FAPPhase 3NCT02175004
Extension Study Assessing Long Term Safety and Efficacy of IONIS-TTR Rx in Familial Amyloid Polyneuropathy (FAP)
A Phase 3 study testing Inotersen in people with FAP and Familial Amyloid Polyneuropathy, run by Ionis Pharmaceuticals, Inc. at 22 sites in 9 countries.
Trial summary
This study evaluates the safety and tolerability of extended dosing with IONIS-TTR Rx in patients with Familial Amyloid Polyneuropathy. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- FAP, Familial Amyloid Polyneuropathy, TTR
- What is being tested?
- Inotersen
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 135 participants
- Where
- 22 sitesin 9 countries
- Study dates
- 26 Jun 2014to 7 Jan 2021
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Satisfactory completion of dosing \& efficacy assessments in ISIS 420915-CS2
Who cannot join
- Any new condition or worsening of existing condition that could make the patient unsuitable for participation, or interfere with the patient participating in and/or completing the study
Trial locations and contacts
22 sites in 9 countries.
22 sites in 9 countries
United States9 sites
Johns Hopkins University Bayview Medical Center
Baltimore, Maryland, 21205
Boston University School of Medicine - Amyloid Treatment & Research Program
Boston, Massachusetts, 02118
Indiana University School of Medicine
Indianapolis, Indiana, 46202
Mount Sinai Medical Center
New York, New York, 10029
Columbia University Medical Center - The Neurological Institute
New York, New York, 10032
University of California, Irvine
Orange, California, 92868
Penn Presbyterian Medical Center
Philadelphia, Pennsylvania, 19104
Oregon Health & Science University
Portland, Oregon, 97239
Mayo Clinic
Rochester, Minnesota, 55905
Brazil2 sites
Federal University of Rio de Janeiro - University Hospital
Rio de Janeiro, CEP 21941913
AACD
São Paulo
France2 sites
CHU Henri Mondor - Department of Neurology
Créteil, 94000
CHU Bicetre Aphp French Referral Center for FAP/Cornamyl Network
Le Kremlin-Bicêtre, 94275
Italy2 sites
Universita Degli Studi Di Messina - Azienda Ospedaliera Universitaria Policlinico "Gaetano Martino"
Messina, Sicily, 98124
Centro per lo Studio e la Cura delle Amiloidosi Sistemiche - Fondazione IRCCS Policlinico San Matteo
Pavia, 27100
Portugal2 sites
CHLN - Hospital de Santa Maria
Lisbon, 1649-035
CHP-HGSA, Unidade Clinica de Paramiloidose
Porto, 4099-001
Spain2 sites
Hospital Universitari Vall D' Hebron
Barcelona, 08035
Hospital Clinic
Barcelona, 08036
Germany1 site
UKM; Universitätsklinikum Münster, Klinik für Transplantationsmedizin
Münster, 48149
United Kingdom1 site
University College London - National Amyloidosis Centre
London, NW3 2PF
About this study
Official title: An Open-Label Extension Study to Assess the Long-Term Safety and Efficacy of ISIS 420915 in Patients With Familial Amyloid Polyneuropathy (FAP)
This study evaluates the safety and tolerability of extended dosing with IONIS-TTR Rx in patients with Familial Amyloid Polyneuropathy.
Read the detailed description
Familial Amyloid Polyneuropathy (FAP) is a rare, hereditary disease caused by mutations in the transthyretin (TTR) protein. TTR is made by the liver and secreted into the blood. TTR mutations cause it to misfold and deposit in multiple organs causing FAP.
IONIS-TTR Rx is an antisense drug that is designed to decrease the amount of mutant and normal TTR made by the liver. It is predicted that decreasing the amount of TTR protein will result in a decrease in the formation of TTR deposits, and thus slow or stop disease progression.
This study evaluates the safety and tolerability of extended dosing with IONIS-TTR Rx in patients with Familial Amyloid Polyneuropathy.
- Conditions
- FAP, Familial Amyloid Polyneuropathy, TTR, Transthyretin, Amyloidosis
- Being tested
- Inotersen
- Keywords
- FAP, Familial Amyloid Polyneuropathy, TTR, Transthyretin, Amyloidosis
- Medical subject headings
- Amyloid Neuropathies, Familial, Amyloidosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
InotersenDrug
Also called TEGSEDI, IONIS-TTR Rx, ISIS 420915
Inotersen SC
| Study group | Role | What they receive |
|---|---|---|
| Previous Placebo-Inotersen 300 mg | Experimental | Participants received subcutaneous (SC) doses of 300 milligrams (mg) inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 (NCT01737398) were included in this group. Receives: Drug: Inotersen |
| Previous Inotersen-Inotersen 300 mg | Experimental | Participants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group. Receives: Drug: Inotersen |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug
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 in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect, or is an important medical event. TEAEs considered related to the study drug as assessed by the Investigator are reported.
Measured: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Percentage of Participants With Change From Baseline in Vital Signs
Vital signs included blood pressure, heart rate, respiratory rate, and temperature. Only categories with at least one participant with event are reported.
Measured: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Percentage of Participants With Change From Baseline in Weight
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.
Measured: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values
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=140×10^9/L to 400×10^9/L.
Measured: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Percentage of Participants With Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) as Determined by Electrocardiogram (ECG)
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.
Measured: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Percentage of Participants Using Concomitant Medication for Nervous and Cardiovascular System Disorders
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.
Measured: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Percentage of Participants With Change From Baseline in Ophthalmic Examination as Assessed by Visual Acuity Changes
Measured: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Percentage of Participants With Change From Baseline in Light Detection Ability Measured by Electroretinography
Measured: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Secondary outcomes (20)
Change From Baseline in the Modified Neuropathy Impairment Score (mNIS)+7 Composite Score at 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.
Measured: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at 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.
Measured: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at 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.
Measured: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at 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.
Measured: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Change From Baseline in the mNIS +7 Component: Touch-Pressure Sensory Score at Weeks 78 and 156
The Touch-Pressure Sensory test uses the CASE IV instrument to perform standardized psychophysical measurement to determine pressure sensory thresholds in response to touch. The score range of this component is 0 to 40 points. Higher scores indicate impairment. MMRM was used for the analysis.
Measured: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Change From Baseline in the Neuropathy Impairment (NIS) Composite Score at Week 52 of Years 4 and 5
The NIS score is a measure of neurologic impairment. The NIS Score has a range of 0 to 244 and a higher NIS score indicates lower function. A positive change from Baseline indicates worsening. MMRM was used for the analysis.
Measured: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
Change From Baseline in the NIS Component: Cranial Nerves Score at Week 52 of Years 4 and 5
Cranial Nerve assessment involves testing 3rd and 6th nerves and facial, palate, and tongue weakness. The score range for this component is 0 to 40 points. Higher scores indicate worsening. MMRM was used for the analysis.
Measured: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
Change From Baseline in the NIS Component: Muscle Weakness Score at Week 52 of Years 4 and 5
Muscle weakness involves testing 19 movements of muscles. The score range of this component is 0 to 152 points. Higher scores indicate worsening. MMRM was used for the analysis.
Measured: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
Change From Baseline in the NIS Component: Reflexes Score at Week 52 of Years 4 and 5
The Reflexes Score involves testing 5 reflexes to stimuli. The score range of this component is 0 to 20 points. Higher scores indicate worsening. MMRM was used for the analysis.
Measured: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
Change From Baseline in the NIS Component: Sensory Score at Week 52 of Years 4 and 5
The Sensory Score is based on testing an index finger and a big toe each to 4 stimuli. The score of this component ranges from 0 to 32 points. Higher scores indicate impairment. MMRM was used for the analysis.
Measured: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire Total Score at Weeks 78 and 156
The Norfolk QoL-DN score is a measure of physical function/large fiber neuropathy, symptoms, activities of daily living, small fiber neuropathy, and autonomic neuropathy. The Norfolk QoL-DN total score has a range of -4 to 136, and a higher Norfolk QoL-DN score indicates poorer QoL. A positive change from Baseline indicates worsening in the QoL. MMRM was used for the analysis.
Measured: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 and at the end of each subsequent treatment year (Week 52 of Years 4 and 5)
Change From Baseline in the Norfolk QoL-DN Physical Functioning/Large Fiber Neuropathy Domain Score
The Norfolk QoL-DN physical functioning/large fiber neuropathy domain score is a sub-score of the total Norfolk QoL-DN Questionnaire. The Norfolk QoL-DN physical function/large fiber neuropathy domain score has a range of -4 to 56, and a higher Norfolk QoL-DN domain score indicates poorer quality of life (QoL). A positive change from Baseline indicates worsening in the QoL. MMRM was used for the analysis.
Measured: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 and at the Week 52 of Year 4
Change From Baseline in the Modified Body Mass Index (mBMI) at Weeks 78 and 156
BMI=weight (kg)/[height (m)^2]. The mBMI is the BMI multiplied by the serum albumin (g/L).
Measured: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Change From Baseline in the Body Mass Index (BMI) at Weeks 78 and 156
BMI=weight (kg)/[height (m)^2].
Measured: Baseline, Weeks 78 and 156
Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score
PND score is defined as I = sensory disturbances in limbs without motor impairment; II = difficulty walking without the need of a walking aid; III = one stick or one crutch required for walking; IV = two sticks or two crutches needed. V = wheelchair required or patient confined to bed. The change from Baseline values have been categorized as: improved, not changed, worsened, and unknown. Percentage of participants with changes from Baseline are presented category-wise in this outcome measure. Only categories with at least one participant with event are reported.
Measured: Baseline, Weeks 78 and 156 and at the end of each subsequent treatment year (Week 52 of each year)
Percent Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) in the Cardiomyopathy-ECHO (CM-ECHO) Set
GLS by ECHO is a measure of cardiac systolic function.
Measured: Baseline, Weeks 78 and 156
Percent Change From Baseline in GLS by ECHO in the CS3 ECHO Subgroup
GLS by ECHO is a measure of cardiac systolic function.
Measured: Weeks 78 and 156
Change From Baseline in Transthyretin (TTR) Level
Transthyretin protein concentration in serum was measured.
Measured: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Change From Baseline in Retinol Binding Protein 4 (RBP4) Level
RBP4 protein concentration in serum was measured.
Measured: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156, and at the end of each subsequent treatment year (Week 52 of Years 4 and 5)
Ctrough: Trough Plasma Concentration of ISIS 420915
Measured: Pre-dose on Days 1, 43, 85, 120, 176, 267, 358, 449, 540, 631, 722, 813, 904, 995, 1086, 1268; Days 1359 and 1450 of Year 4; Days 1632, 1723 and 1814 of Year 5
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Jun 2014 (estimated)
- Study start26 Jun 2014
- Primary completion11 Sep 2020
- Study completion7 Jan 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for FAPStudies of the same condition, open and under way.
- More trials run by Ionis Pharmaceuticals, Inc.The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 135 participants (actual)
Sponsor and investigators
- Lead sponsor
- Ionis Pharmaceuticals, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02175004
- Sponsor's protocol ID
- ISIS 420915-CS3
- Other IDs
- 2013-004561-13
- Status last verified
- Nov 2023
- First submitted
- 12 Jun 2014
- Last updated
- 18 Nov 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Expanded access
- Available
Publications
Brannagan TH, Coelho T, Wang AK, Polydefkis MJ, Dyck PJ, Berk JL, Drachman B, Gorevic P, Whelan C, Conceicao I, Plante-Bordeneuve V, Merlini G, Obici L, Plana JMC, Gamez J, Kristen AV, Mazzeo A, Gentile L, Narayana A, Olugemo K, Aquino P, Benson MD, Gertz M; NEURO-T. T. R. Open-Label Extension Investigators. Long-term efficacy and safety of inotersen for hereditary transthyretin amyloidosis: NEURO-TTR open-label extension 3-year update. J Neurol. 2022 Dec;269(12):6416-6427. doi: 10.1007/s00415-022-11276-8. Epub 2022 Jul 31.
PubMed 35908242Karam C, Brown D, Yang M, Done N, Zhu JJ, Greatsinger A, Bozas A, Vera-Llonch M, Signorovitch J. Long-term treatment effects of inotersen on health-related quality of life in patients with hATTR amyloidosis with polyneuropathy: Analysis of the open-label extension of the NEURO-TTR trial. Muscle Nerve. 2022 Oct;66(4):438-446. doi: 10.1002/mus.27675. Epub 2022 Aug 4.
PubMed 35799473Yarlas A, Lovley A, McCausland K, Brown D, Vera-Llonch M, Conceicao I, Karam C, Khella S, Obici L, Waddington-Cruz M. Early Data on Long-term Impact of Inotersen on Quality-of-Life in Patients with Hereditary Transthyretin Amyloidosis Polyneuropathy: Open-Label Extension of NEURO-TTR. Neurol Ther. 2021 Dec;10(2):865-886. doi: 10.1007/s40120-021-00268-x. Epub 2021 Aug 5.
PubMed 34355354Brannagan TH, Wang AK, Coelho T, Waddington Cruz M, Polydefkis MJ, Dyck PJ, Plante-Bordeneuve V, Berk JL, Barroso F, Merlini G, Conceicao I, Hughes SG, Kwoh J, Jung SW, Guthrie S, Pollock M, Benson MD, Gertz M; NEURO-TTR open-label extension investigators. 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. Eur J Neurol. 2020 Aug;27(8):1374-1381. doi: 10.1111/ene.14285. Epub 2020 May 29.
PubMed 32343462
Study at a glance
From the registry record, last updated by the sponsor on 18 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open-Label Extension Study to Assess the Long-Term Safety and Efficacy of ISIS 420915 in Patients With Familial Amyloid Polyneuropathy (FAP)
- ClinicalTrials.gov ID
- NCT02175004
- Acronym / sponsor ID
- ISIS 420915-CS3
- Conditions
- FAP, Familial Amyloid Polyneuropathy, TTR, Transthyretin, Amyloidosis
- Keywords
- FAP, Familial Amyloid Polyneuropathy, TTR, Transthyretin, Amyloidosis
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 135 participants (actual)
- Lead sponsor
- Ionis Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
- Study start
- 26 Jun 2014 (actual)
- Primary completion
- 11 Sep 2020 (actual)
- Study completion
- 7 Jan 2021 (actual)
- First posted
- 26 Jun 2014 (estimated)
- Results
- Posted 9 Feb 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study evaluates the safety and tolerability of extended dosing with IONIS-TTR Rx in patients with Familial Amyloid Polyneuropathy.
Detailed description
Familial Amyloid Polyneuropathy (FAP) is a rare, hereditary disease caused by mutations in the transthyretin (TTR) protein. TTR is made by the liver and secreted into the blood. TTR mutations cause it to misfold and deposit in multiple organs causing FAP.
IONIS-TTR Rx is an antisense drug that is designed to decrease the amount of mutant and normal TTR made by the liver. It is predicted that decreasing the amount of TTR protein will result in a decrease in the formation of TTR deposits, and thus slow or stop disease progression.
This study evaluates the safety and tolerability of extended dosing with IONIS-TTR Rx in patients with Familial Amyloid Polyneuropathy.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Previous Placebo-Inotersen 300 mg | Experimental | Drug: InotersenParticipants received subcutaneous (SC) doses of 300 milligrams (mg) inotersen once weekly for up to 260 weeks. Participants who received inotersen-matching placebo in the previous study- ISIS 420915-CS2 (NCT01737398) were included in this group. |
| Previous Inotersen-Inotersen 300 mg | Experimental | Drug: InotersenParticipants received SC doses of 300 mg inotersen once weekly for up to 260 weeks. Participants who received inotersen in the previous study- ISIS 420915-CS2 were included in this group. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Satisfactory completion of dosing \& efficacy assessments in ISIS 420915-CS2
Key exclusion criteria (1 listed)
- Any new condition or worsening of existing condition that could make the patient unsuitable for participation, or interfere with the patient participating in and/or completing the study
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| InotersenAlso: TEGSEDI, IONIS-TTR Rx, ISIS 420915Inotersen SC | Drug | Previous Inotersen-Inotersen 300 mg, Previous Placebo-Inotersen 300 mg |
Primary outcome
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug
Time frame: 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 in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect, or is an important medical event. TEAEs considered related to the study drug as assessed by the Investigator are reported.
Percentage of Participants With Change From Baseline in Vital Signs
Time frame: 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.
Percentage of Participants With Change From Baseline in Weight
Time frame: 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.
Percentage of Participants With Clinically Significant Change From Baseline in Laboratory Test Values
Time frame: 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=140×10^9/L to 400×10^9/L.
Percentage of Participants With Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) as Determined by Electrocardiogram (ECG)
Time frame: 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.
Percentage of Participants Using Concomitant Medication for Nervous and Cardiovascular System Disorders
Time frame: 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.
Percentage of Participants With Change From Baseline in Ophthalmic Examination as Assessed by Visual Acuity Changes
Time frame: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)
Percentage of Participants With Change From Baseline in Light Detection Ability Measured by Electroretinography
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
20 secondary outcomes
Change From Baseline in the Modified Neuropathy Impairment Score (mNIS)+7 Composite Score at Weeks 78 and 156
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Change From Baseline in the mNIS +7 Component: Heart Rate to Deep Breathing Score at Weeks 78 and 156
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Change From Baseline in the mNIS +7 Component: Nerve Conduction Score at Weeks 78 and 156
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Change From Baseline in the mNIS +7 Component: Heat-Pain Sensory Score at Weeks 78 and 156
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Change From Baseline in the mNIS +7 Component: Touch-Pressure Sensory Score at Weeks 78 and 156
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Change From Baseline in the Neuropathy Impairment (NIS) Composite Score at Week 52 of Years 4 and 5
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
Change From Baseline in the NIS Component: Cranial Nerves Score at Week 52 of Years 4 and 5
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
Change From Baseline in the NIS Component: Muscle Weakness Score at Week 52 of Years 4 and 5
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
Change From Baseline in the NIS Component: Reflexes Score at Week 52 of Years 4 and 5
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
Change From Baseline in the NIS Component: Sensory Score at Week 52 of Years 4 and 5
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Week 52 of Years 4 and 5
Change From Baseline in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaire Total Score at Weeks 78 and 156
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 and at the end of each subsequent treatment year (Week 52 of Years 4 and 5)
Change From Baseline in the Norfolk QoL-DN Physical Functioning/Large Fiber Neuropathy Domain Score
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156 and at the Week 52 of Year 4
Change From Baseline in the Modified Body Mass Index (mBMI) at Weeks 78 and 156
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Change From Baseline in the Body Mass Index (BMI) at Weeks 78 and 156
Time frame: Baseline, Weeks 78 and 156
Percentage of Participants With Change From Baseline in the Polyneuropathy Disability (PND) Score
Time frame: Baseline, Weeks 78 and 156 and at the end of each subsequent treatment year (Week 52 of each year)
Percent Change From Baseline in Global Longitudinal Strain (GLS) by Echocardiogram (ECHO) in the Cardiomyopathy-ECHO (CM-ECHO) Set
Time frame: Baseline, Weeks 78 and 156
Percent Change From Baseline in GLS by ECHO in the CS3 ECHO Subgroup
Time frame: Weeks 78 and 156
Change From Baseline in Transthyretin (TTR) Level
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156
Change From Baseline in Retinol Binding Protein 4 (RBP4) Level
Time frame: Baseline (Baseline is the Baseline of the Previous Study- Study CS2), Weeks 78 and 156, and at the end of each subsequent treatment year (Week 52 of Years 4 and 5)
Ctrough: Trough Plasma Concentration of ISIS 420915
Time frame: Pre-dose on Days 1, 43, 85, 120, 176, 267, 358, 449, 540, 631, 722, 813, 904, 995, 1086, 1268; Days 1359 and 1450 of Year 4; Days 1632, 1723 and 1814 of Year 5
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Nov 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 35908242Brannagan TH, Coelho T, Wang AK, Polydefkis MJ, Dyck PJ, Berk JL, Drachman B, Gorevic P, Whelan C, Conceicao I, Plante-Bordeneuve V, Merlini G, Obici L, Plana JMC, Gamez J, Kristen AV, Mazzeo A, Gentile L, Narayana A, Olugemo K, Aquino P, Benson MD, Gertz M; NEURO-T. T. R. Open-Label Extension Investigators. Long-term efficacy and safety of inotersen for hereditary transthyretin amyloidosis: NEURO-TTR open-label extension 3-year update. J Neurol. 2022 Dec;269(12):6416-6427. doi: 10.1007/s00415-022-11276-8. Epub 2022 Jul 31.
- Derived from this study: PubMed 35799473Karam C, Brown D, Yang M, Done N, Zhu JJ, Greatsinger A, Bozas A, Vera-Llonch M, Signorovitch J. Long-term treatment effects of inotersen on health-related quality of life in patients with hATTR amyloidosis with polyneuropathy: Analysis of the open-label extension of the NEURO-TTR trial. Muscle Nerve. 2022 Oct;66(4):438-446. doi: 10.1002/mus.27675. Epub 2022 Aug 4.
- Derived from this study: PubMed 34355354Yarlas A, Lovley A, McCausland K, Brown D, Vera-Llonch M, Conceicao I, Karam C, Khella S, Obici L, Waddington-Cruz M. Early Data on Long-term Impact of Inotersen on Quality-of-Life in Patients with Hereditary Transthyretin Amyloidosis Polyneuropathy: Open-Label Extension of NEURO-TTR. Neurol Ther. 2021 Dec;10(2):865-886. doi: 10.1007/s40120-021-00268-x. Epub 2021 Aug 5.
- Derived from this study: PubMed 32343462Brannagan TH, Wang AK, Coelho T, Waddington Cruz M, Polydefkis MJ, Dyck PJ, Plante-Bordeneuve V, Berk JL, Barroso F, Merlini G, Conceicao I, Hughes SG, Kwoh J, Jung SW, Guthrie S, Pollock M, Benson MD, Gertz M; NEURO-TTR open-label extension investigators. 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. Eur J Neurol. 2020 Aug;27(8):1374-1381. doi: 10.1111/ene.14285. Epub 2020 May 29.
Related trials for FAP
RecruitingPhase 2/3
Multicenter Validation Trial of [18F]AlF-FAPI-74 for PET Imaging of Cancer-associated Fibroblasts Through Fibroblast Activation Protein Inhibitors (FAPI) in Different Tumor Types
Oesophageal Cancer, Gastric Cancer
Active, not recruitingPhase 3
A Phase 3 Study of NTLA-2001 in ATTRv-PN
Neuromuscular Disease, Neuromuscular Diseases (NMD)
RecruitingPhase 3
MAGNITUDE: A Phase 3 Study of NTLA-2001 in Participants With Transthyretin Amyloidosis With Cardiomyopathy (ATTR-CM)
Transthyretin Amyloidosis (ATTR) With Cardiomyopathy
RecruitingPhase 1
A Study of LY4337713 in Participants With FAP-Positive Solid Tumors
Ovarian Neoplasms, Breast Neoplasms
RecruitingPhase 2
MP0317 in Combination With Chemoimmunotherapy in First Line Treatment for Patients With Advanced Biliary Tract Carcinoma
Advanced Biliary Tract Carcinoma
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
22 sites in 9 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Inotersen in people with FAP and Familial Amyloid Polyneuropathy, run by Ionis Pharmaceuticals, Inc. at 22 sites in 9 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 22 sites in United States, Brazil, France, Italy, Portugal and 4 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 9 Feb 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Related to Study Drug (time frame: From first dose of study drug up to 3 months post treatment period of 260 weeks (Up to approximately 272 weeks)). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02175004, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Nov 2023.