Hydroxychloroquine for the Prevention of Cardiovascular Events in Myocardial Infarction Patients - a Safety Pilot Trial (OXI)

• ClinicalTrials.gov Identifier: NCT02648464
• Recruitment Status: Completed
• First Posted: January 7, 2016
• Last Update Posted: June 9, 2020
• Sponsor: Helsinki University Central Hospital
• Collaborators: Finnish Foundation for Cardiovascular Research; Orion Corporation, Orion Pharma; Aarne Koskelo Foundation; Finnish Cultural Foundation
• Information provided by (Responsible Party): Otto Hartman, Helsinki University Central Hospital

Tracking Information

• First Submitted Date: December 18, 2015
• First Posted Date: January 7, 2016
• Last Update Posted Date: June 9, 2020
• Actual Study Start Date: February 1, 2016
• Actual Primary Completion Date: December 31, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 7, 2020)

Rate of major cardiovascular adverse events [ Time Frame: Twelve months ]

Myocardial infarction, mortality, hospitalization for unstable angina, and heart failure

Original Primary Outcome Measures (submitted: January 5, 2016)

Rate of major cardiovascular complications [ Time Frame: Six months ]

Investigate whether hydroxychloroquine reduces the rate of death, myocardial infarction, unstable angina pectoris requiring hospitalization, and urgent coronary revascularization among acute coronary syndrome patients.

Current Secondary Outcome Measures (submitted: March 12, 2018)

• Rate of the primary endpoint plus stroke and urgent coronary revascularization [ Time Frame: Twelve months ]
• Effect on the incidence of type 2 diabetes and the level of Hba1c [ Time Frame: Six months ]
• Effect on cholesterol levels [ Time Frame: Six months ]
  The effect of hydroxychloroquine on total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglyceride levels
• Effect on high-sensitivity C-reactive protein (hs-CRP) level [ Time Frame: Six months ]
• Effect on soluble biomarkers of inflammation [ Time Frame: Six months ]
  Frozen samples (plasma and whole blood) will be stored for future evaluation of biomarkers related to inflammation and cardiovascular disease, such as tumor necrosis factor alpha, interleukin 6 (IL-6), IL-1beta, IL-18, and messenger ribonucleic acid (mRNA) analyses.
• Effect on aortic inflammation assessed by PET / CT scan [ Time Frame: Six months ]

Original Secondary Outcome Measures (submitted: January 5, 2016)

• Rate of the primary endpoint plus stroke [ Time Frame: Nine months ]
• Effect on the incidence of type 2 diabetes and the level of Hba1c [ Time Frame: Six months ]
• Effect on cholesterol levels [ Time Frame: Six months ]
  The effect of hydroxychloroquine on total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglyceride levels
• Effect on high-sensitivity C-reactive protein (hs-CRP) level [ Time Frame: Six months ]
• Effect on soluble biomarkers of inflammation [ Time Frame: Six months ]
  Frozen samples (plasma and whole blood) will be stored for future evaluation of biomarkers related to inflammation and cardiovascular disease, such as tumor necrosis factor alpha, interleukin 6 (IL-6), IL-1beta, IL-18, and messenger ribonucleic acid (mRNA) analyses.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Hydroxychloroquine for the Prevention of Cardiovascular Events in Myocardial Infarction Patients - a Safety Pilot Trial
• Official Title: Hydroxychloroquine for the Prevention of Recurrent Cardiovascular Events in Myocardial Infarction Patients - a Safety Pilot Trial
• Brief Summary: This safety pilot study evaluates the effect of hydroxychloroquine on preventing recurrent cardiovascular events among myocardial infarction patients. Half of the participants will receive hydroxychloroquine, whereas the other half will receive placebo during six months.

Detailed Description

Anti-rheumatic medications decrease cardiovascular mortality in rheumatoid arthritis patients, based mainly on their anti-inflammatory effect. No studies have addressed their effect on preventing recurrent cardiovascular events among non-rheumatic patients.

In the pilot phase 200 myocardial infarction patients will be recruited during their index visit to the study hospitals. Patients will be randomized after initial coronary angiography to receive either hydroxychloroquine 300 mg a day or placebo during six months. Patients will be followed up until 12 months at four visits. Visit one is at doctor´s office at 3 to 5 weeks from the day of recruitment. Visit two is at study nurse´s office at 5.5 to 6 months. Visit three is a phone interview by the study nurse at 8.5 to 9.5 months. Visit four at 11.5 to 12.5 months is at doctor´s office.

This study evaluates the safety of hydroxychloroquine in the setting of myocardial infarction, and whether hydroxychloroquine treatment could reduce the incidence of recurrent cardiovascular events among myocardial infarction patients. Furthermore, the effect of hydroxychloroquine on cardiovascular risk factors and systemic inflammation parameters will be studied. In a subgroup of 40 patients, the effect of hydroxychloroquine on aortic inflammation will be assessed by PET/CT scan.

If this safety pilot study with 200 patients proves successful (i.e. no major complications), 2500 patients will be recruited in additional centers in Finland and the Nordic Countries.

Orion Pharma provides the active hydroxychloroquine tablet (Oxiklorin) but provides no other assistance or funding for the study.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment

Condition

• Myocardial Infarction
• Acute Coronary Syndrome
• Inflammation
• Hydroxychloroquine
• Antirheumatic Agents
• Cardiovascular Diseases

Intervention

• Drug: Hydroxychloroquine
  Other Name: Oxiklorin
• Drug: Placebo

Study Arms

• Experimental: Hydroxychloroquine
  Hydroxychloroquine 300 mg tablet by mouth daily for 6 months. Patients under the weight of 60 kg: hydroxychloroquine 300 mg tablet daily for 5 days per week for 6 months.
  Intervention: Drug: Hydroxychloroquine
• Placebo Comparator: Placebo
  Placebo tablet by mouth daily for 6 months. Patients under the weight of 60 kg: placebo tablet daily for 5 days per week for 6 months.
  Intervention: Drug: Placebo

• Publications *: Hartman O, Kovanen PT, Lehtonen J, Eklund KK, Sinisalo J. Hydroxychloroquine for the prevention of recurrent cardiovascular events in myocardial infarction patients: rationale and design of the OXI trial. Eur Heart J Cardiovasc Pharmacother. 2017 Apr 1;3(2):92-97. doi: 10.1093/ehjcvp/pvw035.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 6, 2020): 125
• Original Estimated Enrollment (submitted: January 5, 2016): 200
• Actual Study Completion Date: December 31, 2019
• Actual Primary Completion Date: December 31, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Patients must have high-sensitivity troponin or CKMB above the upper limit of normal with at least one of the following criteria:

1. Anginal symptoms suggestive of cardiac ischemia

   1. Accelerating pattern of anginal pain (episodes of angina that have at least 5 minutes duration and are more frequent, severe, longer in duration and/or precipitated by less exertion).
   2. Prolonged (>20 minutes) or recurrent anginal pain at rest or with minimal effort.
   3. Anginal pain at rest or with minimal exertion, and at least 20 minutes of duration, occurring >48 hours after an acute Q-wave myocardial infarction.

2. ECG criteria

   1. New, persistent or transient ST-segment depression >0,1 mV (0,08 seconds after the J-point) in at least 2 extremity leads or 3 precordial leads.
   2. New, persistent or transient ST-segment elevation in two contiguous leads ≥0.2 mV in men or ≥0.15 mV in women in leads V2-V3, and/or ≥0.1 mV in other leads.

Patients will be enrolled within 96 hours of coronary angiography

Exclusion Criteria:

• Contraindication for hydroxychloroquine (porphyria, psoriasis, retinopathy, hypersensitivity)
• Rheumatoid arthritis or other rheumatic disease
• Significant neuropathy of any cause
• Cardiomyopathy (diagnosed before the onset of index hospitalization)
• Muscle disease (that could worsen by the use of hydroxychloroquine)
• Pregnant or nursing women, and women of childbearing potential without efficient contraceptives.
• Angina precipitated by obvious provoking factors
• Prolonged ECG's corrected QT interval (>480 ms)
• Ongoing antibiotic therapy of any duration
• Uncontrolled severe cardiac arrhythmia resulting in hemodynamic instability
• Severe hepatic failure (alanine transaminase or gamma-glutamyltransferase ≥2 times above normal limits or international normalized ratio (INR) >1,5 and patient not using warfarin, and due to other than cardiac reasons).
• Renal failure, glomerular filtration rate <50 ml/min/1,73m2
• Hemoglobin <100 g/l (if not possible to correct with transfusion)
• Planned percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)
• Index myocardial infarction due to PCI or CABG restenosis.
• Inability to interpret ST-T segment changes on ECG (e.g. complete left bundle branch block or paced rhythm)
• Prior thrombolytic therapy (within 12 hours)
• Inability to give informed consent
• Fulminant vomiting or other disability to give oral medication
• Over 80 years of age
• Life expectancy less than one year
• Receiving another investigational drug within 4 weeks prior to the study. (Patients who have participated in investigational trials before the 4-week time period may be randomized as long as they have reached the primary endpoint).
• Patients with any other medical condition which, in the investigator's opinion, would interfere with optimal participation in the study or produce a significant risk to the patient

In addition, patients are not eligible for the PET/CT subgroup if they have received statin-therapy in the last 2 months prior to the hospitalization (i.e. statin therapy started during the index hospitalization is not an exclusion criteria).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Finland

Administrative Information

• NCT Number: NCT02648464
• Other Study ID Numbers: 2015-000233-73
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Study data is planned to be available at the study organization´s website, and by specific request from the investigator

• Responsible Party: Otto Hartman, Helsinki University Central Hospital
• Study Sponsor: Helsinki University Central Hospital

Collaborators

• Finnish Foundation for Cardiovascular Research
• Orion Corporation, Orion Pharma
• Aarne Koskelo Foundation
• Finnish Cultural Foundation

Investigators

• Study Director: Juha Sinisalo, Professor; Helsinki University Central Hospital

• PRS Account: Helsinki University Central Hospital
• Verification Date: June 2020