Efficacy of LoDoCo in Improving Exercise Capacity Among Patients With HFpEF and Inflammation

Study Overview
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Brief Summary
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The purpose of this research study is to determine the effectiveness of low dose colchicine (LoDoCo) on measures of exercise capacity, physical function, frailty, and quality of life, among patients with heart failure with chronic stable preserved ejection fraction (HFpEF) and systemic inflammation. The use of LoDoCo in this study is considered investigational as it has not been approved by the Food and Drug Administration (FDA) for the treatment of exercise capacity in patients with HFpEF. Participants will undergo a 1-day screening that includes a blood draw and physical examination. If deemed eligible for the study, participants will undergo a baseline visit within 2 weeks of screening visit that includes physical examination, exercise testing, echocardiography and completion of quality-of-life surveys. Participants will also be randomized at this visit (randomly assigned to a group) to receive either LoDoCo or placebo (inactive substance) for 3 months. Participants will be called back at 3 months for repeat physical examination, blood draws, echocardiography, exercise testing and completion of quality-of-life surveys. Each visit will take about 3 hours. Total study duration is about 3 months.

Detailed Description
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The investigators propose a single-center, double-blind placebo-controlled pilot study of LoDoCo vs. matching placebo among patients with chronic stable HFpEF and systemic inflammation. Patients that meet the eligibility criteria will be recruited prospectively from the UT Southwestern HFpEF program. Outcomes of interest will be assessed at baseline and 3 months. The primary outcome of the trial will be VO2peak indexed to body weight, and key secondary outcomes will include - 6MWD, KCCQ, change in structure and functional parameters of heart and hs-CRP levels. Study Site: UT Southwestern HFpEF program: The UT Southwestern HFpEF program, established in 2021 and is an integrated clinical and research enterprise that is responsible for the clinical care of patients with HFpEF and receives internal referrals from primary care, hospital medicine, geriatrics, and cardiology within the UT Southwestern health system and from clinics and hospitals in Texas and neighboring states. In the last year, the clinic has received over 300 referrals. The clinical program is integrated with an active research program that focuses on the phenotypic characterization of patients with HFpEF with an emphasis on exercise phenotyping. All patients with suspicion of HFpEF have a detailed laboratory, invasive hemodynamic, echocardiographic, and cardiopulmonary exercise testing. An active registry of patients is maintained which currently has  150 participants with an established diagnosis of HFpEF and detailed phenotyping assessment. The HFpEF clinic will serve as the clinical site of the study. Dr. Ambarish Pandey (PI) serves as the medical director of the HFpEF program. Recruitment: Detailed eligibility criteria are listed below. Participants will be drawn from the UT Southwestern HFpEF registry. The target enrollment for the study is 60 participants. Historical records and baseline evaluations will be used to determine eligibility for the study. After informed consent, participants will undergo study assessments as listed below followed by randomization. Study Assessments (screening ): Physical exam and vitals: Height, Weight and vitals - blood pressure, heart rate and SpO2 will be measured Blood tests: Routine blood tests including creatinine, liver function tests, hemoglobin, hematocrit, serum chemistries, hs-CRP, and NT-proBNP. Blood assessments will be performed at the time of the baseline visit and 3-months post-treatment. (30 ml blood will be collected in the whole study) Baseline and randomization (within 2 weeks of screening) Physical exam and vitals: Height, Weight and vitals - blood pressure, heart rate and SpO2 will be measured Echocardiography: Echocardiography (ultrasound tests) of the heart before and after exercise and submaximal handgrip will be performed at baseline and follow-up. This is a non-invasive procedure in which the examination will be performed during supine rest to obtain standard two-dimensional images in the parasternal long and short axis and the apical two and four heart chamber