Trial Outcomes & Findings for Evaluation of Succinate Metoprolol on Heart Rate in the Stable Angina Patients (NCT NCT01213173)

NCT ID: NCT01213173

Last Updated: 2014-09-05

Results Overview

Difference of the 24-hr average heart rate between two groups after 8 weeks treatment.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 251 participants
• Primary outcome timeframe: After 8 weeks treatment in the study
• Results posted on: 2014-09-05

Participant Flow

Safety Population is divided according to the actual dosage received by the patient, not the randomization. The patient will be high-dose group if the highest dose ever used is above 95mg; otherwise (if the highest dose ever used is equal to or lower than 95 mg) he/she will be low-dose group.

Safety population- patients who received at least 1 dose of investigational product. During initial 1 week run-in period subjects were treated with 47.5mg Betaloc ZOK®. Patients started to take investigational product before randomization therefore, number of subjects in Safety population (274) is greater than number of randomized and treated (251)

Participant milestones

Measure	Active Comparator lead Electrocardiogram at Week 3, the dosage will be titrated to 95mg and last for another 6 weeks	Experimental lead Electrocardiogram at Week 3，the dosage will be force titrated to 190mg and last for another 6 weeks
Overall Study STARTED	125	126
Overall Study Patients Included in Safety Population	139	112
Overall Study Patients Included in ITT Population	116	115
Overall Study Patients Included in PP Population	102	89
Overall Study COMPLETED	113	110
Overall Study NOT COMPLETED	12	16

Reasons for withdrawal

Measure	Active Comparator lead Electrocardiogram at Week 3, the dosage will be titrated to 95mg and last for another 6 weeks	Experimental lead Electrocardiogram at Week 3，the dosage will be force titrated to 190mg and last for another 6 weeks
Overall Study Protocol Violation	2	0
Overall Study Adverse Event	4	8
Overall Study Withdrawal by Subject	5	5
Overall Study Incorrect Enrollment	1	3

Baseline Characteristics

Evaluation of Succinate Metoprolol on Heart Rate in the Stable Angina Patients

Baseline characteristics by cohort

Measure	Active Comparator n=116 Participants lead Electrocardiogram at Week 3, the dosage will be titrated to 95mg and last for another 6 weeks	Experimental n=115 Participants lead Electrocardiogram at Week 3，the dosage will be force titrated to 190mg and last for another 6 weeks	Total n=231 Participants Total of all reporting groups
Age, Continuous	59.3 Year STANDARD_DEVIATION 7.81 • n=5 Participants	59.2 Year STANDARD_DEVIATION 9.25 • n=7 Participants	59.2 Year STANDARD_DEVIATION 8.53 • n=5 Participants
Sex: Female, Male Female	74 Participants n=5 Participants	81 Participants n=7 Participants	155 Participants n=5 Participants
Sex: Female, Male Male	42 Participants n=5 Participants	34 Participants n=7 Participants	76 Participants n=5 Participants

PRIMARY outcome

Timeframe: After 8 weeks treatment in the study

Population: ITT population was defined as all randomized subjects who had taken at least one dose of trial treatment, who had measurements at baseline for one or more efficacy variables and at least one post baseline measurement for the same variables in the treatment period.

Difference of the 24-hr average heart rate between two groups after 8 weeks treatment.

Outcome measures

Measure	Arm 1 - Active Comparator n=116 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 47.5mg for two weeks, if tolerated and without Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3, the dosage will be titrated to 95mg and last for another 6 weeks	Arm 2 - Experimental n=115 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 95mg for two weeks, and if tolerated and without bradycardia symptoms presented, Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3，the dosage will be force titrated to 190mg and last for another 6 weeks
The Impact on 24-hr Average Heart Rate Between Two Groups (Betaloc ZOK® 95mg vs. 190mg) Week 9	70.9 Bpm Standard Deviation 8.71	68.6 Bpm Standard Deviation 8.40
The Impact on 24-hr Average Heart Rate Between Two Groups (Betaloc ZOK® 95mg vs. 190mg) Baseline	71.4 Bpm Standard Deviation 8.02	70.9 Bpm Standard Deviation 8.19

SECONDARY outcome

Timeframe: After 8 weeks treatment in the study

Population: ITT population was defined as all randomized subjects who had taken at least one dose of trial treatment, who had measurements at baseline for one or more efficacy variables and at least one post baseline measurement for the same variables in the treatment period.

Difference of the 24-hr average heart rate within groups from baseline after 8 weeks treatment.

Outcome measures

Measure	Arm 1 - Active Comparator n=116 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 47.5mg for two weeks, if tolerated and without Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3, the dosage will be titrated to 95mg and last for another 6 weeks	Arm 2 - Experimental n=115 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 95mg for two weeks, and if tolerated and without bradycardia symptoms presented, Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3，the dosage will be force titrated to 190mg and last for another 6 weeks
The Impact on 24-hr Average Heart Rate From Baseline Within Groups	-0.6244 Bpm 95% Confidence Interval 7.16 • Interval -1.94 to 0.69	-2.9858 Bpm 95% Confidence Interval 6.62 • Interval -4.23 to -1.75

SECONDARY outcome

Timeframe: After 2 weeks treatment in the study

Population: ITT population was defined as all randomized subjects who had taken at least one dose of trial treatment, who had measurements at baseline for one or more efficacy variables and at least one post baseline measurement for the same variables in the treatment period.

Difference of the 24-hr average heart rate between two groups after 2 weeks of treatment.

Outcome measures

Measure	Arm 1 - Active Comparator n=116 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 47.5mg for two weeks, if tolerated and without Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3, the dosage will be titrated to 95mg and last for another 6 weeks	Arm 2 - Experimental n=115 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 95mg for two weeks, and if tolerated and without bradycardia symptoms presented, Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3，the dosage will be force titrated to 190mg and last for another 6 weeks
The Different Impact on 24-hr Average Heart Rate Between Two Groups	70.6 Bpm Standard Deviation 7.75	69.2 Bpm Standard Deviation 7.82

SECONDARY outcome

Timeframe: After 2 weeks treatment in the study

Population: ITT population was defined as all randomized subjects who had taken at least one dose of trial treatment, who had measurements at baseline for one or more efficacy variables and at least one post baseline measurement for the same variables in the treatment period.

Difference of the 24-hr average heart rate within groups from baseline after 2 weeks treatment.

Outcome measures

Measure	Arm 1 - Active Comparator n=116 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 47.5mg for two weeks, if tolerated and without Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3, the dosage will be titrated to 95mg and last for another 6 weeks	Arm 2 - Experimental n=115 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 95mg for two weeks, and if tolerated and without bradycardia symptoms presented, Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3，the dosage will be force titrated to 190mg and last for another 6 weeks
The Different Impact on 24-hr Average Heart Rate From Baseline Within Groups	-0.4938 Bpm 95% Confidence Interval 4.69 • Interval -1.4 to 0.41	-2.1383 Bpm 95% Confidence Interval 5.71 • Interval -3.18 to -1.1

SECONDARY outcome

Timeframe: After 2 weeks treatment

Population: ITT population was defined as all randomized subjects who had taken at least one dose of trial treatment, who had measurements at baseline for one or more efficacy variables and at least one post baseline measurement for the same variables in the treatment period.

Difference in proportions of patients who had resting heart rate controlled to ≤60 bpm after 2 weeks treatment between groups

Outcome measures

Measure	Arm 1 - Active Comparator n=116 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 47.5mg for two weeks, if tolerated and without Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3, the dosage will be titrated to 95mg and last for another 6 weeks	Arm 2 - Experimental n=115 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 95mg for two weeks, and if tolerated and without bradycardia symptoms presented, Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3，the dosage will be force titrated to 190mg and last for another 6 weeks
The Proportion of Patients With Resting Heart Rate Controlled to ≤60bpm Between Groups	25 Participants	28 Participants

SECONDARY outcome

Timeframe: After 8 weeks treatment

Population: ITT population was defined as all randomized subjects who had taken at least one dose of trial treatment, who had measurements at baseline for one or more efficacy variables and at least one post baseline measurement for the same variables in the treatment period.

