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
- Conditions
- Familial amyloid polyneuropathy - Transthyretin (TTR) amyloid polyneuropathy10034606
- Registration Number
- NL-OMON55279
- Lead Sponsor
- Ionis Pharmaceuticals, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Withdrawn
- Sex
- Not specified
- Target Recruitment
- 2
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
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 < 1000 mg/g or a quantitative total urine protein measurement of
< 1000 mg/24 hr
b. 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)
c. Positive test (including trace) for blood on urinalysis. In the event of a
positive test, eligibility may be confirmed with urine microscopy showing * 5
red blood cells per high power field
d. Alanine aminotransferase/ aspartate aminotransferase (ALT/AST) > 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 < 125 × 109/L
g. HbA1C * 7%
h. Abnormal thyroid function tests with clinical significance per Investigator
judgement in consultation with the Sponsor Medical Monitor
i. Serum vitamin A (or retinol) level at Screening < lower limit of normal
(LLN). For patients with a TTR mutation at position 84 (e.g., Ile84Ser or
Ile84Asn) and vitamin A < LLN the exclusion criterion is signs or symptoms of
vitamin A deficiency (such as dry eye, Bitots* spot observed in the
ophthalmology exam, that in the opinion of the ophthalmologist is consistent
with vitamin A deficiency)
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 (HIV),
hepatitis C (patients confirmed as cured from previous hepatitis C can be
included) or chronic hepatitis B
4. Uncontrolled hypertension (BP > 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
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Week 35 Interim Analysis: Change from Baseline in serum TTR concentration and<br /><br>the mNIS+7;<br /><br>Week 66 Final Analysis: Change from Baseline in serum TTR concentration,<br /><br>mNIS+7 and Norfolk QOL-DN</p><br>
- Secondary Outcome Measures
Name Time Method