End-stage Renal Disease (ESRD)
Conditions
Brief summary
Evaluation of safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of ISIS 416858 for up to 204 participants with ESRD receiving chronic hemodialysis as assessed by FXI activity reduction.
Detailed description
Evaluation of safety, PK, and PD of ISIS 416858 (Dose # 1, Dose #2 and Dose #3 once weekly) as compared to placebo as assessed by FXI activity reduction.
Interventions
DRUGISIS 416858
Subcutaneous injection
DRUGPlacebo
Subcutaneous injection
Sponsors
Bayer
Ionis Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
• End stage renal disease maintained on outpatient hemodialysis at a healthcare center for \> 3 months from screening with hemodialysis at least 3 times per week for a minimum of 9 hours per week of prescribed treatment time and plan to continue this throughout the study.
Exclusion criteria
* Participants with a history of major medical event (previous acute coronary syndrome, stroke or transient ischemic attack or systemic thromboembolic event) within 3 months of screening, major surgery within 3 months of screening, or new major physical examination finding except for documented atrial fibrillation * Active bleeding within the past 3 months from screening or documented bleeding diathesis (excluding uremia), coagulopathy, or recent prolonged compression time at arteriovenous fistula * Screening values of: * Platelet count \< 150,000 cells per millimeter cube (cells/mm\^3) * \< 180,000 cells/mm\^3 for platelet function/activation subgroup * International normalized ratio (INR) \> 1.4 * Activated partial thromboplastin time (aPTT) \> upper limit of normal (ULN) * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2 x ULN * Total bilirubin \> ULN * Factor XI (FXI) activity \< 0.3 units per milliliter (U/mL) * Malignancy within 5 years, except basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated. Participants with malignancies that have been treated with curative intent and which have no reoccurrence within 5 years may also be eligible if approved by Sponsor Medical Monitor. * Within 6 months prior to screening, have any of the following: * More than 3 episodes of severe hypoglycemia requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions * One event of hypoglycemia in which the participant required hospitalization * Recurrent syncope and recurrent hypotension in the inter-dialytic period requiring intervention * Planned major surgery in the next 6 months, including participants receiving kidney transplant or participants that anticipate changing dialysis modality (i.e. hemodialysis to peritoneal dialysis) * Concomitant use of anticoagulant/antiplatelet agents (e.g., warfarin, dabigatran, rivaroxaban, clopidogrel) that may affect coagulation (except low dose aspirin (≤ 100 mg/day) during Treatment and Post-treatment Evaluation Periods is not allowed. Stable does of heparins during dialysis are permitted * Uncontrolled hypertension as judged by the Investigator. Participants with a pre- or post-dialysis blood pressure (BP) that is \> 180 millimeters of mercury (mmHg) on at least 3 of last 5 dialysis treatments.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Major Bleeding (MB) and Clinically Relevant Non-Major Bleeding (CRNMB) | Up to Day 260 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Factor XI (FXI) Activity | Baseline (Day 1) up to Day 260 | — |
| Number of Participants With Laboratory Abnormalities Related to Platelet Count | Up to Day 260 | 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. |
| Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Baseline (Day 1) up to Day 260 | — |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Up to Day 260 | — |
| Percent Change From Baseline in Factor XI (FXI) Antigen Levels | Baseline (Day 1) up to Day 260 | — |
| Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) | Up to Day 260 | 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. |
Countries
Spain
Participant flow
Recruitment details
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.
Pre-assignment details
A total of 213 participants were enrolled and randomized in the study. Out of 213, 3 participants did not receive the study drug
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period. | 53 |
| 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. | 53 |
| 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. | 54 |
| 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. | 50 |
| Total | 210 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event or Serious Adverse Event (SAE) | 2 | 0 | 5 | 1 |
| Overall Study | Ineligibility | 0 | 0 | 0 | 2 |
| Overall Study | Other | 0 | 0 | 1 | 0 |
| Overall Study | Voluntary Withdrawal | 1 | 1 | 3 | 1 |
Baseline characteristics
| Characteristic | Placebo | Cohort A: ISIS 416858, 200 mg | Cohort B: ISIS 416858, 250 mg | Cohort C: ISIS 416858, 300 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 61 years STANDARD_DEVIATION 13 | 61 years STANDARD_DEVIATION 14 | 63 years STANDARD_DEVIATION 12 | 58 years STANDARD_DEVIATION 14 | 61 years STANDARD_DEVIATION 13 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 6 Participants | 5 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 52 Participants | 53 Participants | 48 Participants | 45 Participants | 198 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 52 Participants | 51 Participants | 50 Participants | 49 Participants | 202 Participants |
| Sex: Female, Male Female | 19 Participants | 23 Participants | 19 Participants | 20 Participants | 81 Participants |
| Sex: Female, Male Male | 34 Participants | 30 Participants | 35 Participants | 30 Participants | 129 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 53 | 0 / 53 | 5 / 54 | 1 / 50 |
| other Total, other adverse events | 25 / 53 | 27 / 53 | 35 / 54 | 39 / 50 |
| serious Total, serious adverse events | 10 / 53 | 6 / 53 | 20 / 54 | 13 / 50 |
Outcome results
Primary
Number of Participants With Major Bleeding (MB) and Clinically Relevant Non-Major Bleeding (CRNMB)
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.
Time frame: Up to Day 260
Population: Safety population included all randomized participants who received at least 1 dose of the study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Major Bleeding (MB) and Clinically Relevant Non-Major Bleeding (CRNMB) | 3 Participants |
| Cohort A: ISIS 416858, 200 mg | Number of Participants With Major Bleeding (MB) and Clinically Relevant Non-Major Bleeding (CRNMB) | 2 Participants |
| Cohort B: ISIS 416858, 250 mg | Number of Participants With Major Bleeding (MB) and Clinically Relevant Non-Major Bleeding (CRNMB) | 3 Participants |
| Cohort C: ISIS 416858, 300 mg | Number of Participants With Major Bleeding (MB) and Clinically Relevant Non-Major Bleeding (CRNMB) | 3 Participants |
Other Pre-specified
Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST)
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.
Time frame: Up to Day 260
Population: Safety population included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) | ALT: >3*ULN, Confirmed | 0 Participants |
| Placebo | Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) | ALT: >5*ULN, Confirmed | 0 Participants |
| Placebo | Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) | AST: >3*ULN, Confirmed | 0 Participants |
| Placebo | Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) | AST: >5*ULN, Confirmed | 0 Participants |
| Cohort A: ISIS 416858, 200 mg | Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) | ALT: >5*ULN, Confirmed | 0 Participants |
| Cohort A: ISIS 416858, 200 mg | Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) | AST: >3*ULN, Confirmed | 0 Participants |
| Cohort A: ISIS 416858, 200 mg | Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) | AST: >5*ULN, Confirmed | 0 Participants |
| Cohort A: ISIS 416858, 200 mg | Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) | ALT: >3*ULN, Confirmed | 0 Participants |
| Cohort B: ISIS 416858, 250 mg | Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) | AST: >3*ULN, Confirmed | 1 Participants |
| Cohort B: ISIS 416858, 250 mg | Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) | ALT: >5*ULN, Confirmed | 1 Participants |
| Cohort B: ISIS 416858, 250 mg | Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) | AST: >5*ULN, Confirmed | 1 Participants |
| Cohort B: ISIS 416858, 250 mg | Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) | ALT: >3*ULN, Confirmed | 1 Participants |
| Cohort C: ISIS 416858, 300 mg | Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) | AST: >5*ULN, Confirmed | 0 Participants |
| Cohort C: ISIS 416858, 300 mg | Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) | ALT: >5*ULN, Confirmed | 0 Participants |
| Cohort C: ISIS 416858, 300 mg | Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) | ALT: >3*ULN, Confirmed | 0 Participants |
| Cohort C: ISIS 416858, 300 mg | Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST) | AST: >3*ULN, Confirmed | 0 Participants |
Other Pre-specified
Number of Participants With Laboratory Abnormalities Related to Platelet Count
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.
Time frame: Up to Day 260
Population: Safety population included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Laboratory Abnormalities Related to Platelet Count | 50 - <75 K/mm^3 | 0 Participants |
| Placebo | Number of Participants With Laboratory Abnormalities Related to Platelet Count | 75 - <100 K/mm^3 | 2 Participants |
| Placebo | Number of Participants With Laboratory Abnormalities Related to Platelet Count | < 25 K/mm^3 | 0 Participants |
| Placebo | Number of Participants With Laboratory Abnormalities Related to Platelet Count | 25 - <50 K/mm^3 | 0 Participants |
| Placebo | Number of Participants With Laboratory Abnormalities Related to Platelet Count | 100 - <140 K/mm^3 | 9 Participants |
| Cohort A: ISIS 416858, 200 mg | Number of Participants With Laboratory Abnormalities Related to Platelet Count | 100 - <140 K/mm^3 | 21 Participants |
| Cohort A: ISIS 416858, 200 mg | Number of Participants With Laboratory Abnormalities Related to Platelet Count | < 25 K/mm^3 | 0 Participants |
| Cohort A: ISIS 416858, 200 mg | Number of Participants With Laboratory Abnormalities Related to Platelet Count | 75 - <100 K/mm^3 | 2 Participants |
| Cohort A: ISIS 416858, 200 mg | Number of Participants With Laboratory Abnormalities Related to Platelet Count | 50 - <75 K/mm^3 | 0 Participants |
| Cohort A: ISIS 416858, 200 mg | Number of Participants With Laboratory Abnormalities Related to Platelet Count | 25 - <50 K/mm^3 | 0 Participants |
| Cohort B: ISIS 416858, 250 mg | Number of Participants With Laboratory Abnormalities Related to Platelet Count | 50 - <75 K/mm^3 | 4 Participants |
| Cohort B: ISIS 416858, 250 mg | Number of Participants With Laboratory Abnormalities Related to Platelet Count | 100 - <140 K/mm^3 | 20 Participants |
| Cohort B: ISIS 416858, 250 mg | Number of Participants With Laboratory Abnormalities Related to Platelet Count | < 25 K/mm^3 | 1 Participants |
| Cohort B: ISIS 416858, 250 mg | Number of Participants With Laboratory Abnormalities Related to Platelet Count | 75 - <100 K/mm^3 | 6 Participants |
| Cohort B: ISIS 416858, 250 mg | Number of Participants With Laboratory Abnormalities Related to Platelet Count | 25 - <50 K/mm^3 | 1 Participants |
| Cohort C: ISIS 416858, 300 mg | Number of Participants With Laboratory Abnormalities Related to Platelet Count | < 25 K/mm^3 | 1 Participants |
| Cohort C: ISIS 416858, 300 mg | Number of Participants With Laboratory Abnormalities Related to Platelet Count | 100 - <140 K/mm^3 | 21 Participants |
| Cohort C: ISIS 416858, 300 mg | Number of Participants With Laboratory Abnormalities Related to Platelet Count | 50 - <75 K/mm^3 | 0 Participants |
| Cohort C: ISIS 416858, 300 mg | Number of Participants With Laboratory Abnormalities Related to Platelet Count | 25 - <50 K/mm^3 | 1 Participants |
| Cohort C: ISIS 416858, 300 mg | Number of Participants With Laboratory Abnormalities Related to Platelet Count | 75 - <100 K/mm^3 | 7 Participants |
Other Pre-specified
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Time frame: Up to Day 260
Population: Safety population included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 33 Participants |
| Cohort A: ISIS 416858, 200 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 37 Participants |
| Cohort B: ISIS 416858, 250 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 46 Participants |
| Cohort C: ISIS 416858, 300 mg | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 44 Participants |
Other Pre-specified
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT)
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 134 | -6.2 percentage change | Standard Deviation 16 |
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 120 | 2.6 percentage change | Standard Deviation 26.6 |
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 50 | 6.8 percentage change | Standard Deviation 46.9 |
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 218 | -0.7 percentage change | Standard Deviation 26.4 |
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 106 | 10.9 percentage change | Standard Deviation 70.7 |
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 92 | 9.5 percentage change | Standard Deviation 58.8 |
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 64 | 6.0 percentage change | Standard Deviation 36.1 |
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 15 | 3.8 percentage change | Standard Deviation 47.7 |
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 78 | 6.6 percentage change | Standard Deviation 49.5 |
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 246 | -0.0 percentage change | Standard Deviation 44.2 |
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 204 | -0.4 percentage change | Standard Deviation 27.9 |
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 5 | -2.8 percentage change | Standard Deviation 23.1 |
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 22 | -0.6 percentage change | Standard Deviation 25.6 |
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 12 | 1.4 percentage change | Standard Deviation 33.5 |
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 190 | -3.6 percentage change | Standard Deviation 12.5 |
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 176 | 3.7 percentage change | Standard Deviation 31.6 |
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 29 | -1.9 percentage change | Standard Deviation 23.8 |
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 260 | 2.3 percentage change | Standard Deviation 50.7 |
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 162 | -1.6 percentage change | Standard Deviation 17.1 |
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 148 | 1.0 percentage change | Standard Deviation 25.8 |
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 36 | -3.1 percentage change | Standard Deviation 17.8 |