views. To take pictures of patient's heart, a small non-invasive scanning probe with gel that will be applied to the participant's chest. Small adhesive pads will also be placed with wires to measure the participant's heart rate. It is anticipated that this procedure will not take more than 1 hour. 6-minute walking distance: The 6MWD assesses the distance a participant can walk in six minutes. It is a direct and timed measure of walking ability, which is technically simple, reproducible, and when administrators. are well trained, and readily standardized. The goal is for the subject to walk as far as possible in six minutes without running. The subject can self-pace and rest as needed as the subjects traverse back and forth along a marked walkway of 66 feet (20 m). Kansas City Cardiomyopathy Questionnaire: (KCCQ): KCCQ measures Health-Related Quality of Life (HRQOL) and is a disease-specific health status instrument for HF. The approximate completion time is 4-6 minutes. Scores range from 0 to 100, with 0 as the lowest score and 100 as the highest score. Higher scores indicate better health status, fewer symptoms, and greater disease-specific health-related quality of life, respectively. The overall summary score and all domains have been independently demonstrated to be valid, reliable, and responsive to clinical change. The questionnaire consists of 23 items yielding: 7 domain scores (score range): Physical limitation (0-100) Symptom frequency (0-100) Symptom severity (0-100) Symptom stability (0-100) Self-efficacy and knowledge (0-100) Quality of life (0-100) Social limitation (0-100) 2 summary scores (score range): Total symptom score (0-100) Clinical summary score (CSS) (0-100) Overall summary score (score range: 0-100). Cardiopulmonary Exercise testing: VO2peak, Participants will perform a maximal stress test on the upright cycle ergometer (Lode Corival CPET, Groningen, Netherlands). Participants will perform a continuous ramp protocol with a continuous increase in workload until maximal exhaustion. Respiratory gases including oxygen and carbon dioxide will be measured continuously using a metabolic cart (Ultima™ CardioO2 ® gas exchange analysis system; Saint Paul, Minnesota, USA) with measurements of expired oxygen and carbon dioxide and analyzed using Breeze Suit (Saint Paul, Minnesota, USA). The study team will determine maximal heart rate, peak oxygen uptake (VO2), carbon dioxide production (VCO2), pulmonary ventilation (VE), ventilatory equivalents for oxygen (VE/VO2), carbon dioxide (VE/CO2), respiratory exchange ratio (RER), end-tidal partial pressure of oxygen (PETO2), and carbon dioxide (PETCO2). Assessments will be performed at the time of the baseline visit, and 3 months post-treatment. Randomization: After review of baseline assessments. Qualifying Participants will be randomized to active study drug or matching placebo using a 1:1 block randomization scheme. The investigational drug service at UT Southwestern will store the study drug, perform randomization, and dispense the investigational product. Both participants and the study team will be blinded to treatment assignment. 3 months Physical exam and vitals: Height, Weight and vitals - blood pressure, heart rate and SpO2 will be measured Blood tests: Routine blood tests including creatinine, liver function tests, hemoglobin, hematocrit, serum chemistries, hs-CRP, and NT-proBNP. Blood assessments will be performed at the time of the baseline visit and 3-months post-treatment. (30 ml blood will be collected in the whole study) Echocardiography: Echocardiography (ultrasound tests) of the heart before and after exercise and submaximal handgrip will be performed. This is a non-invasive procedure in which the examination will be performed during supine rest to obtain standard two-dimensional images in the parasternal long and short axis and the apical two and four heart chamber views. To take pictures of patient's heart, a small non-invasive scanning probe with gel that will be applied to the participant's chest. Small adhesive pads will also be placed with wires to measure the participant's heart rate. It is anticipated that this procedure will not take more than 1 hour. 6-minute walking distance: The 6MWD assesses the distance a participant can walk in six minutes. It is a direct and timed measure of walking ability, which is technically simple, reproducible, and when administrators. are well trained, and readily standardized. The goal is for the subject to walk as far as possible in six minutes without running. The