Trial Outcomes & Findings for A Study of ISIS 416858 Administered Subcutaneously to Participants With End-Stage Renal Disease (ESRD) on Hemodialysis (NCT NCT03358030)

Last Updated: 2023-01-20

Results Overview

MB was defined as one of the following: Fatal bleeding; symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular if in a major joint, or pericardial, or intramuscular with compartment syndrome, clinically overt bleeding leading to transfusion of greater than or equal to (\>=) 2 units of packed red blood cells or whole blood or a fall in hemoglobin of 20 grams per liter (g/L) (1.24 millimoles per liter \[mmol/L\]) or more within 24 hours. CRNMB was defined as overt bleeding not meeting the criteria for MB but that resulted, in either medical examination, intervention, or had clinical consequences for a participant.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

213 participants

Primary outcome timeframe

Up to Day 260

Results posted on

2023-01-20

Participant Flow

The study was conducted in 10 countries (Latvia, Netherlands, Spain, Austria, Belgium, Bulgaria, Czech Republic, Greece, Canada, and Russian Federation) from 26 December 2017 to 10 July 2019.

A total of 213 participants were enrolled and randomized in the study. Out of 213, 3 participants did not receive the study drug

Participant milestones

Participant milestones
Measure	Placebo Participants received placebo, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort A: ISIS 416858, 200 mg Participants received ISIS 416858, 200 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort B: ISIS 416858, 250 mg Participants received ISIS 416858, 250 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort C: ISIS 416858, 300 mg Participants received ISIS 416858, 300 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.
Overall Study STARTED	53	53	55	52
Overall Study Treated	53	53	54	50
Overall Study Per-protocol (PP) Population	49	45	43	35
Overall Study COMPLETED	50	52	46	48
Overall Study NOT COMPLETED	3	1	9	4

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received placebo, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort A: ISIS 416858, 200 mg Participants received ISIS 416858, 200 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort B: ISIS 416858, 250 mg Participants received ISIS 416858, 250 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort C: ISIS 416858, 300 mg Participants received ISIS 416858, 300 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.
Overall Study Adverse Event or Serious Adverse Event (SAE)	2	0	5	1
Overall Study Ineligibility	0	0	0	2
Overall Study Voluntary Withdrawal	1	1	3	1
Overall Study Other	0	0	1	0

Baseline Characteristics

A Study of ISIS 416858 Administered Subcutaneously to Participants With End-Stage Renal Disease (ESRD) on Hemodialysis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=53 Participants Participants received placebo, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort A: ISIS 416858, 200 mg n=53 Participants Participants received ISIS 416858, 200 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort B: ISIS 416858, 250 mg n=54 Participants Participants received ISIS 416858, 250 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort C: ISIS 416858, 300 mg n=50 Participants Participants received ISIS 416858, 300 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Total n=210 Participants Total of all reporting groups
Age, Continuous	61 years STANDARD_DEVIATION 13 • n=5 Participants	61 years STANDARD_DEVIATION 14 • n=7 Participants	63 years STANDARD_DEVIATION 12 • n=5 Participants	58 years STANDARD_DEVIATION 14 • n=4 Participants	61 years STANDARD_DEVIATION 13 • n=21 Participants
Sex: Female, Male Female	19 Participants n=5 Participants	23 Participants n=7 Participants	19 Participants n=5 Participants	20 Participants n=4 Participants	81 Participants n=21 Participants
Sex: Female, Male Male	34 Participants n=5 Participants	30 Participants n=7 Participants	35 Participants n=5 Participants	30 Participants n=4 Participants	129 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	6 Participants n=5 Participants	5 Participants n=4 Participants	12 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	52 Participants n=5 Participants	53 Participants n=7 Participants	48 Participants n=5 Participants	45 Participants n=4 Participants	198 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	3 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants	0 Participants n=4 Participants	3 Participants n=21 Participants
Race (NIH/OMB) White	52 Participants n=5 Participants	51 Participants n=7 Participants	50 Participants n=5 Participants	49 Participants n=4 Participants	202 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants

PRIMARY outcome

Timeframe: Up to Day 260

Population: Safety population included all randomized participants who received at least 1 dose of the study drug.

Outcome measures

Outcome measures
Measure	Cohort C: ISIS 416858, 300 mg n=50 Participants Participants received ISIS 416858, 300 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Placebo n=53 Participants Participants received placebo, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort A: ISIS 416858, 200 mg n=53 Participants Participants received ISIS 416858, 200 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort B: ISIS 416858, 250 mg n=54 Participants Participants received ISIS 416858, 250 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.
Number of Participants With Major Bleeding (MB) and Clinically Relevant Non-Major Bleeding (CRNMB)	3 Participants	3 Participants	2 Participants	3 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Day 1) up to Day 260

Population: PP population: All participants, randomized without missing \> 2 doses during the first 12 weeks or \> 5 doses over the 26-week Treatment Period (TP) and did not have any major protocol violations that would have affected the interpretation/integrity of study results. Number analyzed is the number of participants with data available for analyses at the given time point.

Outcome measures

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Day 1) up to Day 260

Population: PP population: All participants, randomized without missing \> 2 doses during the first 12 weeks or \> 5 doses over the 26-week TP and did not have any major protocol violations that would have affected the interpretation/integrity of study results. Number analyzed is the number of participants with data available for analyses at the given time point.

Outcome measures

Outcome measures
Measure	Cohort C: ISIS 416858, 300 mg n=35 Participants Participants received ISIS 416858, 300 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Placebo n=49 Participants Participants received placebo, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort A: ISIS 416858, 200 mg n=45 Participants Participants received ISIS 416858, 200 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort B: ISIS 416858, 250 mg n=43 Participants Participants received ISIS 416858, 250 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 5	-2.5 percentage change Standard Deviation 18.3	-0.6 percentage change Standard Deviation 14.4	2.5 percentage change Standard Deviation 24.6	-0.0 percentage change Standard Deviation 14.8
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 22	-27.6 percentage change Standard Deviation 19.3	-3.7 percentage change Standard Deviation 18.2	-17.2 percentage change Standard Deviation 16.2	-22.7 percentage change Standard Deviation 19.5
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 29	-37.9 percentage change Standard Deviation 18.5	-3.3 percentage change Standard Deviation 18.3	-21.4 percentage change Standard Deviation 16.9	-31.5 percentage change Standard Deviation 23.4
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 64	-61.7 percentage change Standard Deviation 20.3	-4.5 percentage change Standard Deviation 20.2	-41.8 percentage change Standard Deviation 20.1	-55.1 percentage change Standard Deviation 24.0
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 78	-64.2 percentage change Standard Deviation 19.5	-8.1 percentage change Standard Deviation 19.6	-44.6 percentage change Standard Deviation 20.9	-56.4 percentage change Standard Deviation 23.9
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 92	-66.0 percentage change Standard Deviation 19.0	-6.2 percentage change Standard Deviation 16.0	-45.0 percentage change Standard Deviation 21.6	-60.2 percentage change Standard Deviation 21.8
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 162	-64.1 percentage change Standard Deviation 24.5	-3.1 percentage change Standard Deviation 22.8	-48.9 percentage change Standard Deviation 21.5	-60.0 percentage change Standard Deviation 23.4
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 176	-64.3 percentage change Standard Deviation 17.4	-4.1 percentage change Standard Deviation 23.6	-49.9 percentage change Standard Deviation 24.8	-61.1 percentage change Standard Deviation 21.2
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 204	-52.2 percentage change Standard Deviation 22.1	-1.8 percentage change Standard Deviation 25.0	-36.9 percentage change Standard Deviation 28.7	-48.2 percentage change Standard Deviation 24.3
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 218	-41.8 percentage change Standard Deviation 24.2	-5.6 percentage change Standard Deviation 17.8	-29.3 percentage change Standard Deviation 20.7	-37.4 percentage change Standard Deviation 22.8
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 232	-29.6 percentage change Standard Deviation 25.2	-0.7 percentage change Standard Deviation 18.6	-19.5 percentage change Standard Deviation 24.7	-28.0 percentage change Standard Deviation 21.2
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 246	-22.3 percentage change Standard Deviation 24.0	-2.6 percentage change Standard Deviation 21.0	-13.6 percentage change Standard Deviation 27.6	-20.7 percentage change Standard Deviation 18.4
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 260	-16.0 percentage change Standard Deviation 22.1	-3.8 percentage change Standard Deviation 21.3	-11.1 percentage change Standard Deviation 25.0	-15.3 percentage change Standard Deviation 19.5
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 12	-14.1 percentage change Standard Deviation 16.1	-1.9 percentage change Standard Deviation 13.7	-3.0 percentage change Standard Deviation 17.3	-8.8 percentage change Standard Deviation 18.7
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 15	-18.8 percentage change Standard Deviation 17.3	-0.6 percentage change Standard Deviation 15.1	-7.1 percentage change Standard Deviation 16.2	-14.0 percentage change Standard Deviation 21.3
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 36	-42.8 percentage change Standard Deviation 17.9	-6.0 percentage change Standard Deviation 18.1	-26.3 percentage change Standard Deviation 18.4	-37.3 percentage change Standard Deviation 22.0
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 50	-55.7 percentage change Standard Deviation 20.6	-3.2 percentage change Standard Deviation 19.7	-37.9 percentage change Standard Deviation 22.2	-48.1 percentage change Standard Deviation 24.1
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 106	-67.8 percentage change Standard Deviation 18.4	-6.6 percentage change Standard Deviation 19.2	-49.4 percentage change Standard Deviation 20.4	-58.1 percentage change Standard Deviation 22.2
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 120	-66.9 percentage change Standard Deviation 17.6	-0.8 percentage change Standard Deviation 23.0	-47.8 percentage change Standard Deviation 20.3	-57.2 percentage change Standard Deviation 28.1
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 134	-67.7 percentage change Standard Deviation 19.7	-1.3 percentage change Standard Deviation 18.1	-50.0 percentage change Standard Deviation 19.1	-57.0 percentage change Standard Deviation 28.0
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 148	-65.5 percentage change Standard Deviation 20.0	-4.3 percentage change Standard Deviation 23.6	-50.4 percentage change Standard Deviation 17.5	-59.2 percentage change Standard Deviation 24.0
Percent Change From Baseline in Factor XI (FXI) Activity Percent Change From Baseline at Day 190	-60.9 percentage change Standard Deviation 19.6	-2.7 percentage change Standard Deviation 17.8	-45.4 percentage change Standard Deviation 28.9	-55.2 percentage change Standard Deviation 22.2

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to Day 260

Population: Safety population included all randomized participants who received at least 1 dose of study drug.

Participants were assessed based on pre-defined criteria in the protocol for platelet count abnormality: 100 - less than (\<)140, 75 - \<100, 50 - \<75, 25 - \<50 and \< 25 thousands per cubic millimeter (K/mm\^3) based on investigator's discretion.

Outcome measures

Outcome measures
Measure	Cohort C: ISIS 416858, 300 mg n=50 Participants Participants received ISIS 416858, 300 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Placebo n=53 Participants Participants received placebo, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort A: ISIS 416858, 200 mg n=53 Participants Participants received ISIS 416858, 200 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort B: ISIS 416858, 250 mg n=54 Participants Participants received ISIS 416858, 250 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.
Number of Participants With Laboratory Abnormalities Related to Platelet Count 25 - <50 K/mm^3	1 Participants	0 Participants	0 Participants	1 Participants
Number of Participants With Laboratory Abnormalities Related to Platelet Count < 25 K/mm^3	1 Participants	0 Participants	0 Participants	1 Participants
Number of Participants With Laboratory Abnormalities Related to Platelet Count 50 - <75 K/mm^3	0 Participants	0 Participants	0 Participants	4 Participants
Number of Participants With Laboratory Abnormalities Related to Platelet Count 100 - <140 K/mm^3	21 Participants	9 Participants	21 Participants	20 Participants
Number of Participants With Laboratory Abnormalities Related to Platelet Count 75 - <100 K/mm^3	7 Participants	2 Participants	2 Participants	6 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to Day 260

Population: Safety population included all randomized participants who received at least 1 dose of study drug.

Participants were assessed based on pre-defined criteria in protocol for abnormality in ALT and AST values: Confirmed ALT (serum glutamic pyruvic transaminase \[SGPT\]); greater than (\>) 3\*Upper limit of normal range (ULN), \>5\*ULN and confirmed AST (serum glutamic-oxaloacetic transaminase \[SGOT\]); \>3\*ULN and \>5\*ULN. A confirmed value was based on a consecutive lab value within 7 days of the initial value. If that value was in the same or worse category the initial value was confirmed. If the consecutive value was in a better category then the initial value was confirmed using the consecutive value category. If there were multiple results on the same day, no matter from the same lab vendor or different lab vendors, then the worst value was used in the analysis. Abnormality in laboratory parameter was based on investigator's discretion.

Outcome measures

Outcome measures
Measure	Cohort C: ISIS 416858, 300 mg n=50 Participants Participants received ISIS 416858, 300 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Placebo n=53 Participants Participants received placebo, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort A: ISIS 416858, 200 mg n=53 Participants Participants received ISIS 416858, 200 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort B: ISIS 416858, 250 mg n=54 Participants Participants received ISIS 416858, 250 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.
Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) ALT: >3*ULN, Confirmed	0 Participants	0 Participants	0 Participants	1 Participants
Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) ALT: >5*ULN, Confirmed	0 Participants	0 Participants	0 Participants	1 Participants
Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) AST: >3*ULN, Confirmed	0 Participants	0 Participants	0 Participants	1 Participants
Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) AST: >5*ULN, Confirmed	0 Participants	0 Participants	0 Participants	1 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to Day 260

Population: Safety population included all randomized participants who received at least 1 dose of study drug.

Outcome measures

Outcome measures
Measure	Cohort C: ISIS 416858, 300 mg n=50 Participants Participants received ISIS 416858, 300 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Placebo n=53 Participants Participants received placebo, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort A: ISIS 416858, 200 mg n=53 Participants Participants received ISIS 416858, 200 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort B: ISIS 416858, 250 mg n=54 Participants Participants received ISIS 416858, 250 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	44 Participants	33 Participants	37 Participants	46 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline (Day 1) up to Day 260

Population: PP population: All participants, randomized without missing \> 2 doses during first 12 weeks or \> 5 doses over 26-week TP and did not have any major protocol violations that would have affected interpretation/integrity of study results. Number analyzed is the number of participants with data available for analyses at the given time point.

Outcome measures

Outcome measures
Measure	Cohort C: ISIS 416858, 300 mg n=35 Participants Participants received ISIS 416858, 300 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Placebo n=49 Participants Participants received placebo, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort A: ISIS 416858, 200 mg n=45 Participants Participants received ISIS 416858, 200 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort B: ISIS 416858, 250 mg n=43 Participants Participants received ISIS 416858, 250 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.
Percent Change From Baseline in Factor XI (FXI) Antigen Levels	-13.9 percentage change Standard Deviation 22.7	11.3 percentage change Standard Deviation 27.0	-3.4 percentage change Standard Deviation 17.5	-10.1 percentage change Standard Deviation 21.8

Adverse Events

Placebo

Serious events: 10 serious events

Other events: 25 other events

Deaths: 3 deaths

Cohort A: ISIS 416858, 200 mg

Serious events: 6 serious events

Other events: 27 other events

Deaths: 0 deaths

Cohort B: ISIS 416858, 250 mg

Serious events: 20 serious events

Other events: 35 other events

Deaths: 5 deaths

Cohort C: ISIS 416858, 300 mg

Serious events: 13 serious events

Other events: 39 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Additional Information

Ionis Pharmaceuticals, Inc.

