Trial Information

Thalidomide for the Treatment of Malnutrition Inflammation Syndrome in Peritoneal Dialysis Patients: A Randomized Control Trial

Overall study design

This is a single-center randomized placebo control study on 60 prevalent PD patients.

Recruitment phase will take up to 12 months, and the study phase will be 1 year. Study code
will only be revealed at the end of the study period or if patients develop serious adverse
reactions.

Patient selection

A randomized prospective study will be performed in 60 stable PD patients. Recruitment
criteria are:

- clinically stable adult patients (18 to 80 years old) on PD; and

- evidence of malnutrition:

1. overall subjective global assessment score  5; or

2. malnutrition inflammation score  9; or

3. serum albumin  35 g/L

- written patient informed consent

Exclusion criteria are:

- Patients who are planned to have elective living donor transplant within 6 months

- Patients who are planned to transfer to other renal center within 6 months

- High likelihood of early withdrawal from the study (e.g. myocardial infarction, severe
or unstable coronary disease, stroke, severe liver disease within 3 months)

- Active infection or systemic inflammatory disease.

- Current malignant disease

- Pregnancy or breast-feeding

- Women of childbearing potential with unreliable birth control methods

- Known hypersensitivity to thalidomide

Baseline data including age, sex, underlying renal disease, presence of diabetes, hepatitis
B status, requirement of helper for dialysis procedure, PD regimen and duration on dialysis
are recorded.

Interventions

After initial evaluation in a screening visit at -4 week, patients will be randomly assigned
to receive either oral thalidomide 100 mg nocte or placebo. Thalidomide will be obtained
from Penn Pharmaceuticals Ltd (Gwent, UK) as 100 mg tablets, and prescribed in accordance
with the published guidelines for the clinical use and dispensing of thalidomide [34].
There will be 30 patients on each arm of randomization. Dialysis prescription will be
changed only if there is clinical evidence of underdialysis. Both patients and investigators
will be blinded from the therapy during follow up assessment. Side effects will be recorded
and the drug will be discontinued when clinically necessary.

Clinical follow up

Patients will be followed at at -4 (screening), 0, 4, 8, 12, 18, 24, 30, 36, 44 and 52
weeks. The following clinical data will be documented during each visit:

- Body height and body weight

- Blood pressure

- Compliance to thalidomide by pill count

- Compliance to dialysis exchange by direct questioning

- Skin itchiness score from 0 to 3+, as described previously [31]

Body-mass index and body surface area will be computed. The majority of patients will be on
three or four 2-liter exchanges per day. Blood pressure or edema are controlled with
standard anti-hypertensive agents and/or hypertonic dialysate.

Laboratory parameters

A full panel of biochemical parameters will be monitored:

Hemoglobin, plasma sodium, potassium, urea, creatinine, albumin, calcium, phosphate,
alkaline phosphatase, and alanine transaminase at -4, 0, 4, 8, 12, 18, 24, 30, 36, 44 and 52
weeks Fasting serum glucose, lipid and iron profile at 0, 24 and 52 weeks Serum parathyroid
hormone at 0 and 52 weeks Serum inflammatory markers at 0, 12, 24, 36 and 52 weeks

Inflammatory markers include serum C-reactive protein (CRP), interleukin-6 (IL-6), leptin,
adiponectin, tumor necrosis factor alpha (TNF-) and fibrinogen levels, as suggested by
other groups [35-38].

Nutritional assessment

Nutritional status will assessed by subjective global assessment (SGA), comprehensive
malnutrition-inflammation score (MIS), normalized protein nitrogen appearance (NPNA), serum
albumin level, anthropometric lean body mass (LBM), and fat-free edema-free body mass
(FEBM).

SGA will be performed at -4, 0, 12, 24, 36 and 52 weeks by a single observer. The 4-item
7-point scoring system proposed by Enia et al [39] will be used. MIS will be performed at
-4, 0, 12, 24, 36 and 52 weeks. The calculation of MIS has been described previously [40].
Briefly, MIS consists of 4 main parts and 10 components, all scored from 0 (normal) to 3
(very severe). The total score ranges from 0 to 30.

