Li Peiwen, Li xue, Lin Hongsheng, Wu Liangcun, Huang Zhifen Beijing Sino-Japanese Friendship Hospital

Transcription

1 Summary of hase III Clinical Trials of Kanglaite Injection in China TSummary of hase III Clinical Study of Kanglaite Injection Tin Treating rimary Hepatic Carcinoma Li eiwen, Li xue, Lin Hongsheng, Wu Liangcun, Huang Zhifen Beijing Sino-Japanese Friendship Hospital bstract Kanglaite Injection (KLT), a preparation made with extractions from the traditional Chinese medicine semen coicis through modern scientific procedure by Zhejiang Kanglaite harmaceutical Co. Ltd. In 1995, the product was awarded the Grade National Certificate of New drugs and the relevant Document of Ratification of production. In accordance with the requirement of the Examination Office of New Drugs under the Ministry of ublic Health, the hase III clinical study on KLT in treating primary hepatic carcinoma was performed from March 1996 to May The aim of the trial was to observe the curative effect of KLT in treating primary hepatic carcinoma and the adverse reactions so as to determine its efficacy and safety. The practical plan was performed in accordance with the rinciple of Clinical-Guide of New Medicine (Traditional Chinese Medicine) issued by the harmaceutical ffair gency under the Ministry of ublic Health. This phase III clinical trial was presided by the Beijing Sino-Japanese Friendship Hospital, the coordinative hospitals were the Guang n Men Hospital affiliated to the Chinese Institute of Traditional Chinese Medicine, the Traditional Chinese Medical Hospital of Zhejiang rovince and the Tumor Hospital affiliated to the Guangxi Medical University. The research result showed that the remission rate (CR+R) of KLT on primary hepatic carcinoma was 11.4% while the remission rate in chemotherapy control group was 9.80%. From the view of the traditional Chinese medical theory, KLT was the best effective drug in treating patients with hepatic carcinoma resulted from asthenia of Spleen and Stagnation of Wetness-evil as well as Intense Evil Heat. KLT could markedly improve the major clinical symptoms of patients with primary hepatic carcinoma, its total effective rate of improvement was 80.95%, the survival quality of patients, activity of NK CD4+/CD8+cells, and immunity were also improved after the of KLT yet without influence on peripheral hemogram. No damage on live, kidney function and other evident poisonous or adverse action was observed except of slight nausea, fever and lips and tongue dryness which occurred among a small number of patients and could remit automatically, very few patients were observed of phlebitis which disappeared after suiting the remedy to the case. 1. Case selection and research method 1.1 Diagnostic Standard Traditional Chinese Medical Identification of Symptoms Stagnation of Vital Energy (1) Dull aching of hypochondria, eructation, vomiting sour water, discomfort on gastric cavity, pale tongue and wiry pulse. () Blood Stasis Type

2 Summary of hase III Clinical Trials of Kanglaite Injection in China bdominal and fixed mass under hypochondria, hard and twinge, fleeing to hypochondria, the tongue-body with bruise was red-purple, red purple tongue-body with bruise, irregular pulse. () Intense Evil Heat Type Dry mouth and throat, jaundice in eyes and body, oliguria with reddish urine and dry stool, red tongue with yellow and dry fur, wiry and slippery pulse. (4) Type of Stagnation of Wetness-Evil bdominal distention, aching around body, bad stomach holding, watery stool, oliguria with difficulty, pale tongue and the tip and margin of the tongue look jagged, slow and heavy pulse. (5) Yin-deficiency Type Burning sensation of five centers, dull aching under hypochondria, wan looking, dry mouth and eyes, red tongue with less fur, small pulse Standard of Western Medical Diagnosis (1) athological Diagnosis 1 atients with primary hepatic carcinoma testified by liver tissue inspection. atients with hepatic-cell carcinoma testified by extrahepatic histological inspection () Clinical Diagnosis 1 Subjects whose F result was positive (convection or RI method) >400ng/ml for more than 4 weeks, and subject in pregnancy, with metastatic hepatic carcinoma, gonadial embryonal adeno-myoscarcinoma and actively hepatic diseases were ruled out if without other evidence of hepatic carcinoma. Subjects with or without clinical evidence, whose Image Diagnostic Inspection (B-supersonic diagnosis, CT etc.) results offered clear evidence of the substantive space occupying lesion in liver, subjects who could be ruled out hepatic hemangioma and metastatic hepatic carcinoma, and meanwhile satisfying one of the following conditions:. F>00ug/ml or r-gt rising markedly. B. Image diagnostic evidence of typical primary hepatic carcinoma. C. No jaundice yet F or r-gt rising markedly. D. With definite metastatic focus in further location, or blood-ascites, or carcinoma cells could be detected in ascites. E. Cirrhosis with Definite positive indication of hepatic B Standard of Clinical hase hase I: Without symptom and sign of hepatic carcinoma, single tubercles (<5cm) were detected by CT and B-Supersonic Diagnostic set. hase II: Subjects whose symptoms were not more serious than that of the hase I and without evidence of phase III

