Clinical Trial Results:
Multicenter, Open-Label, Long-Term Safety and Efficacy Study of the Fixed Dose Combination of Nifedipine Gastrointestinal Therapeutic System and Candesartan Cilexetil in Adult Subjects With Moderate to Severe Essential Hypertension
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Summary
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EudraCT number |
2012-004515-32 |
Trial protocol |
DE GB PL |
Global end of trial date |
01 May 2014
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Results information
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Results version number |
v2(current) |
This version publication date |
04 Sep 2016
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First version publication date |
20 Jun 2015
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
BAY98-7106/14801
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01788358 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Bayer AG
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Sponsor organisation address |
Kaiser-Wilhelm-Allee, D-51368, Leverkusen, Germany,
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Public contact |
Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
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Scientific contact |
Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 May 2014
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
01 May 2014
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective was to evaluate the long-term safety and tolerability of Fixed Dose Combination (FDC) of Nifedipine Gastrointestinal Therapeutic System (GITS) / candesartan cilexetil (primarily the highest dose) once daily in subjects with moderate to severe essential hypertension.
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Protection of trial subjects |
The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
14 Feb 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 48
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Country: Number of subjects enrolled |
United States: 277
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Country: Number of subjects enrolled |
United Kingdom: 98
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Country: Number of subjects enrolled |
Canada: 85
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Worldwide total number of subjects |
508
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EEA total number of subjects |
146
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
346
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From 65 to 84 years |
162
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at 70 study centers between 14 February 2013 (first subject first visit) and 1 May 2014 (last subject last visit). | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Of 753 subjects screened, 245 subjects were not enrolled, due to screen failure for 215 subjects, consent withdrawal by 23 subjects, protocol violation by 5 subjects, 1 subject was lost to follow-up and recruitment stopped for 1 subject. Remaining 508 subjects were enrolled and received at least 1 treatment with study drug. | ||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||
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Arms
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Arm title
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Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | ||||||||||||||||||||||||||||||
Arm description |
Subjects received nifedipine GITS/candesartan cilexetil FDC (BAY98-7106) tablet orally, once daily in the morning of Visit 1 (Week 0) for 28 or 52 weeks. The starting dose (30/8 milligram [mg] or 30/16 mg) was determined based on local practice and clinical judgment by the investigator. Based on the experience of symptomatic and asymptomatic hypotension, peripheral edema or significant tolerability, the doses were up-titrated to the highest target dose (60/32 mg). | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Nifedipine gastrointestinal therapeutic system (GITS)/Candesartan cilexetil fixed dose combination (FDC)
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Investigational medicinal product code |
BAY98-7106
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received nifedipine GITS/candesartan cilexetil FDC (BAY98-7106) tablet orally, once daily in the morning of Visit 1 (Week 0) for 28 or 52 weeks. The starting dose (30/8 mg or 30/16 mg) was determined based on local practice and clinical judgment by the investigator. Based on the experience of symptomatic and asymptomatic hypotension, peripheral edema or significant tolerability, the doses were up-titrated to the highest target dose (60/32 mg).
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| Notes [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: As planned, only the first 200 subjects who completed Week 28 visit, continued treatment up to 52 weeks. Hence, the number of subjects at this milestone seems inconsistent with the number of subjects in the arm. [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Of the first 200 subjects who entered Week 52 visit, 193 completed and the remaining 7 subjects did not complete due to consent withdrawal by 2 subjects, 1 subject lost to follow up and 4 subjects due to other reasons. Hence, the number of subjects at this milestone seems inconsistent with the number of subjects in the arm. |
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Baseline characteristics reporting groups
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Reporting group title |
Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106)
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Reporting group description |
Subjects received nifedipine GITS/candesartan cilexetil FDC (BAY98-7106) tablet orally, once daily in the morning of Visit 1 (Week 0) for 28 or 52 weeks. The starting dose (30/8 milligram [mg] or 30/16 mg) was determined based on local practice and clinical judgment by the investigator. Based on the experience of symptomatic and asymptomatic hypotension, peripheral edema or significant tolerability, the doses were up-titrated to the highest target dose (60/32 mg). | |||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106)
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Reporting group description |
Subjects received nifedipine GITS/candesartan cilexetil FDC (BAY98-7106) tablet orally, once daily in the morning of Visit 1 (Week 0) for 28 or 52 weeks. The starting dose (30/8 milligram [mg] or 30/16 mg) was determined based on local practice and clinical judgment by the investigator. Based on the experience of symptomatic and asymptomatic hypotension, peripheral edema or significant tolerability, the doses were up-titrated to the highest target dose (60/32 mg). | ||
Subject analysis set title |
Modified intention-to-treat analysis set (mITT)
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
mITT set (N=508) included all the subjects enrolled into the open-label treatment period and took at least one unit of the study medication.
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Subject analysis set title |
Safety analysis set (SAF)
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
SAF (N=508) was the same as the mITT analysis set which was defined as all the subjects enrolled into the open-label treatment period and took at least one unit of the study medication.
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End point title |
Number of Subjects With All Treatment-emergent Adverse Events (TEAEs) and Drug-related TEAEs up to Week 28 [1] | ||||||||||
End point description |
An adverse event (AE) is any untoward medical occurrence (that is, any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they had started or worsened after first application of study medication.
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End point type |
Primary
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End point timeframe |
From the time of first study drug administration up to Week 28
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were done, no inferential statistical analyses were performed. |
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| Notes [2] - SAF |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Number of Subjects With Treatment-emergent Adverse Events (TEAEs) of Special Interest up to Week 28 [3] | ||||||||||||||||||||
End point description |
An AE is any untoward medical occurrence (that is, any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they had started or worsened after first application of study medication. TEAEs of special interest included the incidence of symptomatic hypotension and the incidence and severity of vasodilatory adverse events (such as oedema, headache, and flushing). Only subjects who had TEAEs of special interest as mild, moderate or severe were reported.
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End point type |
Primary
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End point timeframe |
From the time of first study drug administration up to Week 28
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were done, no inferential statistical analyses were performed. |
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| Notes [4] - SAF |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Number of Subjects With All Treatment-emergent Adverse Events (TEAEs) and Drug-related TEAEs up to Week 52/End of Study (EOS) [5] | ||||||||||
End point description |
An AE is any untoward medical occurrence (that is, any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they had started or worsened after first application of study medication.
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End point type |
Primary
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End point timeframe |
From the time of first study drug administration up to Week 52/EOS
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were done, no inferential statistical analyses were performed. |
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| Notes [6] - SAF |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Number of Subjects With Treatment-emergent Adverse Events (TEAEs) of Special Interest up to Week 52/End of Study (EOS) [7] | ||||||||||||||||||||
End point description |
An AE is any untoward medical occurrence (that is, any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they had started or worsened after first application of study medication. TEAEs of special interest included the incidence of symptomatic hypotension and the incidence and severity of vasodilatory adverse events (such as oedema, headache, and flushing). Only subjects who had TEAEs of special interest as mild, moderate or severe were reported.
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End point type |
Primary
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End point timeframe |
From the time of study treatment up to Week 52/EOS
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were done, no inferential statistical analyses were performed. |
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| Notes [8] - SAF |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Number of Subjects With Clinically Relevant Changes in Laboratory Parameters | ||||||
End point description |
Laboratory evaluations of blood and urine samples were performed, including hematology (hematocrit, hemoglobin, red blood cells count, white blood cells count, neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelets), blood chemistry (sodium, potassium, chloride, bicarbonate, uric acid, total protein, albumin, calcium, blood urea nitrogen, creatinine, aspartate transaminase, alanine transaminase, lactate dehydrogenase, gamma glutamyl transferase, alkaline phosphatase, creatine kinase, total bilirubin, direct bilirubin, total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides, fasting glucose), urinalysis (pH, blood, specific gravity, glucose, protein, cells/sediment). A laboratory test abnormality considered clinically relevant, for example, causing withdrawal by subject, requiring treatment or causing apparent clinical manifestations, or judged relevant by the investigator, were reported as AEs.
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End point type |
Secondary
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End point timeframe |
Baseline (Week 0) up to Week 52/EOS
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| Notes [9] - SAF |
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| No statistical analyses for this end point | |||||||
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End point title |
Change From Baseline In Mean Seated Systolic Blood Pressure (MSSBP) At Weeks 28 And 52 | ||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline (Week 0), Weeks 28 and 52
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| Notes [10] - mITT |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Change From Baseline in Mean Seated Diastolic Blood Pressure (MSDBP) at Weeks 28 and 52 | ||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Baseline (Week 0), Weeks 28 and 52
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| Notes [11] - mITT |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Blood Pressure Control Rate at Weeks 28 and 52 | ||||||||||||
End point description |
Control rate was defined as the percentage of subjects that reached a predetermined blood pressure (BP) target of BP less than (<) 140/90 mmHg.
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End point type |
Secondary
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End point timeframe |
Weeks 28 and 52
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| Notes [12] - mITT |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Blood Pressure Response Rate at Weeks 28 and 52 | ||||||||||||
End point description |
Response rate was defined as the percentage of subjects who achieved a systolic blood pressure response (MSSBP of <140 mmHg or a reduction of MSSBP of more than (>) 20 mmHg from baseline value), or a diastolic blood pressure response (MSDBP of <90 mmHg or a reduction of MSDBP of >10 mmHg from baseline value).
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End point type |
Secondary
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End point timeframe |
Weeks 28 and 52
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| Notes [13] - mITT |
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
TEAEs were collected from the time of first study drug administration up to 7 days after Week 52/EOS
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Adverse event reporting additional description |
One death reported under SAE happened approximately 6 months after the subject had completed the study, not related to the treatment.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.0
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Reporting groups
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Reporting group title |
Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106)
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Reporting group description |
Subjects received nifedipine GITS/candesartan cilexetil FDC (BAY98-7106) tablet orally, once daily in the morning of Visit 1 (Week 0) for 28 or 52 weeks. The starting dose (30/8 mg or 30/16 mg) was determined based on local practice and clinical judgment by the investigator. Based on the experience of symptomatic and asymptomatic hypotension, peripheral edema or significant tolerability, the doses were up-titrated to the highest target dose (60/32 mg). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 3% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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04 Jul 2013 |
This amendment was globally implemented to mainly address questions and comments from regulatory agencies at a scientific advice meeting. This amendment included the addition of blood pressure measurement, updates to the statistical analysis method, updates on pharmacokinetic analysis information, and several clarifications on the renal impairment and estimated glomerular filtration rate calculation. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
