Ignite Creation Date:
2024-05-06 @ 7:49 PM
Last Modification Date:
2024-10-26 @ 3:15 PM
Study NCT ID:
NCT06158698
Status:
RECRUITING
Last Update Posted:
2024-01-09
First Post:
2023-11-15
Brief Title:
CMP-MYTHiC Trial and Registry - CardioMyoPathy With MYocarditis THerapy With Colchicine
Sponsor:
Niguarda Hospital
Organization:
Niguarda Hospital
Study Overview
Official Title:
Single-blinded Randomized Investigator-initiated Controlled Trial to Assess the Efficacy of Colchicine to Treat Patients With Cardiomyopathy With Myocarditis Chronic Inflammatory Cardiomyopathy
Status:
RECRUITING
Status Verified Date:
2024-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
CMP-MYTHiC
Brief Summary:
Two-parallel groups randomized single-blinded multi-center phase III controlled trial in patients with chronic inflammatory cardiomyopathy to assess the efficacy of colchicine and associated prospective registry to assess the prognostic value of positive genetic testing in this population
Detailed Description:
In a proportion of patients myocarditis an inflammatory injury of cardiomyocytes CMs can lead to chronic inflammatory cardiomyopathy Infl-CMP characterized by an increased risk of life-threatening ventricular arrhythmias VA or ventricular dysfunction and heart failure HF Most cases of myocarditis have a viral trigger or an autoimmune etiology while genetic predisposition has been sporadically reported Recent data point to a relevant role of genetics with pathogenic genetic variants associated with dilated or arrhythmic cardiomyopathies found in 8-31 of patients with Infl-CMP and left ventricular LV systolic dysfunction Occasionally patients with myocarditis may have a positive family history of cardiomyopathy or sudden cardiac death SCD which can lead to genetic testing for myopathic cardiac gene variants MCGV Small series showed the co-existence of myocarditis and MCGV in patients with dilated cardiomyopathy In this complex background it is still unclear whether targeting myocardial inflammation with immunomodulating drugs can ameliorate the outcome of these patients
TRIAL - The Investigators will conduct a Trial to assess whether in patients with Infl-CMP with VA or HF phenotype colchicine compared with placebo can reduce myocardial inflammation improving the clinical condition of patients In the trial both patients with positive MCGV and negative MCGV will be randomized and the investigators check if the genetic background can affect the response to colchicine The target of this pilot trial is to randomize 40 patients in each arm and have ideally 15 patients with MCGV in each arm The use of colchicine in our proposal of trial relies on the safety of colchicine and the relatively low rate of side effects at low dosages It has shown that colchicine performs its functions by inhibiting the activation of pore formation carried out by P2X2 and P2X7 receptors that concur to the activation of the inflammasome thus potentially targeting a specific cause observed in Infl-CMP
In a pilot randomized and single-blinded trial the investigators look at the immunomodulating effect of colchicine 05-1 mg vs placebo in patients with Infl-CMP based on cardiac magnetic resonance imaging CMRI or fluorodeoxyglucose FGD-positron emission tomography PET scan with VA including high premature ventricular complexes PVC burden reduced LV ejection fraction EF or significantly increased levels of natriuretic peptides but without indication to immunosuppression ie associated systemic autoimmune disorders to assess whether colchicine can improve myocardial inflammation or decrease troponin release or the burden of PVCs or improve the clinical outcome major VA HF hospitalizations The duration of the trial will be 6 months The rationale of the pilot CMP-MYTHiC CardioMyoPathy with MYocarditis THerapy with Colchicine trial is based on a recent registry of 55 symptomatic patients with 5000 premature ventricular complexes PVCs24 hours with FDG-PET imaging consistent with Infl-CMP where a signal of benefit was observed in patients who received prednisone 40 mg for 3 months The benefit was defined as a reduction in the PVC burden 80 and negative FDG-PET scan at follow-up It must be noted that up to 24 of these cases had a diagnosis of sarcoidosis where there is already an indication to therapy with steroids In this study MAVERIC registry the improvement of patients treated with prednisone alone was 84 vs 33 in patients not taking prednisone As the investigators expect a lower effect of colchicine compared with prednisone but with a safer drug profile than prednisone the investigators considered a theoretical optimal response in patients taking colchicine of 66 while the investigators expected a similar optimal response in patients taking placebo as in the MAVERIC registry in patients not taking prednisone Thus considering an increase in the probability to reach the primary endpoint defined as proportion of patients that are alive and free of any worsening clinical arrhythmic burden and imaging outcome and that shows at least one of the signs of improvements IMAGING or ARRHYTMIC improvements at 6 months from 33 in the placebo arm to 66 in the colchicine therapy arm the planned sample size of 80 patients 40 per group will allow achieving a power of 080 with an overall type I error of 0025 using one-sided Fishers Exact test
Endpoints will be analyzed according to the following principles
1 Intention-to-treat ITT population patients according to assigned randomized treatment arm