3 6 and day). day day. Summary of hase III Clinical Trials of Kanglaite Injection in China hase III: Subjects with one of the following symptoms: evident cachexia, jaundice, ascites or extrahepatic metastasis. 1. Standard of Case in Trial 1..1 Standard of case to be selected Subjects clinically in hase I, hase II and early hase III who were diagnosed of evident primary hepatic carcinoma, in patients whose estimated survival period was over months and whose karnfsky grade of physical condition was above Standard of case to be rejected (1) atients with secondary hepatic carcinoma. () atients with severe cirrhosis and pathological hyperlipemia. () atients aged younger than 18 or older than 70, women in pregnancy, patients allergical to the product. (4) atients who failed to meet the standard, or patients who failed to conform administration and whose curative effect was difficult to evaluated owing to insufficient materials. (5) atients allocated with whole-body chemotherapy and catheterism within 0 days. 1. Clinic Trial Method 1..1 Grouping: Subjects were randomly divided into the observation group and the control group, followed by Expectant Contrast Observation. 1.. Treating Method: Intravenous dip: (1) KLT Group: Subjects were administered with 00ml of KLT through intravenous drip, one time daily, 0 days as a period for total two periods (7-10 days as an interval between two periods was allowed) as a. () Chemotherapy Group: Subjects were allocated with F method, every weeks as a period, for total two periods as a course or once a week, three weeks as a course. 0mg-50mg of DD was transferred into the kettle, followed by normal hydration on 1 - (or st CBDC, 500mg of carboplatin mixed with 500ml of 5% of glucose solution on the 1 50mg of th DM (or 60mg of E-DM) was transferred into the kettle followed by administration on the 4 500mg of 5FU was mixed with 500ml of 0.9% of physiological saline followed by administration on the th th th th th, 9, 1, 16 0 day. Or mg of VCR was transferred into kettle followed by administration on rd, 9th and 16th day (to substitute DD or CBDC) st rd

4 fascicle Summary of hase III Clinical Trials of Kanglaite Injection in China 1.4 Observation Index and Method ccording to the action of KLT, the tumor remission rate, traditional Chinese medical syndrome, changes of Index on body weight, survival quality, relevant immunity, heart, liver and kidney function, hemogram and F before and after were observed. (1) Tumor: Changes of tumor before and after diagnosed by B-supersonic set, CT or MRI. () Traditional Chinese Medical Syndrome: Mental depression and weakness, fever, aching of hypochondria, jaded appetite, nausea and vomit, ascites and jaundice, etc. before and after wee observed. () Body weight: Body-weight of subjects was measured weekly before and after. (4) Healthy condition: Healthy conditions of subjects were graded based on the Karnofsky Grading Standard once a month before after. (5) F: F was recorded before, in and after. + + (6) Immunity: NK cells CD4 /CD8 was recorded before and after. (7) Hemogram: Hemogram (leukocyte, hemoglobin and blood-platelet) of the subjects in chemotherapy group was checked once a week, and once every two weeks in the observation group. (8) Liver function ( LT, /G), kidney function (Cr, BUN), blood lipid, and electrocardiogram etc. were checked monthly before and after. 1.5 Evaluation Standard of Curative Effect The curative effect on tumor was objectively evaluated according to The Evaluation Standard of Curative Effect of nticancer Chemicals in Treating rimary Hepatic Carcinoma, the nd of Diagnostic Standard of Common Malignant Tumors in China issued by the Ministry of ublic Health. (1) Completely remitting: Tumor disappearing could be observed for over one month. () artly remitting: The product of the two max. diameters of the tumor vertical to each other has a reduction of more than 50%, which shall last for over one month. () Stable: The product has a reduction of less than 50% or an increase of no more than 5% which shall last for over one month. (4) Worsen: The product was observed of more than 5% increase The Evaluation Standard of Curative Effect on Clinical Syndromes / decrease of the clinical syndrome grade was defined as remarkably improved ; 1/ decrease of the grade was defined as partly improved ; no change of the grade was defined as not improved Life quality (health) condition: Based on the Karnofsky Grading Standard, every 0 points of increase after was defined as remarkably improved ; 10 points of increase was defined as improved ; no increase or decrease after was defined as stable ; 10 points of decrease after was defined as declined. - -

