Nifedipine (Adalat CR, BAY A1040) High Dose PK/PD Study

Evaluation of the Efficacy, Safety, and Pharmacokinetics/Pharmacodynamics of BAY A1040 CR Tablet on High Dose Administration in Patients With Essential Hypertension.

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00768560

Enrollment

Registered

2008-10-08

Start date

2008-01-31

Completion date

2008-05-31

Last updated

2015-06-08

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hypertension

Brief summary

This is a multi-center, randomized, double-blind, 6 x 3 cross-over study. All patients who meet the entry criteria will be required to stop taking any other anti-hypertensive agents than Adalat CR (controlled release), if taken, before starting 4 weeks (±7days) open-label Adalat CR 40 mg once daily (OD) treatment phase (baseline treatment period). Of them, those who are confirmed with their eligibility as subjects for the present study at the end of the baseline treatment period will be randomly allocated to one of the 6 treatment sequences on the basis of a computer-generated randomization list. Subsequently, BAY A1040 CR tablet 40 mg OD, 40 mg twice daily (BID) or 80 mg OD will be administered to a total of 6 weeks, 2 weeks per each treatment period (Period 1-3) under double-blind conditions using BAY A1040 CR tablet 40 mg and its placebo as follows (Double-blind treatment period).

Detailed description

Issues on safety are addressed in the Adverse Event section.

Interventions

DRUGNifedipine (Adalat CR, BAYA1040) 80mg OD

Nifedipine (Adalat CR, BAYA1040) 80 milligram (mg) once daily (OD) in the morning

DRUGNifedipine (Adalat CR, BAYA1040) 40mg BID

Nifedipine (Adalat CR, BAYA1040) 40 milligram (mg) twice daily (BID). 40 mg in the morning and 40 mg in the evening

DRUGNifedipine (Adalat CR, BAYA1040) 40mg OD

Nifedipine (Adalat CR, BAYA1040) 40 milligram (mg) once daily (OD) in the morning

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

20 Years to 75 Years

Healthy volunteers

Inclusion criteria

* Male and female * 20 years or older and less than 75 years * Outpatient * Untreated or treated patients with antihypertensive agents whose blood pressure (BP) in sitting position at entry (Visit 1) is as follows. * Untreated patients: systolic blood pressure (SBP) \>= 160mmHg or diastolic blood pressure (DBP) \>= 100mmHg * Treated patients: SBP \>= 140mmHg or DBP \>= 90mmHg (at trough)

Exclusion criteria

* Patients whose BP during baseline treatment period is: SBP\>=200mmHg or DBP\>=120mmHg. * Patients with secondary hypertension or hypertensive emergency. * Patients with cardiovascular or cerebrovascular ischemic event (stroke, transient ischemic attack (TIA), myocardial infarction or unstable angina), or with history of these within 6 months prior to the study. * Patients with intracranial or subarachnoid hemorrhage, or with history of these within 6 months prior to the study. * Patients with server hematopoietic dysfunction (acute/chronic leukemia, myeloma, malignant lymphoma, myelodysplastic syndrome, aplastic anemia), or with history of these.

Design outcomes

Primary

Measure	Time frame	Description
Change of Sitting Blood Pressure	Baseline and after 2 weeks treatment	Changes of sitting SBP and DBP (trough values) from baseline (ie \[trough BP at the end of each period during the double-blind treatment period\] minus \[trough BP at the end of the baseline treatment period\])

Secondary

Measure	Time frame	Description
Differences of Diastolic Blood Pressure Profile	Baseline and after 2 weeks treatment	Differences in blood pressure at the same time points (0, 2, 4, 6, 8, 10, 12, 24-hour post-dose) between 2 different days (ie, end of baseline treatment period and end of 2-week treatment period)
Target Blood Pressure Achievement in Elderly (≥65)	After 2 weeks treatment	Elderly subjects (≥65 years) without diabetes mellitus or chronic renal disorders and target BP SBP \<140 mm Hg and DBP \<90 mm Hg
Differences of Systolic Blood Pressure Profile	Baseline and after 2 weeks treatment	Differences in blood pressure at the same time points (0, 2, 4, 6, 8, 10, 12, 24-hour post-dose) between 2 different days (ie, end of baseline treatment period and end of 2-week treatment period)
Target Blood Pressure Achievement in Subjects With Diabetes Mellitus or Chronic Renal Disorder	After 2 weeks treatment	Subjects with diabetes mellitus or chronic renal disorders and target BP SBP \<130 mm Hg and DBP \<80 mm Hg
Target Blood Pressure Achievement in All Subjects	After 2 weeks treatment	Subjects (≥65 years) without diabetes mellitus or chronic renal disorders and target BP SBP \<140 mm Hg and DBP \<90 mm Hg. Subjects (\<65 years) without diabetes mellitus or chronic renal disorder and target BP SBP \<130 mm Hg and DBP \<85 mm Hg. Subjects with diabetes mellitus or chronic renal disorders and target BP SBP \<130 mm Hg and DBP \<80 mm Hg.
Target Blood Pressure Achievement in Non-elderly (<65)	After 2 weeks treatment	Non-elderly subjects (\<65 years) without diabetes mellitus or chronic renal disorder and target BP SBP \<130 mm Hg and DBP \<85 mm Hg

Countries

Japan

Participant flow

Recruitment details

47 subjects were recruited from 30 Jan 2008 to 11 May 2008 by 3 centers in Japan.

Pre-assignment details

After a 4-week baseline treatment with Adalat controlled release (CR) 40 mg once daily (OD), 35 subjects were randomized to double-blind treatment and were included in the safety analysis. 34 subjects were included in the analysis of pharmacokinetics, efficacy and demographic data. 1 subject discontinued the study in Period 1 due to adverse event.

Participants by arm

Arm	Count
Nifedipine 40 mg OD x 40 mg BID x 80 mg OD for 2 Weeks Each	5
Nifedipine 40 mg OD x 80 mg OD x 40 mg BID for 2 Weeks Each	5
Nifedipine 40 mg BID x 80 mg OD x 40 mg OD for 2 Weeks Each	6
Nifedipine 40 mg BID x 40 mg OD x 80 mg OD for 2 Weeks Each	6
Nifedipine 80 mg OD x 40 mg OD x 40 mg BID for 2 Weeks Each	6
Nifedipine 80 mg OD x 40 mg BID x 40 mg OD for 2 Weeks Each	6
Total	34

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005
Intervention Set 1	Adverse Event	0	1	0	0	0	0

Baseline characteristics

Characteristic	Nifedipine 40 mg OD x 40 mg BID x 80 mg OD for 2 Weeks Each	Nifedipine 40 mg OD x 80 mg OD x 40 mg BID for 2 Weeks Each	Nifedipine 40 mg BID x 80 mg OD x 40 mg OD for 2 Weeks Each	Nifedipine 40 mg BID x 40 mg OD x 80 mg OD for 2 Weeks Each	Nifedipine 80 mg OD x 40 mg OD x 40 mg BID for 2 Weeks Each	Nifedipine 80 mg OD x 40 mg BID x 40 mg OD for 2 Weeks Each	Total
Age, Continuous	61.4 years	63.6 years	59.7 years	64.3 years	58.2 years	59.7 years	61.1 years
Blood Pressure (Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)) at Baseline DBP at baseline	94.40 mm Hg STANDARD_DEVIATION 4.98	95.00 mm Hg STANDARD_DEVIATION 6.6	98.00 mm Hg STANDARD_DEVIATION 6.45	91.00 mm Hg STANDARD_DEVIATION 7.07	92.50 mm Hg STANDARD_DEVIATION 3.45	89.83 mm Hg STANDARD_DEVIATION 7.68	93.43 mm Hg STANDARD_DEVIATION 6.4
Blood Pressure (Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)) at Baseline SBP at baseline	150.00 mm Hg STANDARD_DEVIATION 7.91	161.00 mm Hg STANDARD_DEVIATION 16.67	156.33 mm Hg STANDARD_DEVIATION 11.18	155.83 mm Hg STANDARD_DEVIATION 10.96	156.33 mm Hg STANDARD_DEVIATION 14.79	154.83 mm Hg STANDARD_DEVIATION 13.53	155.89 mm Hg STANDARD_DEVIATION 12.38
Heart rate (HR) at Baseline	64.20 beats / min STANDARD_DEVIATION 6.18	72.67 beats / min STANDARD_DEVIATION 13.95	79.00 beats / min STANDARD_DEVIATION 10.81	70.83 beats / min STANDARD_DEVIATION 5.42	68.50 beats / min STANDARD_DEVIATION 7.87	79.50 beats / min STANDARD_DEVIATION 17.84	72.69 beats / min STANDARD_DEVIATION 11.83
Sex: Female, Male Female	1 Participants	3 Participants	0 Participants	2 Participants	1 Participants	1 Participants	8 Participants
Sex: Female, Male Male	4 Participants	2 Participants	6 Participants	4 Participants	5 Participants	5 Participants	26 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	5 / 35	7 / 34	5 / 34
serious Total, serious adverse events	0 / 35	0 / 34	0 / 34