2 Per Protocol PP population only patients allocated to the colchicine therapy arm who took the drug for at least 4 months will be considered in the experimental group Patients assigned to the colchicine therapy arm that will receive less than 4-month colchicine therapy will be excluded from this population Likely patients allocated to the optimal medical therapy with placebo will be included if they have taken the placebo therapy for at least 4 months Patients allocated to the treatment or placebo that will receive any immunosuppressive agents eg corticosteroids for at least 1 month during the trial will be excluded from this population
3 A sensitivity analysis will also be performed on the previously defined populations after excluding patients 1 with an implantable cardioverter defibrillator ICD before randomization 2 who underwent a ventricular ablation before randomization 3 who were diagnosed with a systemic autoimmune disorder or a histological diagnosis of eosinophilic myocarditis cardiac sarcoidosis or giant cell myocarditis after the randomization
REGISTRY - The main aim is to determine if patients with positive MCGV Infl-CMP have a worse outcome compared with patients with negative MCGV - Infl-CMP in terms of recurrence of VA including a high burden of PVCs or HF episodes or reduced improvement of ventricular function or persistence of myocardial inflammation on follow-up CMRI or FDG-PET Furthermore the investigators investigated characteristics that can help to identify patients with likely positive genetic tests among patients presenting with Infl-CMP and variables that are independently associated with prognosis in patients with Infl-CMP If patients have criteria to enter the registry but not the trial or 2 if do not consent to be randomized while they are willing to be followed in the registry or 3 if the number of 80 patients is reached in the trial even if the patients have the criteria to be included in the trial these patients will enter the prospective registry The foreseen number of the patients in the registry is 50-70 during the study period To reach the objectives of the registry deep phenotypical characterization of patients presenting with chronic Infl-CMP with VA and HF phenotypes will be performed in association with genetic testing
TRANSLATIONAL STUDY - the investigators will perform translational experiments from the blood sample and endomyocardial biopsy EMB from patients recruited in the trial and the registry if they consent In particular 50 patients the first 25 with positive genetics and 25 with negative genetics who agree to donate 18 mL of their blood will enter the translational study From the blood the investigators will get human-induced pluripotent stem cells iPSC-CM to unveil the molecular mechanisms that are responsible for the inflammatory response in the myocardium As a control group the investigators will involve the first 25 family members of the probands with the negative cardiac phenotype FMPNCP test that agree to be sampled for the same amount of blood The hypothesis of these experiments is that a specific genetic background identified in patients with Inf-CMP is sufficient to induce an inflammatory myocardial response Briefly the investigators will generate tridimensional cardiac tissues EHTs using CMs derived from human-iPSC-CM from patients with MCGV Infl-CMP versus MCGV- Infl- CMP and FMPNCP EHTs and CMs will be subjected to specific mechanical cellular and pharmacological stimuli to unveil the molecular mechanisms that are responsible for the inflammatory response The results of these experiments together with the molecular analysis of EMBs could reveal novel molecular pathways that will be relevant to specific personalized therapeutic approaches
TRIAL - The Investigators will conduct a Trial to assess whether in patients with Infl-CMP with VA or HF phenotype colchicine compared with placebo can reduce myocardial inflammation improving the clinical condition of patients In the trial both patients with positive MCGV and negative MCGV will be randomized and the investigators check if the genetic background can affect the response to colchicine The target of this pilot trial is to randomize 40 patients in each arm and have ideally 15 patients with MCGV in each arm The use of colchicine in our proposal of trial relies on the safety of colchicine and the relatively low rate of side effects at low dosages It has shown that colchicine performs its functions by inhibiting the activation of pore formation carried out by P2X2 and P2X7 receptors that concur to the activation of the inflammasome thus potentially targeting a specific cause observed in Infl-CMP
In a pilot randomized and single-blinded trial the investigators look at the immunomodulating effect of colchicine 05-1 mg vs placebo in patients with Infl-CMP based on cardiac magnetic resonance imaging CMRI or fluorodeoxyglucose FGD-positron emission tomography PET scan with VA including high premature ventricular complexes PVC burden reduced LV ejection fraction EF or significantly increased levels of natriuretic peptides but without indication to immunosuppression ie associated systemic autoimmune disorders to assess whether colchicine can improve myocardial inflammation or decrease troponin release or the burden of PVCs or improve the clinical outcome major VA HF hospitalizations The duration of the trial will be 6 months The rationale of the pilot CMP-MYTHiC CardioMyoPathy with MYocarditis THerapy with Colchicine trial is based on a recent registry of 55 