Effect of SNF472 on Progression of Cardiovascular Calcification in End-Stage-Renal-Disease (ESRD) Patients on Hemodialysis (HD)

Study Overview
=================
Brief Summary
-----------------
The primary objective is to assess the effect of 2 dose levels of SNF472 (300 mg and 600 mg) compared to placebo on the progression of coronary artery calcium volume score over a 12-month (52 weeks) period in ESRD patients on HD

Detailed Description
-----------------
Reducing the progression of cardiovascular calcification (CVC) in HD patients may improve the severe burden of CV disease related to the underlying ESRD. As no therapy is currently indicated to target CVC, there is a need to investigate the ability of SNF472 to reduce CVC progression and, ultimately, to improve CV outcomes in HD patients. This phase 2b double-blind, randomised, placebo-controlled study is designed to assess the effect of SNF472 on the progression of CVC as measured by calcium volume and CAC/Agatston scores in ESRD patients receiving HD. The study hypothesis is that administration of SNF472 over 52 weeks can slow the progression of CVC in this patient population compared to placebo.

Official Title
-----------------
A Double-blind, Randomised, Placebo-controlled Study to Assess the Effect of SNF472 on Progression of Cardiovascular Calcification on Top of Standard of Care in End-stage-renal-disease (ESRD) Patients on Hemodialysis (HD)

Conditions
-----------------
Cardiovascular Diseases, Cardiovascular Abnormalities, Calcifications, Vascular, Endstage Renal Disease, ESRD, Coronary Artery Calcification

