"APPROVED" by G.I. Vorobiev Full Member of the Russian Academy of Medical Sciences Director of the State Research Centre of Coloproctology, Russian Federal Ministry of Public Health and Medical Industry 16 of October, 1999

"APPROVED" by S.A. Khvorostov General Director of Ecomed Research and Production Association 16 of October, 1999

F I N A L     R E P O R T

Clinical Test Programme
Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes designed and produced by Ecomed Research and Production Association according to Specification TU 9444-014-11555014

Subject: research of therapeutical effect by Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes applied to patients with functional diseases of large intestine

Introduction.

This final report is the conclusive document in execution of the Clinical Test Programme of Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes designed and produced by Ecomed Research and Production Association according to Specification TU 9444-014-11555014 with the subject of research of therapeutical effect by Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes applied to patients with functional diseases of large intestine approved on March 11, 1996.

The results given in this final report represent the collective results from the research cycle carried out by the State Research Centre of Coloproctology, Russian Federal Ministry of Public Health and Medical Industry from April, 1996 to December, 1999. Two interim reports were submitted earlier (Report dated August 29, 1997 and Report dated October 29, 1998).

The principal functions of large intestine include formation and further transit of intestinal contents; however, in realisation of these functions, various disorders are possible in the activity of large intestine, which may result in constipation.

The most common (43 to 50 per cent) diseases of gastrointestinal organs are functional diseases of large intestine, including a series of intestinal disorders caused by disorders of motor and secretory functions of large intestine in the absence of organic (structural) changes, which can be discovered by modern means of diagnostics. Among these functional diseases, about 70 per cent of cases is related to syndrome of irritated large intestine. This disease is characterised with disordered tone and peristalsis all along the gastrointestinal tract.

Chronic or functional constipations, with respect to preferential localisation of the major disorders in large intestine, are classified into cologenic and proctogenic. Cologenic constipation is accounted for by changes in contracting and nervous reflectory activities of large intestine, while proctogenic constipation is related to disordered motor and evacuation functions of large intestine and locking mechanism, including changes in tone of pelvic bottom muscles. Cologenic disorder is the most common cause of chronic constipation. At the same time, in the anamnesis of chronic constipation, some patients show a combination of cologenic and proctogenic disorders.

The event of strong constipation is the principal symptom of chronic stasis of large intestine; stages of this disease are determined both by functional and organic disorders of large intestine.

The differential diagnostics of these kinds of functional disease is provided on the basis of clinical data and results of instrumental and functional research methods.

One of the factors in development of functional disorders of large intestine is disorder of neurohumoral regulation of intestinal wall, which results in discoordination of peristaltic waves, changed tone of intestinal wall, and, finally, in disordered transit of intestinal contents along gastrointestinal tract. Therapy with cleansing enema or purgatives, as a rule, still aggravates the disordered functions of large intestine. Taking into consideration the importance of disorders in nervous regulation in the pathogenesis of these diseases, application of electrical stimulation of organs in gastrointestinal tract is a pathogenetically substantiated method of therapy.


Test goal. The goal of clinical tests is determination of possible application and appraisal of effective therapy of functional disorders of large intestine by means of Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes as compared to the standard scheme of therapy with drugs.

Time of clinical tests: tests were started in April, 1996 and finished in June, 1999.

Place of clinical tests: State Research Centre of Coloproctology at the Russian Federal Ministry of Public Health and Medical Industry. Address: 2 Salyama Adilya Street, Moscow, 123448, Russia.

Director of works: L. F. Podmarenkova, Candidate of Medical Sciences, Senior Researcher, Laboratory of Clinical Pathophisiology, State Research Centre of Coloproctology at the Russian Federal Ministry of Public Health and Medical Industry.

Executor of works: A. P. Tupikova, Candidate of Medical Sciences, Head of Laboratory of Clinical Pathophisiology and Physical Methods of Therapy, State Research Centre of Coloproctology at the Russian Federal Ministry of Public Health and Medical Industry.

Principal: Ecomed Research and Production Association. Address: P. 0. Box 87, Moscow, 129090.

Preparation name: Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes (Electronic Normaliser).

Short name: AES GIT&MM 01.

Producer: Ecomed Research and Production Association. Address: P.O. Box 87, Moscow, 129090.

Standard: Specification TU 9444-014-11555014, Diagram MASI 943.115.002 type 01.

Date of production: for the test purposes, the producer delivered Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes (01) by stages with expiration dates according to the standard.

1. Test Provisions.

1.1. Subjects. - Adult out-patients or in-patients aged 20 to 70 with diagnosis: chronic constipation, syndrome of irritated large intestine, chronic stasis of large intestine.