Outcome results

Primary

Change of Sitting Blood Pressure

Changes of sitting SBP and DBP (trough values) from baseline (ie \[trough BP at the end of each period during the double-blind treatment period\] minus \[trough BP at the end of the baseline treatment period\])

Time frame: Baseline and after 2 weeks treatment

Population: Per-protocol efficacy population: subjects valid for safety analysis who have no critical protocol deviation and have trough BP at the end of baseline treatment period and trough BP at the end of period 1 are considered valid for the analysis.

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Nifedipine (Adalat CR, BAYA1040) 40 mg OD	Change of Sitting Blood Pressure	Systolic Blood Pressure	-10.19 mm Hg	Standard Error 1.24
Nifedipine (Adalat CR, BAYA1040) 40 mg OD	Change of Sitting Blood Pressure	Diastolic Blood Pressure	-4.30 mm Hg	Standard Error 0.65
Nifedipine (Adalat CR, BAYA1040) 40 mg BID	Change of Sitting Blood Pressure	Systolic Blood Pressure	-19.88 mm Hg	Standard Error 1.24
Nifedipine (Adalat CR, BAYA1040) 40 mg BID	Change of Sitting Blood Pressure	Diastolic Blood Pressure	-8.28 mm Hg	Standard Error 0.65
Nifedipine (Adalat CR, BAYA1040) 80 mg OD	Change of Sitting Blood Pressure	Systolic Blood Pressure	-10.13 mm Hg	Standard Error 1.24
Nifedipine (Adalat CR, BAYA1040) 80 mg OD	Change of Sitting Blood Pressure	Diastolic Blood Pressure	-4.98 mm Hg	Standard Error 0.65

Comparison: The point estimate and 90% confidence interval of the difference of changes in SBP from baseline was estimated by using the analysis of variance (ANOVA) model including the terms: group, subject within a group, dosage and administration and stage as fixed effects.90% CI: [-12.62, -6.77]

Comparison: The point estimate and 90% confidence interval of the difference of changes in SBP from baseline was estimated by using the ANOVA model including the terms: group, subject within a group, dosage and administration and stage as fixed effects.90% CI: [-2.87, 2.98]

Comparison: The point estimate and 90% confidence interval of the difference of changes in DBP from baseline was estimated by using the ANOVA model including the terms: group, subject within a group, dosage and administration and stage as fixed effects.90% CI: [-5.5, -2.44]

Secondary

Differences of Diastolic Blood Pressure Profile

Differences in blood pressure at the same time points (0, 2, 4, 6, 8, 10, 12, 24-hour post-dose) between 2 different days (ie, end of baseline treatment period and end of 2-week treatment period)

Time frame: Baseline and after 2 weeks treatment