Intervention / Treatment
-----------------
* Drug: SNF472
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Female or male patients, 18 to 80 years (inclusive) of age at randomisation CAC score of 100 to 3500 AU (Agatston Units) inclusive within a 3-week period prior to randomisation as measured by a multi-detector CT scanner Patients who are EITHER ≥ 55 years OR have a history of diabetes mellitus at randomisation Patients on HD for ≥ 6 months prior to randomisation Willing and able to understand and sign the informed consent Exclusion Criteria: Scheduled date for kidney transplant from a known living donor Weight above 300 lbs (136 kg) Hospitalisation in the previous 3 months prior to randomisation for unstable angina, MI, stroke, transient ischaemic attack, amputation or peripheral or coronary bypass surgery History of unstable heart failure in the previous 3 months, defined as an unplanned presentation to a hospital or dialysis treatment facility with signs/symptoms of acute pulmonary edema and requiring ultrafiltration therapy History of cancer that has been in remission for < 5 years prior to randomisation. A history of basal cell carcinoma or Stage 1 squamous cell carcinoma of the skin is allowed Pregnant or trying to become pregnant, currently breast-feeding, or of child-bearing potential (including peri-menopausal women who have had a menstrual period within one year) and not willing to practice birth control using a double barrier method (criteria apply to women only) at least 30 days post last dose of study medication Hypocalcaemia defined as a serum calcium below 8.0 mg/dL (or 2.0 mmol/L) for the serum calcium most proximal to screening per patient's medical records Extreme elevation in serum phosphorous, defined as a serum phosphorous above 10 mg/dL (or 3.23 mmol/L) within the last 2 months proximal to screening per patient's medical records Uncontrolled hypertension defined as any 2 or more consecutive post-dialysis diastolic blood pressure (DBP) > 100 mmHg within the last 2 months proximal to screening expected survival < 2 years in the Investigator's medical opinion Known active drug or alcohol abuse within 1 year of randomisation Use of other investigational drugs within 30 days of randomisation Non-compliance with dialysis treatment which, in the opinion of the Investigator, evidenced by either repeated missed dialysis treatments or significant non-compliance with the patient's medication regimen Inability to comply with all required study procedures and schedule, inability to speak and read in the protocol-derived language of that patient's clinical site, or unwillingness or inability to give written informed consent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SNF472 300 mg<br>Dose 1 arm (300 mg): 1 vial of physiological saline and 1 vial of active (10 mL SNF472 at 30 mg/mL) | Drug: SNF472<br>* Administered 3 times weekly by intravenous infusion through the dialysis machine in conjunction with the patient's dialysis sessions.<br>|
| Experimental: SNF 472 600 mg<br>Dose 2 arm (600 mg): 2 vials of active (10 mL SNF472 at 30 mg/mL) | Drug: SNF472<br>* Administered 3 times weekly by intravenous infusion through the dialysis machine in conjunction with the patient's dialysis sessions.<br>|
| Placebo Comparator: Matching Placebo<br>Placebo arm: 2 vials of physiological saline | Drug: Placebo<br>* Administered 3 times weekly by intravenous infusion through the dialysis machine in conjunction with the patient's dialysis sessions.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Log CAC Volume Score From Baseline to Week 52 for the Combined Dose Groups vs Placebo | Coronary Artery Calcification (CAC) Volume Score is a calculation to quantify the calcification of coronary artery calcium without factoring in the calcium density as measured by the CAC Agatston Score. The CAC Score was log-transformed and the primary outcome measure was the change in Log CAC Volume Score from Baseline to Week 52 for the combined dose groups vs placebo. The primary analysis used an ANCOVA model with the change in log volume score (log 52-week volume score - log baseline volume score) as the dependent variable and with a fixed effect term for the combined randomized treatment groups and log CAC volume score at baseline as a covariate. The least squares means for the treatment groups was estimated and back transformed. A smaller change from baseline to follow up is a better outcome. | Baseline (Week 1, Day 1) and Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Log CAC Volume Score From Baseline to Week 52 for Each Dose Group (300 mg and 600 mg) vs Placebo | Coronary Artery Calcification (CAC) Volume Score is a calculation to quantify the calcification of coronary artery calcium without factoring in the calcium density as measured by the CAC Agatston Score. The CAC Score was log-transformed and the primary outcome measure was the change in Log CAC Volume Score from Baseline to Week 52 for the combined dose groups vs placebo. This secondary outcome measure was the change in Log CAC Volume Score from Baseline to Week 52 for each dose group vs placebo. The analysis used an ANCOVA model with the change in log volume score (log 52-week volume score - log baseline volume score) as the dependent variable and with a fixed effect term for each randomized treatment groups and log CAC volume score at baseline as a covariate. The least squares means for each of the treatment groups was estimated and back transformed. A smaller change from baseline to follow up is a better outcome. | Baseline (Week 1, Day 1) and Week 52 | 
| Change in Log CAC Agatston Score Between Baseline and Week 52 for Each Dose Group (300 mg and 600 mg) vs Placebo and for the Combined Dose Groups vs the Placebo Group | Coronary Artery Calcification (CAC) Agatston Score is a semi-automated tool to calculate a score the reflects the extent of coronary artery calcification as detected by an unenhanced CT scan. Scores range from 0 to >1000 Agatston units where higher scores indicate an increased amount of calcification and an increased risk for a major adverse cardiac event. This secondary outcome measure was the change in Log CAC Agatston Score from Baseline to Week 52 for each dose group and the treated arms combined vs placebo. The analysis used an ANCOVA model with the change in log score (log 52-week score - log baseline score) as the dependent variable and with a fixed effect term for each randomized treatment groups and log CAC score at baseline as a covariate. The least squares means for each of the treatment groups separately and combined was estimated and back transformed. | Baseline (Week 1, Day 1) and Week 52 | 
| Number of Subjects With <15% Progression in CAC Agatston Score From Baseline to Week 52 for Each Dose Group and the Combined Dose Groups vs Placebo | Agatston score is a semi-automated tool to calculate a score that reflects the extent of coronary artery calcification as detected by an unenhanced CT scan. Scores range from 0 to >1000 Agatston units where higher scores indicate an increased amount of calcification and an increased risk for a major adverse cardiac event. Change in Agatston Score values from baseline to Week 52 were calculated as a percentage of change (progression or worsening of calcification). The number of subjects with <15% progression were counted. | Baseline (Week 1, Day 1) and Week 52 | 
| Number of Subjects With >=15% Progression in CAC Agatston Score at Week 52 for Each Dose Group and the Combined Dose Groups vs Placebo | Agatston score is a semi-automated tool to calculate a score the reflects the extent of coronary artery calcification as detected by an unenhanced CT scan. Scores range from 0 to >1000 Agatston units where higher scores indicate an increased amount of calcification and an increased risk for a major adverse cardiac event. Change in Agatston Score values from baseline to Week 52 was calculated as a percentage of change (progression or worsening of calcification). The number of subjects with >=15% progression were counted for each treatment group, the combined treatments groups and placebo. | Baseline (Week 1, Day 1) and Week 52 | 
| Change in Log Thoracic Aorta Calcification Volume Score Between Baseline and Week 52 for Each Dose Group (300 mg and 600 mg) vs Placebo and the Combined Dose Groups vs Placebo | Coronary Artery Calcification (CAC) Volume Score is a calculation to quantify the calcification of coronary artery calcium without factoring in the calcium density as measured by the CAC Agatston Score. The CAC volume score observed in the thoracic aorta was used for this analysis. The CAC volume Score was log-transformed and the primary outcome measure was the change in Log CAC Volume Score from Baseline to Week 52 for the combined dose groups and each dose group vs placebo. The secondary analysis used an ANCOVA model with the change in log volume score (log 52-week volume score - log baseline volume score) as the dependent variable and with a fixed effect term for the combined randomized treatment groups and log CAC volume score at baseline as a covariate. The least squares means for the treatment groups was estimated and back transformed. A smaller change from baseline to follow up is a better outcome. | Baseline (Week 1, Day 1) and Week 52 | 
| Change in Log Thoracic Aorta Calcification Agatston Score Between Baseline and Week 52 for Each Dose Group (300 mg and 600 mg) vs Placebo and the Combined Dose Groups vs Placebo | Coronary Artery Calcification (CAC) Agatston Score is a semi-automated tool to calculate a score that reflects the extent of coronary artery calcification as detected by an unenhanced CT scan. Scores range from 0 to >1000 Agatston units where higher scores indicate an increased amount of calcification and an increased risk for a major adverse cardiac event. This secondary outcome measure was the change in CAC Agatston Score in the thoracic aorta from Baseline to Week 52 for each dose group and the treated arms combined vs placebo. The analysis used an ANCOVA model with the change in log score (log 52-week score - log baseline score) as the dependent variable and with a fixed effect term for each randomized treatment groups and log CAC score at baseline as a covariate. The least squares means for each of the treatment groups separately and combined was estimated and back transformed. A smaller change from baseline to follow up is a better outcome. | Baseline (Week 1, Day 1) and Week 52 | 
| Change in Log Aortic Valve Calcification Volume Score Between Baseline and Week 52 for Each Dose Group (300 mg and 600 mg) vs Placebo and the Combined Dose Groups vs Placebo | Coronary Artery Calcification (CAC) Volume Score is a calculation to quantify the calcification of coronary artery calcium without factoring in the calcium density as measured by the CAC Agatston Score. The CAC volume score observed in the aortic valve was used for this analysis. The CAC volume Score was log-transformed and the primary outcome measure was the change in Log CAC Volume Score from Baseline to Week 52 for the combined dose groups and each dose group vs placebo. The secondary analysis used an ANCOVA model with the change in log volume score (log 52-week volume score - log baseline volume score) as the dependent variable and with a fixed effect term for the combined randomized treatment groups and log CAC volume score at baseline as a covariate. The least squares means for the treatment groups was estimated and back transformed. A smaller change from baseline to follow up is a better outcome. | Baseline (Week 1, Day 1) and Week 52 | 
| Change in Log Aortic Valve Calcification Agatston Score Between Baseline and Week 52 for Each Dose Group (300 mg and 600 mg) vs Placebo and the Combined Dose Groups vs Placebo | Coronary Artery Calcification (CAC) Agatston Score is a semi-automated tool to calculate a score the reflects the extent of coronary artery calcification as detected by an unenhanced CT scan. Scores range from 0 to >1000 Agatston units where higher scores indicate an increased amount of calcification and an increased risk for a major adverse cardiac event. This secondary outcome measure was the change in Log CAC Agatston Score or the aortic valve from Baseline to Week 52 for each dose group and the treated arms combined vs placebo. The analysis used an ANCOVA model with the change in log score (log 52-week score - log baseline score) as the dependent variable and with a fixed effect term for each randomized treatment groups and log CAC score at baseline as a covariate. The least squares means for each of the treatment groups separately and combined was estimated and back transformed. A smaller change from baseline to follow up is a better outcome. | Baseline (Week 1, Day 1) and Week 52 | 
| Number of Participants With the Composite Safety Endpoint (Cardiovascular Death, Nonfatal Myocardial Infarction, Non-fatal Stroke, Heart Failure or Non-fatal Cardiac Arrest. | The number of subjects meeting this composite safety endpoint were counted and expressed by the randomized arm as a % of patients for the safety population.terms resulting in death from cardiovascular causes, myocardial infarction, stroke, or heart failure for each dose group and placebo were summarized . | Baseline (Week 1, Day 1) and Week 52 | 
| Mortality Rate (All-cause) for Each Dose Group and Placebo | The number of deaths were counted and expressed by the randomized arm as a % of patients for the safety population. | Baseline (Week 1, Day 1) and Week 52 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
CAC, calcium, ESRD, calcification, cardiovascular, heart, kidney, hemodialysis, Agatston