Clinical Trials List
Protocol NumberION-682884-CS3
NCT Number(ClinicalTrials.gov Identfier)NCT04136184
2020-02-01 - 2023-12-15
Phase III
Recruiting4
ICD-10G63
Polyneuropathy in diseases classified elsewhere
ICD-10G65.0
Sequelae of Guillain-Barre syndrome
ICD-10G65.1
Sequelae of other inflammatory polyneuropathy
ICD-10G65.2
Sequelae of toxic polyneuropathy
ICD-9357.4
Polyneuropathy in other diseases classified elsewhere
A Phase 3 Global, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of ION-682884 in Patients With Hereditary Transthyretin-Mediated Amyloid Polyneuropathy
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Trial Applicant
Pharmaceutical Research Associates Taiwan Inc.
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Sponsor
Ionis Pharmaceuticals
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Trial scale
Multi-Regional Multi-Center
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Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- LI-KAI TSAI 無
- HSUEH-WEN HSUEH 無
- Ming-Jen Lee 無
- SUNG-TSANG HSIEH 無
- SHIN-JOE YEH 無
- Jen Jen and I Su 無
- 林昭文 無
- YEN-HUNG LIN 無
- CHIH-HAO CHEN 無
- 高伊慧 無
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- I-Chang Hsieh 未分科
- 洪國竣 無
- 孫銘輝 無
- 張國軒 無
- 呂榮國 無
- 林信瓊 未分科
- 張宏旭 無
- Hong-Chou Kuo 無
- 謝珮甄 無
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
- Wen-Chung Yu 無
- 賴冠霖 無
- Kon-Ping Lin 無
- Mei-Ju Chen 無
- Yi-Chu Liao 無
The Actual Total Number of Participants Enrolled
0 Recruiting
Condition/Disease
Hereditary Transthyretin-Mediated Amyloid Polyneuropathy
Objectives
Primary Objective
To evaluate the efficacy of ION-682884, based on the change from Baseline in serum Transthyretin (TTR) concentration, modified Neuropathy Impairment Score +7 (mNIS+7), and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN) as compared to the historical control of placebo arm in the ISIS 420915-CS2 NEURO-TTR (inotersen) trial
Secondary Objectives
To evaluate the efficacy of ION-682884, as compared to the placebo cohort in the NEURO-TTR trial.
Test Drug
ION-682884 Injection; Inotersen (ISIS 420915) Injection
Active Ingredient
Inotersen (ISIS 420915)
ION-682884
ION-682884
Dosage Form
Solution for subcutaneous injection
Solution for subcutaneous injection
Solution for subcutaneous injection
Dosage
150mg
200mg
200mg
Endpoints
Primary Outcome Measures :
1. Change from baseline in mNIS+7 at Week 66 [ Time Frame: Baseline, Week 66 ]
• 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 score indicates lower function.
2. Change from baseline in the Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66 [ Time Frame: Baseline, Week 66 ]
• 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 score indicates poorer quality of life.
3. Percent change from baseline in serum TTR concentration at Week 66 [ Time Frame: Baseline, Week 66 ]
4. Percent change from baseline in serum transthyretin (TTR) concentration at Week 35 [ Time Frame: Baseline, Week 35 ]
5. Change from baseline in modified neuropathy impairment score plus 7 (mNIS+7) at Week 35 [ Time Frame: Baseline, Week 35 ]
• 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 score indicates lower function.
Secondary Outcome Measures :
1. Change from baseline in Norfolk QOL-DN at Week 35 [ Time Frame: Baseline, Week 35 ]
• 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 score indicates poorer quality of life.
2. Change from baseline in Neuropathy Symptom and Change (NSC) score at Weeks 35 and 66 [ Time Frame: Baseline, Week 35, Week 66 ]
• NSC score is a questionnaire composed of 38 questions that assess the presence and severity of these neuropathy symptoms (including weakness, loss of temperature and pain sensation, and manifestations associated with autonomic nervous system dysfunction).
3. Change from baseline in the Physical Component Summary (PCS) score of the 36-Item Short Form Survey (SF-36) at Week 65 [ Time Frame: Baseline, Week 65 ]
• The SF-36 is composed of 8 multi-item scales (35 items) assessing physical function (10 items), role limitations due to physical health problems (4 items), bodily pain (2 items), general health (5 items), vitality (4 items), social functioning (2 items), role limitations due to emotional problems (3 items) and emotional well-being (5 items). Each of the 8 scales is scored from 0 to 100 with higher scores indicating better health. The 8 scales can be aggregated into a PCS score, which is also scaled from 0 to 100 with higher scores indicating better health.
4. Change from baseline in Polyneuropathy Disability (PND) score at Week 65 [ Time Frame: Baseline, Week 65 ]
• The PND is a 6-stage scoring system: Stage 0: no impairment; Stage 1: sensory disturbances but preserved walking capabilities; Stage 2: impaired walking capacity, but ability to walk without a stick or crutches; Stage 3A/B: walking with help of 1 or 2 sticks or crutches; Stage 4: confined to wheel chair or bedridden.
5. Change from baseline in modified body mass index (mBMI) at Week 65 [ Time Frame: Baseline, Week 65 ]
• mBMI is defined as body mass index in kilograms per square meter (kg/m^2) multiplied by serum albumin in grams per liter (g/L)
1. Change from baseline in mNIS+7 at Week 66 [ Time Frame: Baseline, Week 66 ]
• 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 score indicates lower function.
2. Change from baseline in the Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) Questionnaire at Week 66 [ Time Frame: Baseline, Week 66 ]
• 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 score indicates poorer quality of life.
3. Percent change from baseline in serum TTR concentration at Week 66 [ Time Frame: Baseline, Week 66 ]
4. Percent change from baseline in serum transthyretin (TTR) concentration at Week 35 [ Time Frame: Baseline, Week 35 ]
5. Change from baseline in modified neuropathy impairment score plus 7 (mNIS+7) at Week 35 [ Time Frame: Baseline, Week 35 ]
• 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 score indicates lower function.
Secondary Outcome Measures :
1. Change from baseline in Norfolk QOL-DN at Week 35 [ Time Frame: Baseline, Week 35 ]
• 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 score indicates poorer quality of life.
2. Change from baseline in Neuropathy Symptom and Change (NSC) score at Weeks 35 and 66 [ Time Frame: Baseline, Week 35, Week 66 ]
• NSC score is a questionnaire composed of 38 questions that assess the presence and severity of these neuropathy symptoms (including weakness, loss of temperature and pain sensation, and manifestations associated with autonomic nervous system dysfunction).
3. Change from baseline in the Physical Component Summary (PCS) score of the 36-Item Short Form Survey (SF-36) at Week 65 [ Time Frame: Baseline, Week 65 ]
• The SF-36 is composed of 8 multi-item scales (35 items) assessing physical function (10 items), role limitations due to physical health problems (4 items), bodily pain (2 items), general health (5 items), vitality (4 items), social functioning (2 items), role limitations due to emotional problems (3 items) and emotional well-being (5 items). Each of the 8 scales is scored from 0 to 100 with higher scores indicating better health. The 8 scales can be aggregated into a PCS score, which is also scaled from 0 to 100 with higher scores indicating better health.
4. Change from baseline in Polyneuropathy Disability (PND) score at Week 65 [ Time Frame: Baseline, Week 65 ]
• The PND is a 6-stage scoring system: Stage 0: no impairment; Stage 1: sensory disturbances but preserved walking capabilities; Stage 2: impaired walking capacity, but ability to walk without a stick or crutches; Stage 3A/B: walking with help of 1 or 2 sticks or crutches; Stage 4: confined to wheel chair or bedridden.
5. Change from baseline in modified body mass index (mBMI) at Week 65 [ Time Frame: Baseline, Week 65 ]
• mBMI is defined as body mass index in kilograms per square meter (kg/m^2) multiplied by serum albumin in grams per liter (g/L)
Inclution Criteria
Inclusion Criteria:
1. Aged 18 to 82 years at the time of informed consent (In Taiwan, only subjects between 20 and 82 years of age will be enrolled.)
2. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal or abstinent
3. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the subject or the subject′s non-pregnant female partner must be using a highly effective contraceptive method
4. Diagnosis of hereditary transthyretin-mediated polyneuropathy as defined by meeting all 3 of the following:
• Stage 1 or Stage 2 Familial Amyloid Polyneuropathy (FAP) or Coutinho Stage
• Documented genetic mutation in the TTR gene
• Symptoms and signs consistent with neuropathy associated with transthyretin amyloidosis, including NIS ≥ 10 and ≤ 130
1. Aged 18 to 82 years at the time of informed consent (In Taiwan, only subjects between 20 and 82 years of age will be enrolled.)
2. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal or abstinent
3. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the subject or the subject′s non-pregnant female partner must be using a highly effective contraceptive method
4. Diagnosis of hereditary transthyretin-mediated polyneuropathy as defined by meeting all 3 of the following:
• Stage 1 or Stage 2 Familial Amyloid Polyneuropathy (FAP) or Coutinho Stage
• Documented genetic mutation in the TTR gene
• Symptoms and signs consistent with neuropathy associated with transthyretin amyloidosis, including NIS ≥ 10 and ≤ 130
Exclusion Criteria
Exclusion Criteria:
1. Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a subject unsuitable for inclusion, including but not limited to abnormal safety labs
2. Karnofsky performance status ≤ 50
3. Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease), including uncontrolled diabetes
4. Prior liver transplant or anticipated liver transplant within 1-yr of Screening
5. New York Heart Association (NYHA) functional classification of ≥ 3
6. Acute coronary syndrome within 6 months of screening or major surgery within 3 months of Screening
7. Other types of amyloidosis
8. Have any other conditions, which, in the opinion of the Investigator or Sponsor would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing the Study
9. Current treatment with any approved drug for hereditary TTR amyloidosis such as Vyndaqel® / Vyndamax™ (tafamidis), Tegsedi™ (inotersen), Onpattro™ (patisiran), off-label use of diflunisal or doxycycline, and tauroursodeoxycholic acid (TUDCA). If previously treated with Vyndaqel® / Vyndamax™, diflunisal or doxycycline, and TUDCA, must have discontinued treatment for at least 2 weeks prior to Study Day 1
10. Previous treatment with Tegsedi™ (Inotersen) or Onpattro™ (patisiran), or other oligonucleotide or RNA therapeutic (including siRNA)
1. Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a subject unsuitable for inclusion, including but not limited to abnormal safety labs
2. Karnofsky performance status ≤ 50
3. Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease), including uncontrolled diabetes
4. Prior liver transplant or anticipated liver transplant within 1-yr of Screening
5. New York Heart Association (NYHA) functional classification of ≥ 3
6. Acute coronary syndrome within 6 months of screening or major surgery within 3 months of Screening
7. Other types of amyloidosis
8. Have any other conditions, which, in the opinion of the Investigator or Sponsor would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing the Study
9. Current treatment with any approved drug for hereditary TTR amyloidosis such as Vyndaqel® / Vyndamax™ (tafamidis), Tegsedi™ (inotersen), Onpattro™ (patisiran), off-label use of diflunisal or doxycycline, and tauroursodeoxycholic acid (TUDCA). If previously treated with Vyndaqel® / Vyndamax™, diflunisal or doxycycline, and TUDCA, must have discontinued treatment for at least 2 weeks prior to Study Day 1
10. Previous treatment with Tegsedi™ (Inotersen) or Onpattro™ (patisiran), or other oligonucleotide or RNA therapeutic (including siRNA)
The Estimated Number of Participants
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Taiwan
15 participants
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Global
140 participants