symptomatic patients with 5000 premature ventricular complexes PVCs24 hours with FDG-PET imaging consistent with Infl-CMP where a signal of benefit was observed in patients who received prednisone 40 mg for 3 months The benefit was defined as a reduction in the PVC burden 80 and negative FDG-PET scan at follow-up It must be noted that up to 24 of these cases had a diagnosis of sarcoidosis where there is already an indication to therapy with steroids In this study MAVERIC registry the improvement of patients treated with prednisone alone was 84 vs 33 in patients not taking prednisone As the investigators expect a lower effect of colchicine compared with prednisone but with a safer drug profile than prednisone the investigators considered a theoretical optimal response in patients taking colchicine of 66 while the investigators expected a similar optimal response in patients taking placebo as in the MAVERIC registry in patients not taking prednisone Thus considering an increase in the probability to reach the primary endpoint defined as proportion of patients that are alive and free of any worsening clinical arrhythmic burden and imaging outcome and that shows at least one of the signs of improvements IMAGING or ARRHYTMIC improvements at 6 months from 33 in the placebo arm to 66 in the colchicine therapy arm the planned sample size of 80 patients 40 per group will allow achieving a power of 080 with an overall type I error of 0025 using one-sided Fishers Exact test
Endpoints will be analyzed according to the following principles
1 Intention-to-treat ITT population patients according to assigned randomized treatment arm
2 Per Protocol PP population only patients allocated to the colchicine therapy arm who took the drug for at least 4 months will be considered in the experimental group Patients assigned to the colchicine therapy arm that will receive less than 4-month colchicine therapy will be excluded from this population Likely patients allocated to the optimal medical therapy with placebo will be included if they have taken the placebo therapy for at least 4 months Patients allocated to the treatment or placebo that will receive any immunosuppressive agents eg corticosteroids for at least 1 month during the trial will be excluded from this population
3 A sensitivity analysis will also be performed on the previously defined populations after excluding patients 1 with an implantable cardioverter defibrillator ICD before randomization 2 who underwent a ventricular ablation before randomization 3 who were diagnosed with a systemic autoimmune disorder or a histological diagnosis of eosinophilic myocarditis cardiac sarcoidosis or giant cell myocarditis after the randomization
REGISTRY - The main aim is to determine if patients with positive MCGV Infl-CMP have a worse outcome compared with patients with negative MCGV - Infl-CMP in terms of recurrence of VA including a high burden of PVCs or HF episodes or reduced improvement of ventricular function or persistence of myocardial inflammation on follow-up CMRI or FDG-PET Furthermore the investigators investigated characteristics that can help to identify patients with likely positive genetic tests among patients presenting with Infl-CMP and variables that are independently associated with prognosis in patients with Infl-CMP If patients have criteria to enter the registry but not the trial or 2 if do not consent to be randomized while they are willing to be followed in the registry or 3 if the number of 80 patients is reached in the trial even if the patients have the criteria to be included in the trial these patients will enter the prospective registry The foreseen number of the patients in the registry is 50-70 during the study period To reach the objectives of the registry deep phenotypical characterization of patients presenting with chronic Infl-CMP with VA and HF phenotypes will be performed in association with genetic testing
TRANSLATIONAL STUDY - the investigators will perform translational experiments from the blood sample and endomyocardial biopsy EMB from patients recruited in the trial and the registry if they consent In particular 50 patients the first 25 with positive genetics and 25 with negative genetics who agree to donate 18 mL of their blood will enter the translational study From the blood the investigators will get human-induced pluripotent stem cells iPSC-CM to unveil the molecular mechanisms that are responsible for the inflammatory response in the myocardium As a control group the investigators will involve the first 25 family members of the probands with the negative cardiac phenotype FMPNCP test that agree to be sampled for the same amount of blood The hypothesis of these experiments is that a specific genetic background identified in patients with Inf-CMP is sufficient to induce an inflammatory myocardial response Briefly the investigators will generate tridimensional cardiac tissues EHTs using CMs derived from human-iPSC-CM from patients with MCGV Infl-CMP versus MCGV- Infl- CMP and FMPNCP EHTs and CMs will be subjected to specific mechanical cellular and pharmacological stimuli to unveil the molecular mechanisms that are responsible for the inflammatory response The results of these experiments together with the molecular analysis of EMBs could reveal novel molecular pathways that will be relevant to specific personalized therapeutic approaches
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| PNRR-MAD-2022-12376225 | OTHER_GRANT | European Union- NextGenerationEU | None |