E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hereditary Transthyretin-Mediated Amyloid Polyneuropathy |
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E.1.1.1 | Medical condition in easily understood language |
An inherited condition that causes damage to peripheral nerves |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10057949 |
E.1.2 | Term | Familial amyloid polyneuropathy |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to evaluate the safety and tolerability of extended dosing with ION-682884 in patients with hereditary transthyretin-mediated amyloid polyneuropathy (hATTR-PN). |
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E.2.2 | Secondary objectives of the trial |
The secondary objective is to evaluate the efficacy of extended dosing with ION-682884. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Satisfactory completion of ION-682884-CS3 as judged by the Investigator and Sponsor, OR diagnosis of hATTR-PN and satisfactory completion of either study ISIS 420915-CS101 or study 2018-P001436 (both are Investigator-Sponsored studies with inotersen - the unconjugated version of ION-682884) as judged by the Investigator and Sponsor 2. 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 3. Satisfy the following: a. Females: must be non-pregnant and non-lactating and either: − Surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) − 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) − Abstinent*or − If engaged in sexual relations of child-bearing potential, agree to use highly effective contraceptive methods (Section 6.4.1) from the time of signing the informed consent form until at least 24 weeks after the last dose of ION-682884 and agree to receive pregnancy tests per protocol b. Males: Surgically sterile (i.e., bilateral orchidectomy) or abstinent*, if engaged in sexual relations with a woman of child-bearing potential (WOCBP), the patient’s non-pregnant female partner must use a highly effective contraceptive method (Section 6.4.1) from the time of signing the informed consent form until at least 24 weeks after the last dose of ION-682884 *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. Willingness to adhere to vitamin A supplementation per protocol |
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E.4 | Principal exclusion criteria |
1. Have any new condition or worsening of existing condition that in the opinion of the Investigator or Sponsor would make the patient unsuitable for enrollment, or could interfere with the patient participating in or completing the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoints (PEP) are change from Baseline (Index Study Baseline and separately open-label extension [OLE] Baseline) in the following measures: • Platelet count and renal function • Adverse events (AE) • Use of concomitant medications • Vital signs and weight • Physical examination findings • Clinical laboratory tests • Electrocardiogram (ECG) parameters • Thyroid panel tests • Coagulation tests • Inflammatory panel tests • Complement and immunogenicity tests |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoints (PEP) are change from Baseline (Index Study Baseline and separately open-label extension [OLE] Baseline) in the following measures: • Platelet count and renal function • Adverse events (AE) • Use of concomitant medications • Vital signs and weight • Physical examination findings • Clinical laboratory tests • Electrocardiogram (ECG) parameters • Thyroid panel tests • Coagulation tests • Inflammatory panel tests • Complement and immunogenicity tests |
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E.5.2 | Secondary end point(s) |
The secondary endpoints are Change from Baseline (Index Study Baseline and separately OLE Baseline) in the following measures: • Neuropathy Impairment Score (NIS) • Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire • Neuropathy Symptom and Change score (NSC) • Serum Transthyretin (TTR) concentration • Physical Component Summary score (PCS) of 36-Item Short Form Survey (SF-36) • Polyneuropathy disability score (PND) • Modified body mass index (mBMI) • Composite Autonomic Symptom Score-31 (COMPASS-31) • 5 Level EQ-5D (EQ-5D-5L) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary endpoints are Change from Baseline (Index Study Baseline and separately OLE Baseline) in the following measures: • Neuropathy Impairment Score (NIS) • Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire • Neuropathy Symptom and Change score (NSC) • Serum Transthyretin (TTR) concentration • Physical Component Summary score (PCS) of 36-Item Short Form Survey (SF-36) • Polyneuropathy disability score (PND) • Modified body mass index (mBMI) • Composite Autonomic Symptom Score-31 (COMPASS-31) • 5 Level EQ-5D (EQ-5D-5L) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Brazil |
Canada |
New Zealand |
Taiwan |
Turkey |
United States |
Cyprus |
France |
Germany |
Italy |
Portugal |
Sweden |
Spain |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The End-of-Study is last patient, last visit. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 10 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 8 |