Myocardial Infarction, Anterior WallPhase 2/3NCT03516903
Effect of Methotrexate Carried by a Lipid Nanoemulsion on Left Ventricular Remodeling After STEMI
A Phase 2/3 study testing Methotrexate and Folic Acid in people with Myocardial Infarction, Anterior Wall and Myocardial Remodeling, Ventricular, run by University of Sao Paulo at 1 site in Brazil.
Trial summary
Prospective, randomized, double-blind, placebo-controlled, proof of concept study. Patients with first anterior wall STEMI will be randomized with 4±2 days after symptoms beginning to receive ddMTX-LDE at the dose of 40 mg/m2 IV or placebo-LDE weekly for 6 weeks. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Myocardial Infarction, Anterior Wall, Myocardial Remodeling, Ventricular
- What is being tested?
- Methotrexate and Folic Acid
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 35 participants
- Where
- 1 siteBrazil
- Study dates
- 17 Apr 2018to 17 Dec 2020
- Phase
- Phase 2/3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients with type 1 STEMI, documented by: ischemic symptoms, new ST-elevation at the J-point 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 or new left bundle branch block [LBBB]) and cardiac biomarkers (troponin and/or creatine kinase MB) with at least one value above the 99th percentile of the upper reference limit (URL).
- Submitted to any successful repercussion strategy (thrombolysis or angioplasty).
- Coronary angiography showing successful reperfusion therapy (Thrombolysis in Myocardial Infarction [TIMI] flow grade 3 in the infarct-related artery) and residual obstruction in the infarct-related artery < 50%.
- Asymptomatic, without signs of clinical decompensation (heart rate < 100bpm, systolic blood pressure > 90mmHg, without vasoactive dor inotropic drugs, pulse oximetry > 95% with FiO2 21%).
- Signing the study informed consent.
Who cannot join
- History of AMI.
- Estimated glomerular filtration rate < 40 mL/min/1.73 m2.
- Contraindications for CMR: pacemaker, metallic devices, claustrophobia, obesity over 150 kg total weight.
- Prior history of chronic infectious disease, including tuberculosis, severe fungal disease, or known HIV positive.
- Chronic hepatitis B or C infection.
- Interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis.
Show all 21Show fewer
- Chest x-ray evidence in the past 12 months of interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis.
- Prior history of nonbasal cell malignancy or myeloproliferative or lymphoproliferative disease within the past 5 years.
- White blood cell count <4000/mm3, hematocrit <32%, or platelet count <75000/mm3.
- Alanine aminotransferase levels (ALT) greater than 2-fold the upper limit of normal.
- History of alcohol abuse or unwillingness to limit alcohol consumption to < 4 drinks per week.
- Pregnancy or breastfeeding.
- Women of child bearing potential, even if currently using contraception.
- Men who plan to father children during the study period or who are unwilling to use contraception.
- Requirement for use of drugs that alter folate metabolism (trimethoprim/sulfamethoxazol) or reduce tubular excretion (probenecid) or known allergies to antibiotics making avoidance of trimethoprim impossible.
- Current indication for methotrexate therapy.
- Chronic use of oral steroid therapy or other immunosuppressive or biologic response modifiers.
- Known chronic pericardial effusion, pleural effusion, or ascites.
- New York Heart Association class III-IV congestive heart failure.
- Life expectancy of < 1 years.
- Active infection.
Trial locations and contacts
1 site in 1 country.
Brazil1 site
Heart Institute (InCor) - University of São Paulo Medical School, São Paulo, Brazil
São Paulo
About this study
Official title: Effect of Methotrexate Carried by a Lipid Nanoemulsion on Left Ventricular Remodeling After ST-elevation Myocardial Infarction
Prospective, randomized, double-blind, placebo-controlled, proof of concept study. Patients with first anterior wall STEMI will be randomized with 4±2 days after symptoms beginning to receive ddMTX-LDE at the dose of 40 mg/m2 IV or placebo-LDE weekly for 6 weeks. All study participants will additionally receive folic acid (5 mg po qd) once a week, one day after the study drug. The primary and main secondary endpoints will be analyzed by CMR 3±1 days and at 90±7 days after randomization.
