Familial amyloid polyneuropathy - Transthyretin (TTR) amyloid polyneuropathy
Conditions
Interventions
Please refer to section E6 of the protocol.
Sponsors
Ionis Pharmaceuticals, Inc.
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements 2. Aged 18 to 82 years at the time of informed consent 3. Satisfy the following: a. Females: must be non-pregnant and non-lactating and either: i. Surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) ii. Post-menopausal (defined as 12 months of spontaneous amenorrhea in females > 55 years of age or, in females * 55 years, 12 months of spontaneous amenorrhea without an alternative medical cause and FSH levels in the postmenopausal range for the laboratory involved) iii. Abstinent* or iv. If engaged in sexual relations of child-bearing potential, agree to use highly effective contraceptive methods (refer to Section 6.3.1) from the time of signing the informed consent form until at least 24 weeks after the last dose of ION*682884 or inotersen and agree to receive a monthly pregnancy test b. Males: Surgically sterile (i.e., bilateral orchidectomy) or, if engaged in sexual relations with a woman of child bearing potential (WOCBP), the patient or the patient*s non-pregnant female partner must use a highly effective contraceptive method (refer to Section 6.3.1) from the time of signing the informed consent form until at least 24 weeks after the last dose of ION*682884 or inotersen. * Abstinence (i.e., refraining from heterosexual intercourse throughout the duration of study participation) is only acceptable as true abstinence, i.e., when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods), declaration of abstinence for the duration of a trial and withdrawal are not acceptable methods of contraception. 4. hATTR-PN as defined by meeting all 3 of the following criteria: a. Stage 1 (ambulatory without assistance) or Stage 2 (ambulatory with assistance) according to the Familial Amyloid Polyneuropathy (FAP) or Coutinho Stage b. Documented genetic mutation in the TTR gene c. Symptoms and signs consistent with neuropathy associated with transthyretin amyloidosis, including NIS * 10 and * 130 5. Willingness to adhere to vitamin A supplementation per protocol
Exclusion criteria
Exclusion criteria: 1. Clinically significant abnormalities in medical history (e.g., previous acute coronary syndrome within 6 months of Screening, major surgery within 3 months of Screening) or physical examination 2. Screening laboratory results as follows, or any other clinically significant abnormalities in screening laboratory values that would render a patient unsuitable for inclusion: a. Urine protein/creatinine ratio (UPCR) * 1000 mg/g. In the event of UPCR above this threshold, eligibility may be confirmed by a repeat random urine test with UPCR 2 × upper limit of normal (ULN) e. Bilirubin * 1.5 × ULN (patients with bilirubin * 1.5 × ULN may be allowed on study if indirect bilirubin only is elevated, ALT/AST is not greater than the ULN and genetic testing confirming Gilbert*s disease) f. Platelets 160/100 mm Hg) 5. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated. Patients with a history of other malignancies that have been treated with curative intent and which have no recurrence within 5 years may also be eligible 6. Current treatment with any approved drug for hereditary TTR amyloidosis such as Vyndaqel® / Vyndamax* (tafamidis), Tegsedi* (inotersen), Onpattro* (patisiran), off-label use of diflunisal, doxycycline or tauroursodeoxycholic acid (TUDCA). If previously treated with Vyndaqel® / Vyndamax*, diflunisal or doxycycline, and TUDCA, must have discontinued treatment at least 2 weeks prior to Study Day 1 7. Previous treatment with Tegsedi* (inotersen) or Onpattro* (patisiran) or other
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Week 35 Interim Analysis: Change from Baseline in serum TTR concentration and the mNIS+7; Week 66 Final Analysis: Change from Baseline in serum TTR concentration, mNIS+7 and Norfolk QOL-DN | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary endpoints: Week 35 Interim Analysis: * Change from Baseline in Norfolk QOL-DN Week 66 Final Analysis: * Change from Baseline in the NSC score 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 Additional/Exploratory endpoints: Change from Baseline in mNIS+7 at Week 85 Change from Baseline in Norfolk QOL-DN at Week 85 Change from Baseline in 10MWT at Weeks 37 and 81 Change from Baseline in R-ODS at Weeks 37 and 81 Change from Baseline in COMPASS-31 at Weeks 37 and 81 Change from Baseline in EQ-5D-5L at Weeks 37 and 81 Change from Baseline in the SF-36 at Week 35 Frequency of all cause hospitalizations in all patients by Week 66 Frequency of all cause hospitalizations in patients with cardiac involvement by Week 66 Change from Baseline in ECHO parameters, including LV mass, LV wall thickness, IVS thickness, and GLS, at Week 65 in patients with cardiac involvement Change from Baseline in NT-proBNP at Week 65 in patients with cardiac involvement Change from Baseline in PGIS at Weeks 37 and 85 PGIC at Weeks 37 and 85 Plasma trough and post-treatment concentrations of ION-682884 or inotersen in all patients, area under the curve (AUC), Cmax, and tmax in a subset of patients, and t**z for patients who do not roll over to the OLE study. Safety endpoints: Change from Baseline in platelet count per Common Terminology Criteria for Adverse Events (CTCAE) grade. Change from Baseline in renal function. Additional safety endpoints include: adverse events, vital signs and weight, physical examination, clinical laboratory tests, ECG, use of concomitant medication, ophthalmology examination, thyroid panel, inflammatory panel, coagulation, and immunogenicity | — |
Countries
Netherlands
Outcome results
None listed