Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MEK162 in Noonan Syndrome Hypertrophic Cardiomyopathy

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01556568
First received: March 15, 2012
Last updated: May 12, 2014
Last verified: May 2014
  Purpose

The purpose of the study is to determine whether the ability of MEK162 to antagonize MEK activation in NS HCM patients, who usually have upstream mutations in the Ras-Raf-Mek-Erk pathway that lead to MEK activation, would be beneficial over a 6 month treatment period in hypertrophy regression.


Condition Intervention Phase
Cardiomegaly
Drug: MEK162
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open Label Study to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MEK162 in Noonan Syndrome Hypertrophic Cardiomyopathy

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Change from baseline in Left ventricular mass (LVM) [ Time Frame: Baseline to 3 months and 6 months ] [ Designated as safety issue: No ]
    Change in LVM after 3 months and 6 months of treatment using magnetic resonance imaging.


Secondary Outcome Measures:
  • Change from baseline in Cardiac energetics state at 3 months and 6 months [ Time Frame: Baseline to 3 months and 6 months ] [ Designated as safety issue: No ]
    Energetic state represented by phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio using magnetic resonance spectroscopy.

  • Number of patients with adverse events, serious adverse events and death [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    Abnormalities in Vital signs, ECG evaluations, clinical laboratory evaluations, will be collected.

  • Pharmacokinetics of MEK162 and metabolite (AR00426032): The trough plasma concentration (Ctrough) just prior to drug administration [ Time Frame: Days 1, 8, 15, 28, 56, 84, 140 and 182 ] [ Designated as safety issue: No ]
    pre-dose concentration of MEK162 and its metabolite (AR00426032) in plasma. All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein.

  • Pharmacokinetics of MEK162 and metabolite (AR00426032): maximum drug exposure of MEK162 and its metabolite (AR00426032) in plasma [ Time Frame: Day 1 and Day 8 ] [ Designated as safety issue: No ]
    All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein.

  • Pharmacokinetics of MEK162 and metabolite (AR00426032): time to reach peak concentration (Tmax) in plasma [ Time Frame: Day 1 and Day 8 ] [ Designated as safety issue: No ]
    All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein.

  • Pharmacokinetics of MEK162 and metabolite (AR00426032): Area under the plasma concentration-time profile from time zero to 12 hours post dose (AUC0-12h) [ Time Frame: Day 1 and Day 8 ] [ Designated as safety issue: No ]
    All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein.

  • Pharmacokinetics of MEK162 and metabolite (AR00426032): Area under the plasma concentration-time profile from time zero to the last quantifiable sample (AUClast) [ Time Frame: Day 1 and Day 8 ] [ Designated as safety issue: No ]
    All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein.

  • Pharmacokinetics of MEK162 and metabolite (AR00426032): accumulation ratio (Racc) [ Time Frame: Day 1 and Day 8 ] [ Designated as safety issue: No ]
    Comparison of the drug exposures as AUCs and Cmax of MEK162 and its metabolite (AR00426032) in plasma after 8 days treatment in relation to the data from the first day (Day 8/Day 1)

  • Pharmacokinetics of MEK162: The degree of fluctuation of MEK162 and its metabolite (AR00426032) in plasma at steady state (on Day 8) [ Time Frame: Day 8 ] [ Designated as safety issue: No ]
    All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein. The dgree of fluctuation is calculated as (Cmax,ss - Cmin,ss)/Cav,ss at steady state.

  • Pharmacokinetics of MEK162: The ratio of Metabolite (AR00426032) to MEK162 in plasma on Days 1 and 8 [ Time Frame: Day 1 and Day 8 ] [ Designated as safety issue: No ]
    All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein.

  • Change from baseline in end systolic and end diastolic right and left vetricular volumes in 3 and 6 months [ Time Frame: baseline to 3 and 6 months of treatment ] [ Designated as safety issue: No ]
    These parameters are derived from cine breath-hold magnetic resonance images acquired over the cardiac cycle.

  • Pharmacokinetics of MEK162 and metabolite (AR00426032):observed maximum plasma concentration (Cmax) following drug adminstration [ Time Frame: Day 1 and Day 8 ] [ Designated as safety issue: No ]
    All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein.