Patients will undergo clinical and laboratory safety evaluations before each study drug administration and 90-day post-randomization. Safety evaluations will include assessment of adherence, side effects, safety laboratory tests, and existing medical conditions or planned procedures that might alter study drug dosing. These visits also include screening for the occurrence of clinical events of interest. An algorithm for drug suspension based on clinical and laboratory finding will be followed.
Pre-specified unblinded interim analyses by an independent investigator will be developed when 20% and 50% of the inclusions are reached.
Read the detailed description
Inflammation is extremely important in atherosclerosis and atherothrombosis pathophysiology. It is similarly important after acute myocardial infarction (AMI), with a special participation on healing response and, consequently, on left ventricular remodeling (LVR).
Early successful reperfusion is highly effective for limiting tissue necrosis and improving outcomes in AMI, but many of these patients show microcirculation dysfunction, phenomenon related to inflammation, leading to worse LVR. Additionally, inflammation may extend into the noninfarcted remote myocardium, which also contribute to adverse LVR.
As pointed out by Westman et al in a recent review publication, although infarct size correlates with the development of adverse LVR, some patients with relatively small infarcts have adverse LVR, while others with larger infarcts do not. Individual differences in the inflammatory response, perhaps in part genetically, epigenetically, environmentally, or pathogenically modulated, may contribute to this phenomenon.
The use of inflammatory biomarkers to predict risk, monitor treatments and guide therapy, has shown substantial potential for clinical applicability. Many studies in primary and secondary prevention of cardiovascular disease (CVD) showed that individuals with lower high sensitive C-reactive protein (hsCRP) have better clinical outcomes than those with higher levels.
So, anti-inflammatory therapies may be useful in preventing left ventricular dysfunction following AMI despite reperfusion and anti-remodeling treatments.
Among those, methotrexate (MTX) is an anti-inflammatory drug widely used in rheumatology and oncology. It reduces several inflammatory biomarkers including hs-CRP, interleukin 6 (IL-6), and tumor necrosis factor α (TNF α), without affecting negatively lipid, homocysteine or glucose levels, or blood pressure. Besides that, there are reports showing that MTX directly or indirectly releases endogenous anti-inflammatory adenosine, which could be especially useful in AMI patients.
In a systematic review with rheumatologic patients (including rheumatoid arthritis, psoriasis or polyarthritis), methotrexate was associated with 21% lower risk for total cardiovascular disease (CVD) and 18% lower risk for AMI, suggesting that a direct treatment of inflammation with this drug may reduce the risk of CVD in general.
To explore this option of treatment, the CIRT (Cardiovascular Inflammation Reduction Trial) was designed to evaluate the effect of methotrexate for secondary prevention on high risk patients with chronic stable coronary disease; this study is currently ongoing.
Although a potent anti-inflammatory drug, special attention must be given to methotrexate contraindications and numerous potential adverse effects. To overcome this issue, Moura et al developed a new formulation using a lipophilic derivative of methotrexate, ie, didodecyl methotrexate (ddMTX), associated with a lipid nanoemulsion (ddMTX-LDE).
Lipid nanoemulsions (LDE) that bind to low-density lipoprotein receptors was first developed and studied in the cancer scenario by Maranhão et al, who demonstrated that it concentrates the chemotherapeutic agents in tissues with low-density lipoprotein receptor overexpression, decreasing the toxicity of the treatment. The lipid nanoemulsion was already tested in patients with acute leukaemia, multiple myeloma and Hodgkin's and non-Hodgkin's lymphoma, suggesting that LDE is taken up by malignant cells with increased LDL receptors and that LDE, as drug-targeting vehicle, is suitable for patient use.
The ddMTX-LDE formulation was shown to be stable and uptake of the formulation by neoplastic cells in vitro was remarkably greater than of commercial methotrexate preparation, with much lower haematological toxicity. A study with intravenous ddMTX-LDE in rabbits showed anti-inflammatory effects on the synovia of arthritic joints that were clearly superior to the effects of a commercial methotrexate preparation. These results are conceivably due to greater methotrexate uptake by the joints when the drug is associated with a nanoemulsion. Another study with rabbits fed with high cholesterol diet showed that ddMTX-LDE reduced vessel inflammation and atheromatous lesions.
In Wistar rats with induced AMI treated with LDE without drug, commercial MTX and ddMTX-LDE, we demonstrated significant improvement in LVR along with infarct size reduction in the group ddMTX-LDE, in comparison with the groups commercial MTX and LDE without drug.
The above rational is the basis for the present project, where by the first time the role of LDE methotrexate formulation in humans, regarding LV remodelling post ST-segment elevation myocardial infarction (STEMI), will be tested.
- Being tested
- Methotrexate, Placebo, Folic Acid
- Keywords
- Anterior myocardial infarction, Methotrexate, Myocardial remodeling
- Medical subject headings
- Anterior Wall Myocardial Infarction, Ventricular Remodeling
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MethotrexateDrug
Also called Methotrexate carried by a lipid nanoemulsion (ddMTX-LDE)
ddMTX-LDE (Methotrexate carried by a lipid nanoemulsion)
PlaceboDrug
Also called Placebo-LDE
Placebo-LDE (Lipid nanoemulsion)
Folic AcidDrug
Also called FoliFolin (EMS)
Folic acid pill
| Study group | Role | What they receive |
|---|---|---|
| Methotrexate & Folic acid | Active comparator | ddMTX-LDE 40mg/m2 (100mL total volume) IV and Folic acid 5mg by mouth (the day after ddMTX-LDE) weekly for 6 weeks Receives: Drug: Methotrexate; Drug: Folic Acid |
| Placebo & folic acid | Placebo comparator | Placebo-LDE IV 100mL and Folic acid 5mg by mouth (the day after Placedo-LDE) weekly for 6 weeks Receives: Drug: Placebo; Drug: Folic Acid |
What is being measured
The primary outcome is the main question the study is designed to answer.
Ventricular Remodelling
Compare left ventricular end-diastolic volume (LVEDV) measured by cardiac magnetic resonance (CMR) between ddMTX-LDE and Placebo-LDE groups.
Measured: 90±7 days
Secondary outcomes (15)
Left ventricular end-systolic volume (LVESV)
Compare LVESV measured by CMR between ddMTX-LDE and Placebo-LDE groups.
Measured: 90±7 days
Left ventricular ejection fraction (LVEF)
Compare LVEF measured by CMR between ddMTX-LDE and Placebo-LDE groups.
Measured: 90±7 days
Left ventricular mass (LVM)
Compare LVM measured by CMR between ddMTX-LDE and Placebo-LDE groups.
Measured: 90±7 days
Infarct size
Compare infarct size measured by CMR between ddMTX-LDE and Placebo-LDE groups.
Measured: 90±7 days
Positive remodelling
Compare the percentual of patients with positive (≥20% increase on LVEDV) remodelling measured by CMR between ddMTX-LDE and Placebo-LDE groups.
Measured: 90±7 days
Negative remodelling
Compare the percentual of patients with negative (≥ 10% decrease on LVESV) remodelling measured by CMR between ddMTX-LDE and Placebo-LDE groups.
Measured: 90±7 days
Clinical significant symptoms
Compare the incidence of clinical significant symptoms (new and persistent stomatitis, vomiting, diarrhea, unexplained cough with fever or shortness of breath) reported in each visit between ddMTX-LDE and Placebo-LDE groups.
Measured: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Other adverse events
Compare the incidence of other adverse events (not expected) between ddMTX-LDE and Placebo-LDE groups.
Measured: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Mean red blood cell count
Compare haemoglobin and hematocrits levels between ddMTX-LDE and Placebo-LDE groups.
Measured: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Mean white blood cell count
Compare leucocyte and neutrophil levels between ddMTX-LDE and Placebo-LDE groups.
Measured: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Platelet count
Compare total platelet count between ddMTX-LDE and Placebo-LDE groups.
Measured: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Alanine aminotransferase (ALT)
Compare ALT levels (in units per litre) between ddMTX-LDE and Placebo-LDE groups.
Measured: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Aspartate aminotransferase (AST)
Compare AST levels (in units per litre) between ddMTX-LDE and Placebo-LDE groups.
Measured: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Bilirubin
Compare bilirubin levels (in miligrams per decilitre) between ddMTX-LDE and Placebo-LDE groups.
Measured: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Creatinine clearance
Compare creatinine clearance measured by MDRD-4 variable equation between ddMTX-LDE and Placebo-LDE groups.
Measured: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 May 2018
- Study start17 Apr 2018
- Primary completion17 Dec 2020
- Study completion17 Dec 2020
Why it stopped: Due to the COVID-19 pandemic. With a second wave just beginning, and considering that we are testing an immunosuppressant in patients with high risk for COVID-19 complications, we would not be able to re-start recruitment safely in the near future.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (46)Papers the sponsor has linked to this study.
- Other trials for Myocardial Infarction, Anterior WallStudies of the same condition, open and under way.
- More trials run by University of Sao PauloThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 35 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Sao Paulo
- Sponsor type
- University, hospital or other
- Collaborators
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- Responsible party
- Principal investigator, Jose Carlos Nicolau, University of Sao Paulo
- Investigators
- José C. Nicolau, MD, PhD, Study chair, InCor Heart InstituteAline G. Ferrari, MD, Principal investigator, InCor Heart InstituteRocío Salsoso, PhD, Principal investigator, InCor Heart Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03516903
- Sponsor's protocol ID
- CAAE 68743417.5.0000.0068
- Other IDs
- SCOC SDC: 4508/17/008
- Status last verified
- Jan 2021
- First submitted
- 10 Apr 2018
- Last updated
- 11 Jan 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: IPD can be shared after reasonable request approved by the study coordination.
Publications
Libby P, Ridker PM, Hansson GK; Leducq Transatlantic Network on Atherothrombosis. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009 Dec 1;54(23):2129-38. doi: 10.1016/j.jacc.2009.09.009.
PubMed 19942084Frangogiannis NG. The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol. 2014 May;11(5):255-65. doi: 10.1038/nrcardio.2014.28. Epub 2014 Mar 25.
PubMed 24663091Nicolau JC, Maia LN, Vitola J, Vaz VD, Machado MN, Godoy MF, Giraldez RR, Ramires JA. ST-segment resolution and late (6-month) left ventricular remodeling after acute myocardial infarction. Am J Cardiol. 2003 Feb 15;91(4):451-3. doi: 10.1016/s0002-9149(02)03245-9. No abstract available.
PubMed 12586264Kempf T, Zarbock A, Vestweber D, Wollert KC. Anti-inflammatory mechanisms and therapeutic opportunities in myocardial infarct healing. J Mol Med (Berl). 2012 Apr;90(4):361-9. doi: 10.1007/s00109-011-0847-y. Epub 2012 Jan 7.
PubMed 22228177Westman PC, Lipinski MJ, Luger D, Waksman R, Bonow RO, Wu E, Epstein SE. Inflammation as a Driver of Adverse Left Ventricular Remodeling After Acute Myocardial Infarction. J Am Coll Cardiol. 2016 May 3;67(17):2050-60. doi: 10.1016/j.jacc.2016.01.073.
PubMed 27126533Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, Gotto AM Jr; Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001 Jun 28;344(26):1959-65. doi: 10.1056/NEJM200106283442601.
PubMed 11430324Ridker PM, Morrow DA, Rose LM, Rifai N, Cannon CP, Braunwald E. Relative efficacy of atorvastatin 80 mg and pravastatin 40 mg in achieving the dual goals of low-density lipoprotein cholesterol <70 mg/dl and C-reactive protein <2 mg/l: an analysis of the PROVE-IT TIMI-22 trial. J Am Coll Cardiol. 2005 May 17;45(10):1644-8. doi: 10.1016/j.jacc.2005.02.080. Epub 2005 Apr 25.
PubMed 15893181Morrow DA, de Lemos JA, Sabatine MS, Wiviott SD, Blazing MA, Shui A, Rifai N, Califf RM, Braunwald E. Clinical relevance of C-reactive protein during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial. Circulation. 2006 Jul 25;114(4):281-8. doi: 10.1161/CIRCULATIONAHA.106.628909. Epub 2006 Jul 17.
PubMed 16847150Wilson PW, Pencina M, Jacques P, Selhub J, D'Agostino R Sr, O'Donnell CJ. C-reactive protein and reclassification of cardiovascular risk in the Framingham Heart Study. Circ Cardiovasc Qual Outcomes. 2008 Nov;1(2):92-7. doi: 10.1161/CIRCOUTCOMES.108.831198. Epub 2008 Nov 9.
PubMed 20031795Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, Macfadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ; JUPITER Trial Study Group. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009 Apr 4;373(9670):1175-82. doi: 10.1016/S0140-6736(09)60447-5. Epub 2009 Mar 28.
PubMed 19329177Emerging Risk Factors Collaboration; Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R, Danesh J. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010 Jan 9;375(9709):132-40. doi: 10.1016/S0140-6736(09)61717-7. Epub 2009 Dec 22.
PubMed 20031199Wessels JA, Huizinga TW, Guchelaar HJ. Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis. Rheumatology (Oxford). 2008 Mar;47(3):249-55. doi: 10.1093/rheumatology/kem279. Epub 2007 Nov 28.
PubMed 18045808Rho YH, Oeser A, Chung CP, Milne GL, Stein CM. Drugs Used in the Treatment of Rheumatoid Arthritis: Relationship between Current Use and Cardiovascular Risk Factors. Arch Drug Inf. 2009 Jun;2(2):34-40. doi: 10.1111/j.1753-5174.2009.00019.x.
PubMed 19684849Baggott JE, Morgan SL, Sams WM, Linden J. Urinary adenosine and aminoimidazolecarboxamide excretion in methotrexate-treated patients with psoriasis. Arch Dermatol. 1999 Jul;135(7):813-7. doi: 10.1001/archderm.135.7.813.
PubMed 10411156DiNicola AF. Letter: The endogenous catabolic traumatic triad syndrome. N Z Med J. 1975 Jul 9;82(543):27-8. No abstract available.
PubMed 1057756
Study at a glance
From the registry record, last updated by the sponsor on 11 Jan 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Methotrexate Carried by a Lipid Nanoemulsion on Left Ventricular Remodeling After ST-elevation Myocardial Infarction
- ClinicalTrials.gov ID
- NCT03516903
- Acronym / sponsor ID
- CAAE 68743417.5.0000.0068
- Keywords
- Anterior myocardial infarction, Methotrexate, Myocardial remodeling
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Due to the COVID-19 pandemic. With a second wave just beginning, and considering that we are testing an immunosuppressant in patients with high risk for COVID-19 complications, we would not be able to re-start recruitment safely in the near future.
- Enrolment
- 35 participants (actual)
- Lead sponsor
- University of Sao PauloUniversity, hospital or other
- Collaborators
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- Study start
- 17 Apr 2018 (actual)
- Primary completion
- 17 Dec 2020 (actual)
- Study completion
- 17 Dec 2020 (actual)
- First posted
- 7 May 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Prospective, randomized, double-blind, placebo-controlled, proof of concept study. Patients with first anterior wall STEMI will be randomized with 4±2 days after symptoms beginning to receive ddMTX-LDE at the dose of 40 mg/m2 IV or placebo-LDE weekly for 6 weeks. All study participants will additionally receive folic acid (5 mg po qd) once a week, one day after the study drug. The primary and main secondary endpoints will be analyzed by CMR 3±1 days and at 90±7 days after randomization.
Patients will undergo clinical and laboratory safety evaluations before each study drug administration and 90-day post-randomization. Safety evaluations will include assessment of adherence, side effects, safety laboratory tests, and existing medical conditions or planned procedures that might alter study drug dosing. These visits also include screening for the occurrence of clinical events of interest. An algorithm for drug suspension based on clinical and laboratory finding will be followed.
Pre-specified unblinded interim analyses by an independent investigator will be developed when 20% and 50% of the inclusions are reached.