1.2. Safety measures. - The test groups included no patients with accompanying diseases of cardiovascular and pulmonary systems. The test groups will exclude patients with syndrome of irritated large intestine and diarrhoea.

1.3. Number of subjects. - In total, 140 patients took part in principal (104 patients) and control (36 patients) groups.

1.4. Test plan. - The test patients were selected in the course of their stationary hospitalisation or polyclinical consultation after clinical, diagnostical, roentgenological and endoscopic studies. The patients were distributed into groups with respect to their diagnosis. Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes (01) will be tested by per os or per rectum administration or in combination of these methods. The control group of patients will be treated with standard drugs.

1.5. Duration of treatment. - For the test purposes, Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes (01) was administered twice with the interval often days. The patients stayed under observation for twelve weeks.

1.6. Observation of patients. - Observation of the patients and estimation of the results of their condition as compared to the initial level was carried out on the days of visit:
      - first visit - initial;
      - second visit - in 10 days (± 1.2);
      - third visit - in 20 days (± 2.2).

1.7. Therapy. - The patients were appointed to the principal or control group as follows.
Group A: single administration of capsule of Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes (01).
Group B: double per os administration of capsule of Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes (01) with the interval often days.
Group C: double administration of capsule of Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes (01) with the interval often days (first capsule per rectum, second capsule per os).
Group D: control group of patients treated with standard drugs.

1.8. Appraisal of results. - Primary results: appraisal of general feeling of patients and independent stool. Secondary results of efficiency: determined according to changes in parameters of functional status of large intestine by functional research methods during and after therapy in comparison with the initial parameters. Physician's General Appraisal (PGA). Patient's General Impression (PGI) as compared to the initial status.

1.9. Safety appraisal. - The safety appraisal parameter is aggravation of the patient's feeling.

1.10. Medical equipment required for tests. - Polygram produced by Synectics (Sweden). Russian Registration No. 98/215. Article No. 712-2890. This instrument contains a series of units providing appraisal of any aspects in the activities of gastrointestinal tract: 1) enterography and 2) colography provides registration of motor function of gastrointestinal tract with electrophysiological methods using electrodes applied to skin and installed in projection of the organ to be studied; 3) electromanonetry as a method of appraisal of motor activity of large intestine by recording the internal pressure with 5-channel probe introduced to the opening of large intestine; 4) sensometry as a method to determine sensitivity of rectum.

2. Test Procedure.

2.1. Patient's selection criteria. - The patients with clinical diagnosis: chronic constipation, syndrome of irritated large intestine, chronic stasis of large intestine were selected for tests in accordance with the following criteria:

out-patients or in-patients aged 20 to 70 (men and women);
agreement signed by informed patients;
diagnosis: chronic constipation, syndrome of irritated large intestine, chronic stasis of large intestine confirmed by clinical, functional and instrumental studies;
chronic constipation and syndrome of irritated large intestine with cdlogenic or proctogenic disorders, chronic stasis of large intestine in compensated and subcompensated form;
all women in fertile age passed obligatory consultation by gynaecologist and ultrasonic study of uterus with respect to exclusion of pregnant patients.

This test included 60 per cent patients, whose professions are related to intellectual work (teachers, physicians, scientists, etc.) and 40 per cent of patients, whose professions are related to physical work (workers, farmers, etc.).

3. Test Procedure.

The tests was carried out in two groups: principal and control.

With respect to form of application, the patients were appointed to the principal or control group as follows: Group A: single per os administration of capsule of Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes (01); Group B: double per os administration of capsule of Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes (01) with the interval often days; Group C: double administration of capsule of Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes (01) with the interval often days (first capsule per rectum, second capsule per os); Group D: control group of patients treated with standard drugs.

The capsule was prescribed to the patients after the initial visit in the case of earlier or newly discovered disease confirmed by clinical, functional and instrumental studies.

5. Therapy Efficiency Appraisal.

All 66 patients in Group A noted appearance of independent stool at the second visit, the first stool was accompanied with excretion of exhausted capsule. Further observation (third visit) showed good results in 54 of 66 patients (81.8 %), satisfactory results of 5 patients (7.6 %) and only 7 patients (10.7%) noted no effect.

The completed functional studies before and after therapy of gastrointestinal tract with Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes (01) (Table 3) in patients of Group A showed positive dynamics in the parameters characterising electrical and motor activities of large intestine: 59 of 66 patients in Group A (89.4 %) increased electrical activity and index of motor activity and percentage of peristaltic waves in spectrum as compared to the initial level, which confirms positive dynamics in the status of motor function of gastrointestinal tract.