Phone: 800-679-4747

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Cohort C: ISIS 416858, 300 mg n=35 Participants Participants received ISIS 416858, 300 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Placebo n=49 Participants Participants received placebo, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort A: ISIS 416858, 200 mg n=45 Participants Participants received ISIS 416858, 200 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort B: ISIS 416858, 250 mg n=43 Participants Participants received ISIS 416858, 250 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 12	3.6 percentage change Standard Deviation 19.5	1.4 percentage change Standard Deviation 33.5	9.4 percentage change Standard Deviation 25.9	0.8 percentage change Standard Deviation 21.9
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 92	42.1 percentage change Standard Deviation 57.2	9.5 percentage change Standard Deviation 58.8	19.1 percentage change Standard Deviation 27.1	52.5 percentage change Standard Deviation 83.1
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 106	44.8 percentage change Standard Deviation 60.7	10.9 percentage change Standard Deviation 70.7	38.9 percentage change Standard Deviation 71.7	28.5 percentage change Standard Deviation 46.1
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 134	50.1 percentage change Standard Deviation 98.1	-6.2 percentage change Standard Deviation 16.0	42.9 percentage change Standard Deviation 86.6	29.5 percentage change Standard Deviation 49.8
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 148	38.7 percentage change Standard Deviation 61.5	1.0 percentage change Standard Deviation 25.8	26.1 percentage change Standard Deviation 28.7	34.0 percentage change Standard Deviation 53.5
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 162	33.3 percentage change Standard Deviation 34.9	-1.6 percentage change Standard Deviation 17.1	27.6 percentage change Standard Deviation 30.1	31.6 percentage change Standard Deviation 39.3
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 176	32.3 percentage change Standard Deviation 34.6	3.7 percentage change Standard Deviation 31.6	28.8 percentage change Standard Deviation 35.0	36.3 percentage change Standard Deviation 79.0
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 190	23.5 percentage change Standard Deviation 20.2	-3.6 percentage change Standard Deviation 12.5	38.3 percentage change Standard Deviation 92.9	20.5 percentage change Standard Deviation 31.6
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 204	16.9 percentage change Standard Deviation 32.1	-0.4 percentage change Standard Deviation 27.9	17.4 percentage change Standard Deviation 39.3	13.3 percentage change Standard Deviation 27.1
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 218	13.2 percentage change Standard Deviation 30.3	-0.7 percentage change Standard Deviation 26.4	13.1 percentage change Standard Deviation 25.8	7.0 percentage change Standard Deviation 24.6
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 246	3.6 percentage change Standard Deviation 20.6	-0.0 percentage change Standard Deviation 44.2	10.0 percentage change Standard Deviation 26.9	3.5 percentage change Standard Deviation 25.2
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 260	3.6 percentage change Standard Deviation 30.1	2.3 percentage change Standard Deviation 50.7	16.1 percentage change Standard Deviation 54.4	-2.9 percentage change Standard Deviation 21.6
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 5	0.7 percentage change Standard Deviation 18.2	-2.8 percentage change Standard Deviation 23.1	9.3 percentage change Standard Deviation 41.5	-2.8 percentage change Standard Deviation 19.2
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 15	12.5 percentage change Standard Deviation 38.4	3.8 percentage change Standard Deviation 47.7	7.5 percentage change Standard Deviation 29.0	12.5 percentage change Standard Deviation 39.8
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 22	16.6 percentage change Standard Deviation 32.0	-0.6 percentage change Standard Deviation 25.6	11.4 percentage change Standard Deviation 38.1	8.4 percentage change Standard Deviation 30.4
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 29	18.8 percentage change Standard Deviation 46.6	-1.9 percentage change Standard Deviation 23.8	11.0 percentage change Standard Deviation 28.4	11.4 percentage change Standard Deviation 30.7
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 36	16.9 percentage change Standard Deviation 21.0	-3.1 percentage change Standard Deviation 17.8	7.1 percentage change Standard Deviation 18.2	13.2 percentage change Standard Deviation 35.5
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 50	24.3 percentage change Standard Deviation 34.3	6.8 percentage change Standard Deviation 46.9	24.1 percentage change Standard Deviation 53.4	27.5 percentage change Standard Deviation 42.4
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 64	40.5 percentage change Standard Deviation 53.7	6.0 percentage change Standard Deviation 36.1	20.3 percentage change Standard Deviation 25.8	29.9 percentage change Standard Deviation 75.6
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 78	42.9 percentage change Standard Deviation 47.8	6.6 percentage change Standard Deviation 49.5	27.9 percentage change Standard Deviation 49.2	27.9 percentage change Standard Deviation 38.6
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 120	41.4 percentage change Standard Deviation 49.4	2.6 percentage change Standard Deviation 26.6	28.5 percentage change Standard Deviation 43.1	22.5 percentage change Standard Deviation 33.1
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) Percent Change From Baseline at Day 232	3.1 percentage change Standard Deviation 14.8	-0.7 percentage change Standard Deviation 41.8	8.6 percentage change Standard Deviation 24.0	16.8 percentage change Standard Deviation 44.0