| Placebo | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 232 | -0.7 percentage change | Standard Deviation 41.8 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 190 | 38.3 percentage change | Standard Deviation 92.9 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 5 | 9.3 percentage change | Standard Deviation 41.5 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 12 | 9.4 percentage change | Standard Deviation 25.9 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 15 | 7.5 percentage change | Standard Deviation 29 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 22 | 11.4 percentage change | Standard Deviation 38.1 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 29 | 11.0 percentage change | Standard Deviation 28.4 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 36 | 7.1 percentage change | Standard Deviation 18.2 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 50 | 24.1 percentage change | Standard Deviation 53.4 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 64 | 20.3 percentage change | Standard Deviation 25.8 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 78 | 27.9 percentage change | Standard Deviation 49.2 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 92 | 19.1 percentage change | Standard Deviation 27.1 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 106 | 38.9 percentage change | Standard Deviation 71.7 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 120 | 28.5 percentage change | Standard Deviation 43.1 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 134 | 42.9 percentage change | Standard Deviation 86.6 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 148 | 26.1 percentage change | Standard Deviation 28.7 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 162 | 27.6 percentage change | Standard Deviation 30.1 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 176 | 28.8 percentage change | Standard Deviation 35 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 204 | 17.4 percentage change | Standard Deviation 39.3 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 218 | 13.1 percentage change | Standard Deviation 25.8 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 232 | 8.6 percentage change | Standard Deviation 24 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 246 | 10.0 percentage change | Standard Deviation 26.9 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 260 | 16.1 percentage change | Standard Deviation 54.4 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 190 | 20.5 percentage change | Standard Deviation 31.6 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 134 | 29.5 percentage change | Standard Deviation 49.8 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 15 | 12.5 percentage change | Standard Deviation 39.8 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 29 | 11.4 percentage change | Standard Deviation 30.7 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 204 | 13.3 percentage change | Standard Deviation 27.1 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 260 | -2.9 percentage change | Standard Deviation 21.6 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 162 | 31.6 percentage change | Standard Deviation 39.3 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 5 | -2.8 percentage change | Standard Deviation 19.2 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 218 | 7.0 percentage change | Standard Deviation 24.6 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 232 | 16.8 percentage change | Standard Deviation 44 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 64 | 29.9 percentage change | Standard Deviation 75.6 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 36 | 13.2 percentage change | Standard Deviation 35.5 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 78 | 27.9 percentage change | Standard Deviation 38.6 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 246 | 3.5 percentage change | Standard Deviation 25.2 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 176 | 36.3 percentage change | Standard Deviation 79 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 12 | 0.8 percentage change | Standard Deviation 21.9 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 92 | 52.5 percentage change | Standard Deviation 83.1 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 120 | 22.5 percentage change | Standard Deviation 33.1 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 50 | 27.5 percentage change | Standard Deviation 42.4 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 22 | 8.4 percentage change | Standard Deviation 30.4 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 106 | 28.5 percentage change | Standard Deviation 46.1 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 148 | 34.0 percentage change | Standard Deviation 53.5 |
| Cohort C: ISIS 416858, 300 mg | 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 |
| Cohort C: ISIS 416858, 300 mg | 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 |
| Cohort C: ISIS 416858, 300 mg | 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 |
| Cohort C: ISIS 416858, 300 mg | 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 |
| Cohort C: ISIS 416858, 300 mg | 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 |
| Cohort C: ISIS 416858, 300 mg | 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 |
| Cohort C: ISIS 416858, 300 mg | 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 |
| Cohort C: ISIS 416858, 300 mg | 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 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 22 | 16.6 percentage change | Standard Deviation 32 |
| Cohort C: ISIS 416858, 300 mg | 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 |
| Cohort C: ISIS 416858, 300 mg | 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 |
