Studies to date indicate that percutaneous endoscopic gastrostomy (PEG) -- insertion of a feeding tube in the stomach -- and noninvasive positive pressure ventilation (NIPPV), mechanically assisted breaths delivered through a tightly fitting nasal or facial mask -- may improve survival in amyotrophic lateral sclerosis (ALS), even when introduced late in the disease.

Edward Kasarskis, M.D., Ph.D., at the University of Kentucky, and his research team, believe early intervention with these treatments may improve patients outcome even further. However, many issues regarding the early use of these treatments prevent the design of a phase 3 clinical trial to test this hypothesis.

Common to both NIPPV and nutrition research in ALS is a lack of a reliable indicator of early respiratory or nutritional insufficiency. With respect to nutrition, reliable and cost-effective methods are needed to determine a patient's energy (i.e., caloric) requirements at different stages of the illness to establish a basis for recommending PEG on the adequacy of energy intake.

For NIPPV, factors that influence acceptance and tolerability of this therapy, and measurements of early respiratory dysfunction, need to be identified.

The purposes of this trial are to develop and validate strategies to improve tolerability of NIPPV, identify factors that influence acceptance of NIPPV, and evaluate measures of early respiratory failure, other than percentage of forced vital capacity (FVC).

Researchers will also develop and validate methods to determine energy balance in and evaluate the nutritional status of patients with ALS that will be applicable to a multicenter, phase 3 study of nutrition and NIPPV.

The study will be conducted at 11 sites across the United States. Some study sites will focus on the nutritional aspects of the trial, while the others will focus on NIPPV treatment. The study will last two years.

For the NIPPV research, the investigators will determine whether patients attempt to use NIPPV therapy within six weeks of its being offered; and determine which, if any, demographic, physical or psychosocial factors predict this.

For the nutrition part of the study, investigators will measure total daily energy expenditure with a variety of techniques.

There is a sequence of three visits in a 10-day period every four months, for a total of 12 visits. The sequence consists of one overnight hospitalization, followed by two outpatient visits.

The techniques used to measure total daily energy expenditure consist of the following:

- The participant will be asked to provide a urine sample and then asked to drink a small amount of two rare forms of water. These are known as “D2O” and “H2O18”.  Both forms are non-radioactive and taste just like regular tap water.  There will be a collection of urine samples seven times throughout the course of a visit session. 

 This “doubly labeled water” (DLW) technique provides a sensitive, reliable determination of total daily energy expenditure over a 10-day period.  There is no known risk to drinking DLW for the fact that it is simply water and non-radioactive.  After a few weeks, the participant will excrete all of the DLW in their urine and none will remain in the body. 

- Resting metabolic rate (RMR), expressed in kilocalories per hour, will be determined in a recumbent position after an overnight fast in the alert, awake state using indirect calorimetry. The ventilated hood technique to measure resting metabolic rate may cause a slight claustrophobic sensation in some participants. This is unlikely, since the hood is a clear Plexiglas hood, which will allow viewing of the room.  

- A pulmonary function test will be administered to check lung capacity. 

- An electrocardiogram will be performed at the baseline visit.

- Blood will be drawn to test for thyroid hormone and measurements of nutritional status. When the blood samples are drawn, the participant may experience bruising and bleeding or have slight irritation where the needle goes in. Some people may feel faint or have soreness or pain from the needle. Very rarely, an infection may occur.

- Dual energy X-ray (DXA) will be administered. The dual energy X-ray absorption method (DXA) measures the amount of muscle, bone and fat in the body. Some participants experience difficulty with breathing when lying flat with the DXA scan. The participant’s head can be slightly elevated to help with breathing if this occurs. DXA scanning exposes individuals to minimal radiation (0.02 - 0.05 mRem), which is much lower than the average chest X-ray (40 mRem). There are no known side effects to DXA scanning. 

- Bioimpedance spectroscopy (BIS) will be administered. The BIS measurement will be used to determine total body water, fat-free mass and fat mass. The participant will not feel a thing with this measurement. The entire BIS procedure takes less than 10 seconds.

- A random 24-hour dietary recall using a national database system will be obtained. The dietician will ask the participant to recall their entire food intake with the past 24 hours.

- The research nutritionist will instruct each participant how to weigh and record all nutrient intake for a three-day period. This approach will be validated against DLW and the 24-hour dietary recall. 

- A questionnaire will be administered at each visit.

- Physical activity will be measured using commercially available Actigraph accelerometers worn on each extremity.  Measurements will be obtained during the same three-day time food intake is recorded. The Actigraph devices have been widely used commercially and pose no risk to the wearer.

Edward Kasarskis, MD, PhD, professor of neurology at the University Of Kentucky College Of Medicine in Lexington, is the principal investigator. Dr. Kasarskis can be reached at ejkas@uky.edu

Inclusion Criteria

All races and ethnic backgrounds and both genders are eligible.

Participants must:

• be between 18 and 80 years old
• have clinically possible, definite or probable sporadic or familial ALS, or laboratory-supported probable sporadic or familial ALS, according to the revised Escorial criteria
• have experienced onset of progressive weakness within five years of entry into the study
• if in the NIPPV group, have a best sitting forced vital capacity (FVC) between 50 percent and 95 percent of predicted normal
• if in the nutrition group, have a best sitting FVC greater than 50 percent of predicted normal
• be willing and able to give informed consent
• be willing to return for visits as scheduled and adhere to protocol requirements
• have a negative pregnancy test and be willing to use an effective method of birth control if female and of childbearing age

Exclusion Criteria

Participants must not:

• be using NIPPV, mechanical ventilation or tracheostomy at the time of consent
• have any motor neuron or neurodegenerative disease in addition to ALS
• have any thyroid disease, inflammatory bowel disease, malabsorption condition or any other medical condition that the study investigators believe will interfere with study results or endanger participants
• be pregnant or able to become pregnant, or be lactating (producing milk)
• lack a reliable caregiver, if one is needed
• be unable to adhere to the study visit schedule