Clinical Trial Page

Clinical Trial Results:
A randomized, double-blind, parallel group study to evaluate metabolic effects of LCZ696 and amlodipine in obese hypertensive subjects

Summary
EudraCT number
 2012-002606-40
Trial protocol
 DE   NL  
Global end of trial date
29 Jul 2013

Results information
Results version number
 v1(current)
This version publication date
13 Jul 2016
First version publication date
18 Jul 2015
Other versions

Trial information

 Close Top of page
Trial identification
Sponsor protocol code
CLCZ696B2207
Additional study identifiers
ISRCTN number
 -
US NCT number
 NCT01631864
WHO universal trial number (UTN)
 -
Sponsors
Sponsor organisation name
Novartis Pharma AG
Sponsor organisation address
CH-4002 , Basel, Switzerland,
Public contact
Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
Scientific contact
Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)
No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
No
Results analysis stage
Analysis stage
Final
Date of interim/final analysis
29 Jul 2013
Is this the analysis of the primary completion data?
No
Global end of trial reached?
Yes
Global end of trial date
29 Jul 2013
Was the trial ended prematurely?
No
General information about the trial
Main objective of the trial
To evaluate the effect of LCZ696 400 mg QD as compared to amlodipine 10 mg QD on insulin sensitivity after 8 weeks of treatment in obese hypertensive subjects.
Protection of trial subjects
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
Background therapy
 -
Evidence for comparator
 -
Actual start date of recruitment
23 Oct 2012
Long term follow-up planned
No
Independent data monitoring committee (IDMC) involvement?
Yes
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled
Netherlands: 27
Country: Number of subjects enrolled
Germany: 71
Worldwide total number of subjects
98
EEA total number of subjects
98
Number of subjects enrolled per age group
In utero
0
Preterm newborn - gestational age
0
Newborns (0-27 days)
0
Infants and toddlers (28 days-23 months)
0
Children (2-11 years)
0
Adolescents (12-17 years)
0
Adults (18-64 years)
91
From 65 to 84 years
7
85 years and over
0

Subject disposition

 Close Top of page
Recruitment
Recruitment details
 -

Pre-assignment
Screening details
 After signing the Informed Consent, patients underwent screening assessments. If eligibility criteria were met, patients proceeded to the wash-out period (wash-out from previous anti-hypertensive medication).

Period 1
Period 1 title
Double-blind treatment period (overall period)
Is this the baseline period?
 Yes
Allocation method
Randomised - controlled
Blinding used
 Double blind
Roles blinded
 Subject, Investigator, Monitor, Data analyst, Assessor

Arms
Are arms mutually exclusive
Yes

Arm title
 LCZ696
Arm description
 LCZ696 400 mg + placebo to amlodipine 10 mg (2 x placebo to matching amlodipine 5 mg)
Arm type
 Experimental

Investigational medicinal product name
LCZ696
Investigational medicinal product code
Other name
Pharmaceutical forms
Tablet
Routes of administration
Oral use
Dosage and administration details
Patients received LCZ696 400 mg tablets for oral administration for 56 days.

Investigational medicinal product name
Matching placebo for amlodipine
Investigational medicinal product code
Other name
Pharmaceutical forms
Tablet
Routes of administration
Oral use
Dosage and administration details
Patients received matching placebo 10 mg (2 x placebo to matching amlodipine 5 mg) for 56 days.

