is a decline in these levels over the course of treatment	1 year

Collaborators and Investigators

• Sponsor: Phoenix Neurological Associates, LTD
• Investigators: Principal Investigator: David S Saperstein, MD, Phoenix Neurological Associates, LTD

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (Actual): January 1, 2012
• Study Completion (Actual): March 1, 2012

Study Registration Dates

• First Submitted: December 10, 2010
• First Submitted That Met QC Criteria: December 10, 2010
• First Posted (Estimate): December 13, 2010

Study Record Updates

• Last Update Posted (Estimate): March 12, 2012
• Last Update Submitted That Met QC Criteria: March 9, 2012
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Keywords: ALS; Zinc; Copper; BMAA; ALS treatment
• Additional Relevant MeSH Terms: Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Physiological Effects of Drugs; Trace Elements; Micronutrients; Copper
• Other Study ID Numbers: Zinc-ALS