Study to determine the effectiveness and safety of ION-682884 in patients with Hereditary Transthyretin-Mediated Amyloid Polyneuropathy

• Register: EUCTR
• Last refreshed on: 5 April 2021
• Main ID: EUCTR2019-001698-10-CY
• Date of registration: 11/09/2020
• Prospective Registration: Yes
• Primary sponsor: Ionis Pharmaceuticals, Inc.
• Public title: Study to determine the effectiveness and safety of ION-682884 in patients with Hereditary Transthyretin-Mediated Amyloid Polyneuropathy
• Scientific title: 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 - NEURO – TTRANSFORM
• Date of first enrolment: 24/09/2020
• Target sample size: 140
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2019-001698-10
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: yes; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, China, Colombia, Cyprus, Estonia, France, Germany, Greece, Ireland, Israel, Italy, Japan, Korea, Democratic People's Republic of, Latvia, Malaysia, Mexico, Netherlands, New Zealand, Portugal, Spain, Sweden, Switzerland, Taiwan, Turkey, United Kingdom

Contacts

• Name: Ionis Clinical Trial Information
• Affiliation: Ionis Pharmaceuticals, Inc.

• Name: Ionis Clinical Trial Information
• Affiliation: Ionis Pharmaceuticals, Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Aged 18 to 82 years at the time of informed consent
2. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal
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 FAP
• Documented genetic mutation in the TTR gene
• Symptoms and signs consistent with polyneuropathy as measured by NIS score = 10 and = 130
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 86
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 54

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 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 2 weeks prior to Study Day 1
10. Previous treatment with TegsediTM (Inotersen) or OnpattroTM (patisiran), or other oligonucleotide or RNA therapeutic (including siRNA)


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Hereditary Transthyretin-Mediated Amyloid Polyneuropathy
MedDRA version: 20.0 Level: LLT Classification code 10057949 Term: Familial amyloid polyneuropathy System Organ Class: 100000004850

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Intervention(s)

Product Name: ION-682884
Product Code: ION-682884
Pharmaceutical Form: Solution for injection
INN or Proposed INN: ION-682884
CAS Number: 1637600-16-8
Current Sponsor code: ION-682884
Other descriptive name: ION-682884
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 150-

Product Name: inotersen
Product Code: ISIS 420915
Pharmaceutical Form: Solution for injection in pre-filled syringe
INN or Proposed INN: INOTERSEN
CAS Number: 1432726-13-0
Current Sponsor code: ISIS 420915
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 200-

Primary Outcome(s)

Primary end point(s): Interim Analysis Co-Primary Efficacy Endpoints at Week 35
- Percent change from Baseline in serum TTR concentration
- Change from Baseline in mNIS+7

Final Analysis Co-Primary Efficacy Endpoints
- Percent change from Baseline in serum TTR concentration
- Change from Baseline in mNIS+7
- Change from Baseline in Norfolk QOL-DN

Timepoint(s) of evaluation of this end point: Interim Analysis Co-Primary Efficacy Endpoints at Week 35
Final Analysis Co-Primary Efficacy Endpoints
- Percent change from Baseline in serum TTR concentration at Week 65
- Change from Baseline in mNIS+7 at Week 66
- Change from Baseline in Norfolk QOL-DN at Week 66

Secondary Objective: To evaluate the efficacy of ION-682884, as compared to the placebo cohort in the NEURO-TTR trial, based on the change from Baseline in the following measures:
- Neuropathy Symptom and Change Score (NSC)
- Physical component summary (PCS) score of 36-Item Short Form Survey (SF-36)
- Polyneuropathy disability (PND) score
- Modified body mass index (mBMI)

Main Objective: To evaluate the efficacy of ION-682884 after administration for 65 weeks, as compared to the historical control of the placebo cohort in the NEURO-TTR trial, based on the change from Baseline in serum TTR concentration, mNIS+7 and in the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN) in patients with hATTR.

Secondary Outcome(s)

Secondary end point(s): Interim Analysis Key Secondary Efficacy Endpoint at Week 35
- Change from Baseline in Norfolk QOL-DN
Final Analysis Secondary Endpoint
- Change from Baseline in Norfolk QOL-DN
- Change from Baseline in the PCS score of SF-36
- Change from Baseline in PND score
- Change from Baseline in mBMI
Interim Analysis Key Secondary Efficacy Endpoint at Week 35
Change from Baseline in NSC at Weeks 35 and 66
Change from Baseline in the PCS score of SF-36 at Week 65
Change from Baseline in PND score at Week 65
Change from Baseline in mBMI at Week 65

Timepoint(s) of evaluation of this end point: Interim Analysis Key Secondary Efficacy Endpoint at Week 35

Change from Baseline in NSC at Weeks 35 and 66
Change from Baseline in the PCS score of SF-36 at Week 65
Change from Baseline in PND score at Week 65
Change from Baseline in mBMI at Week 65

Secondary ID(s)

ION-682884-CS3

2019-001698-10-GB

Source(s) of Monetary Support

Ionis Pharmaceuticals, Inc.

Ethics review

Status: Approved
Approval date: 24/09/2020
Contact: