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NCT02175004

Extension Study Assessing Long Term Safety and Efficacy of IONIS-TTR Rx in Familial Amyloid Polyneuropathy (FAP)

Completed Phase 3 Results posted Last updated 18 November 2023
What this trial tests

Phase 3 trial testing Inotersen in FAP in 135 participants. Completed in 7 January 2021.

Timeline
26 June 2014
Primary endpoint
11 September 2020
7 January 2021

Quick facts

Lead sponsorIonis Pharmaceuticals, Inc.
PhasePhase 3
StatusCompleted
Study typeINTERVENTIONAL
Allocationnon randomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment135
Start date26 June 2014
Primary completion11 September 2020
Estimated completion7 January 2021
Sites22 locations across France, Italy, United Kingdom, Germany, Argentina, Portugal, Spain, United States

Drugs / interventions tested

Conditions studied

Sponsor

Ionis Pharmaceuticals, Inc. — full company profile →

Who can join

18 and older, any sex, with FAP or Familial Amyloid Polyneuropathy. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug Primary · From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)

An adverse event (AE) is any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. An SAE is any untoward medical occurrence that at any dose that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results

TEAEs
GroupValue95% CI
Previous Placebo-Inotersen 300 mg100
Previous Inotersen-Inotersen 300 mg96.5
Serious TEAEs
GroupValue95% CI
Previous Placebo-Inotersen 300 mg36.0
Previous Inotersen-Inotersen 300 mg54.1
TEAEs Related to Study Drug
GroupValue95% CI
Previous Placebo-Inotersen 300 mg82.0
Previous Inotersen-Inotersen 300 mg69.4
Percentage of Participants With Change From Baseline in Vital Signs Primary · From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)

Vital signs included blood pressure, heart rate, respiratory rate, and temperature. Only categories with at least one participant with event are reported.

Systolic Blood Pressure: <90 millimeters of mercury (mmHg)
GroupValue95% CI
Previous Placebo-Inotersen 300 mg12.0
Previous Inotersen-Inotersen 300 mg18.8
Systolic Blood Pressure: >140 mmHg
GroupValue95% CI
Previous Placebo-Inotersen 300 mg32.0
Previous Inotersen-Inotersen 300 mg41.2
Systolic Blood Pressure: >160 mmHg
GroupValue95% CI
Previous Placebo-Inotersen 300 mg8.0
Previous Inotersen-Inotersen 300 mg20.0
Diastolic Blood Pressure: <50 mmHg
GroupValue95% CI
Previous Placebo-Inotersen 300 mg6.0
Previous Inotersen-Inotersen 300 mg9.4
Diastolic Blood Pressure: >90 mmHg
GroupValue95% CI
Previous Placebo-Inotersen 300 mg30.0
Previous Inotersen-Inotersen 300 mg28.2
Diastolic Blood Pressure: >100 mmHg
GroupValue95% CI
Previous Placebo-Inotersen 300 mg10.0
Previous Inotersen-Inotersen 300 mg7.1
Heart Rate: <60 beats per minute (bpm)
GroupValue95% CI
Previous Placebo-Inotersen 300 mg30.0
Previous Inotersen-Inotersen 300 mg38.8
Heart Rate: >100 bpm
GroupValue95% CI
Previous Placebo-Inotersen 300 mg16.0
Previous Inotersen-Inotersen 300 mg9.4
Percentage of Participants With Change From Baseline in Weight Primary · From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)

As prespecified in the protocol, percentage of participants with change from baseline in weight is reported in 2 categories, decrease of ≥7% from Baseline and increase of ≥7% from Baseline.

Weight (kg): Decrease of ≥7% From Baseline
GroupValue95% CI
Previous Placebo-Inotersen 300 mg30.0
Previous Inotersen-Inotersen 300 mg47.1
Weight (kg): Increase of ≥7% From Baseline
GroupValue95% CI
Previous Placebo-Inotersen 300 mg24.0
Previous Inotersen-Inotersen 300 mg11.8
Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values Primary · From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)

Clinical laboratory tests included the analysis of chemistry, haematology, and urinalysis. Any value outside the normal range will be flagged for the attention of the investigator who will assess whether or not a flagged value is of clinical significance. Only those categories with at least one participant with event are reported. Normal range of creatinine clearance is 110 to 150 mL/min in males and 100 to 130 mL/min in females. Normal urine protein to creatinine (P/C) ratio= \<0.2. Normal range for Alanine Aminotransferase (ALT) is 4 to 36 units per liter (U/L). Platelets normal range=140×10

Confirmed Creatinine Clearance by CKD-EPI <30 ml/min/1.73m^2
GroupValue95% CI
Previous Placebo-Inotersen 300 mg4.0
Previous Inotersen-Inotersen 300 mg4.7
Confirmed Urine P/C Ratio >5 × Upper Limit of Normal (ULN)
GroupValue95% CI
Previous Placebo-Inotersen 300 mg8.0
Previous Inotersen-Inotersen 300 mg10.6
Confirmed Alanine Aminotransferase (ALT) ≥3 x ULN
GroupValue95% CI
Previous Placebo-Inotersen 300 mg4.0
Previous Inotersen-Inotersen 300 mg4.7
Confirmed Value of Platelets <75 × 10^9/L
GroupValue95% CI
Previous Placebo-Inotersen 300 mg12.0
Previous Inotersen-Inotersen 300 mg12.9
Percentage of Participants With Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) as Determined by Electrocardiogram (ECG) Primary · From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)

Normal QTcF at Baseline is defined as ≤450 milliseconds (ms) for males or ≤470 ms for females. Percentage of participants with QT interval outside of normal range are reported.

QTcF >450 ms
GroupValue95% CI
Previous Placebo-Inotersen 300 mg44.0
Previous Inotersen-Inotersen 300 mg43.5
QTcF >480 ms
GroupValue95% CI
Previous Placebo-Inotersen 300 mg20.0
Previous Inotersen-Inotersen 300 mg23.5
QTcF >500 ms
GroupValue95% CI
Previous Placebo-Inotersen 300 mg12.0
Previous Inotersen-Inotersen 300 mg16.5
Percentage of Participants Using Concomitant Medication for Nervous and Cardiovascular System Disorders Primary · From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)

A concomitant therapy was any non-protocol-specified drug or substance (including over-the counter medications, herbal medications, and vitamin supplements) administered between signing of informed consent and the final post-treatment visit for treating nervous and cardiovascular system disorders.

Nervous System Disorders
GroupValue95% CI
Previous Placebo-Inotersen 300 mg88.0
Previous Inotersen-Inotersen 300 mg81.2
Cardiovascular System Disorders
GroupValue95% CI
Previous Placebo-Inotersen 300 mg68.0
Previous Inotersen-Inotersen 300 mg75.3
Percentage of Participants With Change From Baseline in Ophthalmic Examination as Assessed by Visual Acuity Changes Primary · From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
GroupValue95% CI
Previous Placebo-Inotersen 300 mg0.0
Previous Inotersen-Inotersen 300 mg2.4
Percentage of Participants With Change From Baseline in Light Detection Ability Measured by Electroretinography Primary · Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Participants With Change From Baseline at Week 78
GroupValue95% CI
Previous Placebo-Inotersen 300 mg25.0
Previous Inotersen-Inotersen 300 mg12.7
Participants With Change From Baseline at Week 156
GroupValue95% CI
Previous Placebo-Inotersen 300 mg31.3
Previous Inotersen-Inotersen 300 mg9.1
Change From Baseline in the Modified Neuropathy Impairment Score (mNIS)+7 Composite Score at Weeks 78 and 156 Secondary · Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156

The mNIS+7 composite score is a measure of neurologic impairment that evaluates muscle weakness, sensation, reflexes, nerve conduction, and autonomic function. The mNIS+7 Composite Score has a range of -22.32 to 346.32 and a higher mNIS+7 composite score indicates worsening disease. A positive change from Baseline indicates worsening of polyneuropathy impairments. Mixed Effects Model with Repeated Measures (MMRM) was used for the analysis.

Change From Baseline at Week 78
GroupValue95% CI
Previous Placebo-Inotersen 300 mg33.11± 28.915
Previous Inotersen-Inotersen 300 mg10.11± 18.204
Change From Baseline at Week 156
GroupValue95% CI
Previous Placebo-Inotersen 300 mg37.34± 29.030
Previous Inotersen-Inotersen 300 mg17.21± 27.307
Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at Weeks 78 and 156 Secondary · Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156

Heart rate to deep breathing is a quantitative autonomic test using the CASE IV instrument that measures a participant's change in heart rate after deep breathing. The score of this component ranges from 0 to 3.72 points. Higher scores indicate impairment. MMRM was used for the analysis.

Change From Baseline at Week 78
GroupValue95% CI
Previous Placebo-Inotersen 300 mg0.23± 0.977
Previous Inotersen-Inotersen 300 mg0.11± 0.761
Change From Baseline at Week 156
GroupValue95% CI
Previous Placebo-Inotersen 300 mg0.44± 1.099
Previous Inotersen-Inotersen 300 mg0.30± 0.504
Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at Weeks 78 and 156 Secondary · Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156

The nerve conduction tests are quantitative tests that measure the conduction attributes of preselected nerves. The score range of this component is 0 to 18.6 points. Higher scores indicate impairment. MMRM was used for the analysis.

Change From Baseline at Week 78
GroupValue95% CI
Previous Placebo-Inotersen 300 mg1.86± 2.313
Previous Inotersen-Inotersen 300 mg0.57± 1.361
Change From Baseline at Week 156
GroupValue95% CI
Previous Placebo-Inotersen 300 mg2.05± 2.351
Previous Inotersen-Inotersen 300 mg0.77± 1.724
Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at Weeks 78 and 156 Secondary · Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156

The Heat-Pain Sensory test uses the CASE IV instrument to perform standardized psychophysical measurement to determine pain sensory thresholds in response to heat. The maximum score of this component is 0 to 40 points. Higher scores indicate impairment. MMRM was used for the analysis.

Change From Baseline at Week 78
GroupValue95% CI
Previous Placebo-Inotersen 300 mg2.60± 8.440
Previous Inotersen-Inotersen 300 mg2.45± 7.557
Change From Baseline at Week 156
GroupValue95% CI
Previous Placebo-Inotersen 300 mg2.90± 9.224
Previous Inotersen-Inotersen 300 mg3.40± 8.774

Adverse events — posted to ClinicalTrials.gov

Time frame: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Previous Placebo-Inotersen 300 mg
Serious: 18/50 (36%)
Deaths: 2/50
Previous Inotersen-Inotersen 300 mg
Serious: 46/85 (54%)
Deaths: 15/85

Serious adverse events (111 terms)

ReactionSystemPrevious Placebo-Inotersen…Previous Inotersen-Inoters…
Cardiac failure congestiveCardiac disorders
PneumoniaInfections and infestations
Cardiac failureCardiac disorders
CellulitisInfections and infestations
SepsisInfections and infestations
SyncopeNervous system disorders
HypotensionVascular disorders
ThrombocytopeniaBlood and lymphatic system disorders
Cardiac failure acuteCardiac disorders
VomitingGastrointestinal disorders
Clostridium difficile colitisInfections and infestations
Urinary tract infectionInfections and infestations
Subarachnoid haemorrhageInjury, poisoning and procedural complications
HyponatraemiaMetabolism and nutrition disorders
MalnutritionMetabolism and nutrition disorders
Acute kidney injuryRenal and urinary disorders
HaematuriaRenal and urinary disorders
HypertensionVascular disorders
Orthostatic hypotensionVascular disorders
AnaemiaBlood and lymphatic system disorders
Angina unstableCardiac disorders
ArrhythmiaCardiac disorders
BradycardiaCardiac disorders
Cardiac arrestCardiac disorders
Cardiac tamponadeCardiac disorders
Other adverse events (61 terms — click to expand)

ReactionSystemPrevious Placebo-Inotersen…Previous Inotersen-Inoters…
NauseaGastrointestinal disorders
ThrombocytopeniaBlood and lymphatic system disorders
DiarrhoeaGastrointestinal disorders
FatigueGeneral disorders
Urinary tract infectionInfections and infestations
FallInjury, poisoning and procedural complications
ChillsGeneral disorders
VomitingGastrointestinal disorders
Oedema peripheralGeneral disorders
Injection site painGeneral disorders
Injection site erythemaGeneral disorders
ConstipationGastrointestinal disorders
PyrexiaGeneral disorders
Muscular weaknessMusculoskeletal and connective tissue disorders
SyncopeNervous system disorders
AnaemiaBlood and lymphatic system disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
Abdominal painGastrointestinal disorders
HeadacheNervous system disorders
ArthralgiaMusculoskeletal and connective tissue disorders
CoughRespiratory, thoracic and mediastinal disorders
Orthostatic hypotensionVascular disorders
HypotensionVascular disorders
DizzinessNervous system disorders
Pain in extremityMusculoskeletal and connective tissue disorders
NasopharyngitisInfections and infestations
Injection site pruritusGeneral disorders
Weight decreasedInvestigations
MyalgiaMusculoskeletal and connective tissue disorders
HypoaesthesiaNervous system disorders
Back painMusculoskeletal and connective tissue disorders
AstheniaGeneral disorders
Muscle atrophyMusculoskeletal and connective tissue disorders
ParaesthesiaNervous system disorders
InsomniaPsychiatric disorders
HypertensionVascular disorders
RashSkin and subcutaneous tissue disorders
BronchitisInfections and infestations
Upper respiratory tract infectionInfections and infestations
Atrial fibrillationCardiac disorders

Most-reported serious reactions: Cardiac failure congestive, Pneumonia, Cardiac failure, Cellulitis, Sepsis, Syncope, Hypotension, Thrombocytopenia.

Data from ClinicalTrials.gov NCT02175004 adverse events section.

Sponsor's own description

This study evaluates the safety and tolerability of extended dosing with IONIS-TTR Rx in patients with Familial Amyloid Polyneuropathy.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Evolving landscape in the management of transthyretin amyloidosis.
    Hawkins PN, Ando Y, Dispenzeri A, Gonzalez-Duarte A, et al · · 2015 · cited 178× · PMID 26611723 · DOI 10.3109/07853890.2015.1068949
  2. ATTR Amyloidosis: Current and Emerging Management Strategies: <i>JACC: CardioOncology</i> State-of-the-Art Review.
    Griffin JM, Rosenthal JL, Grodin JL, Maurer MS, et al · · 2021 · cited 110× · PMID 34729521 · DOI 10.1016/j.jaccao.2021.06.006
  3. Advances in the treatment of hereditary transthyretin amyloidosis: A review.
    Gertz MA, Mauermann ML, Grogan M, Coelho T. · · 2019 · cited 66× · PMID 31368669 · DOI 10.1002/brb3.1371
  4. Landscape of small nucleic acid therapeutics: moving from the bench to the clinic as next-generation medicines.
    Liu M, Wang Y, Zhang Y, Hu D, et al · · 2025 · cited 62× · PMID 40059188 · DOI 10.1038/s41392-024-02112-8
  5. Early data on long-term efficacy and safety of inotersen in patients with hereditary transthyretin amyloidosis: a 2-year update from the open-label extension of the NEURO-TTR trial.
    Brannagan TH, Wang AK, Coelho T, Waddington Cruz M, et al · · 2020 · cited 59× · PMID 32343462 · DOI 10.1111/ene.14285
  6. Tegsedi (Inotersen): An Antisense Oligonucleotide Approved for the Treatment of Adult Patients with Hereditary Transthyretin Amyloidosis.
    Gales L. · · 2019 · cited 55× · PMID 31117178 · DOI 10.3390/ph12020078
  7. Transthyretin Cardiac Amyloidosis in Older Americans.
    Brunjes DL, Castano A, Clemons A, Rubin J, et al · · 2016 · cited 51× · PMID 27769906 · DOI 10.1016/j.cardfail.2016.10.008
  8. Progress and challenges in the treatment of cardiac amyloidosis: a review of the literature.
    Adam RD, Coriu D, Jercan A, Bădeliţă S, et al · · 2021 · cited 40× · PMID 34089308 · DOI 10.1002/ehf2.13443

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Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing