A controlled study to assess the effectiveness and safety of study drug, ISIS 420915, in patients with Familial Amyloid Polyneuropathy

INTERVENTION: Product Name: Human Transthyretin Antisense Oligonucleotide Product Code: ISIS 420915 Pharmaceutical Form: Solution for injection INN or Proposed INN: ISIS 420915 Current Sponsor code: ISIS 420915 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 200‐ Pharmaceutical form of the placebo: Solution for injection Route of administration of the placebo: Subcutaneous use CONDITION: Familial Amyloid Polyneuropathy ; MedDRA version: 19.1 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] PRIMARY OUTCOME: Main Objective: To evaluate the efficacy of ISIS 420915 as compared to placebo, given for 65 weeks, as measured by the change from baseline in the modified Neuropathy Impairment Score +7 (mNIS+7) and in the Norfolk Quality of Life‐Diabetic Neuropathy (Norfolk QOL‐DN) questionnaire total score, in patients with Familial Amyloid Polyneuropathy (FAP). Primary end point(s): Change in mNIS+7 score from baseline to Week 66 and the change in the Norfolk QOL‐DN questionnaire total score from baseline to Week 66 Secondary Objective: To evaluate the efficacy of ISIS 420915 as compared to placebo based on the change from baseline in the following measures:; • Norfolk QOL‐DN questionnaire symptoms domain score in Stage 1 patients and Norfolk QOL‐DN questionnaire physical functioning/large fiber neuropathy domain score in Stage 2 patients; • Modified body mass index (mBMI) and body mass index (BMI); • NIS and modified +7; • NIS+7; • Global longitudinal strain (GLS) by echocardiogram (ECHO) in the ECHO subgroup and in the Cardiomyopathy‐ECHO (CM‐ECHO) Set; ; To evaluate the pharmacodynamic (PD) effect of ISIS 420915 as compared to placebo, based on the change from baseline in transthyretin (TTR) and retinol binding protein 4 (RBP4).; ; To evaluate the safety and tolerability of ISIS 420915.; ; To evaluate the plasma trough levels of ISIS 420915 in all patients and to evaluate the plasma pharmacokinetic parameters of ISIS 420915 in a subset of patients. Timepoint(s) of evaluation of this end point: 66 Weeks SECONDARY OUTCOME: Secondary end point(s): • Change in the Norfolk QOL‐DN questionnaire symptoms domain score (Stage 1 patients only) and Norfolk QOL‐DN questionnaire physical functioning/large fiber neuropathy domain score (Stage 2 patients only) from baseline to Week 66 ; ; • Change in the mBMI and BMI from baseline to Week 65 ; ; • Change in NIS and modified +7 from baseline to Week 66 ; ; • Change in NIS+7 score from baseline to Week 66 ; ; • Changes in Global longitudinal strain (GLS) by echocardiogram (ECHO) in the ECHO subgroup and in the Cardiomyopathy‐ECHO (CM‐ECHO) Set ; Timepoint(s) of evaluation of this end point: 66 Weeks INCLUSION CRITERIA: • Diagnosed Stage 1 or Stage 2 FAP patient • Meets NIS requirements • Male or female aged 18 to 82 years old at the time of informed consent 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 70 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 65