PRISMA: Prospective Randomised Investigation of the Safety and Efficacy of Micardis® vs Ramipril Using ABPM

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00274612
• Collaborator: (none)
• Enrollment: 801
• Locations: 62
• Duration (Months): 13
• Patients Per Site: 12.9
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

The primary objective of this study is to demonstrate that telmisartan 80 mg (MICARDIS®) is at least as effective and possibly superior to ramipril 5mg and 10mg in lowering mean ambulatory diastolic blood pressure (DBP) and systolic blood pressure (SBP) during the last 6 hours of the 24-hour dosing interval in mild-to-moderate hypertensive patients at the end of an 8 and 14-week treatment period, respectively.

Condition or Disease	Intervention/Treatment	Phase
Hypertension	Drug: Telmisartan; Drug: Ramipril	Phase 4

Detailed Description

Secondary objectives will compare telmisartan (80 mg) (MICARDIS® and ramipril (5 mg and 10 mg) on: 1) the reduction in the last 6-hour ABPM mean pulse pressure (PP) relative to dosing, 2) the reductions in the 24-hour ABPM mean DBP, SBP and PP relative to dosing, 3) reductions in ABPM mean DBP, SBP and PP during other periods of the 24-hour dosing interval (i.e., morning, daytime, and nighttime) relative to clock time, 4) change from baseline in systolic and diastolic blood pressure load during the 24-hour dosing interval, 5) reductions in the mean seated trough DBP and SBP measured using a manual in-clinic cuff sphygmomanometer, 6) responder rates as determined by both ABPM and manual in-clinic cuff measurements and 7) Health-Related Quality of Life (HRQL).

Study Hypothesis:

It is hypothesised that the rise of blood pressure (BP) during the last hours of the sleeping period is a cause of the high incidence of cardiovascular events in the morning. The purpose of the present study is to demonstrate that telmisartan (MICARDIS®) is not inferior to ramipril in lowering blood pressure in patients with mild-to-moderate hypertension. Blood pressure will be assessed by ambulatory blood pressure monitoring (ABPM) as this will allow comparison of the full 24-hour effects of both treatments without artefacts (e.g., white-coat hypertension) introduced by measurement of blood pressure in the clinic. This will measure diastolic blood pressures over the entire 24-hour dosing interval, with primary attention focused on the last six hours of the dosing interval.

NULL AND ALTERNATIVE HYPOTHESES In order to test the multiple hypotheses (e.g., non-inferiority and superiority of telmisartan compared to ramipril), multiple dosages (i.e., telmisartan 80mg (MICARDIS®) versus ramipril 5mg and ramipril 10mg after 8 and 14 weeks of treatment, respectively), and the two endpoints (i.e., reduction in DBP and SBP during the last 6 hours of the 24-hour dosing interval) as measured by ABPM, a completely hierarchical, closed testing procedure will be used.

Hierarchical Closed Testing Procedure:

1. Non-inferiority of telmisartan 80 mg (MICARDIS®) compared to ramipril 5 mg at the end of the 8 week treatment period in the reduction of DBP during the last 6 hours of the 24 hour dosing interval; if significant then,

2. Superiority of telmisartan 80 mg (MICARDIS®) compared to ramipril 5 mg at the end of the 8-week treatment period in the reduction of DBP during the last 6 hours of the 24-hour dosing interval; if significant then,

3. Superiority of telmisartan 80mg (MICARDIS®) compared to ramipril 5 mg at the end of the 8-week treatment period in the reduction of SBP during the last 6 hours of the 24-hour dosing interval; if significant then,

4. Non-inferiority of telmisartan 80mg (MICARDIS®) compared to ramipril 10 mg at the end of an 14 week treatment period in the reduction of DBP during the last 6 hours of the 24-hour dosing interval; if significant then,

5. Superiority of telmisartan 80mg (MICARDIS®) compared to ramipril 10 mg at the end of an 14-week treatment period in the reduction of DBP during the last 6 hours of the 24-hour dosing interval; and if significant then,

6. Superiority of telmisartan 80mg (MICARDIS®) compared to ramipril 10mg at the end of an 14-week treatment period in the reduction of SBP during the last 6 hours of the 24-hour dosing interval.

