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NCT Number: NCT02966028

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

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

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Key information

Conditions

Cardiovascular Diseases Calcifications, Vascular Calcinosis Calcium Metabolism Disorders Cardiovascular Abnormalities Chronic Disease Congenital Abnormalities Congenital, Hereditary, and Neonatal Diseases and Abnormalities Coronary Artery Calcification Disease Attributes ESRD Endstage Renal Disease Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Kidney Diseases Kidney Failure, Chronic Male Urogenital Diseases Metabolic Diseases Nutritional and Metabolic Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms Renal Insufficiency Renal Insufficiency, Chronic Urogenital Diseases Urologic Diseases Vascular Calcification

Age range

18 year–80 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Palma, Balearic Islands, Spain

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

SNF472

Drug

Administered 3 times weekly by intravenous infusion through the dialysis machine in conjunction with the patient's dialysis sessions.

Placebo

Drug

Administered 3 times weekly by intravenous infusion through the dialysis machine in conjunction with the patient's dialysis sessions.

Primary outcomes

  1. Change in Log CAC Volume Score From Baseline to Week 52 for the Combined Dose Groups vs Placebo

    Time frame: Baseline (Week 1, Day 1) and Week 52

    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.

Secondary outcomes

  1. Change in Log CAC Volume Score From Baseline to Week 52 for Each Dose Group (300 mg and 600 mg) vs Placebo

    Time frame: Baseline (Week 1, Day 1) and Week 52

    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.

  2. 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

    Time frame: Baseline (Week 1, Day 1) and Week 52

    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.

  3. 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

    Time frame: Baseline (Week 1, Day 1) and Week 52

    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.

  4. Number of Subjects With >=15% Progression in CAC Agatston Score at Week 52 for Each Dose Group and the Combined Dose Groups vs Placebo

    Time frame: Baseline (Week 1, Day 1) and Week 52

    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.

  5. 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

    Time frame: Baseline (Week 1, Day 1) and Week 52

    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.

  6. 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

    Time frame: Baseline (Week 1, Day 1) and Week 52

    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.

  7. 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

    Time frame: Baseline (Week 1, Day 1) and Week 52

    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.

  8. 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

    Time frame: Baseline (Week 1, Day 1) and Week 52

    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.

  9. Number of Participants With the Composite Safety Endpoint (Cardiovascular Death, Nonfatal Myocardial Infarction, Non-fatal Stroke, Heart Failure or Non-fatal Cardiac Arrest.

    Time frame: Baseline (Week 1, Day 1) and Week 52

    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 .

  10. Mortality Rate (All-cause) for Each Dose Group and Placebo

    Time frame: Baseline (Week 1, Day 1) and Week 52

    The number of deaths were counted and expressed by the randomized arm as a % of patients for the safety population.

Sponsors and collaborators

Lead sponsor

Sanifit Therapeutics S. A.

Other

Collaborators

  • Clinipace Worldwide

Registry information

Official study 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)

Important dates

Study start
2016
Primary completion
2019
Study completion
2019
First posted
Nov 17, 2016
Registry last updated
Apr 15, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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