FEDERAL STATE-FUNDED EDUCATIONAL INSTITUTION OF HIGHER
PROFESSIONAL EDUCATION “NORTHWESTERN STATE MEDICAL
UNIVERSITY OF MINISTRY OF HEALTH OF THE RUSSIAN FEDERATION
NAMED AFTER I.I. MECHNIKOV”
APPROVED:
_______________________
Vice-rector for scientific and international Cooperation
Federal State-funded Educational Institution of higher professional education
“Northwestern State Medical University of Ministry of Health of the Russian
Federation named after I.I. Mechnikov”
Silin A.V, MD
RESEARCH REPORT
"Single-center, prospective, open, controlled study of the efficacy and safety
of Enterosgel® in nephrology, administered to predialysis CRF patients"
St. Petersburg, 2014
Authors:
Study director: Head of Department of Internal Diseases and Nephrology, MD,
Professor Radchenko V.G.
Principal investigator: Ph.D., Assistant Professor, Department of Internal
Diseases and Nephrology Seliverstov P.V.
Investigators: MD, Professor Radchenko V.G.; PhD, Assistant Professor
Seliverstov P.V.
Clinical research phase: clinical research phase IV (post-marketing trials)
according to classification of ICH GCP.
Study sponsor: "TNK Silma", Russia.
SUMMARY
Report parameters: the report is outlined on 34 pages, contains 6 tables, 1 figure, 1
appendix and 17 literary sources.
List of key words: chronic renal diseases, sorbent, Enterosgel, dialysis.
In the following research feasibility of sorbent Enterosgel® has been studied in
predialysis patients with CRF. The work presented has scientifically proven that
use of Enterosgel® is effective and safe.
MAIN PART
Study purpose
The purpose of this study was to determine efficiency and safety of application of
Enterosgel®, indicated for the treatment of chronic renal failure in predialysis
patients.
Study objectives
1. To assess the dynamics of clinical symptoms and laboratory data in predialysis
patients with chronic renal failure.
2. To study tolerability and safety of Enterosgel® in predialysis patients with
chronic renal failure, during its constant administration for four weeks.
Materials and methods:
Single-center, open, prospective study of the efficiency and safety of Enterosgel®
was conducted in the nephrology clinic of North-West state medical University
named after I.I. Mechnikov.
The object of study - 30 predialysis patients with CRF.
The average age of the patients was 36 ± 3.7 years. Gender distribution: men - 13,
women - 17.
The present study is an open (in the period of treatment physicians and researchers
as well as patients involved in the study knew what kind of medication the patients
received), prospective (patients were recruited in accordance with the criteria set
out in the study protocol and were observed for some time, patient groups were
formed before fixing the results), post-marketing (this investigation related to
phase IV of clinical trials according to classification ICH GCP).
The inclusion criteria included the presence of verified CRF, absence of dialysis,
age 18 years and older as well as signing the informed consent form.
The screening examination excluded patients in which the following criteria were
determined:
pregnancy or breast-feeding;
inability or unwillingness to sign the informed consent to participate in the study or
to fulfill the research requirements;
intake of any other drugs with sorption properties for 14 days before receiving the
first dose of study enterosorbent;
clinically significant abnormal laboratory parameters indicating the presence of an
unknown disease or requiring additional clinical survey (by the investigator);
symptoms of acute inflammatory diseases;
the presence of significant allergic reactions in the medical history;
the presence of clinically significant severe neurological, cardiovascular,
gastrointestinal, liver, immune and other diseases;
mental diseases, including previous ones, which, in the opinion of the investigator,
make unacceptable the patient’s participation in the study;
drug addiction within a year before inclusion in the study;
severe seizure disorders in the history;
liability to resignation from the study and implementation of the doctor’s orders;
participation in other clinical trials.
Depending on the treatment, all the patients included in the study were divided into
two groups:
- Group 1 (n = 15), patients receiving Enterosgel® one dose three times a day
60 minutes before meal for four weeks.
- Group 2 (n = 15), patients receiving standard therapy for chronic renal
failure.
All 30 patients successfully have completed the study and performed the
completion of the study visit. None of the patients have been excluded from the
study.
Within four weeks, the patient performed four clinical visits for examination:
screening visit, baseline visit (Visit 1) to include the patient in the study and
initiate the medication intake, visit 2 (two weeks after beginning of
administration), visit 3 - four weeks after the beginning of treatment.
Screening study. Screening study was carried out before administration of the first
dose of study medication. The purpose of the screening was to determine whether
the patients corresponded to patient inclusion/exclusion criteria. The patients were
questioned, their medical history study was studied, clinical and laboratory data
were evaluated, psychological testing and assessment of quality of life was
performed. Duration of the screening was 2-7 days.
The data obtained for each patient during the screening are shown in Table 1.
Table 1
Basic data for each patient registered in the screening period
№
Patient’s history and physical examination, including height and weight
1.
Standardized questionnaire of
patient complaints
Questioning to find out the patient’s complaints
regarding the main organ systems.
2.
Study of psychical and
emotional values
Evaluation of depression levels, trait and state anxiety,
asthenia
3.
Quality of life questionnaire SF36
Determining physical and psychical health values
4.
Vital signs
Systolic and diastolic BP, heart rate, ECG
5.
Glomerular infiltration rate
Renal function is valued
6.
Urinalysis (diagnostic dipsticks)
Specific gravity, рН, glucose, protein, ketones, nitrites,
bilirubin, urobilinogen, blood, leukocytes
7.
Biochemical blood analysis
Protein, urea, creatinin, K, Mg, Na, Ca, Fe, P, cholesterol,
glucose, ALT, AST, bilirubin
8.
Pregnancy test
For potentially fertile women, a negative test result for
urinal HCG should be confirmed not earlier than 24 h
before the first dose
9.
Blood analysis for fat-soluble
vitamins
Level of vitamins is studied (А, D, Е)
Table 2
Schedule of clinical and laboratory examinations
Visit
Days / Weeks
Interval (days)
Standardized questioning
Evaluation of psychic and emotional status
Evaluation of quality of life
Evaluation of physical data
Complete blood count
Biochemical blood analysis
Urinalysis
Pregnancy test*
Glomerular infiltration rate
Screening
-7/-1
0
Х
Х
Х
Х
Х
Х
Х
Х
Х
V1
0/0
0
Х
V2
14/3
±2
Х
Х
Х
Х
Х
Х
Х
Х
Х
V3
28/5
±3
Х
Х
Х
Х
Х
Х
Х
Х
Х
Drug administration
Blood analysis for vitamins А.E D
Evaluation of adverse events*
Х
X
Х
Х
X
Х
Х
*For fertile women
During the baseline visit (В1) presence of exclusion criteria was evaluated
as well as absence of exclusion criteria, the patient was included in the study and
randomized. The study medication was given for administration at the Visit 1, five
packages considering one dose three times a day within 14 days. The patients
started taking the medication on the same day.
Visit 2 (В2) was performed two weeks after the first visit. During this visit
adverse events and the patient’s diary were evaluated, standardized complaint
questioning was performed, and vital signs were registered. Complete blood count,
urinalysis and biochemical blood analysis were performed. The returned
medication doses were counted, thus the patient’s adherence to the treatment was
accessed. The medication was given for the next administration (five packages of
the medication considering one dose three times a day within 14 days).
Visit 3 (V3) (end of observation) was performed four weeks after the first visit.
During this visit adverse events and the patient’s diary were evaluated as well,
standardized complaint questioning was performed, and vital signs were registered.
Complete blood count, urinalysis and biochemical blood analysis were performed
as well as psychological testing and evaluation of quality of life. The returned
medication doses were counted, thus the compliance was counted.
To evaluate efficiency and safety of the application, the following methods
were used:
Patient questioning was standardized. During the questioning higher
attention was paid to nephrology complaints. Unified patient questioning chart is
shown in Appendix 1.