Arm title
 Amlodipine
Arm description
 Patients received amlodipine 10 mg for 56 days.
Arm type
 Experimental

Investigational medicinal product name
Amlodipine
Investigational medicinal product code
Other name
Pharmaceutical forms
Tablet
Routes of administration
Oral use
Dosage and administration details
Amlodipine 10 mg provided 5 mg tablets

Investigational medicinal product name
Matching placebo for LCZ696
Investigational medicinal product code
Other name
Pharmaceutical forms
Tablet
Routes of administration
Oral use
Dosage and administration details
Placebo to LCZ696 400 mg

Number of subjects in period 1
LCZ696 Amlodipine
Started
50
48
Completed
48
44
Not completed
2
4
     'Subject/guardian decision '
-
1
     Adverse event, non-fatal
2
3

Baseline characteristics

 Close Top of page
Baseline characteristics reporting groups
Reporting group title
LCZ696
Reporting group description
 LCZ696 400 mg + placebo to amlodipine 10 mg (2 x placebo to matching amlodipine 5 mg)

Reporting group title
Amlodipine
Reporting group description
 Patients received amlodipine 10 mg for 56 days.

Reporting group values
 LCZ696 Amlodipine Total
Number of subjects
 50 48 98
Age categorical
Units: Subjects
    Adults (18-64 years)
 47 44 91
    From 65-84 years
 3 4 7
Age continuous
Units: years
    arithmetic mean (standard deviation)
 51.9 ± 9.6 50.5 ± 9.4 -
Gender categorical
Units: Subjects
    Female
 9 13 22
    Male
 41 35 76

End points

 Close Top of page
End points reporting groups
Reporting group title
LCZ696
Reporting group description
 LCZ696 400 mg + placebo to amlodipine 10 mg (2 x placebo to matching amlodipine 5 mg)

Reporting group title
Amlodipine
Reporting group description
 Patients received amlodipine 10 mg for 56 days.

Primary: Change from baseline in insulin sensitivity index (SI) to Day 56

 Close Top of page
End point title
 Change from baseline in insulin sensitivity index (SI) to Day 56
End point description
The insulin sensitivity index was assessed by hyperinsulinemic euglycemic clamp. The insulin sensitivity index was calculated from steady-state glucose infusion rates, and blood insulin and glucose concentrations. The unit of measure is (μg/kg*min/(mmol/L*pmol/L)). The pharmacodynamic (PD) set was used for the analysis. The PD analysis set included all patients with available PD data and no protocol deviations with relevant impact on PD data.
End point type
Primary
End point timeframe
Baseline, Day 56
End point values
 LCZ696 Amlodipine
Number of subjects analysed
48 [1]
41 [2]
Units: µg/kg*min/(mmol/L*pmol/L
least squares mean (confidence interval 95%)
    Mean Change from baseline
0.192 (0.025 to 0.359)
0.065 (-0.116 to 0.246)
Notes
[1] - PD analysis set- Only patients who had both baseline and Day 56 values are included in the analysis
[2] - PD analysis set- Only patients who had both baseline and Day 56 values are included in the analysis
Statistical analysis title
 change from baseline-LCZ696 400mg-Amlodipine 10mg
Statistical analysis description
Comparison of change from baseline in insulin sensitivity index (SI) between treatments. Data were analyzed using an ANCOVA with treatment as fixed effect and baseline as covariate
Comparison groups
LCZ696 v Amlodipine
Number of subjects included in analysis
89
Analysis specification
Pre-specified
Analysis type
 equivalence
Method
Parameter type
 ANCOVA
Point estimate
0.128
Confidence interval
     level
 95%
     sides
2-sided
     lower limit
 -0.119
     upper limit
 0.374

Secondary: Subcutaneous adipose tissue lipolysis - Glycerol (free)

 Close Top of page
End point title
 Subcutaneous adipose tissue lipolysis - Glycerol (free)
End point description
Lipolysis was assessed through subcutaneous adipose tissue microdialysis in the fasted state before (Day 1) and at the end of the eight week treatment period (Day 57). Lipolysis was assessed during a 30 min and 45 min interval at rest. Pharmacodynamic set was included analysis.
End point type
Secondary
End point timeframe
After 8 weeks of treatment (Day 57)
End point values
 LCZ696 Amlodipine
Number of subjects analysed
47
42
Units: µmol/L
geometric mean (confidence interval 95%)
    30 minutes
83.74 (75.35 to 94.61)
67.89 (60.18 to 76.59)
    45 minutes
80.53 (72.81 to 89.06)
63.99 (57.52 to 71.2)
No statistical analyses for this end point

Secondary: oxidative metabolism as assessed by indirect calorimetry

 Close Top of page
End point title
 oxidative metabolism as assessed by indirect calorimetry
End point description
Oxidative metabolism at rest was assessed through measurement of oxygen consumption and carbon dioxide production (indirect calorimetry) at baseline and day 57.
End point type
Secondary
End point timeframe
Day 57
End point values
 LCZ696 Amlodipine
Number of subjects analysed
46
40
Units: Carbon Dioxide to Oxygen Ratio
    arithmetic mean (confidence interval 95%)
0.787 (0.76 to 0.814)
0.775 (0.746 to 0.804)
No statistical analyses for this end point

Secondary: Percentage of patients that experienced at least one adverse event (AE)

 Close Top of page
End point title
 Percentage of patients that experienced at least one adverse event (AE)
End point description
End point type
Secondary
End point timeframe
8 weeks
End point values
 LCZ696 Amlodipine
Number of subjects analysed
50
48
Units: percentage of participants
    number (not applicable)
60
77.1
No statistical analyses for this end point

Adverse events

 Close Top of page
Adverse events information
Timeframe for reporting adverse events
Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
Assessment type
 Systematic
Dictionary used for adverse event reporting
Dictionary name
 MedDRA
Dictionary version
16.1
Reporting groups
Reporting group title
Amlodipine 10mg QD
Reporting group description
 Amlodipine 10mg QD

Reporting group title
LCZ696 400mg QD
Reporting group description
 LCZ696 400mg QD

Serious adverse events
 Amlodipine 10mg QD LCZ696 400mg QD
Total subjects affected by serious adverse events
     subjects affected / exposed
1 / 48 (2.08%)
1 / 50 (2.00%)
     number of deaths (all causes)
0
0
     number of deaths resulting from adverse events
0
0
Nervous system disorders
RUPTURED CEREBRAL ANEURYSM
     subjects affected / exposed
0 / 48 (0.00%)
1 / 50 (2.00%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Renal and urinary disorders
NEPHROLITHIASIS
     subjects affected / exposed
1 / 48 (2.08%)
0 / 50 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events
 Amlodipine 10mg QD LCZ696 400mg QD
Total subjects affected by non serious adverse events
     subjects affected / exposed
31 / 48 (64.58%)
24 / 50 (48.00%)
Vascular disorders
CIRCULATORY COLLAPSE
     subjects affected / exposed
7 / 48 (14.58%)
2 / 50 (4.00%)
     occurrences all number
8
2
Nervous system disorders
DIZZINESS
     subjects affected / exposed
1 / 48 (2.08%)
3 / 50 (6.00%)
     occurrences all number
1
3
HEADACHE
     subjects affected / exposed
7 / 48 (14.58%)
4 / 50 (8.00%)
     occurrences all number
9
4
General disorders and administration site conditions
OEDEMA PERIPHERAL
     subjects affected / exposed
16 / 48 (33.33%)
1 / 50 (2.00%)
     occurrences all number
16
1
Gastrointestinal disorders
DIARRHOEA
     subjects affected / exposed
1 / 48 (2.08%)
3 / 50 (6.00%)
     occurrences all number
1
3
Skin and subcutaneous tissue disorders
PRURITUS
     subjects affected / exposed
0 / 48 (0.00%)
5 / 50 (10.00%)
     occurrences all number
0
5
Infections and infestations
NASOPHARYNGITIS
     subjects affected / exposed
8 / 48 (16.67%)
9 / 50 (18.00%)
     occurrences all number
9
9

More information

 Close Top of page

Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date
Amendment
01 Sep 2012
Added a clarification to the statistical analysis section as requested by the German ethical committee.

Interruptions (globally)
Were there any global interruptions to the trial? No

Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
None reported

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe