Evaluation of Drug-drug Interaction Between LCZ696 and Sildenafil in Subjects With Mild to Moderate Hypertension

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01601470
First received: May 16, 2012
Last updated: February 8, 2013
Last verified: February 2013
  Purpose

This study is being conducted to investigate the potential for a pharmacokinetic drug-drug interaction in support of the co-administration of LCZ696 and sildenafil.


Condition Intervention Phase
Mild to Moderate Hypertension
Drug: LCZ696
Drug: Sildenafil
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Official Title: An Open Label, Three-period, Single Sequence Study to Evaluate the Pharmacokinetic Drug-drug Interaction Between LCZ696 and Sildenafil in Subjects With Mild to Moderate Hypertension

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Pharmacokinetics of LCZ696: Area under the plasma concentration-time curve from time zero to the end of the dosing interval (AUCtau) [ Time Frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose ] [ Designated as safety issue: No ]
    The effect of co-administration of sildenafil on the pharmacokinetics of LCZ696 (analytes of LCZ696: AHU377, LBQ657 and valsartan) will be assessed.

  • Pharmacokinetics of LCZ696: Observed maximum plasma concentration following drug administration at steady state (Cmax,ss) [ Time Frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose ] [ Designated as safety issue: No ]
    The effect of co-administration of sildenafil on the pharmacokinetics of LCZ696 (analytes of LCZ696: AHU377, LBQ657 and valsartan) will be assessed.

  • Pharmacokinetics of LCZ696: Observed minimum plasma concentration following drug administration at steady state (Cmin,ss) [ Time Frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose ] [ Designated as safety issue: No ]
    The effect of co-administration of sildenafil on the pharmacokinetics of LCZ696 (analytes of LCZ696: AHU377, LBQ657 and valsartan) will be assessed.

  • Pharmacokinetics of LCZ696: Time to reach the maximum concentration after drug administration (Tmax) [ Time Frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose ] [ Designated as safety issue: No ]
    The effect of co-administration of sildenafil on the pharmacokinetics of LCZ696 (analytes of LCZ696: AHU377, LBQ657 and valsartan) will be assessed.

  • Pharmacokinetics of Sildenafil and N-desmethyl-sildenafil: Area under the plasma concentration-time curve from time zero to infinity (AUCinf) [ Time Frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose ] [ Designated as safety issue: No ]
    The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil will be assessed.

  • Pharmacokinetics of Sildenafil and N-desmethyl-sildenafil: Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration [ Time Frame: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose ] [ Designated as safety issue: No ]
    The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil will be assessed.

  • Pharmacokinetics of Sildenafil and N-desmethyl-sildenafil: Terminal elimination half-life (T1/2) [ Time Frame: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose ] [ Designated as safety issue: No ]
    The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil will be assessed.

  • Pharmacokinetics of Sildenafil and N-desmethyl-sildenafil: Observed maximum plasma concentration following drug administration (Cmax) [ Time Frame: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose ] [ Designated as safety issue: No ]
    The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil will be assessed

  • Pharmacokinetics of Sildenafil and N-desmethyl-sildenafil: Time to reach the maximum concentration after drug administration (Tmax) [ Time Frame: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose ] [ Designated as safety issue: No ]
    The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil will be assessed


Secondary Outcome Measures:
  • Number of patients with adverse events, serious adverse events and death [ Time Frame: From day -28 (screening) until 30 days past the final study assessment ] [ Designated as safety issue: Yes ]
    Number of patients with adverse events, serious adverse events and death


Enrollment: 102
Study Start Date: September 2012
Study Completion Date: January 2013
Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sildenafil/LCZ696/LCZ696+Sildenafil
During Treatment Period 1, on study Day 1, subjects will receive a single dose of sildenafil followed by wash out on Day 2. In Period 2 (study Days 3-7), subjects will receive LCZ696 once daily. In Period 3, on study Day 8, subjects will receive LCZ696 , co-administered at the same time with a single dose of sildenafil
Drug: LCZ696
LCZ696 400mg QD will be administerd alone for 4 days and in combination with sildenafil for 1 day
Drug: Sildenafil
Sildenafil 50 mg single dose will be administerd alone for 1 days and in combination with LCZ696 400mg QD for 1 day

Detailed Description:

This study is being conducted to investigate the potential for a pharmacokinetic drug-drug interaction in support of the co-administration of LCZ696 and sildenafil. Furthermore, this study is being conducted to explore the potential for a pharmacodynamic interaction as measured by additive effects on cyclic Guanosine MonoPhosphate (cGMP) in urine and plasma and on blood pressure.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

-Male subjects with mild to moderate hypertension, either treated or not currently on treatment, between age 18 and 65 years of age, and otherwise in good health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests at screening except for hypertension.

  • At screening: systolic blood pressure 120-140 mmHg on therapy, or 140-160 mmHg if untreated
  • At screening: diastolic blood pressure, 70-95 mmHg on therapy, or 90-100 mmHg if untreated
  • Baseline: BP ≥140/90
  • Subjects currently on hypertension treatment should be on stable single drug antihypertensive medication during 2 months prior to screening.

Exclusion Criteria:

  • Use of non-antihypertensive prescription drugs, herbal supplements, and/or over-the-counter (OTC) medication, dietary supplements (vitamins included) within two (2) weeks prior to initial dosing
  • History of documented symptomatic orthostatic hypotension or syncope

Other protocol-defined inclusion/exclusion criteria may apply.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01601470

Locations
Germany
Novartis Investigative Site
Berlin, Germany, 14050
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01601470     History of Changes
Other Study ID Numbers: CLCZ696B2225, 2012-001632-64
Study First Received: May 16, 2012
Last Updated: February 8, 2013
Health Authority: Germany: Federal Institute for Drugs and Medicinal Products

Keywords provided by Novartis:
LCZ696, sildenafil, pharmacokinetics, mild to moderate hypertension

Additional relevant MeSH terms:
Hypertension
Vascular Diseases
Cardiovascular Diseases
Sildenafil
Vasodilator Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 23, 2014