A difference of 2 mmHg was determined to be the maximum difference between the mean reductions in DBP during the last 6 hours of the 24-hour dosing interval for the two treatments which would be considered to have no clinical importance (i.e., the limit for non inferiority). Thus non-inferiority of telmisartan compared to ramipril will be tested using the following set of hypotheses:

Null Hypothesis:

The overall mean reduction from baseline in ABPM mean DBP during the last 6 hours of the 24-hour dosing interval for telmisartan 80 mg (MICARDIS®) is inferior to that for ramipril by at least 2 mmHg.

Alternative Hypothesis: The overall mean reduction from baseline in ABPM mean DBP during the last 6 hours of the 24-hour dosing interval for telmisartan 80mg (MICARDIS®) is less than 2 mmHg smaller than that for ramipril.

These hypotheses can be stated as:

H0: dT - dR less than or equal to -2 mmHg versus HA: dT - dR > -2 mmHg where dT and dR represent the overall mean reduction from baseline in ABPM mean DBP during the last 6 hours of the 24-hour dosing interval for telmisartan and ramipril, respectively, adjusted for any other factors included in the statistical model.

If the lower limit of the two-sided 95% confidence interval for the difference between the least square means of both treatments (telmisartan - ramipril) lies above -2 mmHg, then it will be concluded that telmisartan 80mg (MICARDIS®) is at least as effective as ramipril (5mg after 8 weeks of treatment or 10mg after 14 weeks of treatment, depending upon the comparison) in reducing DBP during the last 6 hours of the 24-hour dosing interval.

Superiority of telmisartan (MICARDIS®) compared to ramipril will be tested using the following set of hypotheses:

Null Hypothesis:

The overall mean reduction from baseline in the ABPM mean during the last 6 hours of the 24-hour dosing interval for telmisartan 80mg (MICARDIS®) is less than or equal to that for ramipril.

Alternative Hypothesis: The overall mean reduction from baseline in the ABPM mean during the last 6 hours of the 24-hour dosing interval for telmisartan 80mg (MICARDIS®) is greater than that for ramipril.

These hypotheses can be stated as:

H0: dT - dR less than or equal to 0 mmHg versus HA: dT - dR > 0 mmHg where dT and dR represent the overall mean reduction from baseline in ABPM mean DBP during the last 6 hours of the 24-hour dosing interval for telmisartan and ramipril, respectively, adjusted for any other factors included in the statistical model.

If the lower limit of the two-sided 95% confidence interval for the difference between the least square means of both treatments (telmisartan (MICARDIS®) - ramipril) is greater than zero, then it will be concluded that telmisartan 80mg (MICARDIS®) is statistically superior to ramipril (5mg after 8 weeks of treatment or 10mg after 14 weeks of treatment, depending upon the comparison) in reducing blood pressure (DBP or SBP, depending upon the comparison) during the last 6 hours of the 24-hour dosing interval.

Comparison(s):

Reductions in blood pressure during the last 6 hours of the 24-hour dosing interval as measured by ABPM in patients treated with telmisartan (MICARDIS®) compared to patients treated with ramipril. The primary analysis will consist of a closed testing procedure first testing for non-inferiority of telmisartan 80mg (MICARDIS®) compared to ramipril 10mg after fourteen weeks of treatment in the reduction in diastolic blood pressure (DBP); if significant, testing for superiority of telmisartan 80 mg (MICARDIS®) compared to ramipril 10 mg in the reduction in DBP; if significant, testing for superiority of telmisartan 80 mg (MICARDIS®) compared to ramipril 10 mg in the reduction of systolic blood pressure (SBP); if significant, testing for non-inferiority of telmisartan 80 mg (MICARDIS®) compared to ramipril 5 mg after eight weeks of treatment in the reduction in DBP; if significant, testing for superiority of telmisartan 80 mg (MICARDIS®) compared to ramipril 5 mg in the reduction in DBP; and if significant, testing for superiority of telmisartan 80mg (MICARDIS®) compared to ramipril 5mg in the reduction in SBP.

Study Design

• Study Type: Interventional
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• Official Title: A Prospective Randomised Open- Label Blinded-Endpoint (PROBE) Trial Comparing Telmisartan (MICARDIS®) (40-80-80mg QD) and Ramipril (2.5-5--10mg QD) in Patients With Mild-to-Moderate Hypertension Using Ambulatory Blood Pressure Monitoring. PRISMA = Prospective Randomised Investigation of the Safety and Efficacy of Micardis® vs Ramipril Using ABPM
• Study Start Date: Oct 1, 2002
• Actual Primary Completion Date: Nov 1, 2003
• Study Completion Date: Nov 1, 2003

Outcome Measures

Primary Outcome Measures

1. Changes in the last 6-hour mean (relative to dose time) diastolic and systolic blood pressure (DBP and SBP) as measured by ABPM [after 8 and 14 weeks]

Secondary Outcome Measures

1. Changes in the last 6-hour ABPM mean (relative to dosing time) for pulse pressure (PP) [after 8 and 14 weeks]

2. Changes in the 24-hour ABPM mean (relative to dosing time) for DBP, SBP and PP [after 8 and 14 weeks]

3. Changes in the ABPM mean (relative to clock-time) for DBP, SBP and PP during the morning, daytime and night-time periods of the 24-hour dosing interval. [after 8 and 14 weeks]

4. Changes in SBP and DBP load during the 24-hour dosing interval [after 8 and 14 weeks]

5. Changes in mean seated trough DBP and SBP as measured by manual in-clinic cuff sphygmomanometer [after 8 and 14 weeks]

6. Responder rates based on both the 24-hour ABPM mean (relative to dose time) BPs and manual in-clinic trough cuff measurements [after 8 and 14 weeks]

7. Changes from baseline in patient Health Related Quality of Life (HRQL) as measured by Psychological General Wellbeing Index (PGWB). [week 8 and 14]

8. Manually triggered BP measurements before going to bed and upon arising in the morning [after 8 and 14 weeks]

9. Incidence of adverse events [up to 14 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Mild-to-moderate hypertension defined as a mean seated diastolic blood pressure of greater than or equal to 95 mmHg and less than or equal to 109 mmHg, measured by manual cuff sphygmomanometer at Visit 2.

2. 24-hour mean DBP of greater than or equal to 85 mmHg at Visit 3 as measured by ABPM.

3. Age 18 years or older.

4. Ability to stop any current antihypertensive therapy without risk to the patient (investigator's discretion).

5. Ability to provide written informed consent in accordance with GCP and local legislation.

Exclusion Criteria:

1. Pre-menopausal women (last menstruation approximately less than or equal to 1 year prior to signing informed consent) who:

• Are not surgically sterile

• Are nursing,

• Are of child-bearing potential and are NOT practicing acceptable methods of birth control, or do NOT plan to continue practicing an acceptable method throughout the study. Acceptable methods of birth control include intra uterine device, oral, implantable or injectable contraceptives.

1. Night shift workers who routinely sleep during the daytime and whose work hours include midnight to 4:00 A.M.

2. Mean sitting SBP greater than or equal to180 mmHg or mean sitting DBP greater than or equal to 110 mmHg during any visit of the placebo run-in period.

3. Known or suspected secondary hypertension (i.e., pheochromocytoma).

4. Hepatic and/or renal dysfunction as defined by the following laboratory parameters:

• SGPT (ALT) or SGOT (AST) > 2 times the upper limit of normal range.

