search
Back to results

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

Primary Purpose

HCM - Hypertrophic Non-Obstructive Cardiomyopathy

Status
Completed
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
Ranolazine PR (prolonged-release) 500 mg 1 tablet bis in die and 750 mg 1 tablet bis in die
Sponsored by
IRCCS San Raffaele
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HCM - Hypertrophic Non-Obstructive Cardiomyopathy

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • IRCCS Ospedale San Raffaele

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Patients with hypertrophic cardiomyopathy

Arm Description

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

Outcomes

Primary Outcome Measures

Myocardial Blood Flow during hyperemia ml/min/g
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)
Coronary Flow Reserve (hyperaemic MBF /resting MBF = CFR).
Change of CFR after treatment with ranolazine for four months
Coronary resistance
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

Symptoms
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.

Full Information

First Posted
May 13, 2019
Last Updated
December 9, 2020
Sponsor
IRCCS San Raffaele
Collaborators
Menarini International Operations Luxembourg SA
search

1. Study Identification

Unique Protocol Identification Number
NCT03953989
Brief Title
Effects of Ranolazine on Coronary Microvascular Dysfunction in Patients With Hypertrophic Cardiomyopathy
Official Title
A Pilot Study Assessing the Effects of Ranolazine on Coronary Microvascular Dysfunction in Patients With Hypertrophic Cardiomyopathy
Study Type
Interventional

2. Study Status

Record Verification Date
December 2020
Overall Recruitment Status
Completed
Study Start Date
October 2016 (Actual)
Primary Completion Date
February 1, 2020 (Actual)
Study Completion Date
March 6, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
IRCCS San Raffaele
Collaborators
Menarini International Operations Luxembourg SA

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HCM - Hypertrophic Non-Obstructive Cardiomyopathy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
A pilot study, one center, open, non-controlled, one group pre-post treatment
Masking
None (Open Label)
Allocation
N/A
Enrollment
26 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Patients with hypertrophic cardiomyopathy
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Ranolazine PR (prolonged-release) 500 mg 1 tablet bis in die and 750 mg 1 tablet bis in die
Other Intervention Name(s)
Ranexa
Intervention Description
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
Primary Outcome Measure Information:
Title
Myocardial Blood Flow during hyperemia ml/min/g
Description
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)
Time Frame
At baseline and after 4 months of treatment
Title
Coronary Flow Reserve (hyperaemic MBF /resting MBF = CFR).
Description
Change of CFR after treatment with ranolazine for four months
Time Frame
At baseline and after 4 months of treatment
Title
Coronary resistance
Description
Change of Resting coronary resistance (Mean Arterial Pressure rest/ MBF rest) and minimal (during hyperemia) coronary resistance (Mean arterial Pressure hyperemia/ MBF hyperemia)
Time Frame
At baseline and after 4 months of treatment
Secondary Outcome Measure Information:
Title
Symptoms
Description
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.
Time Frame
through 4 month of treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Paolo Camici, MD
Organizational Affiliation
IRCCS Ospedale San Raffaele
Official's Role
Principal Investigator
Facility Information:
Facility Name
IRCCS Ospedale San Raffaele
City
Milan
ZIP/Postal Code
20132
Country
Italy

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

We'll reach out to this number within 24 hrs