Detailed description
Inflammation is extremely important in atherosclerosis and atherothrombosis pathophysiology. It is similarly important after acute myocardial infarction (AMI), with a special participation on healing response and, consequently, on left ventricular remodeling (LVR).
Early successful reperfusion is highly effective for limiting tissue necrosis and improving outcomes in AMI, but many of these patients show microcirculation dysfunction, phenomenon related to inflammation, leading to worse LVR. Additionally, inflammation may extend into the noninfarcted remote myocardium, which also contribute to adverse LVR.
As pointed out by Westman et al in a recent review publication, although infarct size correlates with the development of adverse LVR, some patients with relatively small infarcts have adverse LVR, while others with larger infarcts do not. Individual differences in the inflammatory response, perhaps in part genetically, epigenetically, environmentally, or pathogenically modulated, may contribute to this phenomenon.
The use of inflammatory biomarkers to predict risk, monitor treatments and guide therapy, has shown substantial potential for clinical applicability. Many studies in primary and secondary prevention of cardiovascular disease (CVD) showed that individuals with lower high sensitive C-reactive protein (hsCRP) have better clinical outcomes than those with higher levels.
So, anti-inflammatory therapies may be useful in preventing left ventricular dysfunction following AMI despite reperfusion and anti-remodeling treatments.
Among those, methotrexate (MTX) is an anti-inflammatory drug widely used in rheumatology and oncology. It reduces several inflammatory biomarkers including hs-CRP, interleukin 6 (IL-6), and tumor necrosis factor α (TNF α), without affecting negatively lipid, homocysteine or glucose levels, or blood pressure. Besides that, there are reports showing that MTX directly or indirectly releases endogenous anti-inflammatory adenosine, which could be especially useful in AMI patients.
In a systematic review with rheumatologic patients (including rheumatoid arthritis, psoriasis or polyarthritis), methotrexate was associated with 21% lower risk for total cardiovascular disease (CVD) and 18% lower risk for AMI, suggesting that a direct treatment of inflammation with this drug may reduce the risk of CVD in general.
To explore this option of treatment, the CIRT (Cardiovascular Inflammation Reduction Trial) was designed to evaluate the effect of methotrexate for secondary prevention on high risk patients with chronic stable coronary disease; this study is currently ongoing.
Although a potent anti-inflammatory drug, special attention must be given to methotrexate contraindications and numerous potential adverse effects. To overcome this issue, Moura et al developed a new formulation using a lipophilic derivative of methotrexate, ie, didodecyl methotrexate (ddMTX), associated with a lipid nanoemulsion (ddMTX-LDE).
Lipid nanoemulsions (LDE) that bind to low-density lipoprotein receptors was first developed and studied in the cancer scenario by Maranhão et al, who demonstrated that it concentrates the chemotherapeutic agents in tissues with low-density lipoprotein receptor overexpression, decreasing the toxicity of the treatment. The lipid nanoemulsion was already tested in patients with acute leukaemia, multiple myeloma and Hodgkin's and non-Hodgkin's lymphoma, suggesting that LDE is taken up by malignant cells with increased LDL receptors and that LDE, as drug-targeting vehicle, is suitable for patient use.
The ddMTX-LDE formulation was shown to be stable and uptake of the formulation by neoplastic cells in vitro was remarkably greater than of commercial methotrexate preparation, with much lower haematological toxicity. A study with intravenous ddMTX-LDE in rabbits showed anti-inflammatory effects on the synovia of arthritic joints that were clearly superior to the effects of a commercial methotrexate preparation. These results are conceivably due to greater methotrexate uptake by the joints when the drug is associated with a nanoemulsion. Another study with rabbits fed with high cholesterol diet showed that ddMTX-LDE reduced vessel inflammation and atheromatous lesions.
In Wistar rats with induced AMI treated with LDE without drug, commercial MTX and ddMTX-LDE, we demonstrated significant improvement in LVR along with infarct size reduction in the group ddMTX-LDE, in comparison with the groups commercial MTX and LDE without drug.