• Serum creatinine > 2.3mg/dL (or > 203 micromol/l).

1. Bilateral renal artery stenosis, renal artery stenosis in a solitary kidney, post-renal transplant patients or patients with only one kidney.

2. Clinically relevant sodium depletion, hypokalaemia or hyperkalaemia.

3. Uncorrected volume depletion.

4. Primary aldosteronism.

5. Hereditary fructose intolerance.

6. Biliary obstructive disorders.

7. Congestive heart failure (NYHA functional class CHF III-IV).

8. Unstable angina within the past three months prior to start of run in period.

9. Stroke within the past six months prior to start of run in period.

10. Myocardial infarction or cardiac surgery within the past three months prior to start of run in period.

11. PTCA (percutaneous transluminal coronary angioplasty) within the past three months prior to start of run in period.

12. Sustained ventricular tachycardia, atrial fibrillation, atrial flutter or other clinically relevant cardiac arrhythmias as determined by the investigator.

13. Hypertrophic obstructive cardiomyopathy, aortic stenosis, haemodynamically relevant stenosis of the aortic or mitral valve.

14. Patients with insulin-dependent diabetes mellitus whose diabetes has not been stable and controlled for at least the past three months as defined by an HbA1C greater than or equal to 10%.

15. Patients who have previously experienced symptoms characteristic of angioedema during treatment with ACE inhibitors or angiotensin II receptor antagonists.

16. History of drug or alcohol dependency within 6 months prior to start of run in period.

17. Concomitant administration of any medications known to affect blood pressure, except medication allowed by the protocol.

18. Any investigational therapy within one month of start of run in period.

19. Known hypersensitivity to any component of the formulations.

20. Any clinical condition which, in the opinion of the investigator would not allow safe completion of the protocol and safe administration of trial medication.

21. Inability to comply with the protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rehabilitationszentrum für Herz- und Kreislauferkrankungen	Bad Tatzmannsdorf		Austria	7431
2	A.ö. Landeskrankenhaus Bruck a. d. Mur	Bruck a. d. Mur		Austria	8600
3	Landeskrankenhaus Graz West	Graz		Austria	8020
4	Medizinische Universitätsklinik Graz	Graz		Austria	8036
5	Landeskrankenhaus Villach	Villach		Austria	9500
6	Univ.-Klinik für Innere Medizin III	Wien		Austria	1090
7	Boehringer Ingelheim Investigational Site	Angers		France	49000
8	Boehringer Ingelheim Investigational Site	Angers		France	49100
9	Hôpital Saint André	Bordeaux cedex		France	33075
10	Boehringer Ingelheim Investigational Site	Laval		France	53000
11	Boehringer Ingelheim Investigational Site	Mayenne		France	53100
12	Boehringer Ingelheim Investigational Site	Saint Laurent du Medoc		France	33112
13	Boehringer Ingelheim Investigational Site	Saumur		France	49400
14	Boehringer Ingelheim Investigational Site	Gaggenau		Germany	76571
15	Boehringer Ingelheim Investigational Site	Haag		Germany	83527
16	Boehringer Ingelheim Investigational Site	Linkenheim-Hochstetten		Germany	76351
17	Boehringer Ingelheim Investigational Site	Mühldorf am Inn		Germany	84453
18	Boehringer Ingelheim Investigational Site	Plattling		Germany	94447
19	Boehringer Ingelheim Investigational Site	Unterschneidheim		Germany	73485
20	Boehringer Ingelheim Investigational Site	Villingen-Schwenningen		Germany	78054
21	Boehringer Ingelheim Investigational Site	Vilsbiburg		Germany	84137
22	Boehringer Ingelheim Investigational Site	Westerkappeln		Germany	49492
23	Boehringer Ingelheim Investigational Site	Bennebroek		Netherlands	2121 BB
24	Boehringer Ingelheim Investigational Site	Heerlen		Netherlands	6415 HT
25	Boehringer Ingelheim Investigational Site	Nijverdal		Netherlands	7441 BN
26	Boehringer Ingelheim Investigational Site	Rotterdam		Netherlands	3082 DC
27	Boehringer Ingelheim Investigational Site	Bellville		South Africa	7531
28	Health Emporium	Midrand		South Africa	1685
29	Boehringer Ingelheim Investigational Site	Vanderbijlpark		South Africa	1911
30	1 Military Hospital	Vootrekkehoogte		South Africa	0143
31	Boehringer Ingelheim Investigational Site	Barcelona		Spain	08003
32	Hospital de Galdakao	Galdakao / Vizcaya		Spain	48680
33	Pabellon de Consultas	Madrid		Spain	28007
34	Edificio de Consultas Externas	Oviedo		Spain	33006
35	Boehringer Ingelheim Investigational Site	Salamanca		Spain	37007
36	Centro de Diagnostico y Tratamiento	Sevilla		Spain	41013
37	Pabellon B / 1 piso	Sta Coloma de Gramanet		Spain	08923
38	Universitätsspital Basel	Basel		Switzerland	4031
39	Boehringer Ingelheim Investigational Site	Basel		Switzerland	4055
40	Schweizerisches Herz- und Gefässzentrum	Bern		Switzerland	3010
41	Cardiocentro Ticino	Lugano		Switzerland	6900
42	Boehringer Ingelheim Investigational Site	Muralto		Switzerland	6600
43	Boehringer Ingelheim Investigational Site	Münsterlingen		Switzerland	8596
44	Boehringer Ingelheim Investigational Site	Ashford		United Kingdom	TW15 3EA
45	Boehringer Ingelheim Investigational Site	Atherstone		United Kingdom	CV9 1EU
46	Boehringer Ingelheim Investigational Site	Bath		United Kingdom	BA2 3HAT
47	Boehringer Ingelheim Investigational Site	Bedworth		United Kingdom	CV6 4DD
48	Boehringer Ingelheim Investigational Site	Coventry		United Kingdom	CV7 8LA
49	Boehringer Ingelheim Investigational Site	Doncaster		United Kingdom	DN1 2EG
50	Boehringer Ingelheim Investigational Site	Fowey		United Kingdom	PL23 1DT
51	Boehringer Ingelheim Investigational Site	Frome		United Kingdom	BA11 2QE
52	Boehringer Ingelheim Investigational Site	Glasgow		United Kingdom	G69 7AD
53	Boehringer Ingelheim Investigational Site	Ilford		United Kingdom	IG3 8BG
54	Boehringer Ingelheim Investigational Site	Leamington Spa		United Kingdom	CV32 4RA
55	Boehringer Ingelheim Investigational Site	Lesley		United Kingdom	KY6 3LG
56	Boehringer Ingelheim Investigational Site	Lostwithiel		United Kingdom	PL22 0EF
57	Boehringer Ingelheim Investigational Site	Ryde		United Kingdom	PO33 2PT
58	Boehringer Ingelheim Investigational Site	Trowbridge		United Kingdom	BA14 7EG
59	Boehringer Ingelheim Investigational Site	Wells Next to the Sea		United Kingdom	NR23 1JP
60	Boehringer Ingelheim Investigational Site	Whitstable		United Kingdom	CT5 1BZ
61	Boehringer Ingelheim Investigational Site	Whitstable		United Kingdom	CT5 3QU
62	York District Hospital	York		United Kingdom	YO31 8HE

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim Study Coordinator, Boehringer Ingelheim Ltd./Bracknell

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info
• Related Info

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00274612
• Other Study ID Numbers: 502.391
• First Posted: Jan 11, 2006
• Last Update Posted: Nov 1, 2013
• Last Verified: Oct 1, 2013

• Additional relevant MeSH terms: Hypertension; Telmisartan; Ramipril

Study Results

No Results Posted as of Nov 1, 2013