Abdominal Compression Elastic Support (ACES)

I. Study Design: Biomedical

1. Controls will be used. For the safety of ACES five healthy subjects will be used as controls to assess the safety and tolerability of the device. The regular HD treatments of each study patient will serve as their own control in assessing the effect of ACES use on their HD treatments. The control data are derived from the treatment logs of four to eight HD regular treatments taken by the patient.

2. The study design is an open trial.

3. No placebo is involved

4. This is a single center study to be done only at the Medical Center of University of Virginia (UVa).

II. Human Participants Ages: 18 or older Sex: Male and Female Race: All

Subjects or Patients:

1. 5 healthy subjects and 20 dialysis patients to complete protocol.

2. There could be a 50% drop out rate for the dialysis patients.

3. 30 (Up to 5 healthy subjects and Up to 35 dialysis patients) will be enrolled at all sites

4. All 30 subjects and patients will sign a consent form under this protocol.

5. The estimated time line for the study is 100% enrollment within 10 months III. Statistical Considerations

1. Is stratification/randomization involved? No

2. What are the statistical considerations for the protocol? In analyzing the data, if the systolic blood pressure (SBP) of a given patient compared with the first blood pressure reading after initiating dialysis is larger than the threshold 20 mmHg (condition A) or the decrease in mean arterial pressure is larger than 10 mmHg and the development of hypotensive symptoms (condition B), this session (hour) will be identified as an IDH session (hour). The data may be divided into two groups (one under condition A and one under condition B) for further analysis on the impact of the conditions on the effectiveness of ACES.

In our study design, the countermeasure implemented in each "control" session may be different. Our study can lead to an answer on whether the use of ACES is more effective in alleviating IDH than the "control" countermeasure.

The researchers will only handle the quantitative data and the analysis of enumeration and quantitative data. To assure integrity in and correctness of data analysis, all data will be forwarded to a statistician who is not physically involved with the study for an independent evaluation.

3. Provide a justification for the sample size used in this protocol.

A. On the safety issue: Due to the low compression pressure and no adverse effects seen in the use of IAB, we expect that the investigators should not see the development of any adverse effect in the current clinical trial. When the investigators carry out 40 ACES session in Phase II and show no adverse effect, then the likely hood for an adverse effect to develop will be at most 2.5%. Even if the occurrence frequency were at 25%, a sample size of 16 sessions will be more than adequate to demonstrate the safety hypothesis with a confidence better than 99% (i.e. P<0.01).

B. On the reduction in occurrence frequency. The patients participated in the study will have at least 2 episodes in a month. It can add up to an occurrence frequency of 25%. This is to say that 20 out of the 80 control sessions will have IDH developed. If the occurrence frequency is reduced to 12.5% (i.e. 12 sessions with IDH out of the 80 ACES sessions), the data of 80 ACES session will be adequate to show a confidence level of 99% by the chi square test (P<0.01) that the use of ACES is effective in reducing the occurrence frequency. On the other hand, if the frequency estimated from the data of Phase II is reduced to 18% (instead of 12.5%), then the data of 80 ACES sessions in Phase II will yield a χ2 of about 2.0. With data of 80 more ACES sessions in Phase II, the value of χ2 for the same decrease in occurrence frequency may increase to 4 to indicate that the reduction in occurrence frequency has a confidence level of 95% (P<0.05).

The above computation analysis has been expanded to examine how test size and the values of occurrence rate affect the value of χ2 and subsequently whether the occurrence rate is significantly reduced with the use of ACES. The investigators find that the three test sizes (80 tests mentioned here, 160 tests and 480 periods mentioned later) set for use in the protocol are adequate to carry out the statistical determination.

Currently the investigators do not have a certain way to predict when IDH will develop. Thus, the investigators consider each HD session done on the same patient as independent.

4. The investigators have worked with a retired statistician in designing this protocol.

IV. Biomedical Research

1. Healthy subjects:

In order to fulfill the study statistical requirements, up to five (5) healthy subjects will be tested for safety and tolerability of wearing ACES for 3 hours. Each healthy individual will then wear the ACES for three consecutive hours in a supine or seated position, except for use of the restroom if needed, and assess the measured parameters.

If no major concerns are identified with this healthy population the use of ACES device will be offered for use in dialysis patients who have three or more episodes of IDH in the 4 weeks leading up to recruitment.

2. Dialysis Patients

Hemodialysis patients at the University of Virginia Kidney Center have their hemodialysis done in a seated position (30° to 90°). The investigators will be using the ACES device on these patients in a seated position.

In order to fulfill the study statistical requirements, up to ten (10) ESRD patients on HD will be tested for safety and tolerability of wearing ACES during their dialysis sessions.

Screening trial session for Dialysis Patients After the patient reads and signs the consent form and passes the inclusion and exclusion criteria, the investigators will have him or her to undergo a trial session of ACES. This trial session can be done on the same day as the consent form or it can be done on another day that the patient is coming for a regular dialysis session. This trial session is designed to find out whether the patient can tolerate the compression of the ACES and whether his/her SBP and heart rate can be significantly altered by the compression. Over the course of this screening trial, the patient will be advised that he can request removal of the ACES whenever he/she wishes.

3. Control & ACES Sessions:

The patients will undergo a HD treatment as prescribed by their attending nephrologists. The investigators expect that the characteristics of these treatments will have the following general features:

• The HD setting can lead to a Kt/V larger than 1.2

• A procedure or countermeasure will have been prescribed and set up as standard of care to deal with the development of IDH.

- The measurement of blood pressure and heart rate will be performed by the usual dialysis machine for a given patient, providing internal equipment standardization

- The blood pressure cuff will be applied to bare skin on the patient's arm

- The data obtained for eight regular HD treatments without wearing the ACES will be identified as the control data. For each patient, four HD treatment sessions will be conducted with the use of ACES in Phase II and four more will be done in Phase III if the data of Phase II calls for.

Preparation to start the hemodialysis with ACES

• Before the screening test of the patient, the investigators will get the waist circumference of the patient. The size of the ACES is chosen from this specification: 22"~27" (56~68cm)-Small, 28"~33" (71~84cm)-Medium, 34"~40" (86~101cm)-Large, 41"~47" (104~119cm)-Extra-Large, 48"~54" (122~137cm)-Extra-Extra-Large 55"~61" (140~155cm).

• Put on the ACES with its band tips already aligned with the white marking. At this "no load" marking, the compression pressure imposed by the ACES is less than 2 mmHg. This step is done before the patient is seated and attached to the blood lines.

• The HD treatment will start as usual.

During HD Control and ACES session if the patient experiences IDH or SBP drop If the study investigators deem that the patient is experiencing symptoms of IDH or sees that the SBP drops 20 mm Hg, then a charted course will be used on what countermeasures are to be employed.

Post-dialytic care and data collection • Post dialytic procedure and care will include:

o Removal of the ACES and one more BP and pulse measurement,

o Discharge of the patient who is diagnosed as having no PDOH,

o Whether the patient is asked to come back for another HD treatment the next day,

o If the patient is classified as one with PDOH, the procedure to discharge the patient as prescribed by the physician will be followed. If it is prescribed to take a standing up test, it will be done with the ACES on. If the patient is to be sent home, then the ACES will be taken off the patient and another standing up test be done. If the patient is to be sent to an emergency center, then the physician will make a decision on whether to send the patient with the ACES on or with it off.

4. Events calling for decompression of the ACES.

If the following complications develop while the ACES is in use the device will be removed • A decrease in toe O2 saturation below 90%, • An increase in leg circumference by more than 10% to indicate leg edema,

• Pain or cramping in the abdominal area and/or lower extremities being more severe than the norm

- Vomiting more severe than the norm

- Any other threatening complication

- The patient requests removal of the device (reason for request will be recorded)

The study team will investigate whether the complications result from abdominal compression imposed by the ACES. If ACES is deemed as the cause, then the ACES will be decompressed. When the level of aspartate aminotransferase (AST) alanine aminotransferase (ALT) become available to Global Monitor, Inc. and is found to be higher than the norm, then a retrospective analysis will be made to determine whether the level increase relates to the use of ACES.

V. Data and Safety Monitoring Plan An adverse event will be considered any undesirable sign, symptom or medical or psychological condition even if the event is not considered to be related to the investigational drug/device/intervention. Medical condition/diseases present before starting the investigational drug/intervention will be considered adverse events only if they worsen after starting study treatment/intervention. An adverse event is also any undesirable and unintended effect of research occurring in human patients as a result of the collection of identifiable private information under the research. Adverse events also include any problems associated with the use of an investigational device that adversely affects the rights, safety or welfare of patients.

The symptoms or disease developments described as the exclusion criteria (i.e. beyond the first six) will be considered as adverse effect. The symptoms or excessive decrease in SBP, for example, that are normally associated with hypotension development and are found to be common in HD patients of UVa clinics will be reported but not considered as adverse event and not used as a trigger to discontinue the ACES session.

The adverse event will be reported to FDA in a case report form.