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Effects of Ranolazine on Coronary Microvascular Dysfunction in Patients With Hypertrophic Cardiomyopathy

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ClinicalTrials.gov Identifier: NCT03953989
Recruitment Status : Recruiting
First Posted : May 17, 2019
Last Update Posted : May 20, 2019
Sponsor:
Collaborator:
Menarini International Operations Luxembourg SA
Information provided by (Responsible Party):
Prof. Paolo G Camici MD FACC, IRCCS San Raffaele

Brief Summary:
To demonstrate the efficacy of ranolazine in improving coronary microvascular and diastolic dysfunction in patients affected by HCM evaluating changes in maximum (i.e. during dipyridamole-induced coronary vasodilatation) myocardial blood flow (MBF) measured by PET at baseline and after 4 months of treatment with ranolazine in patients with non obstructive HCM.

Condition or disease Intervention/treatment Phase
HCM - Hypertrophic Non-Obstructive Cardiomyopathy Drug: Ranolazine PR (prolonged-release) 500 mg 1 tablet bis in die and 750 mg 1 tablet bis in die Phase 2

Detailed Description:

This pilot study aimed at assessing the effects of treatment with ranolazine, on top of optimal standard medical therapy (according to international guidelines), on microvascular dysfunction using PET in patients with HCM.

Thirty months of enrolment are foreseen. Patients enrolled in the study, at the end of the titration phase will be treated with ranolazine 750 mg or 500 mg, 1 oral tablet twice a day for 4 months on top of standard of care treatment. Visit 0,1,2,3 may be performed 3 days before or 3 days after the planned date. Visit 4 and final PET scan may be performed 15 days before or 15 days after the planned date.

This is a superiority study. The sample size calculation is based on the ANOVA model, but the statistical analysis will be performed applying the ANCOVA model for the absence of data on the correlation between basal and end of study values of the primary variable studied. As previously reported (Camici et al. J Am Coll Cardiol 1991; 17:879-86) maximum (i.e. during dipyridamole stress) MBF is severely blunted in HCM (1.63±0.58 mL/min/g) compared to control subjects (2.99±1.06 mL/min/g). For the primary end-point of the study using a two-sided test at 5% significance level, with a power of 90% and a SD of ± 0.7 mL/min/gr, in order to detect a change of 0.5 mL/min/gr in maximum MBF before and after treatment, 24 patients valid per protocol are required.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 26 participants
Intervention Model: Single Group Assignment
Intervention Model Description: A pilot study, one center, open, non-controlled, one group pre-post treatment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Study Assessing the Effects of Ranolazine on Coronary Microvascular Dysfunction in Patients With Hypertrophic Cardiomyopathy
Actual Study Start Date : October 2016
Estimated Primary Completion Date : July 2019
Estimated Study Completion Date : September 2019


Arm Intervention/treatment
Experimental: Patients with hypertrophic cardiomyopathy

Thestudy is articulated into Screening visit plus other 3 visits. One visit (V2 ) for dose titration. V0 screening eligibility, consent, Medical History, physical examination, BP, ECG, Echocardiography, Biochemistry (haematology, electrolytes, glycaemia, ALS and bilirubin, creatinine and urine-analysis) V1 Baseline PET scan, physical examination, vital signs, and drug supply (500 mg bid).

V2 physical examination, safety check, biochemistry, drug compliance and up-titration (750 mg bid), drug supply.

V3 (2 months)safety check ,drug supply, drug compliance V4 (4 months, end of treatment) repeat PET scan, physical examination, BP, ECG, drug compliance, safety.

Drug of the study Ranolazine PR (prolonged-release) 500 mg 1 tablet bis in die and 750 mg 1 tablet bis in die

Drug: Ranolazine PR (prolonged-release) 500 mg 1 tablet bis in die and 750 mg 1 tablet bis in die
Patients enrolled in the study, at the end of the titration phase will be treated with ranolazine 750 mg or 500 mg, 1 oral tablet twice a day for 4 months on top of standard of care treatment
Other Name: Ranexa




Primary Outcome Measures :
  1. Myocardial Blood Flow during hyperemia ml/min/g [ Time Frame: At baseline and after 4 months of treatment ]
    Change of near maximal hyperemic myocardial blood flow (MBF ml/min/g) after treatment with ranolazine of at least 0.5 ml/min/g. Myocardial perfusion measured with 13N-ammonia and positron emission tomography at rest and during hyperemia; Hyperaemic Myocardial Blood Flow (MBF) measured following i.v. dipyridamole (0.56 mg/Kg in 4 mins)

  2. Coronary Flow Reserve (hyperaemic MBF /resting MBF = CFR). [ Time Frame: At baseline and after 4 months of treatment ]
    Change of CFR after treatment with ranolazine for four months

  3. Coronary resistance [ Time Frame: At baseline and after 4 months of treatment ]
    Change of Resting coronary resistance (Mean Arterial Pressure rest/ MBF rest) and minimal (during hyperemia) coronary resistance (Mean arterial Pressure hyperemia/ MBF hyperemia)


Secondary Outcome Measures :
  1. Symptoms [ Time Frame: through 4 month of treatment ]
    Number of participants with absence of symptoms accountable for drug intolerability ,assessed through customized questionnaire. If symptoms are accountable for drug intolerability are referred, the patient will come back to 500 mg/bid.



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male and female gender (females of childbearing potential must be using highly effective contraceptive precautions such as implants, injectables, combined oral contraceptives, intrauterine devices, sexual abstinence or vasectomised partner);
  • Females of childbearing potential or within two years from the menopause must have a negative urine pregnancy test;
  • Patients which fulfill conventional echocardiographic criteria for the diagnosis of HCM: maximum LV wall thickness ≥ 15 mm;
  • Patients aged > 18 years and < 80 years;
  • Sinus rhythm accepted isolated Supraventricular and Ventricular Premature Beats (VPB);
  • Absence of severe resting LV outflow tract obstruction (peak gradient ≤ 50 mmHg);
  • Written informed consent prior to enrolment into the study;

Exclusion Criteria:

  • Females of childbearing potential not using highly effective contraceptive precautions;
  • Presence of known coronary artery disease (CAD);
  • Presence of Chronic Obstructive Airways Disease;
  • Asthma;
  • Other causes of microvascular dysfunction including long-standing history of arterial hypertension, diabetes, uncontrolled dyslipidemia;
  • Body mass index >32 kg/m2; < 17 kg/m2
  • Overt LV systolic dysfunction with end-stage progression (LV-EF <50%);
  • Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazol, posaconazol, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone);
  • Patients treated with sotalol, dronedarone, class I antiarrhythmics (see appendix 4) or other QT-prolonging drugs; stable treatment with amiodarone is permitted;
  • Patients with QTc (Bazett's formula) at baseline ≥ 450 ms males; ≥470 msec females;
  • Any clinically relevant haematological or biochemical abnormality on routine screening, according to Investigator's judgment;
  • Severe concurrent pathology, including terminal illness (cancer, AIDS, etc.);
  • Severe renal impairment defined as GFR < 29 mL/min/1.73m2 or creatinine level > 2.5 mg/dL or BUN >60 mg/dL;
  • Moderate or severe hepatic impairment or hepatic insufficiency defined as SGOT or SGPT > 2 times greater than normal upper limit of the local laboratory or total serum bilirubin > 1.5 times greater than normal upper limit of the local laboratory;
  • Dementia, psychosis, alcoholism (>350 g ethanol/week) or chronic abuse of medicaments, drugs or psychoactive substances;
  • Claustrophobia;
  • Females who are pregnant or lactating;
  • Conditions that in the Investigator's opinion may interfere with the study's execution or due to which the patient should not participate for safety reasons;
  • Risk of poor patient cooperation;
  • Participation in a clinical study ≤ 2 months before enrolment;
  • Inability or unwillingness to issue the informed consent;
  • Concomitant use of > 20 mg daily dose of Simvastatin during the study (in case of patients taking simvastatin > 20 mg daily, the switch to other statins not metabolized by the CYP3A4 could be considered);
  • Concomitant use of Atorvastatin (> 80 mg daily)
  • Concomitant use of > 1000 mg daily dose of metformin during the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03953989


Contacts
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Contact: Paolo Camici, MD camici.paolo@hsr.it

Locations
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Italy
IRCCS Ospedale San Raffaele Recruiting
Milan, Italy, 20132
Contact: Paolo G Camici, MD       camici.paolo@hsr.it   
Contact: Ornella P Rimoldi, MD       rimoldi.ornella@hsr.it   
Sponsors and Collaborators
IRCCS San Raffaele
Menarini International Operations Luxembourg SA
Investigators
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Principal Investigator: Paolo Camici, MD IRCCS Ospedale san Raffaele

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Responsible Party: Prof. Paolo G Camici MD FACC, Professor of Cardiology, IRCCS San Raffaele
ClinicalTrials.gov Identifier: NCT03953989     History of Changes
Other Study ID Numbers: HCMRanIT001
First Posted: May 17, 2019    Key Record Dates
Last Update Posted: May 20, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Cardiomyopathies
Hypertrophy
Cardiomyopathy, Hypertrophic
Heart Diseases
Cardiovascular Diseases
Pathological Conditions, Anatomical
Aortic Stenosis, Subvalvular
Aortic Valve Stenosis
Heart Valve Diseases
Ranolazine
Sodium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action