Margaret Francis, ARNP
Clinical Coordinator 
JHMHC Box 100226
Gainesville, FL 32610-0226
Tel: (352) 392-2321 
Fax: (352) 846-0990 
francma@medicine.ufl.edu

What is the Purpose of the DCA/NTBC clinical trial?

The purpose of this study is to determine whether the drug NTBC (nitisinone (Orfadin®)) reduces or prevents the undesirable side effects, (toxicity) of the investigational drug, dichloroacetate (DCA), in patients with Congenital Lactic Acidosis (CLA).

What is Congenital Lactic Acidosis?

CLA is a metabolic disease that leads to the abnormal buildup in the blood and spinal fluid of a substance called lactic acid. This buildup makes the blood, spinal fluid and tissues too acidic.  Cells may also lack enough energy to work properly. CLA can be life threatening and can also lead, in many patients, to progressive nerve and muscle damage that may be associated with problems related to thinking, talking, walking, balancing, or growing. 

What is DCA?

DCA is an investigational drug that we believe has helped patients with CLA, in terms of reducing the acidity of their blood, improving energy metabolism and preventing or decreasing neuromuscular damage. Our belief is based on studies that indicate the drug can reduce lactic acid levels in the blood and tissues of patients and may also lead to stabilization or improvement of the clinical complications of CLA. 

How does DCA work?

DCA stimulates the activity of an enzyme called pyruvate dehydrogenase (PDH), which increases the efficiency by which cells make energy. DCA also lowers the lactic acid level in the blood, spinal fluid and tissues by converting lactic acid to harmless byproducts. 

What is NTBC?

NTBC is a drug that has recently been approved for children and adults with a rare metabolic disease called Hereditary Tyrosinemia Type I (HT). Persons with HT build up some of the same toxic chemicals in the blood and urine that persons taking DCA accumulate. Studies have shown that giving NTBC to persons with HT prevents the build up of these chemicals. We think NTBC will reduce the toxicity of DCA in patients with CLA. However, we cannot be sure that NTBC is effective for CLA patients who are taking DCA unless we conduct what is called a "double-blind", parallel study. This means NTBC is compared to a "placebo." A placebo is a chemical that is safe to take but has absolutely no therapeutic benefit. NTBC may also have toxic side effects if the person has large amounts of tyrosine in his or her diet. NTBC is not harmful if it is given with a diet low in tyrosine. All patients enrolled in this study will receive a diet low in tyrosine and phenylalanine (low tryosine diet, or LTD). 

What is the DCA/NTBC Clinical Trial?

We have designed a double-blinded, parallel design clinical trial that has been approved by the FDA to assess the ability of NTBC to reduce the toxicity of DCA. During the trial, patients will not know which drugs they are receiving. For the 1st month of the trial, patients will be placed on a weight-maintaining low tyrosine diet. Afterwards, patients will be separated into two groups.  One group will receive DCA + NTBC + LTD and the other group will receive DCA + Placebo + LTD for 12 months. The placebo group is essential because no one knows whether NTBC will be effective against DCA toxicity. It should be emphasized that not everyone who receives DCA develops adverse effects. At present, we do not know why some subjects are more vulnerable than others.  Various blood and urine studies are performed, as well as repeated tests of peripheral nerve conduction velocity and clinical neurological status. If a peripheral neuropathy is suspected, a sural nerve biopsy is performed, in which approximately 1/2 inch of the nerve in the lower leg is removed and examined to confirm the diagnosis and to determine the cause of the neuropathy. This sural nerve biopsy is routine standard of care and done only once, if there is reason to suspect the presence of a peripheral neuropathy. The procedure is generally well tolerated, leaving only a small area of numbness over the biopsy site.  