5 Summary of hase III Clinical Trials of Kanglaite Injection in China Body weight: Body weight increased or decreasing for 1kg was defined as increased or decreased ; body weight increasing or decreasing within 1kg was defined as stable Evaluation of Immunity: 10% increase of NK was defined as improved ; no evident decline after was defined as stable ; 10% decrease of NK was defined as declined. The classification standard of poisoning reaction degree was based on WHO Standard The grading standard of toxic reaction is in conformity to WHO standard 1.6 Observation of dverse Reactions The adverse reactions occurred among patients in Kanglaite Group during the were observed and the time, lasting hours, degree as well as measures adopted were also recorded.. Results.1 General materials and comparability test between groups.1.1 Source of cases From Feb. of 1996 to May of 1997, overall 156 inpatients were selected from the Sino-Japanese Friendship Hospital, the Traditional Chinese Medical Hospital of Zhejiang rovince, the Guang n Men Hospital attached to the Chinese Institute of Traditional Chinese Medicine and the Tumor Hospital attached to the Guang Xi Medical University, among them 105 subjects were allocated in the Kanglaite Group, which 51 subjects were allocated in the control group, and all of then met the Clinical Diagnostic Standard of rimary Hepatic Carcinoma. See Table 1. Table 1. Clinical distribution of cases Hospital Kanglaite group Chemotherapy group Total Sino-Japanese Friendship Hospital Tumor Hospital attached to Guangxi Medical University Traditional Chinese Medical Hospital of Zhejiang rovince 8 8 Total nalysis of Clinical Materials (1) Sex Male 11, 8.97%; female 5, 16.0%; ratio of male vs female was 5.4:1, no remarkable difference was observed between the two groups (>0.05). See Table. - -

6 X Summary of hase III Clinical Trials of Kanglaite Injection in China Table. Sex distribution of the two groups Groups No. of cases Male Female Male: Female KLT group :1 Chemotherapy group :1 Total :1 =0.61 >0.05 () Distribution of ge ge ranged from to 70, the oldest was 75 years old, and the youngest years old, the average was 54.97, no remarkable difference on age distribution existed between the two groups (>0.05). See Table. Table. Distribution of age Groups < <70 Total KLT group Chemotherapy group Total Ridit test : >0.05 () Division of hase Total 156 subjects in the groups were testified of material space occupying lesion by B-supersonic diagnostic set or CT before, while patients with hemanogioma and metastatic hepatic carcinoma were ruled out. mong them there were patients in hase I, 1.9%; 4 patients in II, 7.56%; 110 patients in III, 70.51%. No remarkable difference existed on clinical-phase division between the two groups (>0.05) See Table 4. Table 4. Clinical phase division of hepatic carcinoma (WHO) Groups I II III Total KLT group Chemotherapy group Total Statistic procession of the two groups, Ridit test : >0.05 (4) Karnofsky Grades of the two groups KS grades of the two groups before were mainly within 60-70, no remarkable difference was observed between the two groups. (>0.05) See Table 5. Table 5. KS distribution of the two groups before and after Groups No. of cases (cases) (cases) (cases) (cases) KLT group Chemotherapy group Ridit test : >

7 X X Summary of hase III Clinical Trials of Kanglaite Injection in China (5) Traditional Chinese Medical Identification and the Distribution of major clinical syndromes Traditional Chinese Medical Identification was performed referring to the Guide rinciple of Clinical Research on New Chinese Medicine. No remarkable difference was observed between the two groups (>0.05); no remarkable difference was observed on major clinical syndromes such as weakness, bad stomach holding, nausea, vomit, abdominal distention, aching in hepatic region and ascites etc. (>0.05) See Table 6, 7. Table 6. Classification based on the Traditional Chinese Medical identification Groups Stagnation of Blood Intense of Stagnation of vital energy stasis wetness-evil wetness-evil Yin-deficiency Total KLT group Chemo-group Total =1.97 >0.05 Table 7. nalysis of syndromes KLT group Chemotherapy Group Syndrome No. of cases Effective rate (%) No. of cases Effective rate (%) Weakness Bad stomach holding Fever Nausea Vomiting Blood-vomit Blood-stool bdominal distention ching in Hepatic region ching scites Jaundice (6) Distribution of the tongue-body, tongue-fur and pulse condition No remarkable difference on the distribution of tongue-body, tongue-fur and pulse condition was observed between the two groups through statistic procession. (>0.05) See Table 8, table 9, table 10. Table 8. Traditional Chinese Medical analysis of tongue Syndrome KLT Group Chemotherapy Group X Slight white Slight red Red Red purple, purple

8 X Summary of hase III Clinical Trials of Kanglaite Injection in China Table 9. Traditional Chinese Medical analysis of pulse condition Syndrome KLT Group Chemotherapy Group X Thin and whitish Thin and yellow White and greasy Yellow and greasy No fur Table 10. Traditional Chinese Medical analysis of pulse condition Syndrome KLT Group Chemotherapy Group X Small and rapid Small and faint Slippery and soft Deep and small Stringy and large T. Comparison of Curative EffectT T.1 Objective curative effect on tumor Overall 156 subjects were observed including 105 subjects in the Kanglaite group, 1 subjects were reported effective (CR+R) in the group, (11.4%), while only 5 subjects (9.80%) were observed in the chemotherapy group. No remarkable difference was observed between the two groups (>0.05). See Table 11. Table 11. Comparison of the changes of the carcinoma focus between the two groups after Group No. of cases CR R MR SD D Effective rate (%) KLT group Chemotherapy group Relation between the Curative Effect and Traditional Chinese Medical Identification The statistic results showed that the best curative effect could be achieved in treating sthenia of Spleen and Stagnation of wetness-evil and Intense Evil Heat Syndrome, the least effect in treating Blood Stasis Syndrome. While in the chemotherapy group, the best curative effect was achieved in treating Intense Evil Heat Syndrome, the least effect in treating sthenia of Spleen and Stagnation of Wetness-evil. No remarkable difference was observed between other groups. (>0.05) See Table 1. Table 1. Relation between the curative effect and identifiable classification KLT group Chemotherapy group BT* No. Effective Rate BT No. Effective rate Stagnation of vital-energy Blood stasis Stagnation of wetness-evil Yin-deficiency Intense evil-heat

9 X Summary of hase III Clinical Trials of Kanglaite Injection in China Note: BT*-before. Relation between curative effect and syndromes Varying degrees of improvements of major clinical syndromes such as weakness, bad stomach holding, nausea, vomit, abdominal distention, aching in hepatic region and fever etc. were observed both in the two groups before and after. The total effective rate of improvement was 80.95% in the Kanglaite group, while only 5.49% in the chemotherapy group, existing remarkable difference between the two groups (<0.05). Especially, the improvement of symptoms like weakness, bad stomach holding, nausea, vomit, abdominal distention, aching in hepatic region in Kanglaite group was more evident than that in chemotherapy group (<0.05). See Table 1, Table 14. Table 1. Curative effect of syndromes before and after KLT group(n=105) Chemotherapy group(n=51) BT NE* Effective Effective BT NE Rate % rate % Weakness Bad stomach holding Fever Nausea Vomiting Blood-vomit Blood stool bdominal distention Hepatic region aching ching scites Jaundice Note: BT -before ; NE* -number of effect Comparing the Kanglaite group with the control group: most remarkable difference on aching, abdominal distention, bad stomach holding and weakness. (<0.01) Table 14. Improvement of syndromes of the two groups Group Remarkably effective Effective Ineffective Total effective rate (%) KLT group Chemotherapy group Ridit test: > Relation of curative effect between body of the tongue, tongue-fur and pulse condition No other remarkable differences except of most remarkable difference (<0.05) on number of subjects with slightly red tongue were observed (>0.05) in the Kanglaite group before and after. No remarkable difference on tongue condition and pulse condition existed in the chemotherapy group before and after (>0.05). No remarkable difference was also observed between the two groups after (>0.05). See Table 15, 16,

10 Summary of hase III Clinical Trials of Kanglaite Injection in China Table 15. nalysis of tongue before and after KLT group Chemotherapy group Tongue Before fter Before fter Slightly white Slightly red Red Red-purple, purple >0.05 Table 16. nalysis of tongue-fur before and after KLT group Chemotherapy group Tongue-fur Before fter Before fter Thin and white Thin and yellow White and greasy Yellow and greasy No fur Comparing KLT group with the chemotherapy group before and after : >0.05 Comparing the KLT group before with the same group after : >0.05 Table 17. nalysis of pulse conditions before and after KLT group Chemotherapy group ulse condition Before fter Before fter Small and rapid Small and faint Slippery and soft Deep and small Stringy and large Comparing the KLT group with the chemotherapy group before and after : >0.05 Comparing the KLT group before vs after : > Comparison of General Conditions Karnofsky Grading: In the KLT group overall 46 subjects were observed of increase, 14 subjects were of decline, remarkable difference existed between the two groups, this indicated that Kanglaite could markedly improve the survival quality. Change of body-weight: Overall subjects in KLT group were reported of body-weight loss corresponding to 6 subjects in the chemotherapy group, and overall 6 subjects in the KLT group were observed of weight increasing corresponding to only 7 subjects in the chemotherapy group. Remarkable difference existed between the two groups based on statistic procession (<0.05), this indicated that Kanglaite could markedly increase patients body weight. See Table

11 existed existed /CDB8BB which Summary of hase III Clinical Trials of Kanglaite Injection in China Table 18. Comparison of general conditions Group Karnofsky grade Change of body weight Rising Stable Declining Rising Stable Declining KLT group Chemotherapy group <0.05 < Change of Natural Killer Cells (NK cells) and CDB4B /CDB8B Remarkable difference existed on the activity of NK cells between the two groups after (<0.05), this indicated that Kanglaite could markedly improve the activity of NK cells, and the effect was better than that of chemotherapy. See Table 19(1), 19(). Table 19 (1). Change of the activity of natural killer cells (NK cells) Group No. of cases Rising Stable Declining Rate of improvement (%) KLT group Chemo-group < Table 19(). Change of the activity of NK cells before and after (X±SD) Group No. of cases Before s fter KLT group 4 1.±. 1.45±.40 Chemotherapy group ± ±4.84 <0.05 Comparing the KLT group with the chemotherapy group after : t=.75 <0.05 Comparing the KLT group before vs after : t=0.47 >0.05 Comparing the chemotherapy group before vs after : t=.85 < Remarkable difference of CDB4B /CDB8B in KLT group before and after (<0.05), yet no remarkable difference in the chemotherapy group before and after (>0.05). Remarkable + + difference of CDB4B /CDB8B by comparing the KLT group and the chemotherapy group after + + (<0.01), yet no remarkable difference existed by comparing number of CDB4B /CDB8B increased. (<0.05). See Table 0(1), Table 0(). Table 0(1). Change of CDB4BB of the two groups Group Before fter t KLT group 1.10± ± Chemotherapy group 1.07± ± Comparing the KLT group with the chemotherapy group before : t=0.75 =0.047 Comparing the KLT group with the chemotherapy group after : t=.46 =0.001 Comparing the KLT group before vs after :t=.80 =0.011 Comparing the chemotherapy group before vs after : t=0.54 =0.59 Change of eripheral Hemogram before and after

12 /CDB8BB Summary of hase III Clinical Trials of Kanglaite Injection in China Table 0 (). CDB4BB Group No. of cases Rising Stable Declining Rate of improvement (%) KLT group Chemo-group > Change of peripheral hemogram before and after (1) Leukocyte (WBC) counting The count of leukocytes >4.0/mm was defined as normal, the count <4.0/mm was defined as declined. It could be observed from table 1 that before there were 9.8% subjects in Kanglaite group whose counts of leukocytes were >4.0/mm, 7.6% subjects whose counts of leukocytes were <4.0/mm. fter the 97.14% subjects were observed in counts of leukocytes >4.0/mm and.86% subjects were observed in counts of leukocytes <4.0/mm. Before there were 9.16% subjects whose counts of leukocytes >4.0/mm and 7.84% subjects whose counts of leukocytes <4.0/mm in the chemotherapy group. fter 86.7% subjects were observed in counts of leukocytes >4.0/mm and 1.7% subjects were observed in counts of leukocytes<4.0/mm. No remarkable difference on leukocytes level existed in the Kanglaite group based on statistic procession (>0.05). No remarkable difference was also observed by comparing the two groups after (>0.05). This indicated that Kanglaite had no evident influence on peripheral leukocytes. See Table 1. Table 1. Comparison of leukocytes before and after (10 / mm TT)T Group No. of cases <1.0 Before/after Before/after Before/after Before/after Before/after KLT group /10 5/ /0 0/0 0/0 Chemo-group 51 47/44 4/5 0/ 0/0 0/0 Comparing the KLT group with the chemotherapy group before : (RIDIT): >0.05 Comparing the KLT group with the chemotherapy group after : (RIDIT): >0.05 Comparing the KLT group before vs after :(RIDIT): >0.05 Comparing the chemotherapy group before vs after : (RIDIT): >0.05 () Change of Hemoglobin (Hb) No remarkable difference on hemoglobin was observed in KLT group before and after (>0.05), while remarkable difference existed by comparing KLT group and chemotherapy group after (<0.05), this indicated that chemotherapy might result in marked decline of hemoglobin, KLT however had no such effect on hemoglobin. See Table. Table. Comparison of hemoglobin before and after (g/100 ml) Group No. of cases <6.5 Before/after Before/after Before/after Before/after Before/after KLT group 105 8/86 1/11 8/6 1/ 1,/0 Chemo-group 51 7/5 1/5 1/1 0/0 0/0 Comparing the KLT group with the chemotherapy group before : (RIDIT): >0.05 Comparing the KLT group with the chemotherapy group after : (RIDIT): <

13 Summary of hase III Clinical Trials of Kanglaite Injection in China Comparing the KLT group before vs after :(RIDIT): >0.05 Comparing the chemotherapy group before vs after : (RIDIT): >0.05 () Change of Blood-platelet (BC) No remarkable difference was observed in the KLT group before and after (>0.05), and no remarkable difference existed by comparing KLT group and chemotherapy group after (<0.05). This indicated that KLT had no evident influence on blood-platelet. See Table. 4 Table. Changes of platelet before and after (10 /mm ) <.5 Group No. of cases Before/after Before/after Before/after Before/after KLT group 105 8/85 11/1 8/4 / 1/0 Chemo-group 51 45/44 6/6 0/1 0/0 0/0 Comparing the KLT group with the chemotherapy group before : (RIDIT): >0.05 Comparing the KLT group with the chemotherapy group after : (RIDIT): >0.05 Comparing the KLT group before vs after :(RIDIT): >0.05 Comparing the chemotherapy group before vs after : (RIDIT): >0.05 Before/after.8 Observation of dverse Reaction (1) Influence on Liver and Kidney Function The grades (Grade 0, Grade I, Grade II, Grade III, Grade IV or None, ( expressed as 0,1,,,4 respectively) were statistically proceeded based on WHO Classification Standard on cute, Sub-acute and poisoning anticancer drugs (toxicity), through observing the results of overall 156 patients with primary hepatic carcinoma, no remarkable difference was observed on liver function in the KLT group (>0.05), however remarkable difference was observed by comparing the kidney function of the subjects in KLT group before and after (<0.05). This indicated that Kanglaite had a protective action on kidney function. See Table 4. Table 4 Comparison of the number of adverse reactions before and after KLT group Chemotherapy group Grade BT* T** BT T Liver Function Kidney Function BT*-before, T**-after - 1 -

14 X Summary of hase III Clinical Trials of Kanglaite Injection in China Liver function: SGT, Bilirubin, K, GT, Jaundice index, Comparing liver function of the two groups before >0.05 Comparing liver function of the two groups after <0.05 Comparing liver function of the Kanglaite group before VS after >0.05 Comparing liver function of the chemotherapy group before VS after <0.05 Comparing kidney function of the two groups before >0.05 Comparing kidney function of the two groups after <0.05 Comparing kidney function of the Kanglaite group before VS after >0.05 Comparing kidney function of the chemotherapy group before VS after >0.05 () llergic Reaction No allergic reaction or rash occurred in the KLT group during the administration. () dverse Reactions The major adverse reactions clinically included 14 cases of nausea, 6 cases of fever, 1 case of dizziness, 1 case of phlebitis and 1 case of dry mouth and tongue, all of which were not very severe and could remit after adapting the remedy to the cases or stopping administration. See Table 5. Table 5. General information of adverse reactions No. Clinical symptom Degree Lasting time Treating measures 6 Fever days Disappear after suiting the remedy or stopping administration 14 Nausea Slight 1-7 days utomatically remit after stopping administration 1 Dizziness Slight Transient Remit automatically 1 hlebitis Slight 1-7 days Suit the remedy 1 Mouth and Remit automatically after stopping Slight 1 days tongue dry administration.9 The final accomplishment of the mong original 166 subjects, 156 subjects successively completed 1- within the fixed time, 8 of them failed to complete, 6 in the KLT group and in the chemotherapy group. No remarkable difference was observed by comparing the two groups (>0.05). When in summary of cases, there were 4 subjects in the KLT group eventually exited the trial due to higher expenditure, or were rejected owing to losing connection; there were 6 subjects in the chemotherapy group were rejected due to severe marrow inhibition, poisoning and adverse alimentary reactions or losing connection. (See Table 6, 7) Table 6. Comparison of the performance between the two groups No. of cases No. of subjects failed to complete two s No. of subjects who completed two s KLT group Chemo-group Total =0.001 >

15 Summary of hase III Clinical Trials of Kanglaite Injection in China Table 7. nalysis of clinical characteristics of cases quitting, lost connection or rejected before Group No. of cases Main reason to quit or to be rejected KLT group 4 High fee, lost connection, died of complication Chemo-group 6 Marrow inhibition, severe alimentary reaction, lost connection 4. Discussion Kanglaite Injection was a preparation developed from the extract of the traditional Chinese medicine Job s Tear Semen Coicis through modern scientific method by Zhejiang Kanglaite harmaceutical Co. Ltd. The primary hepatic carcinoma belongs to the traditional Chinese medical category of Evil-mass, ching of Hypochondria and Distention. The pathogenesis of hepatic carcinoma mainly attributes to sthenia of Vital-energy, Depression of Liver-energy and sthenia of Spleen, Latency of oison and Evil which accumulate and enter the Lung-collateral and Spleen-collateral. The semen coicis with slightly sweet flavor, innocuity, can enter the Lung-collateral and Spleen-collateral to exert its action of strengthening the middle warmer and benefiting the vital-energy, invigorating the spleen and eliminating the wetness-evil and the evil-mass. From March of 1996 to May of 1997, the hase III clinical observation of KLT was performed to determine its curative effect as well as the clinical safety based on the coordination of several hospitals. Overall 156 subjects were selected all of whom met the clinical diagnostic standard of primary hepatic carcinoma, and were divided into the Kanglaite group and the chemotherapy group randomly. Overall 156 cases were clinically observed, among them 109 subjects were in the Kanglaite group in which 4 were rejected eventually, and 51 subjects were in the chemotherapy group in which 6 were rejected eventually. When in summary of cases, the actual number of subjects in Kanglaite group were 105 corresponding to 51 subjects in the chemotherapy group. No remarkable differences on sex, age, division of clinical phase, traditional Chinese medical syndrome identification, major clinical syndrome, tongue-body, tongue-fur, pulse condition, survival quality as well as body immunity etc. were observed in the two groups respectively; through the clinical observation the remission rate of primary hepatic carcinoma (CR+R) was reported of 11.4% in the Kanglaite group corresponding to 9.80% in the chemotherapy. nd it was also observed that KLT could achieve its best effect in treating sthenia of Spleen and Stagnation of Wetness-evil, and Intense Evil-heat syndrome, yet the least effect in treating Blood Stasis Syndrome. Besides KLT could markedly improve patients major clinical syndromes, the total effective rate of improvement was 80.95%, which was evidently better than that of the chemotherapy (5.49%) particularly on syndromes like weakness, bad stomach holding, abdominal distention, aching in hepatic region, nausea, vomit, etc. Its effects in improving survival quality, Karnofsky grades and body weight were also very much better than those Indexes in the chemotherapy group. The immunological tests indicated that KLT could enhance not only the activity of NK cells, but also the immunity. Neither remarkable influence on peripheral hemogram nor damage on liver and kidney function and allergic reactions were observed in the Kanglaite group. The major adverse reactions included nausea, fever, dizziness and phlebitis which occurred occasionally, lasted for 1-7 days and could remit after suiting the remedy to the case or stopping administration, only 1 of the whole subjects was observed of lips and throat dryness during the whole, which could remit automatically after stopping administration. dditionally nausea and vomit as the symptoms never occurred among some patients with primary hepatic carcinoma before administration appeared only as slight symptoms after administration, which could remit automatically once administration was stopped. - -

16 . Summary of hase III Clinical Trials of Kanglaite Injection in China 5. Typical Case Wei, male, 66 yrs, No.81. The patient was hospitalized on ugust 1, 1996 owing to discomfort in upper abdomen for weeks, Hepatic Space-occupying Lesion was testified by B-supersonic diagnostic set. When in hospital, his abdominal CT result showed: Space-occupying Lesion of 15 0 cm at the right lobe of liver, the abdominal B-supersonic diagnostic result showed: Space-occupying Lesion of cm at the right lobe of liver, and Serum test: F 84.8 ug/l, SH (specific antigen of hepatic carcinoma) +, γ-gt. 17 Iu/L, anti-hbc g (+), no other pathological changes were found after checking his alimentary canal, lung etc. the man was thus diagnosed of primary hepatic carcinoma. During in hospital, the man was once allocated with pulmonary artery catheter chemotherapy. CT results showed: The focus at the right lobe of liver shrank to 8 9 cm The therapy was broken off because the patient failed to endure the poisoning and adverse reactions. The size of the tumor was still in 8 9 cm indicated by B-supersonic diagnostic result, F 18.4 ug/l. The patient was allocated with 00ml of intravenous drip of KLT, once daily, for total 0 days. Before the symptoms of the patient included weakness, aching in hepatic region, jaundice and ascites, F 400 ug/l, γ-gt 151U/L, Karnofsky grade: 60, body weight: 5kg. fter symptoms like weakness, aching in hepatic region, jaundice and ascites were improved, Karnofsky grade: 80, body weight: 5kg, abdominal CT results showed: the Space-occupying Lesion at the right lobe of liver shrank to 6 6 cm, F 477ug/L, γ-gt: normal, and the patient had no recount of unwell, the tumor in his liver remained stable one month after. Till now the man has been surviving with the tumor for 5 months. 6. Summary (1) Kanglaite Injection had the action of strengthening the middle warmer and benefiting vital-energy, invigorating the spleen and eliminating the wetness-evil and evil-mass. It could effectively remit carcinoma focus, the effective rate (CR+R) was 11.4%, and it was the best effective in treating asthenia of spleen and stagnation of wetness-evil as well as intense evil heat syndrome, meanwhile it could remarkably improve syndromes, the total effective rate was 80.95%. Besides, the product had the action of improving survival quality and immunity. () The observation of clinical safety of KLT showed that no inhibition on marrow, obvious damage on liver, kidney function and allergic reactions occurred during the. The adverse reactions included slight nausea, fever and momentary dizziness which could remit automatically after stopping administration. () The result of phase III clinical observation of KLT in treating primary hepatic carcinoma indicated that KLT had a definite remission effect on carcinoma focus, equal to that of the chemotherapy group; meanwhile it was effective in improving clinical symptoms, the survival quality and immunity as well. In a word, KLT brings the advantage of traditional Chinese medicine into full play in supporting health energy and resisting carcinoma, and it is a better therapy drug comparing with all other present anti-hepatic carcinoma drugs