The above rational is the basis for the present project, where by the first time the role of LDE methotrexate formulation in humans, regarding LV remodelling post ST-segment elevation myocardial infarction (STEMI), will be tested.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Methotrexate & Folic acid | Active comparator | Drug: Methotrexate, Drug: Folic AcidddMTX-LDE 40mg/m2 (100mL total volume) IV and Folic acid 5mg by mouth (the day after ddMTX-LDE) weekly for 6 weeks |
| Placebo & folic acid | Placebo comparator | Drug: Placebo, Drug: Folic AcidPlacebo-LDE IV 100mL and Folic acid 5mg by mouth (the day after Placedo-LDE) weekly for 6 weeks |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Patients with type 1 STEMI, documented by: ischemic symptoms, new ST-elevation at the J-point 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 or new left bundle branch block [LBBB]) and cardiac biomarkers (troponin and/or creatine kinase MB) with at least one value above the 99th percentile of the upper reference limit (URL).
- Submitted to any successful repercussion strategy (thrombolysis or angioplasty).
- Coronary angiography showing successful reperfusion therapy (Thrombolysis in Myocardial Infarction [TIMI] flow grade 3 in the infarct-related artery) and residual obstruction in the infarct-related artery < 50%.
- Asymptomatic, without signs of clinical decompensation (heart rate < 100bpm, systolic blood pressure > 90mmHg, without vasoactive dor inotropic drugs, pulse oximetry > 95% with FiO2 21%).
- Signing the study informed consent.
Key exclusion criteria (21 listed)
- History of AMI.
- Estimated glomerular filtration rate < 40 mL/min/1.73 m2.
- Contraindications for CMR: pacemaker, metallic devices, claustrophobia, obesity over 150 kg total weight.
- Prior history of chronic infectious disease, including tuberculosis, severe fungal disease, or known HIV positive.
- Chronic hepatitis B or C infection.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MethotrexateAlso: Methotrexate carried by a lipid nanoemulsion (ddMTX-LDE)ddMTX-LDE (Methotrexate carried by a lipid nanoemulsion) | Drug | Methotrexate & Folic acid |
| PlaceboAlso: Placebo-LDEPlacebo-LDE (Lipid nanoemulsion) | Drug | Placebo & folic acid |
| Folic AcidAlso: FoliFolin (EMS)Folic acid pill | Drug | Methotrexate & Folic acid, Placebo & folic acid |
Primary outcome
Ventricular Remodelling
Time frame: 90±7 days
Compare left ventricular end-diastolic volume (LVEDV) measured by cardiac magnetic resonance (CMR) between ddMTX-LDE and Placebo-LDE groups.
15 secondary outcomes
Left ventricular end-systolic volume (LVESV)
Time frame: 90±7 days
Left ventricular ejection fraction (LVEF)
Time frame: 90±7 days
Left ventricular mass (LVM)
Time frame: 90±7 days
Infarct size
Time frame: 90±7 days
Positive remodelling
Time frame: 90±7 days
Negative remodelling
Time frame: 90±7 days
Clinical significant symptoms
Time frame: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Other adverse events
Time frame: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Mean red blood cell count
Time frame: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Mean white blood cell count
Time frame: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Platelet count
Time frame: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Alanine aminotransferase (ALT)
Time frame: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Aspartate aminotransferase (AST)
Time frame: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Bilirubin
Time frame: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Creatinine clearance
Time frame: 7±1, 14±1, 21±1, 28±1, 35±1 and 90±7 days
Results and safety
The study was stopped early (reason given: Due to the COVID-19 pandemic. With a second wave just beginning, and considering that we are testing an immunosuppressant in patients with high risk for COVID-19 complications, we would not be able to re-start recruitment safely in the near future.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Jan 2021.
- Background: PubMed 19942084Libby P, Ridker PM, Hansson GK; Leducq Transatlantic Network on Atherothrombosis. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009 Dec 1;54(23):2129-38. doi: 10.1016/j.jacc.2009.09.009.
- Background: PubMed 24663091Frangogiannis NG. The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol. 2014 May;11(5):255-65. doi: 10.1038/nrcardio.2014.28. Epub 2014 Mar 25.
