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SYNOPSIS

The study was intended to be a five-centre study running in Denmark. After 12 months it was decided to stop the trial due to the unexpected low recruitment. Only 12 patients were recruited. Of the 12 patients 5 patients did not fulfil the inclusion criteria and did not receive active treatment. The first patient was enrolled on October 10, 1995 and the last visit for the last patient took place on January 16, 1997. The study was then terminated. One patient was reported by use of two case record forms, visits 1-2 in one case record form and visits 3-9 in another case record form (C~.

The study was conducted according to the study protocol.

Due to the low recruitment no conclusions can be made, and in the following data are collected from the 12 patients and presented separately.

In the safety section (laboratory data) it should be noted that "Visit 1" is identical with "Uge -4".

Thfl e owe h t f th tud ar or es ty was as f 11 0 ows:

Wash-out Wash-out Randomi-

Control Control Control Control Control EOT sation

Visit no. 1 2 3 4 5 6 7 8 9

Week -4 -2 0 4 8 12 16 20 24

Informed consent • Criteria • • History • Clin. assessm. • • • • • • * • * Randomi-sation * Blood Press. * * * • * * * * • Biochemistry * *

., *

., *

., • U-Aibumin * * * * Urine stix • Adv. Events • • * * • * * Drug supply • * • * Compliance and drug

* * * * retrieval 1 S-sodium, S-potassium and S-creatinine (non-fasting)

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CE9402DK 10 October, 1997

PATIENT DATA

Patientl (CRF- randomisation no .•

Demography

The patient was treated with glipizide for NIDDM during the study and treated with atenolol and bendroflumethiazid + potassium for hypertension before inclusion in the study.

After 4 weeks wash-out period, the patient was trea ted 4 weeks with bendroflumethiazid 1,25 rng, followed by 4 weeks treatment with bendroflumethiazid 2,5 mg and at last 4 weeks treatment with enalaprillO mg.

Efficacy The diastolic blood pressure, the systolic blood pressure and the heart rate at visits 1 - 6 were as follows:

Table 1

Visit 1 Visit 2 Visit3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9

Diastolic Blood Pressure 109.5 107.5 105.0 91.0 112.5 107.5

Systolic Blood Pressure 184.5 162.5 175.0 :167.0 177.5 195.0 ::':

Heart rate 84.0 86.0 76.0 ::,,

72.0 80.0 ~ 80.0 ;•·

Safety

By a mistake, the 3 active treatment periods were 4 weeks instead of 8 weeks as scheduled. Due to this mistake the patient was withdrawn at visit 6.

No adverse events were registered during the treatment period.

No concurrent medication was taken during the study period.

. 10 October, 1997 CE 9402DK

Laboratory data were as follows:

C£9402 DK 10 October, 1997

Patientl (CRF . randomisation no.

D h ;e •

i I

The patient was treated with glibenclamide and metformin for NIDDM during the study. l The patient was treated for hypertension with ramipril 2.5 mg until the wash-out period.

During the first study period, the patient was treated with enalapril 10 mg. During the second period the patient was treated with bendroflumethiazid 1.25 mg, and during the third and last period the patient was treated with bendroflumethiazid 2.5 mg.

Efficacy The diastolic blood pressure, the systolic blood pressure and the heart rate at visits 1 - 9 was as follows:

Table 3

Visit 1 Visit 2 Visit 3 visit 4 . Visit 5 Visit 6 Visit 7 Visit 8 ) .. Visit ~· Diastolic Blood Pressure 95.0 99.5 100.0 . 80.0 . 90.0 97.5 100.0 94.D 96.5

~ystolic Blood Pressure 145.0 149.5 150.0 130.0. 130.0 142.5 130.0 144.0 .. 156.5 .. Heart rate 72.0 72.0 80.0 64.0 74.0 75.0 76.0 82.0 72.0

Safety Adverse events were registered for the last 2 treatment periods. The patient suffered from intermittent headache and oedema.

No concurrent medication was taken during the study period except the above mentioned medication for NIDDM.

Laboratory data were as follows:

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10 October, 1997 CE9402DK

During the study the patient was treated with metformin for NIDDM. Before enrollment in the study the patient was treated with amilorid + hydrochlorthiazid for hypertension.

After 4 weeks wash-out period, the patient was treated for 8 weeks with bendroflumethia-zid 2,5 mg, followed by 8 weeks treatment with bendroflumethiazid 1,25 mg, and at last 8 weeks treatment with enalaprillO mg

Efficacy The diastolic blood pressure, the systolic blood pressure and the heart rate at visits 1 - 9 were as follows:

Table 5 Visit 1 Visit 2 Visit 3 Visit 4' ,~~,Vfsii 5 Visit 6 Visit 7 VisitS ·V'"-~~ . :.1$1 ' '

Diastolic Blood Pressure 100.0 95.0 100.0 99.0 ·: . ..so.o 90.5 100.0 90.0 --~- ~.0 Systolic Blood Pressure 145.0 150.0 155.0 150.0 135.0 136.0 170.0 150.0 ~. J-55.0

' .:'.Eis.o Heart rate 64.0 72.0 87.0 70.0 72.0 68.0 ~76,0 .. ~ 68.0

Safety At the end of the second treatment period the patient reported periodical exercise induced dyspnea.

No concurrent medication was taken during the study period except the above mentioned medication for NIDDM.

Laboratory data were as follows:

CE9402DK 10 October, 1997

10 October, 1997 CE9402DK

Patient. (CRF -' not randomised)

The patient was treated for NIDDM with metformin and glibenclamide. The patient was treated for hypertension with bendroflumethiazide 2,5 mg +potassium.

During the 4 weeks wash-out period the diastolic blood pressure was below 90 mrnHg. Due to inclusion criteria (diastolic blood pressure between 90-110 mmHg), the patient was not randornised.

Efficacy The diastolic blood pressure, the systolic blood pressure and the heart rate at visits 1-3 were as follows:

Table 7 Visit 1 Visit 2 Visit 3 Visit 4 . Visit 5 Visit6 Visit 7

Diastolic Blood Pressure 80.0 88.0 79.0

Systolic Blood Pressure 140.0 157.0 140.0

eart rate 60.0 60.0 70.0

Safety Cough and decreased diuresis were reported as adverse events after 2 weeks of wash-out period. ·

No concurrent medication was notified except the above mentioned medication for NIDDM.

Laboratory parameters were as follows:

CE9402DK 10 October, 1997

Patient I (CRF- not randomised)

Hypertension was treated with ram.ipril 2,5 mg, and NIDDM was treated with metform.in.

Due to a mistake the patient was allocated to active treatment instead of placebo treatment

for the first 2 weeks of the wash-out period.

Efficacy The diastolic blood pressure, the systolic blood pressure and the heart rate at visits 1 - 2 were as follows:

Table 9

1Dia1slollic Blood Pressure

1:-.vsrouc Blood Pressure

Safety

139.0

76.0 80.0

The patient reported dizziness and general indisposition 2 weeks after inclusion in the study.

As mentioned earlier the patient was withdrawn due to active treatment instead of placebo treatment during the wash-out period.

No concurrent medication was taken during the observed period except the above mentioned medication for NIDDM.

Laboratory parameters were as follows:

10 October, 1997 CE 9402DK

Patienti (CRF- randomisation no .•

D h ~ .

No medical treatment for NIDDM. The hypertension was treated with benazepril 20 mg.

After 4 weeks washout period the patient was treated with bendroflumethiazid 1,25 mg for the first 8 weeks. For the next 8 weeks the patient was treated with ena1april10 mg. For the last 8 weeks of the study the patient was treated with bendroflumethiazid 2,5 mg.

Efficacy The diastolic blood pressure, the systolic blood pressure and the heart rate at visits 1 - 9 were as follows:

Table 11

Visit 1 Visit 2 Visit 3 Visit 4~ .,,Visit 5 · VisitS

Diastolic Blood Pressure 95.0 92.5 100.0 S8.5 ·"'::'"Y 93:5 101.0

Systolic Blood Pressure 146.5 160.0 150.0 153.5 ' 1·4a:s 155.0 ' .

Heart rate 65.0 78.0 68.0 69.0 71 :0 70.0

Safety No adverse events were reported during the study period.

No concurrent medication was taken during the observed period.

No laboratory datea are available for visit 3.

Laboratory parameters were as follows:

Table 12

Visit 7 Visit a · Visit ~t 98.0 T· 79.0 , '':'81.0

174.5 146.5 >'154:0

74.0 69.0 70.0

CE9402DK 10 October, 1997

Patien. CRF- randomisation no .•

NIDDM was treated with tolbutamide; hypertension was treated with bendroflurnethiazid + potassium.

After 4 weeks washout period the patient was allocated to 8 weeeks treatment with bendroflumethiazid 1,25 mg. During the next 8 weeks the patient received bendroflumethiazid 2,5 mg, and for the last 8 weeks the patient received enalapril10 mg.

Efficacy The diastolic blood pressure, the systolic blood pressure and the heart rate at visits 1 - 9 were as follows: ·

Table13 Visit 1 Visit 2 Visit 3 visit4 -~Visit 5 .• Visit 6 Visit 7 )Jisit 8 ~ Ms~ 9

piastolic Blood Pressure 94.0 91 .0 90.0 ~.8');.0 '~~ 81 o· 97.5 100.0 · 97.o\:.l'l ;t97.o 't I• • ' -... ·· . !systolic Blood Pressure 138.0 129.0 117.0 122:0 ; . 121 .0 137.5 139.0 134.0. 146.0

·' ~earl rate 93.0 98.0 104.0 86.0 98.0 102.0 98.0 90.0 .:, 94.0

Safety No adverse events were reported during the study period.

No concurrent medication was used during the observed period except the above mentioned medication for NIDDM.

No laboratory data are available for visit 4.

Laboratory parameters were as follows:

Table 14

10 October, 1997

Patient I (C~ not randomised)

NIDDM was treated with glibenclamide. No antihypertensive treatment.

The patient was not randomised due to diabetic nephropathy.

Efficacy

C£ 9402 DK

The diastolic blood pressure, the systolic blood pressure and the heart rate at visits 1 - 2 were as follows:

Table 15

Visit 1 Visit2 Visit 3 Visit 4 . Visit 5 Visit 6 Visit 7 VisitS ··~Visit\9 · "'-· .... . , ,_ .. ..

:ii!.~t: .. ·· Diastolic Blood Pressure 105.0 93.0 '• ., ""' ' ., .. Systolic Blood Pressure 169.0 156.0

Heart rate 74.0 84.0 :, .. ,· . "

Safety No adverse events were reported in the observed period

No concurrent medication was taken except the above mentioned medication for NIDDM.

Laboratory parameters were as follows:

Table 16

CE9402DK 10 October, 1997

Patient.(CRF- randomisation no.

Hypertension was treated with losartan 50 mg and bendroflumethiazid 2,5 mg.

After the washout period the patient was treated with bendroflumethiazid 1,25 mg for 8 weeks. For the next 8 weeks the patient was treated with enalapril 10 mg. For the last 8 weeks the patient was treated with bendroflumethiazid 2,5 mg.

Efficacy The diastolic blood pressure, the systolic blood pressure and the heart rate at visits 1 - 9 were as follows:

Table 17

Visit 1 Visit2 Visit 3 Visit 4 Visit 5 Visit 6 Visit7 Visit 8 . 'Visit 9

Diastolic Blood Pressure 84.0 86.5 94.5 105.0 86:0 95.0 94.0 108.0 99.0

~ystolic Blood Pressure 163.0 186.5 184.0 218.0 176.0 180.0 172.0 180.0 :

.172.0

Heart rate 82.0 78.0 74.0 81 .0 •• ,66.0 76.0 76.0 " 84.0 .$:~ 76.0 . I b

f s•~ I During the wash-out period the patient reported dizziness and headache. Dizziness was reported again by the end of the second treatment period. Nausea was also reported as an adverse event by the end of the second treatment period.

Precardial pain was reported in the first and third treatment periods By the end of the second treatment period the patient was treated 4 days with nitroglycerin 0.5 rng twice daily.

Laboratory parameters were as follows:

Table 18

10 October, 1997 CE 9402 DK

Patient I (CRF- randomisation no .•

For NIDDM the patient was treated with metform.in and tolbutamide. The hypertension was treated with verapamil240 mg.

After 4 weeks wash-out period the patient was allocated to 8 weeks treatment with bendroflumethiazid 2,5 mg followed by 8 weeks treatment with bendroflumethiazid 1,25 mg. In the last 8 weeks treatment period the patient received enalaprillO mg.

Efficacy The diastolic blood pressure, the systolic blood pressure and the heart rate at visits 1 - 9 were as follows:

Table 19

Visit 1 Visit 2 Visit 3 Visit4 Visit 5 VisitS Visit 7 VisitS Visit 9

Diastolic Blood Pressure 88.0 107.0 105.0 107.0 102.0 . 105.0 106.0 104.0 . 92.0.

Systolic Blood Pressure 164.0 169.0 173.0 168.0 .169.0 165.0 159.0 167.0 •. 152.0 ,

Heart rate 68.0 76.0 78.0 90.0 81 .0 . 80.0 86.0 80.0 74.0 '.

Safety During the washout period the patient reported otitis media. In the beginning of the treatment periods the patient reported a precardial pricking sensation. The symp toms continued until the middle of the third treatment period.

The patient was treated with phenoxymethylpenicillin, ibuprofen and paracetamol for otitis media.

Laboratory parameters were as follows:

Table 20

CE9402DK 10 October, 1997

Patient- (C~ not randomised)

No medical treatment for NIDDM. Hypertension was treated with amlodipine.

The patient was not randomised due to diabetic nephropathy.

Efficacy The diastolic blood pressure, the systolic blood pressure and the heart rate at visits 1 - 2 were as follows:

Table 21

Visit 1 Visit 2 Visit 3 ,,Visit 4 VisitS Visit 6 Visit 7 . Visit 8 .*Visit 9 >.

,,

[';(~\, Diastolic Blood Pressure 83.0 90.0 Systolic Blood Pressure 143.5 166.0 '

Heart rate 80.0 88.0 __._ -

Safety In the wash-out period diabetic nephropathy was reported. Positive urine stixJ but no urine-albumin value was registered.

Acetylsalicylic acid as a prophylaxis f.or trombosis was reported as concurrent medication.

Laboratory parameters were as follows:

Table 22

10 October, 1997 CE9402DK

Patient.CRF- randomisation no.-

D h !"' •

No medical treatment for NIDDM. Hypertension was treated with amlodipine.

The patient did not receive active treatment due to diabetic nephropathy - an exclusion criteria.

Efficacy The diastolic blood pressure, the systolic blood pressure and the heart rate at visits 1 - 2 were as follows:

Table 23

Visit 1 Visit 2 Visit 3 Visit 4 -Visit 5 Visit 6 Visit 7 Visit 8 Visit 9

Diastolic Blood Pressure 106.0 100.0 98.0

Systolic Blood Pressure 164.0 151.0 152.0 ..

Heart rate 78.0 96.0 92.0

Safety During the wash-out period diabetic nephropathy was reported - urine-albumin was elevated.

Acetylsalicylic acid was reported as concurrent medication · used as a prophylaxis for thrombosis, and quinine hydrochloride was used against leg muscle cramp.

Laboratory parameters were as follows:

Table 24

CE9402 DK 10 October, 1997

CONCLUSION

The study was terminated after inclusion of 12 patients. Seven patients received active treatment; bendroflumethiazid 1,25 mg, bendroflumethiazid 2,5 mg and enalaprillO mg in a cross over design. Each treatment period should be of 8 weeks' duration

Due to the small sample size efficacy parameters are not evaluated- no statistical analyses are performed.

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