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

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)

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02966028

Enrollment

274

Registered

2016-11-17

Start date

2016-11-30

Completion date

2019-09-30

Last updated

2021-04-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

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

Keywords

CAC, calcium, ESRD, calcification, cardiovascular, heart, kidney, hemodialysis, Agatston

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.

Interventions

DRUGSNF472

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

DRUGPlacebo

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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Change in Log CAC Volume Score From Baseline to Week 52 for the Combined Dose Groups vs Placebo	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

Measure	Time frame	Description
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	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.
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	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.
Number of Subjects With >=15% Progression in CAC Agatston Score at Week 52 for Each Dose Group and the Combined Dose Groups vs Placebo	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.
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	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.
Change in Log CAC Volume Score From Baseline to Week 52 for Each Dose Group (300 mg and 600 mg) vs Placebo	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.
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	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.
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	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.
Number of Participants With the Composite Safety Endpoint (Cardiovascular Death, Nonfatal Myocardial Infarction, Non-fatal Stroke, Heart Failure or Non-fatal Cardiac Arrest.	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 .
Mortality Rate (All-cause) for Each Dose Group and Placebo	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.
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	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.

Countries

Spain, United Kingdom, United States

Participant flow

Participants by arm

Arm	Count
SNF472 300 mg Dose 1 arm (300 mg): 1 vial of physiological saline and 1 vial of active (10 mL SNF472 at 30 mg/mL) SNF472: Administered 3 times weekly by intravenous infusion through the dialysis machine in conjunction with the patient's dialysis sessions.	92
SNF 472 600 mg Dose 2 arm (600 mg): 2 vials of active (10 mL SNF472 at 30 mg/mL) SNF472: Administered 3 times weekly by intravenous infusion through the dialysis machine in conjunction with the patient's dialysis sessions.	91
Matching Placebo Placebo arm: 2 vials of physiological saline Placebo: Administered 3 times weekly by intravenous infusion through the dialysis machine in conjunction with the patient's dialysis sessions.	90
Total	273

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	7	13	10
Overall Study	Kidney transplant Changed dialysis units	9	16	14
Overall Study	Physician Decision	1	0	2
Overall Study	Withdrawal by Subject	7	5	5

Baseline characteristics

Characteristic	SNF472 300 mg	SNF 472 600 mg	Matching Placebo	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	38 Participants	40 Participants	50 Participants	128 Participants
Age, Categorical Between 18 and 65 years	54 Participants	51 Participants	40 Participants	145 Participants
Age, Continuous	63 years STANDARD_DEVIATION 9.5	64 years STANDARD_DEVIATION 8.9	64. years STANDARD_DEVIATION 8.2	63.5 years STANDARD_DEVIATION 8.9
CAC Agatston Score	917 units on a scale STANDARD_DEVIATION 697	963 units on a scale STANDARD_DEVIATION 702	965 units on a scale STANDARD_DEVIATION 762	948 units on a scale STANDARD_DEVIATION 744
Ethnicity (NIH/OMB) Hispanic or Latino	31 Participants	36 Participants	32 Participants	99 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	60 Participants	51 Participants	56 Participants	167 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants	4 Participants	2 Participants	7 Participants
Race (NIH/OMB) American Indian or Alaska Native	2 Participants	0 Participants	0 Participants	2 Participants
Race (NIH/OMB) Asian	2 Participants	4 Participants	4 Participants	10 Participants
Race (NIH/OMB) Black or African American	27 Participants	15 Participants	19 Participants	61 Participants
Race (NIH/OMB) More than one race	1 Participants	0 Participants	0 Participants	1 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants	4 Participants	5 Participants	10 Participants
Race (NIH/OMB) White	59 Participants	67 Participants	62 Participants	188 Participants
Region of Enrollment Spain	28 participants	35 participants	31 participants	94 participants
Region of Enrollment United Kingdom	6 participants	3 participants	5 participants	14 participants
Region of Enrollment United States	58 participants	53 participants	54 participants	165 participants
Sex: Female, Male Female	38 Participants	36 Participants	33 Participants	107 Participants
Sex: Female, Male Male	54 Participants	55 Participants	57 Participants	166 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	1 / 92	6 / 91	5 / 90
other Total, other adverse events	62 / 92	64 / 91	67 / 90
serious Total, serious adverse events	38 / 92	55 / 91	49 / 90

Outcome results

Primary

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.