바이오테크 seoul food 2013

Double blind, randomized, cross over, controlled clinical trial of Symbosial (NaCl + Chitosan 3%) vs NaCl on high blood pressure parameters during the diet and lifestyle improvement period before an eventual prescription of an antihypertensive treatment

CLINICAL STUDY 2011

Anti-Hypertension Salt

OBJECTIVESPrimary Objective:The primary objective of this clinical trial is to show an eventual decrease of the high blood pressure parameter more important with symbosial (NaCl + Chitosan 3%) than with NaCl during the diet and lifestyle improvement period which must be prescribed to the patient before an eventual antihypertensive treatment

Secondary Objective:The secondary objectives are to compare between groups:- the patient’s satisfaction especially through the evaluation of food hedonism;- the modification of blood and urinary ionograms and glycemia;- the symbosial ( NaCl+ Chitosan 3%) tolerance and especially the patient’s opinion on its taste;- the patient’s compliance to salt-restricted diet.

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Inclusion Criteria:Subjects must demonstrate willingness to participate in the study and to adhere to dose and visit schedules and satisfy the following criteria before being enrolled into the study:- Male or female patients, older than 18 years old;- Capable of consent;- Having given their written informed consent;- Willingness to adhere to the protocol requirement;- Beneficiaries of the French national health insurance;- Presenting a mild hypertension defined by a SBP between 140-159 mmHg and a DBP between 9 0-99 mmHg according international standard for mild to moderate hypertension.- Who have never been previously treated with an antihypertensive treatment.

Non inclusion Criteria:- Patients to whom any of the following applies will be not included in the study:- Pregnant women, menopaused for less than 2 years or not under effective contraception or women breastfeeding women;- Patient older than 85;- Patient presenting allergic reaction to seafood;- Patient already included in one other clinical trial;- Patient presenting a severe disease which may lead to a an early patient drop out;- Patient having a high risk cardiovascular profile due to many associated cardiovascular risk factors;- Hypertension discovered during a acute cardiovascular event;- Patient having a poor motivation, mental deficiency or administrative and legal decision likely to limit the validity of consent to participate in the study or limit the patients’ ability to comply with the protocol requirement;- Inability to understand and to observe the instructions of the physician.

- Patient older than 85;- Patient presenting allergic reaction to seafood;- Patient already included in one other clinical trial;

OBJECTIVES

The primary objective of this clinical trial is to show an eventual decrease of the high blood pressure parameter more important with symbosial (NaCl + Chitosan 3%) than with NaCl during the diet and lifestyle improvement period which must be prescribed to the patient before an eventual antihypertensive treatment

The secondary objectives are to compare between groups:- the patient’s satisfaction especially through the evaluation of food hedonism;

- Having given their written informed consent;- Willingness to adhere to the protocol requirement;- Beneficiaries of the French national health insurance;- Presenting a mild hypertension defined by a SBP between 140-159 mmHg and a DBP between 9 0-99 mmHg according international standard for mild to moderate hypertension.- Who have never been previously treated with an antihypertensive treatment

Non inclusion Criteria:- Patients to whom any of the following applies will be not included in the study:- Pregnant women, menopaused for less than 2 years or not under effective contraception or

- Patient presenting a severe disease which may lead to a an early patient drop out;- Patient having a high risk cardiovascular profile due to many associated cardiovascular risk factors;

POPULATIONThe 38 patients respecting all inclusion and non-inclusion criteria and presenting all CRF are described: 18 patients taking treatment A at first period and treatment B at second period (AB group) 20 patients taking treatment B at first period and treatment A at second period (BA group)

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Patients characteristics' at inclusion visit

Patients' demographic characteristics

Age

Sex

AB BA

Anova: 0.2144 p-value: 0.6461

80%

41.2%33.3%

58.8%

66.7%

Male Female

70%

60%

50%

40%

30%

20%

10%

0%

Khi²: 0.2304 p-value: 0.6313

N MV

ABBATotal

18

20

38

0

0

0

57.4 years old

59.3 years old

58.4 years old

12.8

11.9

12.2

56.0

56.0

56.0

32.0

38.0

32.0

80.0

81.0

81.0

Means SD Median Min Max

BMI

ABBATotal

18

20

38

0

0

0

27.8

24.9

26.3

5.9

3.7

5.0

27.2

25.2

25.9

17.7

18.3

17.7

39.1

31.5

39.1

Weight (Kg) : AB = 79.5 ± 22.2 Kg BA = 69.6 ± 14.3 Kg

High (cm) : AB = 167.8 ± 9.9 cm BA = 166.8 ± 7.6 cm

Waist circumference (cm) : AB = 92.9 ± 16.3 cm BA = 89.1 ± 14.2 cm

Hip circumference (cm) : AB = 99.2 ± 9.4 cm BA = 96.6 ± 9.2 cm

No significantly differences was observed about Place of residence, Family status, Study level and Professional status

Anova: 2.6752 p-value: 0.1106

Anova: 0.1327 p-value: 0.7178

Anova: 0.5691 p-value: 0.4557

Anova: 0.7054 p-value: 0.4667

AB BA

80%

41.2%

33.3%

33.3%25.0%25.0%

16.7%

0%Never smoked SmokingStopped smoking

70%

60%

50%

40%

30%

20%

10%

0%

AB BA100%

90%

80%

94.4% 95.0%

5.6% 5.0%

Any diabete Type 2 diabete

70%

60%

50%

40%

30%

20%

10%

0%

Cardiovalscular context

Ficher: 0.0180p-value: 0.0998


DiabeteTabagism



Anova: 3.59 p-value: 0.0660

N MV Means SD Median Min Max

0504 /

Last blood glucose levelAB BA80%

66.7%62.3%

22.2% 21.1%

11.1%5.3%

%

11.1%

0%

10.5%

Non MixedHypercholesterolemia Hypetry glicemia

70%

60%

50%

40%

30%

20%

10%

0%

Cardiovalscular context

The HbA1c value was present for only 3 patients of group BA; the comparison between 2 groups could not be calculated


Dyslipidemia

ABBATotal

11

15

26

7

5

12

0.5 g/l

2.1 g/l

2.1 g/l

0.1

0.2

0.2

0.5

0.5

0.5

0.4

0.1

0.1

0.6

0.8

0.8

ABBATotal

12

18

30

6

2

8

1.3 g/l

1.5 g/l

1.4 g/l

0.4

1.1

0.9

1.4

1.3

1.4

0.5

0.6

0.5

1.7

5.3

5.3

Anova: 0.1517 p-value: 0.6995

Anova: 0.2589 p-value: 0.6155

Anova: p-value: 0.5221

Anova: 0.0029 p-value: 0.9571

ABBATotal

17

19

36

1

1

2

5.3 mmol/l

5.4 mmol/l

5.3 mmol/l

0.7

2.2

1.7

5.4

5.2

5.3

N MV Means SD Median

N MV

ABBATotal

15

18

33

3

2

5

2.1 g/l

2.1 g/l

2.1 g/l

0.2

0.4

0.3

2.1

2.1

2.1

1.8

1.7

1.7

2.5

3.1

3.1

Means SD Median Min Max

Last total cholesterol value (g/l)


Last HDL cholesterol level (g/l)


Last tryglycerides value (g/l)

Patients evolution during first period (W0-W8)

Weight (Kg) evolution between W0 and W8 (W0-W8)

SBP mean value (mmHg) evolution between W0 and W8 (W0-W8)

W0 W8

90

A(n=18) B(n=20)

80 79.5 ± 22.2 79.8 ± 21.6 ∆ (w0-w8)=0.3 ± 2.3

69.9 ± 14.3 69.3 ± 14.1 ∆ (w0-w8)=-0.3 ± 0.9 70

60

A(n=18) B(n=20)

W0 W8

160

140

149.8 ± 4.7

143.5 ± 7.4 ∆ (w0-w8)=-6.2 ± 7.3 149.0 ± 5.0

135.9 ± 9.7 ∆ (w0-w8)=-13.2 ± 11.1

130

120

150

Anova W0p=0.1106

Anova W0p=0.6500

Anova W8p=0.0104

Anova ∆p=0.0309

Anova W8p=0.0831

Anova ∆p=0.2612

Repeated Measures Analysis of Variance:Anova treatment: p-value: 2.92 Signi�cation: 0.0959Anova time: p-value: 0.01 Signi�cation: 0.9094Anova treatment* time: p-value: 1.30 Signi�cation: 0.2612

Repeated Measures Analysis of Variance:Anova treatment: p-value: 6.08 Signi�cation: 0.0186Anova time: p-value: 40.93 Signi�cation: <0.0001Anova treatment* time: p-value: 5.05 Signi�cation: 0.0309

Blood pressure parameters evolution between W0 and W8



0706 /

DBP mean value (mmHg) evolution between W0 and W8 (W0-W8)

Percentage of patients with blood pressure under control at the end of first period

Heart rate mean value (b/min.) evolution between W0 and W8 (W0-W8)

B(n=20)

A(n=18) B(n=20)

A(n=18) B(n=19)

A(n=18)