- Background: PubMed 12586264Nicolau JC, Maia LN, Vitola J, Vaz VD, Machado MN, Godoy MF, Giraldez RR, Ramires JA. ST-segment resolution and late (6-month) left ventricular remodeling after acute myocardial infarction. Am J Cardiol. 2003 Feb 15;91(4):451-3. doi: 10.1016/s0002-9149(02)03245-9. No abstract available.
- Background: PubMed 22228177Kempf T, Zarbock A, Vestweber D, Wollert KC. Anti-inflammatory mechanisms and therapeutic opportunities in myocardial infarct healing. J Mol Med (Berl). 2012 Apr;90(4):361-9. doi: 10.1007/s00109-011-0847-y. Epub 2012 Jan 7.
- Background: PubMed 27126533Westman PC, Lipinski MJ, Luger D, Waksman R, Bonow RO, Wu E, Epstein SE. Inflammation as a Driver of Adverse Left Ventricular Remodeling After Acute Myocardial Infarction. J Am Coll Cardiol. 2016 May 3;67(17):2050-60. doi: 10.1016/j.jacc.2016.01.073.
- Background: PubMed 11430324Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, Gotto AM Jr; Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001 Jun 28;344(26):1959-65. doi: 10.1056/NEJM200106283442601.
- Background: PubMed 15893181Ridker PM, Morrow DA, Rose LM, Rifai N, Cannon CP, Braunwald E. Relative efficacy of atorvastatin 80 mg and pravastatin 40 mg in achieving the dual goals of low-density lipoprotein cholesterol <70 mg/dl and C-reactive protein <2 mg/l: an analysis of the PROVE-IT TIMI-22 trial. J Am Coll Cardiol. 2005 May 17;45(10):1644-8. doi: 10.1016/j.jacc.2005.02.080. Epub 2005 Apr 25.
- Background: PubMed 16847150Morrow DA, de Lemos JA, Sabatine MS, Wiviott SD, Blazing MA, Shui A, Rifai N, Califf RM, Braunwald E. Clinical relevance of C-reactive protein during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial. Circulation. 2006 Jul 25;114(4):281-8. doi: 10.1161/CIRCULATIONAHA.106.628909. Epub 2006 Jul 17.
- Background: PubMed 20031795Wilson PW, Pencina M, Jacques P, Selhub J, D'Agostino R Sr, O'Donnell CJ. C-reactive protein and reclassification of cardiovascular risk in the Framingham Heart Study. Circ Cardiovasc Qual Outcomes. 2008 Nov;1(2):92-7. doi: 10.1161/CIRCOUTCOMES.108.831198. Epub 2008 Nov 9.
- Background: PubMed 19329177Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, Macfadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ; JUPITER Trial Study Group. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009 Apr 4;373(9670):1175-82. doi: 10.1016/S0140-6736(09)60447-5. Epub 2009 Mar 28.
- Background: PubMed 20031199Emerging Risk Factors Collaboration; Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R, Danesh J. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010 Jan 9;375(9709):132-40. doi: 10.1016/S0140-6736(09)61717-7. Epub 2009 Dec 22.
- Background: PubMed 18045808Wessels JA, Huizinga TW, Guchelaar HJ. Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis. Rheumatology (Oxford). 2008 Mar;47(3):249-55. doi: 10.1093/rheumatology/kem279. Epub 2007 Nov 28.
- Individual participant dataSharing planned: Yes. IPD can be shared after reasonable request approved by the study coordination.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
José C. Nicolau, MD, PhD study chair
InCor Heart Institute
Aline G. Ferrari, MD principal investigator
InCor Heart Institute
Rocío Salsoso, PhD principal investigator
InCor Heart Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Methotrexate and Folic Acid in people with Myocardial Infarction, Anterior Wall and Myocardial Remodeling, Ventricular, run by University of Sao Paulo at 1 site in Brazil.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 11 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Brazil. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Due to the COVID-19 pandemic. With a second wave just beginning, and considering that we are testing an immunosuppressant in patients with high risk for COVID-19 complications, we would not be able to re-start recruitment safely in the near future.). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Ventricular Remodelling (time frame: 90±7 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03516903, which also lists 46 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jan 2021.