| Cohort C: ISIS 416858, 300 mg | 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 |
| Cohort C: ISIS 416858, 300 mg | 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 |
| Cohort C: ISIS 416858, 300 mg | 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 |
| Cohort C: ISIS 416858, 300 mg | 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 |
| Cohort C: ISIS 416858, 300 mg | 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 |
| Cohort C: ISIS 416858, 300 mg | 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 |
| Cohort C: ISIS 416858, 300 mg | 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 |
| Cohort C: ISIS 416858, 300 mg | 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 |
| Cohort C: ISIS 416858, 300 mg | 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 |
| Cohort C: ISIS 416858, 300 mg | 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 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT) | Percent Change From Baseline at Day 36 | 16.9 percentage change | Standard Deviation 21 |
Comparison: Day 12 through Day 260p-value: <0.05ANOVA
Comparison: Day 15 through Day 232p-value: <0.05ANOVA
Other Pre-specified
Percent Change From Baseline in Factor XI (FXI) Activity
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 190 | -2.7 percentage change | Standard Deviation 17.8 |
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 120 | -0.8 percentage change | Standard Deviation 23 |
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 246 | -2.6 percentage change | Standard Deviation 21 |
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 134 | -1.3 percentage change | Standard Deviation 18.1 |
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 22 | -3.7 percentage change | Standard Deviation 18.2 |
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 176 | -4.1 percentage change | Standard Deviation 23.6 |
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 148 | -4.3 percentage change | Standard Deviation 23.6 |
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 260 | -3.8 percentage change | Standard Deviation 21.3 |
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 162 | -3.1 percentage change | Standard Deviation 22.8 |
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 29 | -3.3 percentage change | Standard Deviation 18.3 |
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 12 | -1.9 percentage change | Standard Deviation 13.7 |
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 232 | -0.7 percentage change | Standard Deviation 18.6 |
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 36 | -6.0 percentage change | Standard Deviation 18.1 |
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 50 | -3.2 percentage change | Standard Deviation 19.7 |
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 218 | -5.6 percentage change | Standard Deviation 17.8 |
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 64 | -4.5 percentage change | Standard Deviation 20.2 |
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 78 | -8.1 percentage change | Standard Deviation 19.6 |
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 15 | -0.6 percentage change | Standard Deviation 15.1 |
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 204 | -1.8 percentage change | Standard Deviation 25 |
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 92 | -6.2 percentage change | Standard Deviation 16 |
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 106 | -6.6 percentage change | Standard Deviation 19.2 |
| Placebo | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 5 | -0.6 percentage change | Standard Deviation 14.4 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 36 | -26.3 percentage change | Standard Deviation 18.4 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 12 | -3.0 percentage change | Standard Deviation 17.3 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 120 | -47.8 percentage change | Standard Deviation 20.3 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 218 | -29.3 percentage change | Standard Deviation 20.7 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 176 | -49.9 percentage change | Standard Deviation 24.8 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 15 | -7.1 percentage change | Standard Deviation 16.2 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 134 | -50.0 percentage change | Standard Deviation 19.1 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 50 | -37.9 percentage change | Standard Deviation 22.2 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 5 | 2.5 percentage change | Standard Deviation 24.6 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 190 | -45.4 percentage change | Standard Deviation 28.9 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 148 | -50.4 percentage change | Standard Deviation 17.5 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 106 | -49.4 percentage change | Standard Deviation 20.4 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 162 | -48.9 percentage change | Standard Deviation 21.5 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 64 | -41.8 percentage change | Standard Deviation 20.1 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 22 | -17.2 percentage change | Standard Deviation 16.2 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 260 | -11.1 percentage change | Standard Deviation 25 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 232 | -19.5 percentage change | Standard Deviation 24.7 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 246 | -13.6 percentage change | Standard Deviation 27.6 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 29 | -21.4 percentage change | Standard Deviation 16.9 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 204 | -36.9 percentage change | Standard Deviation 28.7 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 92 | -45.0 percentage change | Standard Deviation 21.6 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 78 | -44.6 percentage change | Standard Deviation 20.9 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 148 | -59.2 percentage change | Standard Deviation 24 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 5 | -0.0 percentage change | Standard Deviation 14.8 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 12 | -8.8 percentage change | Standard Deviation 18.7 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 15 | -14.0 percentage change | Standard Deviation 21.3 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 22 | -22.7 percentage change | Standard Deviation 19.5 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 29 | -31.5 percentage change | Standard Deviation 23.4 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 36 | -37.3 percentage change | Standard Deviation 22 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 50 | -48.1 percentage change | Standard Deviation 24.1 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 64 | -55.1 percentage change | Standard Deviation 24 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 78 | -56.4 percentage change | Standard Deviation 23.9 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 92 | -60.2 percentage change | Standard Deviation 21.8 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 106 | -58.1 percentage change | Standard Deviation 22.2 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 120 | -57.2 percentage change | Standard Deviation 28.1 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 134 | -57.0 percentage change | Standard Deviation 28 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 162 | -60.0 percentage change | Standard Deviation 23.4 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 176 | -61.1 percentage change | Standard Deviation 21.2 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 190 | -55.2 percentage change | Standard Deviation 22.2 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 204 | -48.2 percentage change | Standard Deviation 24.3 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 218 | -37.4 percentage change | Standard Deviation 22.8 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 232 | -28.0 percentage change | Standard Deviation 21.2 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 246 | -20.7 percentage change | Standard Deviation 18.4 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 260 | -15.3 percentage change | Standard Deviation 19.5 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 92 | -66.0 percentage change | Standard Deviation 19 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 12 | -14.1 percentage change | Standard Deviation 16.1 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 190 | -60.9 percentage change | Standard Deviation 19.6 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 78 | -64.2 percentage change | Standard Deviation 19.5 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 64 | -61.7 percentage change | Standard Deviation 20.3 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 260 | -16.0 percentage change | Standard Deviation 22.1 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 204 | -52.2 percentage change | Standard Deviation 22.1 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 50 | -55.7 percentage change | Standard Deviation 20.6 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 36 | -42.8 percentage change | Standard Deviation 17.9 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 246 | -22.3 percentage change | Standard Deviation 24 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 218 | -41.8 percentage change | Standard Deviation 24.2 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 29 | -37.9 percentage change | Standard Deviation 18.5 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 22 | -27.6 percentage change | Standard Deviation 19.3 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 5 | -2.5 percentage change | Standard Deviation 18.3 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 148 | -65.5 percentage change | Standard Deviation 20 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 232 | -29.6 percentage change | Standard Deviation 25.2 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 162 | -64.1 percentage change | Standard Deviation 24.5 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 134 | -67.7 percentage change | Standard Deviation 19.7 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 120 | -66.9 percentage change | Standard Deviation 17.6 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 15 | -18.8 percentage change | Standard Deviation 17.3 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 176 | -64.3 percentage change | Standard Deviation 17.4 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Activity | Percent Change From Baseline at Day 106 | -67.8 percentage change | Standard Deviation 18.4 |
Comparison: Day 15 through Day 176p-value: <0.05Wilcoxon Rank Sum Test
Comparison: Day 12 through Day 176p-value: <0.05Wilcoxon Rank Sum Test
Other Pre-specified
Percent Change From Baseline in Factor XI (FXI) Antigen Levels
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Factor XI (FXI) Antigen Levels | 11.3 percentage change | Standard Deviation 27 |
| Cohort A: ISIS 416858, 200 mg | Percent Change From Baseline in Factor XI (FXI) Antigen Levels | -3.4 percentage change | Standard Deviation 17.5 |
| Cohort B: ISIS 416858, 250 mg | Percent Change From Baseline in Factor XI (FXI) Antigen Levels | -10.1 percentage change | Standard Deviation 21.8 |
| Cohort C: ISIS 416858, 300 mg | Percent Change From Baseline in Factor XI (FXI) Antigen Levels | -13.9 percentage change | Standard Deviation 22.7 |