Complete blood count was performed with determination of Hb, RBC,
WBC levels, leukocytal formula, thrombocytes as well as hematocrit. The study
was performed using standardized methods. CBC reference data are shown in
Appendix 1.
Biochemical blood analysis was performed including evaluation of total
protein, urea, creatinin, K, Mg, Na, Ca, Fe, P, cholesterol, glucose, ALT, AST and
total bilirubin. The results were assessed using the equipment «Spectrum»
(«Abbot») and apparatus «Technicon». Bilirubin level was determined using Ilk
method with acetic anhydride. Blood glucose level was evaluated using glucoseoxidase level of phenolphthalein method of phenolphthalein oxidation. Plasma
electrolyte concentration (K, Mg, Na, Ca, Fe, P) was studied using flame
photometry. Total serum protein was evaluated using unified method of biuret
reaction. Reference ranges for biochemical blood values are shown in Appendix 1.
Evaluation of the patients’ quality of life using SF-36 questionnaire.
Quantitative evaluation was carried out using the following values:
Physical Functioning (Physical Functioning - PF), reflecting the extent to
which body condition limits physical activities (self-care, walking, stair climbing,
load carriage etc.). Low values on this scale testify that the patient’s physical
activity is essentially limited by his/her health.
Рrole-physical functioning (Role-Physical Functioning - RP) – influence of
body condition on the everyday role activities (work, daily duties). Low values on
this scale testify that the patient’s everyday activity is essentially limited by the
patient’s body condition.
Bodily pain (Bodily pain - BP) and its influence on ability to perform
everyday activities, including housework and outdoor activities. Low values on
this scale testify that the pain significantly limits the patient’s activity.
General health (General Health - GH) – subjective evaluation of the
patient’s health by the patient at the moment as well as treatment perspectives. The
lower is the score, the lower is the health evaluation.
Vitality (Vitality - VT) refers to feeling active and energetic or on the
contrary, tired. Low values on this scale testify that the patient is weary and the
vitality has reduced.
Social functioning (Social Functioning - SF) is determined by the extent to
which physical or emotional conditions limit the social activity (conversation).
Low values on this scale testify for the essential reduction of social contacts and
reduction of conversational level due to deterioration of physical or emotional
state.
Role-Emotional Functioning (Role-Emotional - RE) supposes evaluation of
the extent to which emotional state prevents the patient from works of other
everyday activity (включая большие затраты времени, reduction of work
volume, heavy time expenses, deterioration of its quality etc.). Low values on this
scale are considered to be a limitation of the work performance caused by
emotional state deterioration.
Mental Health (Mental Health - MH) is characterized by the presence of
depression, anxiety as well as total positive emotions. Low values indicate the
presence of depressive, anxious experiences mental ill.
Evaluation of trait and state anxiety was performed using Spielberg-Hanin scale
(see Appendix 1).
Assessment of asthenia severity was carried out using asthenia scale (AS)
(Appendix 1).
Statistical analysis was performed using the program «SPSS Statistics 17.0»
(SPSS Inc., USA). Before the statistical comparison verification of the test
characteristics was performed for their normal distribution. In connection with the
detection of pronounced deviations of analyzed data from the normal distribution,
the use of parametric data processing methods (Student's t-test) was considered
invalid and excluded from the statistical analysis of this study. Thus,
nonparametrics methods waere used for the statistical analysis. Choice of statistical
processing algorithm was determined by the study endpoints and design of each of
the study subdivisions.
Algorithm for statistical comparison of the main group (group 1) and control group
(group 2) of the patients was as follows:
- calculation of the parameter variations as a result of the treatment (dynamics
parameter) in the study group and the control group;
- assessment of the statistical significance of the differences between the
dynamics of the parameter in the study group and the dynamics of the
parameter values in the control group using Mann-Whitney test (test for
non-paired samples).
For a more detailed assessment of the treatment impact on the value dynamics
within each of the groups unpaired Wilcoxon criterion was used.
Differences between measures were regarded as statistically significant and
reliable, if p value was less than 0.05.
Efficiency and safety of the study medication
Evaluating the efficiency of treatment using the study medication was conducted
on the following parameters: rate of disappearance of subjective clinical
symptoms, value dynamics of quality of life.
Safety assessment was conducted by monitoring subjective state of patients for the
observation period and in accordance with the dynamics of physical data, clinical
and biochemical blood parameters as well as urinalysis dynamics.
RESULTS AND DISCUSSION
Dynamics of subjective and objective values
The main complaints in patients of all groups were weakness, fatigue, abdominal
and lumbar pain, headaches, nausea, periodic vomiting and dysuria. Complaints of
patients in all the groups and their dynamics are shown in Table 3.
Table 3.
Dynamics of the major clinical indicators in treatment groups (abs.), %
№
Symptoms
Group 1, n=15
Group 2, n=15
Before
After
Before
After
treatment
treatment
treatment
treatment
1
Hyperthermia
7 (46,7)
0 (0)
6 (40,0)
5 (33,3)
2
Abdominal and lumbar
pain
9 (60,0)
1 (6,7)
10 (66,7)
9 (60,0)
3
Asthenia syndrome
15 (100,0)
3 (20,0)
15 (100,0)
13 (86,7)
4
Dysuria
7 (46,7)
1 (6,7)
6 (40,0)
6 (40,0)
5
Nausea
5 (33,3)
0 (0)
6 (40,0)
5 (33,3)
6
Periodic vomiting
3 (20,0)
(0) 0
3 (20,0)
3 (20,0)
7
Headache
10 (66,7)
1 (6,7)
9 (60,0)
9 (60,0)
An objective examination of all the patients observed showed that the disease
manifestation was accompanied by clinical signs of intoxication expressed by
weakness, nausea, hyperthermia, abdominal and lumbar pain, nausea, vomiting and
periodic headaches. On the background of the therapy, the patients of the first
group receiving Enterosgel noted improvement in all the values, unlike patients in
group 2 (Table 3).
In all the patients under observation, no significant physical changes of vital organs
and organ systems were observed for 28 days. Stable blood pressure, heart rate and
respiratory rate were noted. During the physical examination at the end-of-study
visit, no evidences of change in the major body systems were noted.
Dynamics of CBC values in the patient groups and the statistical analysis results
are presented in Table 4.
Table 4
Dynamics of CBC values, (M ± s)
Value
Reference
values
Group 1, n=15,
Group 2, n=15,
Difference
significance
between
Red blood
cells,
×1012/l
М 4,0-5,1
After
Before
After
the groups
treatment
treatment
treatment
treatment
(p)*
4,5±0,4
4,7±0,4
4,6±0,5
4,5±0,4
p>0,05
143,8±9,6
142,7±8,3
7,8±1,8
7,2±1,8
W 3,7-4,7
М 130-160
Hb,
Before
144,0±15,2 139,7±16,0 p>0,05
W 120140
g/l
White blood
cells,
6,8±1,8
7,8±1,1
p>0,05
4-9
×109/l
Thrombocytes,
×109/l
Blood
sedimentation
rate,
180-320
225,3±38,3 236,2±47,7 275,7±92,1 272,8±93,7 p>0,05
16,8±8,3
16,1±7,4
8,8±6,2
12,1±6,8
p>0,05
3-15
mm/h
*p <0.05
As can be seen from the data presented, in all the patients in both groups, no
significant dynamics of clinical blood values was found before and after the
treatment. No statistically significant differences were found between the groups.
The dynamics of biochemical blood parameters
The dynamics of biochemical blood parameters in all the patients under
observation and the results of statistical analysis are shown in Table 5.
Table 5
The dynamics of blood biochemical parameters (M ± s)
Group 1, n=15,
Values
Referenc
e values
Before
treatment
After
treatment
Group 2, n=15,
Before
treatment
After
treatment
Difference
significance
between
the groups
(p)*
Total protein, g/l
65-85
91,8±3,3
70,5±3,2
69,2±3,4
72,4±4,5
p< 0.05*
ALT, U
5-42
35,6±5,4
34,4±5,3
31,0±8,1
32,3±7,3
p>0,05
AST, U
5-42
32,0±6,1
34,9±4,9
33,0±8,7
32,0±9,6
p>0,05
3,4-19,0
12,1±6,2
12,5±5,1
11,5±5,3
11,3±4,3
p>0,05
1,3-8,3
16,4±2,9
13,4±3,5
15,2±6,1
14,5±5,9
p<0,05*
3,4-5,2
3,9±1,1
4,0±1,1
3,9±0,8
4,1±0,9
p>0,05
155,4±9,2
120,1±7,3
157,8±8,6
153,1±6,2
p<0,05*
3,3- 6,2
3,1±2,1
3,3±2,4
3,2±2,2
3,6±2,2
p>0,05
3,4-5,1
4,1±0,8
4,0±0,8
3,9±0,6
4,0±0,7
p>0,05
Mg, mmol/l
0,64-1,05
0,76±0,12
0,77±0,13
0,76±0,11
0,77±0,9
p>0,05
Na, mmol/l
135-145
139,2±6,2
141,3±3,1
140,2±3,1
139,1±4,6
p>0,05
Ca, mmol/l
2,2-2,7
2,4±0,12
2,4±0,13
2,5±0,11
2,4±0,13
p>0,05
Fe, µmol/l
10,6-30,4
18,2±4,9
17,1±5,1
17,5±5,2
18,2±4,9
p>0,05
P, mmol/l
0,87-1,45
0,91±0,12
0,93±0,11
0,89±0,13
0,88±0,15
p>0,05
73,2±6,3
92,5±4,2
75,6±4,6
79,3±5,1
p<0,05*
Bilirubin,
µmol/l
Urea,
mmol/l
Cholesterol,
mmol/l
Creatinin,
М 62-132
µmol/l
W 44-106
Glucose,
mmol/l
K, mmol/l
М 97-137
GFR, ml/min
Ж 88-128
Vitamin А, µg/ml
0,3-1
0,6±0,03
0,6±0,04
0,5±0,05
0,5±0,04
p>0,05
Vitamin Е, µg/ml
5-18
11,2±1,9
11,4±2,1
11,3±2,0
11,2±1,9
p>0,05
Vitamin D, nmol/l
75-250
125,3±7,9
127,8±8,1
147,3±6,7
141,5±8,1
p>0,05
* p<0.05
On the background of the therapy in patients of Group 1 normalization of renal
filtration function was shown, mainly by reducing the level of total protein, urea,
creatinine and increase in glomerular filtration rate. The remaining values (ALT,
AST, glucose, cholesterol, bilirubin, K, Mg, Na, Ca, Fe, P), including vitamins A,
E and D were within the reference ranges both before and after treatment (Table 5).
No changes of biochemical blood values characterizing liver function show that the
administration of the study medication Enterosgel for four consecutive weeks is
safe. When using standard doses of Enterosgel, no toxic effects on the vital body
systems has been received.
Urinalysis
The study of urinalysis in the patients of all groups showed decrease of urine
specific gravity and, on the contrary, the increase of such bye-indicators, such as:
white blood cells, bacteria, protein. Against the background of the therapy, the
group receiving №1 Enterosgel, recorded a positive trend in all indicators (Table
6).
Table 6
Dynamics of urinalysis parameters, (M ± s)
Group 1, n=15,
Value
Reference
values
Before
treatment
After
treatment
Group 2, n=15,
Before
treatment
After
treatment
Difference
significance
between
the groups
(p)*
Specific
gravity, U
1,010-1,025
1,005±0,002
1,012±0,00
1
1,005±0,003
1,006±0,003
p<0,05*
0-5
55,6±6,5
36,4±3,3
56,0±4,1
54,3±7,5
p>0,05
Bacteria,
per HPF
0
168000,2±24
,1
91,3±6,7
171000,3±8,
7
Protein, g/l
0
12,1±6,2
12,5±5,1
11,5±5,3
Leukocytes,
per HPF
168000,0±19,
p<0,05*
1
11,3±4,3
p>0,05
* p <0.05
The received data may be a confirmation of improvement of renal function and, as
a result, of urinalysis values.
Quality of life
In assessing the quality of life using SF-36 questionnaire, before treatment in all
the patients (100%) a decrease in values characterizing physical and psychological
health components was noted. After the treatment a significantly (p <0.05)
improvement of the physical health components was detected: physical functioning
improvement (PF), reduction of the bodily pain (BP), vitality (VT), social
functioning (SF) and mental health (MH); due to their change, improvement of role
functioning due to the physical condition (RP) was observed, thus the overall
health state was improved (GH). (Figure 1).
Quality of life: PF - physical functioning, RF – role-physical functioning-set, BP – bodily pain,
GH - general health, VT - vitality, SF - social functioning, RE – role-emotional functioning, MH
- mental health.
Figure 1. Dynamics of values of quality of life (SF-36) on the background of
treatment with Enterosgel.
Evaluation of psychic and emotional sphere
Evaluation of state anxiety. Before the treatment, state anxiety had been identified
in all the patients: in 22 patients (73.3%) - moderate state anxiety, in the remaining
8 patients (26.7%) - high state anxiety. After the treatment, no changes of the test
results were found.
Trait anxiety. Prior to the treatment state anxiety had been determined in 4 patients
(13.3%), 26 patients (86.7%) had a high trait anxiety. After the treatment, the
values did not change as well.
Assessment of asthenia. According to the results of the questionnaire, asthenia was
detected in 4 patients of Group 1 included in the study, after end of treatment – in
only one. In the rest of the patients no asthenic condition was diagnosed.
These data confirm the close relationship of renal disease and psychic and
emotional status of the patients to improvement of data in stabilization of the
clinical performance.
Adverse events
During the observation and as a result of laboratory methods, no adverse events
and serious adverse events were recorded in the observed patients. All patients
receiving the study medication indicated good tolerability and obvious beneficial
effect on the disease clinical symptoms after the treatment.
Adherence to the treatment
According to the analysis of visits, count of restitution of the apply means and the
patients’ diaries, high compliance of predialysis patients with CRF should be
noted. Average compliance in all the groups was 97% over 28 days of
administration.
CONCLUSION
The study results indicate the efficiency of Enterosgel at a dose three times a day
60 minutes before meals for four weeks in predialysis patients with chronic renal
failure, as it promoted positive clinical effect on all the patients observed.
On the background of treatment with Enterosgel, the patients experienced
reduction in the abdominal and luumbar pain, in the majority of patients, asthenia,
endointoxication and dysuria manifestations disappeared. Improvement of mental
and emotional state was also achieved as well as tendency to improvement of
quality of life.
Study medication Enterosgel taken for 4 consecutive weeks is safe for patients,
which was confirmed by subjective, physical and laboratory studies. Enterosgel
used for 4 weeks did not cause any undesirable effects.
Enterosgel can be used in the treatment predialysis CRF patients. To determine the
resistance of clinical effect, a further monitoring of patients in study group is
necessary, with prolonged administration of Enterosgel (from 3 to 6 months).
CONCLUSIONS
- "Enterosgel" has a positive effect on the clinical performance in predialysis
patients with chronic renal failure;
- "Enterosgel" has a sorption effect, which helps to reduce endogenic
intoxication and improve kidney function.
- When using Enterosgel in predialysis patients with chronic renal failure, the
quality of life and psycho-emotional state improve;
- Enterosgel has a good tolerance, is safe and improves renal function; it can
be recommended for use in predialysis patients with chronic renal failure;
- Treatment regimens with Enterosgel which can be recommended in the renal
pathology to achieve clinical effect – one dose three times a day 60 minutes
before meals for four weeks.
Principal Investigator,
MD, Professor Radchenko V.G.