Measure	Placebo n=53 participants at risk Participants received placebo, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort A: ISIS 416858, 200 mg n=53 participants at risk Participants received ISIS 416858, 200 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort B: ISIS 416858, 250 mg n=54 participants at risk Participants received ISIS 416858, 250 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.	Cohort C: ISIS 416858, 300 mg n=50 participants at risk Participants received ISIS 416858, 300 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.
Blood and lymphatic system disorders Anaemia	1.9% 1/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	1.9% 1/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	9.3% 5/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	4.0% 2/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	7.5% 4/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	11.1% 6/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	14.0% 7/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Diarrhoea	1.9% 1/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	7.5% 4/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	0.00% 0/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	0.00% 0/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Nausea	3.8% 2/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	3.8% 2/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	7.4% 4/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	2.0% 1/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Gastrointestinal disorders Vomiting	1.9% 1/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	7.5% 4/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	3.7% 2/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	0.00% 0/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
General disorders Injection site bruising	1.9% 1/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	3.8% 2/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	5.6% 3/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	8.0% 4/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
General disorders Injection site discolouration	0.00% 0/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	1.9% 1/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	3.7% 2/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	6.0% 3/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
General disorders Injection site erythema	1.9% 1/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	11.3% 6/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	11.1% 6/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	28.0% 14/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
General disorders Injection site haematoma	3.8% 2/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	22.6% 12/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	14.8% 8/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	18.0% 9/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
General disorders Injection site pain	3.8% 2/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	7.5% 4/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	13.0% 7/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	12.0% 6/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
General disorders Injection site pruritus	3.8% 2/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	9.4% 5/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	11.1% 6/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	22.0% 11/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
General disorders Pyrexia	1.9% 1/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	0.00% 0/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	1.9% 1/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	6.0% 3/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Bronchitis	7.5% 4/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	3.8% 2/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	1.9% 1/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	6.0% 3/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Respiratory tract infection	11.3% 6/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	1.9% 1/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	3.7% 2/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	4.0% 2/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Infections and infestations Urinary tract infection	1.9% 1/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	0.00% 0/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	1.9% 1/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	6.0% 3/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Injury, poisoning and procedural complications Arteriovenous fistula site complication	5.7% 3/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	5.7% 3/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	7.4% 4/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	12.0% 6/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Injury, poisoning and procedural complications Arteriovenous fistula site haematoma	1.9% 1/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	3.8% 2/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	5.6% 3/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	2.0% 1/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Injury, poisoning and procedural complications Arteriovenous fistula site haemorrhage	0.00% 0/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	3.8% 2/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	5.6% 3/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	10.0% 5/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Injury, poisoning and procedural complications Procedural hypotension	0.00% 0/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	0.00% 0/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	9.3% 5/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	4.0% 2/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Investigations Haemoglobin decreased	0.00% 0/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	5.7% 3/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	3.7% 2/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	2.0% 1/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Investigations Platelet count decreased	0.00% 0/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	0.00% 0/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	7.4% 4/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	2.0% 1/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	1.9% 1/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	7.4% 4/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	4.0% 2/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Muscle spasms	1.9% 1/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	7.5% 4/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	3.7% 2/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	6.0% 3/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Musculoskeletal and connective tissue disorders Pain in extremity	1.9% 1/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	3.8% 2/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	5.6% 3/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	2.0% 1/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Nervous system disorders Headache	7.5% 4/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	5.7% 3/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	3.7% 2/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	10.0% 5/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Psychiatric disorders Insomnia	5.7% 3/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	3.8% 2/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	0.00% 0/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	2.0% 1/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Cough	5.7% 3/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	3.8% 2/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	5.6% 3/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	2.0% 1/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Epistaxis	1.9% 1/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	1.9% 1/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	3.7% 2/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	10.0% 5/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Vascular disorders Hypertension	5.7% 3/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	3.8% 2/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	1.9% 1/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	2.0% 1/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.
Vascular disorders Hypotension	1.9% 1/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	7.5% 4/53 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	5.6% 3/54 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.	4.0% 2/50 • Up to Day 260 Safety population included all randomized participants who received at least 1 dose of study drug.