subject can self-pace and rest as needed as the subjects traverse back and forth along a marked walkway of 66 feet (20 m). Kansas City Cardiomyopathy Questionnaire: (KCCQ): KCCQ measures Health-Related Quality of Life (HRQOL) and is a disease-specific health status instrument for HF. The approximate completion time is 4-6 minutes. Scores range from 0 to 100, with 0 as the lowest score and 100 as the highest score. Higher scores indicate better health status, fewer symptoms, and greater disease-specific health-related quality of life, respectively. The overall summary score and all domains have been independently demonstrated to be valid, reliable, and responsive to clinical change. The questionnaire consists of 23 items yielding: 7 domain scores (score range): Physical limitation (0-100) Symptom frequency (0-100) Symptom severity (0-100) Symptom stability (0-100) Self-efficacy and knowledge (0-100) Quality of life (0-100) Social limitation (0-100) 2 summary scores (score range): Total symptom score (0-100) Clinical summary score (CSS) (0-100) Overall summary score (score range: 0-100). Cardiopulmonary Exercise testing: VO2peak, Participants will perform a maximal stress test on the upright cycle ergometer (Lode Corival CPET, Groningen, Netherlands). Participants will perform a continuous ramp protocol with a continuous increase in workload until maximal exhaustion. Respiratory gases including oxygen and carbon dioxide will be measured continuously using a metabolic cart (Ultima™ CardioO2 ® gas exchange analysis system; Saint Paul, Minnesota, USA) with measurements of expired oxygen and carbon dioxide and analyzed using Breeze Suit (Saint Paul, Minnesota, USA). The study team will determine maximal heart rate, peak oxygen uptake (VO2), carbon dioxide production (VCO2), pulmonary ventilation (VE), ventilatory equivalents for oxygen (VE/VO2), carbon dioxide (VE/CO2), respiratory exchange ratio (RER), end-tidal partial pressure of oxygen (PETO2), and carbon dioxide (PETCO2). Assessments will be performed at the time of the baseline visit, and 3 months post-treatment.

Official Title
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Pilot Study to Evaluate the Efficacy of Low Dose Colchicine (LoDoCo ®) to Improve Exercise Capacity Among Patients With Chronic Stable HFpEF and Systemic Inflammation

Conditions
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Heart Failure, Inflammation

Intervention / Treatment
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* Drug: Low Dose Colchicine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Informed consent was obtained before any study-related activities. Study-related activities are any procedures that are carried out as part of the study, including activities to determine suitability for the study. 2. Age 50 years or above at the time of signing the informed consent. 3. Serum hs-CRP 2 mg/L at the time of baseline testing. 4. Diagnosis of chronic HFpEF within 6 months of enrolment must have one of the following: a. Structural Heart Disease with one of the following on echocardiography within 12 months of enrolment. i. LA volume index > 34 ml/m2. ii. LA diameter ≥ 3.8 cm. iii. LA length ≥ 5.0 cm. iv. LA area ≥ 20 cm2. v. LA volume ≥ 55 mL. vi. Intraventricular septal thickness ≥1.1 cm. vii. Posterior wall thickness ≥1.1 cm. viii. LV mass index ≥115 g∕m2 in men or ≥ 95 g∕m2 in women. ix. E/e' (mean septal and lateral) ≥ 10. x. e' (mean septal and lateral) < 9 cm/s b. Pulmonary capillary wedge pressure (PCWP) at rest³15 mmHg or Left ventricular end-diastolic pressure (LVEDP) ³18 mmHg, (PCWP) with exercise ³25 mmHg or (³ 2 mmHg/L/min) c. HF hospitalization or urgent/unplanned visit with a primary diagnosis of decompensated heart failure which required intravenous loop diuretic treatment, within the last 9 months prior to enrolment in combination with NT-proBNP ≥ 125 pg/mL within 1 month of enrolment for patients without ongoing atrial fibrillation/flutter. If ongoing atrial fibrillation/flutter at screening NT-proBNP must be ≥ 300 pg/mL 5. Ambulatory participants who can perform cardiopulmonary exercise testing. 6. Stable doses of HF-specific medications within the last 1 month. 7. Stable level of physical activity 8. Stable dose of any weight loss medications. Exclusion Criteria: 1. Do not otherwise meet the inclusion criteria. 2. Women who are pregnant, breastfeeding, or may be considering pregnancy during the study period. 3. Renal impairment: eGFR <30mL/min 4. Severe valvular heart disease is considered likely to require intervention. 5. Life expectancy <1 year. 6. Unable to perform cardiopulmonary exercise testing. 7. ALT or AST >2.5 ULN at time of screening