W0 W8

100

90

93.2 ± 3.5

75.5 ± 7.1

87.1 ± 7.6 ∆ (w0-w8)=-6.1 ± 7.1

93.2 ± 3.0

75.5 ± 9.074.2 ± 8.6 ∆ (w0-w8)=-1.3 ± 6.2 75.6 ± 9.2 ∆ (w0-w8)=0.1 ± 6.5

81.9 ± 7.8 ∆ (w0-w8)=-11.4 ± 7.6 80

70

W0 W8

90

80

70

60

Anova W0p=0.9919

Anova W8p=0.6244

Anova ∆p=0.5014

Anova W0p=0.9919

Anova W8p=0.6244

Anova ∆p=0.5014


Repeated Measures Analysis of Variance:Anova treatment: p-value: 3.0 Signi�cation: 0.0919Anova time: p-value: 55.23 Signi�cation: <0.0001Anova treatment* time: p-value: 4.85 Signi�cation: 0.0342

90%

38.9%

80.0%

33.3%

75.0%

SBP<140mmHg

80%

70%

60%

50%

40%

30%

20%

10%

0%

Khi²: 6.7017 p-value: 0.0096 Khi²: 6.6527 p-value: 0.0099

SBP<140mmHg and DBP<90mmHg

Sodium value (mmol/l) evolution between W0 and W8 (W0-W8)

A(n=18) B(n=19)

140.1 ± 2.4141.1 ± 1.7

140.4 ± 1.4 ∆ (w0-w8)=0.3 ± 2.3 141.4 ± 1.8 ∆ (w0-w8)=0.3 ± 1.6

W0 W8120

130

140

150

160

2

3

4

5

6

Anova W0p=0.1532

Anova W8p=0.0594

Anova ∆p=0.9824


Potassium value (mmol/l) evolution between W0 and W8 (W0-W8)

A(n=17) B(n=19)

4.1 ± 0.34.1 ± 0.4

4.0 ± 0.3 ∆ (w0-w8)=-0.1 ± 0.2

4.3 ± 0.4 ∆ (w0-w8)=0.2 ± 0.4

W0 W8

Anova W0p=0.7550

Anova W8p=0.0132

Anova ∆p=0.0009


Chlorine value (mmol/l) evolution between W0 and W8 (W0-W8)

A(n=16) B(n=18)

103.9 ± 2.6104.9 ± 2.1

103.3 ± 3.0 ∆ (w0-w8)=-0.6 ± 1.2 104.1 ± 2.3 ∆ (w0-w8)=-0.8 ± 1.7

W0 W8

120

110

100

90

Anova W0p=0.2219

Anova W8p=0.3833

Anova ∆p=0.6726


Biologics parameters evolution between W0 and W8: blood ionogram



0908 /

Biologics parameters evolution between W0 and W8: urinary ionogram

Bicarbonates value (mmol/l) evolution between W0 and W8 (W0-W8)

A(n=11) B(n=14)

26.8 ± 2.328.0 ± 2.5

27.6 ± 2.0 ∆ (w0-w8)=0.8 ± 1.9 28.5 ± 2.9 ∆ (w0-w8)=0.6 ± 2.9

W0 W820

25

30

35

2

3

4

5

6

7

8

Anova W0p=0.2141

Anova W8p=0.3344

Anova ∆p=0.7868 Repeated Measures Analysis of Variance:

Anova treatment: p-value: 1.71 Signi�cation: 0.2043Anova time: p-value: 2.20 Signi�cation: 0.1520Anova treatment* time: p-value: 0.07 Signi�cation: 0.7868

Glycemia value (mmol/l) evolution between W0 and W8 (W0-W8)

A(n=15) B(n=18)

5.5 ± 0.85.6 ± 1.4

5.1 ± 1.4 ∆ (w0-w8)=-0.5 ± 1.4

5.3 ± 0.8 ∆ (w0-w8)=-0.1 ± 0.6

W0 W8

Anova W0p=0.6988

Anova W8p=0.6142

Anova ∆p=0.3398


Sodium value (mmol/24h) evolution between W0 and W8 (W0-W8)

A(n=14) B(n=18)

118.2 ± 49.9

155.6 ± 73.6142.9 ± 69.9 ∆ (w0-w8)=24.8 ± 69.3

189.1 ± 93.2 ∆ (w0-w8)=33.6 ± 96.5

W0 W880

90

100

110

120

130140

150

160170

180

190

200

Anova W0p=0.0973

Anova W8p=0.1192

Anova ∆p=0.7660


Potassium value (mmol/24h) evolution between W0 and W8 (W0-W8)

A(n=14) B(n=18)

61.8 ± 25.663.1 ± 29.2

67.8 ± 34.7 ∆ (w0-w8)=6.0 ± 28.6 68.8 ± 33.2 ∆ (w0-w8)=5.7 ± 32.8

W0 W840

50

60

70

80

Anova W0p=0.9020

Anova W8p=0.9350

Anova ∆p=0.9832


Chlorine value (mmol/24h) evolution between W0 and W8 (W0-W8)

A(n=8) B(n=11)

Anova W0p=0.4166

Anova W8p=0.5225


Biologics parameters evolution between W0 and W8: blood ionogram

Any secondary effect was observed during first period

Anova: 0.0944 p-value: 0.76051 patient of group A didn’t report the saltcellar at W8 visit

142.0 ± 69.9

187.8 ± 86.3 ∆ (w0-w8)=45.8 ± 103.3

120.1 ± 45.1

165.9 ± 59.9 ∆ (w0-w8)=45.8 ± 50.6

Anova ∆p=0.9985

W0 W8

200

80

190

180

170

160

150

140

130

120

110

100

90



Salt consomption during first period (gr.)

N MV

ABBATotal

17

20

37

1

0

1

169.0 gr.

178.2 gr.

173.9 gr.

90.5

90.1

89.1

42.0

197.5

176.0

Means SD Median

1110 /

Crossover analysis

The cross over analysis on the two periods con�rmed the results showing signi�cant time e�ect(p:0.0006)and treatment e�ect (p:0.0156) concerning SBP either for DBP: time e�ect (p<0.0001)and treatment e�ect(p:0.0285).The salt intake was relatively moderate in both groups when compared to the standardpatients’ intake and comparable between SYMBIOSAL and traditional salt:2.9±1 g/d vs 3.0±1.5 g/d (p:0.9412 NS)

Crossover analysis:Order*Group interaction: p-value: -0.81 Signi�cation: 0.4243Group e�ect: p-value: -2.54 Signi�cation: 0.0156Order e�ect: p-value: 3.78 Signi�cation: 0.0006

t-test W8 vs W10BA : p=0.6001

t-test W8 vs W10AB : p=0.6938

Anova W0p=0.6500

Anova W8p=0.0104

Anova W10p=0.0233

Anova W18p=0.3046

First period evolution (W0-W8):A : -6.2 ± 7.3

B: -13.2 ± 11.1Anova

p=0.0309

Second period evolution (W10-W18):B : -3.6 ± 8.4A: 0.2 ± 8.2

Anovap=0.1634

SBP mean value(mmHg)

ABA B

B ABA

W0 W8 w10 w18

First period Wash Out Second period

149.8 ± 4.7

136.6 ± 9.2 136.8 ± 11.6

143.5 ± 7.4 144.3 ± 10.9 140.7 ± 11.5

149.0 ± 5.0 135.9 ± 9.7

Crossover analysis:Order*Group interaction: p-value: -1.16 Signi�cation: 0.2524Group e�ect: p-value: -2.28 Signi�cation: 0.0285Order e�ect: p-value: 4.53 Signi�cation: <0.0001

DBP mean value(mmHg)

First period Wash Out Second period

t-test W8 vs W10BA : p=0.6001

t-test W8 vs W10AB : p=0.6938

Anova W0p=0.9761

Anova W8p=0.0439

Anova W10p=0.0317

Anova W18p=0.2881

First period evolution (W0-W8):A : -6.1 ± 7.1B: -11.4 ± 7.6

Anovap=0.0342

Second period evolution (W10-W18):B : -2.5 ± 6.0A: -0.5 ± 5.1

Anovap=0.2716

ABA B

B ABA

W0 W8 w10 w18

93.2 ± 3.5

82.1 ± 7.0 81.6 ± 9.3

87.1 ± 7.6 87.3 ± 7.4 84.8 ± 9.2

93.2 ± 3.0 81.9 ± 7.8

Switching traditional Nacl by SYMBIOSAL significantly contributes to a better controlof hypertension in association to the lifestyle and diet recommendations and may delay the prescription of antihyper-tensive drugs.

The study shows that in association with cardiovascular lifestyle improvements (salt reduction, physical exercice…) the intake of Symbosial significantly contributes to obtain patients’ blood pressure reductions and blood pressure controls when compared to placebo.

04.01.2013 Published International Angiology Journal/London

#1236-5, Yeonsan-dong, Mokpo-city, Jeonnam, KoreaTel : +82-61-278-0963 Fax : +82-61-278-7611 E-mail : [email protected] (c)2013 BIOTECH CO.,LTD. All Rights Reserved.BIOTECH CO., LTD.

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바이오테크 seoul food 2013

Health & Medicine