Principal Investigator: Kelsey Barrell
Keywords: Clinical Trial , Neurology , Neuromuscular , Polyneuropathy , Transthyretin-Mediated Amyloid Polyneuropathy Department: Neurology
IRB Number: 00130689
Specialty: Neurology, Neurology
Sub Specialties: Neuromuscular Diseases, Neuropathology
Recruitment Status: Recruiting

Contact Information

Cathy Revere

Brief Summary

Primary and Secondary Objectives

Primary Objectives
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 hA

Secondary Objectives
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)

Safety Objectives
To evaluate safety and tolerability in hATTR-PN patients treated with ION-682884 including the
change from Baseline in platelet count and renal function, the presence of adverse events (AEs).

Additional/Exploratory Objectives

Efficacy Objectives
To evaluate the efficacy of ION-682884 in mNIS+7 at Week 85, compared to Baseline.

To evaluate the efficacy of ION-682884 in the change from Baseline in the Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change (PGIC) at Weeks 37 and 85

To evaluate the efficacy of ION-682884, as compared to the historical control of the placebo arm
included in the ALN-TTR02-004 (APOLLO trial, Identifier: NCT01960348)
in the following measures:
 Change from Baseline in Norfolk QOL-DN at Week 85
 Change from Baseline in 10-Meter Walk Test (10MWT)
 Change from Baseline in Rasch-built Overall Disability Score (R-ODS)
 Change from Baseline in Composite Autonomic Symptom Score-31 (COMPASS-31)
 Change from Baseline in 5-level EQ-5D version (EQ-5D-5L)

To evaluate the efficacy of ION-682884 as compared to the placebo cohort of the NEURO-TTR
trial in:
 Change from Baseline in the SF-36
 Frequency of all-cause hospitalizations (in all patients and in patients with cardiac
 Change from Baseline in transthoracic echocardiogram (ECHO) parameters,
including left ventricular (LV) mass, LV wall thickness, intraventricular septum
(IVS) thickness, and global longitudinal strain (GLS), in patients with cardiac
 Change from Baseline in N-terminal pro b-type natriuretic peptide (NT-proBNP) in
patients with cardiac involvement

Pharmacokinetic Objectives
To evaluate the plasma trough and post-treatment concentrations of ION-682884 or inotersen in
all patients, and to evaluate plasma pharmacokinetic (PK) parameters in a subset of patients.

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:
    1. Females:  must be non-pregnant and non-lactating and either;
      1. Surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy)
      2. Postmenopausal (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)

  1. Abstinent* or
  2. 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 once every 4 weeks pregnancy test
  3. 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.

  1. hATTR-PN as defined by meeting all 3 of the following criteria:
    1. Stage 1 (ambulatory without assistance) or Stage 2 (ambulatory with assistance) according to the Familial Amyloid Polyneuropathy (FAP) or Coutinho Stage
    2. Documented genetic mutation in the TTR gene
    3. Symptoms and signs consistent with neuropathy associated with transthyretin amyloidosis, including NIS ≥ 10 and ≤ 130
  2. 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:
    1. 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

< 1000 mg/g or a quantitative total urine protein measurement of < 1000 mg/24 hr

  1. Renal insufficiency as defined by estimated glomerular filtration rate (eGFRcreat-cys)

< 45 mL/min/1.73 m2 at Screening (eGFRcreat-cys is calculated using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] creatinine-cystatin C equation from 2012) (Inker et al. 2012)

  1. Positive test for blood (including trace) on urinalysis that is subsequently confirmed with urine microscopy showing > 5 red blood cells per high power field and is related to glomerulopathies.  In women, this exclusion criterion must be assessed outside of menstrual period.  If in the opinion of the Investigator the hematuria is not considered related to glomerulopathies the patient may be considered eligible, pending proper follow-up and a discussion with the medical monitor. Patients with history of bladder cancer must have been treated with curative intent and have not presented recurrence within the prior 5 years.
  2. Alanine aminotransferase/ aspartate aminotransferase (ALT/AST) > 2 × upper limit of normal (ULN)
  3. 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 known to have Gilbert’s disease)
  4. Platelets < 125 × 109/L
  5. HbA1C ≥ 7%
  6. Abnormal thyroid function tests with clinical significance per Investigator judgement
  1. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1
  2. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator
  3. Known history of or positive test for human immunodeficiency virus (as evidenced by positive tests for HIV antibody and HIV RNA), hepatitis C (as evidenced by positive tests for HCV antibody and HCV RNA) or hepatitis B (as evidenced by a positive test for hepatitis B surface antigen)
  4. Uncontrolled hypertension (BP > 160/100 mm Hg)
  5. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin, melanoma in situ, prostate carcinoma grade group 1, breast ductal carcinoma in situ, or carcinoma in situ of the cervix.  Patients with a history of other malignancies who have been treated with curative intent and without recurrence within 5 years may also be eligible per Investigator judgement
  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 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
  7. Previous treatment with Tegsedi™ (inotersen) or Onpattro™ (patisiran) or other oligonucleotide or RNA therapeutic (including siRNA)
  8. Treatment with another investigational drug, biological agent, or device within 3 months of screening, or 5 half-lives of study agent, whichever is longer
  9. History of bleeding, diathesis or coagulopathy (e.g., liver cirrhosis, hematologic malignancy, antiphospholipid antibody syndrome, congenital disorders such as hemophilia A, B, and Von Willebrand disease)
  10. Recent history of, or current drug or alcohol abuse.
  11. Use of oral anticoagulants, unless the dose has been stable for 4 weeks prior to the first dose of ION‑682884 or inotersen and regular clinical monitoring is performed
  12. Karnofsky performance status ≤ 50%
  13. Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease, diabetic neuropathy)
  14. Prior liver transplant or anticipated liver transplant within 1 year of Screening


  1. New York Heart Association (NYHA) functional classification of ≥ 3
  2. Known immunoglobulin light chain amyloidosis (AL amyloidosis)
  3. Known leptomeningeal amyloidosis
  4. Known multiple myeloma
  5. Monoclonal gammopathy of undetermined significance (MGUS) and/or alterations in immunoglobulin free light chain (FLC) ratio, unless fat, bone marrow, or heart biopsy confirming the absence of light chain and the presence of TTR protein by mass spectrometry or immunoelectron microscopy. For patients with CKD and without presence of monoclonal protein in blood and urine, the acceptable FLC ratio is 0.26-2.25. Results different from that may be discussed with local hematologist, Investigator and Medical Monitor if the risks associated with the biopsy outweigh the benefits.
  6. Presence of known type 1 or type 2 diabetes mellitus
  7. Anticipated survival less than 2 years
  8. Have any other conditions, which, in the opinion of the Investigator would make the patient unsuitable for inclusion, or could interfere with the subject participating in or completing the study