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low dose colchicine<br>Low dose colchicine 0.5 mg once a day orally for 3 months | Drug: Low Dose Colchicine<br>* Colchicine has been demonstrated to improve cardiovascular outcomes among patients with cardiovascular disease. In the COLCOT trial, the use of low-dose colchicine resulted in a reduction of major adverse cardiovascular events among participants with recent MI. The trial demonstrated the utility of anti-inflammatory therapies in improving cardiovascular outcomes. Colchicine has been widely used for decades and its safety profile is well established.<br>* Other names: LoDoCo;|
| Placebo Comparator: Placebo<br>Placebo once a day orally for 3 months | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak VO2 indexed to body weight | The primary outcome of the trial will be VO2peak indexed to body weight. (mL/kg/min). The data will be analyzed on an intention-to-treat basis comparing the outcomes across treatment arms (LoDoCo vs. placebo) using analysis of variance for repeated measures (ANOVA). Randomization of 60 participants (30 in LoDoCo vs. placebo) will provide >80% power at a two-sided level of significance of 0.05 to detect a >15% difference in VO2peak at the end of the study period. This estimate assumes a target population mean VO2peak of 10.5 ml/kg/min (SD 2.9) based on data from our local registry. Assuming a dropout rate of  20%, we will plan to enroll 72 participants. We will also evaluate the association between changes in hs-CRP with changes in VO2peak across the entire cohort of participants using adjusted linear and logistic regression models | Over 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in 6 minute walk distance | It will be assessed using analysis of covariance (ANCOVA). The randomized arm will be the between-subject grouping variable; covariates will be baseline value, baseline age, sex, and hs-CRP. The least-square means will be used to estimate intervention effects. Tests will be conducted at the 5% two-sided level of significance. The appropriate transformation will be used for biomarkers with skewed distributions to stabilize variance and achieve better approximation to normality. | 3 months | 
| Difference in Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score (KCCQ) Score | It will be assessed using analysis of covariance (ANCOVA). The randomized arm will be the between-subject grouping variable; covariates will be baseline value, baseline age, sex, and hs-CRP. The least-square means will be used to estimate intervention effects. Tests will be conducted at the 5% two-sided level of significance. The appropriate transformation will be used for biomarkers with skewed distributions to stabilize variance and achieve better approximation to normality. Scores range from 0 to 100, with 0 as the lowest score and 100 as the highest score. Higher scores indicate better health status, fewer symptoms, and greater disease-specific health-related quality of life, respectively. | 3 months | 
| Percent change cardiac structure and function | Echocardiography at baseline and follow-up will be used to determine changes in cardiac structure and function. Left atrial, and ventricular sizes will be measured at end-diastole and end-systole. Cardiac systolic function will be measured using left ventricular ejection fraction. Diastolic function will be measured as tissue Doppler velocities - E/e', and e' velocities. Absolute, and percent changes in these parameters between baseline and follow-up will be measured as an exploratory outcome. Analysis of covariance (ANCOVA) will be used for the analysis of the effect of the intervention. The randomized arm will be the between-subject grouping variable; covariates will be baseline value, baseline age, sex The least-square means will be used to estimate intervention effects. | Baseline and 3 months | 
| Difference in hs-CRP levels | It will be assessed using analysis of covariance (ANCOVA). The randomized arm will be the between-subject grouping variable; covariates will be baseline value, baseline age, sex, and hs-CRP. The least-square means will be used to estimate intervention effects. Tests will be conducted at the 5% two-sided level of significance. The appropriate transformation will be used for biomarkers with skewed distributions to stabilize variance and achieve better approximation to normality. | 3 months |