The patients in Group B administered two electrical stimulators with the interval of 10 days. After the first administration of Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes (01), independent stool was noted by all 22 patients. Observation at the second visit showed normal stool in 17 of 22 patients, irregular stool in 4 patients, and no effect in one case. Observation at the third visit (in 10 days after administration of the second capsule) showed good feeling of all the patients, independent stool in 20 of 22 patients (90.9 %) and independent but irregular stool in two patients.

The functional parameters after the completed therapy were essentially improved to approach to the normal parameters.

Group C included 16 patients suffering from proctogenic form of chronic constipation. For ten days after the first visit, the patients applied per rectum one capsule of Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes (01) and then administered per os the second capsule. The positive results of this therapy were noted by 12 patients (75%).

The functional results indicated a more active function of large intestine, at the same time the time of defecation was reduced by three times and the rectal filling sensitivity was improved.

Group D included 36 patients treated with drugs regulating motor function of gastrointestinal tract, in particular, large intestine; Debridat (France) 200 mg x 3 times daily and Motilium (France) 10 mg x 3 times daily. For tone normalising of intestinal walls, patients with spastic symptoms administered Methiospasmil (Germany) 1 tablet x 3 times daily. Mucofalk (Germany) or Agiolax (Germany) was administered as 1 teaspoonful x 2 times daily with water. The appropriate drinking mode and diet was prescribed.

The efficiency of drug therapy for 36 patients of Group D was significantly lower: only 19 of 36 treated patients showed normalised stool (52.8 %), while the duration of this effect was two weeks for 10 patients, and about one month for 9 patients. The positive changes in the parameters of functional status were noted by 19 patients (Table 6); however, the increase in the parameters of motor function of large intestine in this group of patients was significantly lower than those in Groups A, B and C.

5.2. Physician's general appraisal. - The absolute efficiency of Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes (01) as compared to the scheme of therapy with standard drugs will be determined additionally in the final point and level of physician's general appraisal (PGA). This appraisal will be made by the physician for each visit with the six-point scale.

5.3. Patient's general impression (PGI). - The additional appraisal of efficiency was made at the third visit by means of the patient's general impression (PGI). For 104 patients treated with Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes (01), PGI was 125 points.

my feeling is much better - 1 x 89 patients (89 points)
my feeling is somewhat better -2 x 9 patients (18 points)
my feeling is unchanged - 3 x 6 patients (18 points)
my feeling is worse - 0
my feeling is worse - 0

6. Safety Appraisal.

6.1. Unfavourable events. - There were no unfavourable events in the course of tests.

6.3. Laboratory tests for safety appraisal. - There was no need to carry out any laboratory tests for safety appraisal in the absence of relevant complaints of aggravated status of any patients.

7. Accompanying Drug Use.

No accompanying drugs will be used in the course of tests.

8. Patient's Discharge Criteria and Termination of Study.

No patient was discharged from the test.

9. Data Processing.

9.1. All the data in statistical form were recorded in the given form of report.

10.1. Ethical issues. - This test was carried out in accordance with Helsinki Declaration (1964) as well as with the amendments adopted in Tokyo (1975), Venice (1983) and Hong Kong (1989). The patient's consent form was received in writing before admission of this patient to the test.

10.4. Patient's data confidentiality. - In order to provide the patient's data confidentiality, the information, which is represented in the report, contains only the patient's number of medical history or out-patient card and initials.

10.9. Information confidentiality and use. - The objectives and contents of this study as well as the results obtained in connection thereof are confidential and will not be disclosed to any third persons without the consent given by the executors and the principal of tests.

CONCLUSION

Electrical stimulation of gastro intestinal tract with Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes is a pathogenetically substantiated and highly effective method for therapy of diseases of alimentary system. This kind of electrical stimulation affects actively the neuromuscular system of gastrointestinal tract, recovers motor and evacuation functions, as well as promotes better feeling, higher working capacity and normalised mental and emotional status of patients.

Upon application of Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes to patients with diseases of gastrointestinal tract, a stable positive effect was achieved in total for 89.4 % of cases.

No side adverse effects were observed upon application of Autonomous Electrical Stimulator of Gastrointestinal Tract and Mucous Membranes.

The apparently positive results, which were observed and confirmed with the completed cycle of tests, assume the necessity of recommendations to be given for wide application in therapeutical practice not only in stationary but also in ambulatory and home conditions.

The executors of tests do recommend patenting of this method of therapy and publication of the final test results in scientific press.