FEBM and PNA will be measured by creatinine kinetics at 0, 24 and 52 weeks. A 24-hour
dialysate and urine collections will be performed. Total and peritoneal Kt/V are determined
by standard methods. Residual GFR is calculated as average of 24-hour urinary urea and
creatinine clearance. FEBM is calculated according to the formula of Forbes and Brunining
[41]. PNA is derived from the Randerson’s formula [42]. It is further normalized to standard
body weight.

Anthropometric measurements will be performed at 0, 12, 24, 36 and 52 weeks by a single
observer. This include bicep, tricep, subscapular and supra-iliac skin fold thickness, and
midarm muscle circumference. Derived variables by anthropometric measurements, including
lean body mass (LBM) and percentage of body fat, will be computed by standard formula [43].

Pulse wave velocity

Pulse wave velocity (PWV), an index of aortic stiffness, is measured using an automatic
computerized recorder at 0, 24 and 52 weeks. The results will be analyzed by the Complior
SP program (Artech Medical, France). Briefly, pressure-sensitive transducers are placed over
the neck (carotid artery), wrist (radial artery) and groin (femoral artery) with the patient
in the supine position on day of haemodialysis treatment before putting patient to the
dialysis machine. PWV of the carotid-femoral and carotid-radial territory is calculated by
dividing the distance between the sensors by the time corresponding to the period separating
the start of the rising phase of the carotid pulse wave and that of the femoral and also the
radial pulse waves. The procedure takes 10 to15 seconds to complete. The test will be
performed by the same observer to eliminate effect of intra-observer variation.

Health-related quality of life

Patient acceptance and satisfaction will be assessed by the Chinese translation of “Kidney
Disease Quality of Life Short Form (KDQOL-SFTM), version 1.3”, at 0 and 52 weeks.

Outcome

The major outcome measure is nutritional status, as detailed above. The schedule of various
tests is summarized in Appendix 2. Secondary outcomes include the followings:

- Change in arterial pulse wave velocity

- Total number of days of hospital admission during study period

- Composite cardiovascular end point: cardiovascular death, non-fatal myocardial
infarction or stroke, hospital admission for unstable angina, coronary intervention,
transient ischemic attack, or lower limb ischemia

- Number of episode of peritonitis during study period

- All cause mortality

Transplantation, conversion to hemodialysis, recovery of renal function, and transfer out of
the unit will also be recorded.

4. Potential Outcomes

In Hong Kong, 80% of end-stage renal failure patients are treated with peritoneal dialysis
(PD). In 2004, there were over 3000 PD patients in Hong Kong. Malnutrition, cardiovascular
disease and systemic inflammatory state are all common in our clinical practice. They are
major causes of patient morbidity and mortality. The financial implication is considerable.

As a readily available anti-cytokine therapy, thalidomide may represent a valuable treatment
of the MIA syndrome. The proposed study will provide important insight on the clinical
benefit of thalidomide treatment in malnourished PD patients, which accounts for about
one-third of our dialysis population.

Data Analysis

Statistical analysis will be performed by SPSS for Windows software version 11.5 (SPSS Inc.,
Chicago, IL). All data will be expressed in mean  standard deviation unless otherwise
specified. Serial changes of nutritional parameters, dialysis adequacy, and inflammatory
markers will be compared to the baseline values by analysis of variance for multiple
measures (MANOVA). Serial change in residual GFR is examined by Wilcoxon’s rank sum test
with Bonferroni’s correction for multiple comparison because of skewed data. Nutritional
status and systemic inflammatory markers after one year will be compared between the 2
groups by Student’s t-test for parametric data. Hospitalization and peritonitis rate between
the groups are compared by Kruskal-Wallis test because the data will be highly skewed.
Actuarial patient survival will be compared by logrank test with Kaplan-Meier survival
curves and treatment group as stratifying variable.