Patients who meet specific entry criteria will be studied over a 13 month period at the University of Florida's General Clinical Research Center (GCRC), a specialized facility funded by the National Institutes of Health (NIH) to support patient research. Patients and their families will not be directly charged for their participation in this study. However, the patients' insurance companies may be billed. The patients will be responsible for meeting their deductible. A charitable pilot's foundation, Mercy Medical Airlift, coordinates a nationwide effort to provide free round-trip transportation for each patient and an accompanying parent. The study requires that each adult patient or each pediatric patient and parent come to the GCRC six times over a 13-month period. During each admission of a child, the parent stays in the room with their child at no charge. Food is provided at no cost for each child and parent. 

What are the entry criteria for the DCA/NTBC trial?

There are 3 main criteria each patient must have before he or she may be enrolled. They are:

1. Proof of a mitochondrial defect by tissue biopsy. 
AND
2. A clinical history consistent with CLA. This includes prior documentation of signs (such as high basal lactates, stroke-like episodes, muscle weakness, and seizures). 
AND 
3. Ability to withstand an 8 hour fast (if younger than 2 years old) or 12 hour fast (if older 2 years old) without developing low blood sugar (blood glucose less than 50 mg/dl). 

Will the patient need to eat special foods while he/she is a part of the DCA/NTBC trial?

Yes, as a patient in the study you will need to be on a special diet for the duration of this study. If you eat solid foods or baby foods, the portions will need to be carefully measured and a special formula will be supplemented. High protein foods, such as beef, chicken, fish, and cheese, will be restricted during the study. Foods allowed on the diet include cereals, breads, pasta, fruit, juice, vegetables, cookies, and candy in small amounts. If you are not able to consume solid foods and uses a formula for your dietary needs, the amount of the formula will be decreased and another formula will be supplemented. The formula used during this study will provide adequate amounts of protein. Your diet will provide sufficient calories based on your needs. 

Will all patients enrolled in the study receive NTBC?

No.  For the duration of the clinical trial. only half of the patients will receive NTBC.  Those patients will be part of the DCA + NTBC + LTD group.  However, during the entire length of the trial, patients will not know when they receive NTBC.  The purpose of this is to meet FDA regulations regarding the appropriate evaluation of the safety of DCA. An ethics committee of outside experts oversees the study and is always aware of the distribution of DCA and NTBC versus placebo treatment for each patient. Throughout the trial, we will evaluate the neurological and behavioral status and the overall quality of life of each patient, in addition to the biochemical effects of DCA and NTBC. We hope this trial will show NTBC is effective in preventing DCA toxicity in patients with CLA and will support the value of DCA as potentially life-long treatment for CLA. 
 

Other Commonly Asked Questions

Q. Is this study FDA approved?

A. Yes.

Q. Will patients/families be charged for their (child's) participation in this study?

A. No. Patients and their families will not be charged directly for participating in this study. Their insurance companies may be charged for some of the cost. The patients will be responsible for meeting their deductible.

Q. Who provides the transportation to and from Gainesville, Florida?

A. A charitable pilots' foundation, Mercy Medical Airlift, provides round-trip, nationwide transportation for each patient and an accompanying parent, if the patient is a child.

Q. How often do patients/families have to travel to the University of Florida?

A. Each patient is evaluated at the GCRC six times over a 13-month period. The duration of each visit is 2 to 3 days with an exception to the very first visit, which last 4-6 days. Children must have an accompanying parent or guardian who will room with the child during his or her stay.

Q. What happens when the study is completed?

A. Patients who participate in this controlled clinical trial may have the opportunity to continue on "open label" DCA and NTBC and a low tyrosine diet thereafter, providing the parents and physicians feel that the combination of DCA and NTBC and a low tyrosine diet is not harmful to CLA patients. Families may receive open-label DCA without a direct cost until the drug is approved.  The availability of NTBC and LTD will depend on the manufacturer’s willingness to provide the medication and supplemental diet to our subjects indefinitely. 

Q. What organizations support and fund the DCA/NTBC Clinical Trial?

A. Funding for this study has been provided by the FDA and the NIH.