Difference in proportions of patients who had resting heart rate controlled to ≤60 bpm after 8 weeks treatment between groups

Outcome measures

Measure	Arm 1 - Active Comparator n=116 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 47.5mg for two weeks, if tolerated and without Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3, the dosage will be titrated to 95mg and last for another 6 weeks	Arm 2 - Experimental n=115 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 95mg for two weeks, and if tolerated and without bradycardia symptoms presented, Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3，the dosage will be force titrated to 190mg and last for another 6 weeks
The Proportion of Patients With Resting Heart Rate Controlled to ≤60bpm Between Groups	28 Participants	46 Participants

SECONDARY outcome

Timeframe: After 2 weeks treatment

Population: ITT population was defined as all randomized subjects who had taken at least one dose of trial treatment, who had measurements at baseline for one or more efficacy variables and at least one post baseline measurement for the same variables in the treatment period.

Difference in change from baseline in TIB between two groups after 2 weeks treatment.

Total Ischemic Burden (TIB) was defined as the sum of product of each ischemia episode lasting time and maximal ST elevation: TIB=Σ(STmax×Tisc).

Outcome measures

Measure	Arm 1 - Active Comparator n=116 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 47.5mg for two weeks, if tolerated and without Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3, the dosage will be titrated to 95mg and last for another 6 weeks	Arm 2 - Experimental n=115 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 95mg for two weeks, and if tolerated and without bradycardia symptoms presented, Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3，the dosage will be force titrated to 190mg and last for another 6 weeks
The Difference of Change From Baseline in Total Ischemic Burden Between Groups	-5.3353 mm*min 95% Confidence Interval 69.0874 • Interval -15.1422 to 4.4716	-12.9874 mm*min 95% Confidence Interval 66.3041 • Interval -20.8416 to 5.1332

SECONDARY outcome

Timeframe: After 8 weeks treatment

Population: ITT population was defined as all randomized subjects who had taken at least one dose of trial treatment, who had measurements at baseline for one or more efficacy variables and at least one post baseline measurement for the same variables in the treatment period.

Difference in change from baseline in TIB between two groups after 8 weeks treatment.

Total Ischemic Burden (TIB) was defined as the sum of product of each ischemia episode lasting time and maximal ST elevation: TIB=Σ(STmax×Tisc).

Outcome measures

Measure	Arm 1 - Active Comparator n=116 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 47.5mg for two weeks, if tolerated and without Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3, the dosage will be titrated to 95mg and last for another 6 weeks	Arm 2 - Experimental n=115 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 95mg for two weeks, and if tolerated and without bradycardia symptoms presented, Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3，the dosage will be force titrated to 190mg and last for another 6 weeks
The Difference of Change From Baseline in Total Ischemic Burden Between Groups	22.2905 mm*min 95% Confidence Interval 112.1215 • Interval -14.3181 to 58.8992	-7.6586 mm*min 95% Confidence Interval 79.1887 • Interval -18.6777 to 3.3604

SECONDARY outcome

Timeframe: After 2 weeks treatment

Population: ITT population was defined as all randomized subjects who had taken at least one dose of trial treatment, who had measurements at baseline for one or more efficacy variables and at least one post baseline measurement for the same variables in the treatment period.

Difference in change from baseline of angina pectoris frequency between two groups after 2 weeks treatment.

Outcome measures

Measure	Arm 1 - Active Comparator n=116 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 47.5mg for two weeks, if tolerated and without Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3, the dosage will be titrated to 95mg and last for another 6 weeks	Arm 2 - Experimental n=115 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 95mg for two weeks, and if tolerated and without bradycardia symptoms presented, Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3，the dosage will be force titrated to 190mg and last for another 6 weeks
The Difference of Change From Baseline in Angina Frequency Between Groups	-0.044 Attacks per week Interval -0.4 to 0.31	-0.3243 Attacks per week Interval -0.55 to -0.1

SECONDARY outcome

Timeframe: After 8 weeks treatment

Population: ITT population was defined as all randomized subjects who had taken at least one dose of trial treatment, who had measurements at baseline for one or more efficacy variables and at least one post baseline measurement for the same variables in the treatment period.

Difference in change from baseline of angina pectoris frequency between two groups after 8 weeks treatment.

Outcome measures

Measure	Arm 1 - Active Comparator n=116 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 47.5mg for two weeks, if tolerated and without Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3, the dosage will be titrated to 95mg and last for another 6 weeks	Arm 2 - Experimental n=115 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 95mg for two weeks, and if tolerated and without bradycardia symptoms presented, Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3，the dosage will be force titrated to 190mg and last for another 6 weeks
The Difference of Change From Baseline in Angina Frequency Between Groups	-0.3930 Attacks per week Interval -0.64 to -0.14	-0.4453 Attacks per week Interval -0.71 to -0.18

SECONDARY outcome

Timeframe: After 8 weeks treatment

Population: All subjects who received at least one dose of randomized investigational product was included in the safety population.

Difference of change from baseline in TC after 8 weeks treatment between groups.

Outcome measures

Measure	Arm 1 - Active Comparator n=139 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 47.5mg for two weeks, if tolerated and without Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3, the dosage will be titrated to 95mg and last for another 6 weeks	Arm 2 - Experimental n=112 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 95mg for two weeks, and if tolerated and without bradycardia symptoms presented, Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3，the dosage will be force titrated to 190mg and last for another 6 weeks
The Change From Baseline in Total Cholesterol	-0.0505 mmol/L 95% Confidence Interval 0.8949 • Interval -0.711 to 0.6101	0.5825 mmol/L 95% Confidence Interval 4.6175 • Interval -0.1029 to 1.2678

SECONDARY outcome

Timeframe: After 8 weeks treatment

Population: All subjects who received at least one dose of randomized investigational product was included in the safety population.

Difference of change from baseline in FPG after 8 weeks treatment between groups.

Outcome measures

Measure	Arm 1 - Active Comparator n=139 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 47.5mg for two weeks, if tolerated and without Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3, the dosage will be titrated to 95mg and last for another 6 weeks	Arm 2 - Experimental n=112 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 95mg for two weeks, and if tolerated and without bradycardia symptoms presented, Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3，the dosage will be force titrated to 190mg and last for another 6 weeks
The Change From Baseline in Fasting Plasma Glucose	0.3844 mmol/L 95% Confidence Interval 1.7130 • Interval -0.1127 to 0.656	0.2487 mmol/L 95% Confidence Interval 0.8809 • Interval -0.0344 to 0.5318

SECONDARY outcome

Timeframe: After 8 weeks treatment

Population: All subjects who received at least one dose of randomized investigational product was included in the safety population.

Difference of change from baseline in TG after 8 weeks treatment between groups.

Outcome measures

Measure	Arm 1 - Active Comparator n=139 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 47.5mg for two weeks, if tolerated and without Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3, the dosage will be titrated to 95mg and last for another 6 weeks	Arm 2 - Experimental n=112 Participants Drug: Succinate Metoprolol (Betaloc ZOK®) Treatment with 95mg for two weeks, and if tolerated and without bradycardia symptoms presented, Systolic blood pressure\<100mmHg and heart rate \<45 bpm according to 12-lead Electrocardiogram at Week 3，the dosage will be force titrated to 190mg and last for another 6 weeks
The Change From Baseline in Triglycerides	0.1295 mmol/L 95% Confidence Interval 0.7607 • Interval -0.0375 to 0.2965	0.0937 mmol/L 95% Confidence Interval 1.1520 • Interval -0.081 to 0.2683

Adverse Events

Active Comparator

Serious events: 1 serious events

Other events: 0 other events

Deaths: 0 deaths

Experimental

Serious events: 3 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Measure	Active Comparator n=139 participants at risk lead Electrocardiogram at Week 3, the dosage will be titrated to 95mg and last for another 6 weeks	Experimental n=112 participants at risk lead Electrocardiogram at Week 3，the dosage will be force titrated to 190mg and last for another 6 weeks
Nervous system disorders VIIth nerve paralysis	0.72% 1/139	0.00% 0/112
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Genital neoplasm malignant female	0.00% 0/139	0.89% 1/112
Cardiac disorders Angina pectoris	0.00% 0/139	0.00% 0/112
Cardiac disorders angina unstable	0.00% 0/139	0.89% 1/112
Cardiac disorders Coronary artery occlusion	0.00% 0/139	0.89% 1/112

Other adverse events

Adverse event data not reported

Additional Information

Gerard Lynch

AstraZeneca

Phone: +44 1625 518062

Email: aztrial_results_posting@astrazeneca.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: LTE60