  • Change from baseline in stroke volume and stroke output during 3 and 6 months [ Time Frame: baseline to 3 and 6 months of treatment ] [ Designated as safety issue: No ]
    These parameters are derived from cine breath-hold magnetic resonance images acquired over the cardiac cycle.

  • Ejection fraction [ Time Frame: baseline, 3 and 6 months of treatment ] [ Designated as safety issue: No ]
    This parameter is derived from cine breath-hold magnetic resonance images acquired over the cardiac cycle.

  • Cardiac index [ Time Frame: baseline, 3 and 6 months of treatment ] [ Designated as safety issue: No ]
    This parameters is derived from cine breath-hold magnetic resonance images acquired over the cardiac cycle.


Estimated Enrollment: 22
Study Start Date: February 2012
Estimated Study Completion Date: March 2017
Estimated Primary Completion Date: March 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: MEK162
Patients will be treated with MEK162 only and will be uptitrated or down titrated based on safety and tolerability observed.
Drug: MEK162

Detailed Description:

This study is designed as a proof of concept of MEK162 in NS HCM patients. The purpose of the present study is to determine whether the ability of MEK162 to antagonize MEK activation in NS HCM patients, who usually have upstream mutations in the Ras-Raf-Mek-Erk pathway that lead to MEK activation, would be beneficial over a 6 month treatment period by causing hypertrophy regression. Such regression might result in cardiovascular clinical benefits with longer term treatment.

The information gained from this study will be three fold:

  1. the safety/tolerability of treatment with MEK162 over 6 month in the NS HCM patient population
  2. the pharmacokinetics and pharmacodynamics of MEK162 in the target patient population
  3. proof of the therapeutic concept that MEK inhibition will reduce cardiac hypertrophy in the target NS HCM patient population
  Eligibility

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

Inclusion:

  • Male and female Noonan syndrome patients with confirmed cardiac hypertrophy, age 18 to 65 years of age included, and in general good health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests at screening.
  • Cardiac hypertrophy is defined by left ventricular wall thickness greater than or equal to 12 mm by echocardiography or MRI, or the change in wall thickness is accompanied by an associated increase in left ventricular mass which is defined by echo or MRI as greater than 134 g/m2 and 110 g/m2 in men and women, respectively.
  • Subjects must weigh at least 45 kg to participate in the study, and must have a body mass index (BMI) within the range of 18 - 34 kg/m2.

Exclusion criteria:

  • Primary Long QT syndrome or a history of significant ECG abnormalities judged by the investigators to be inappropriate for participation in the current study.
  • History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
  • Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant.
  • Sexually active males must use a condom during intercourse while taking the drug during treatment, for 5 half lives after stopping treatment and should not father a child in this period.
  • Use of any prescription drugs other than beta-blockers, diuretics, CCB, amiodarone, disopyramide, herbal supplements, within four (4) weeks prior to initial dosing, and/or over-the-counter (OTC) medication, dietary supplements (vitamins included) within two (2) weeks prior to initial dosing. If needed, (i.e. an incidental and limited need) paracetamol or acetaminophen is acceptable, but must be documented in the Concomitant medications/Significant non-drug therapies page of the eCRF.

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: NCT01556568

Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals

Locations
United States, Massachusetts
Novartis Investigative Site Not yet recruiting
Boston, Massachusetts, United States, 02115
United Kingdom
Novartis Investigative Site Recruiting
London, United Kingdom, W1G 8PH
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: NCT01556568     History of Changes
Other Study ID Numbers: CMEK162Y2201, 2011-003392-10
Study First Received: March 15, 2012
Last Updated: May 12, 2014
Health Authority: United States: Food and Drug Administration
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Novartis:
Noonan Syndrome, hypertrophic cardiomyopathy.

Additional relevant MeSH terms:
Noonan Syndrome
Cardiomyopathy, Hypertrophic
Cardiomegaly
Hypertrophy
Cardiomyopathies
Heart Diseases
Cardiovascular Diseases
Aortic Stenosis, Subvalvular
Aortic Valve Stenosis
Heart Valve Diseases
Pathological Conditions, Anatomical
Craniofacial Abnormalities
Musculoskeletal Abnormalities
Musculoskeletal Diseases
Heart Defects, Congenital
Cardiovascular Abnormalities
Congenital Abnormalities
Connective Tissue Diseases

ClinicalTrials.gov processed this record on August 20, 2014