E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Transthyretin mediated amyloidosis (ATTR) |
|
E.1.1.1 | Medical condition in easily understood language |
ATTR is a hereditary disease caused by protein aggregates in the heart and the nervous system. It leads to heart dysfunction , damages to the nerves, and gastrointestinal and bladder dysfunctions. |
|
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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10007509 |
E.1.2 | Term | Cardiac amyloidosis |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10019889 |
E.1.2 | Term | Hereditary neuropathic amyloidosis |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To evaluate the safety and tolerability of multiple doses of ALN-TTR02. |
|
E.2.2 | Secondary objectives of the trial |
• To characterize the plasma and urine PK of ALN-TTR02.
• To assess preliminary evidence of the PD effect of ALN-TTR02 on serum total TTR levels. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female aged 18 years or older.
2. Patients has a biopsy-proven diagnosis of TTR amyloidosis with documented signs/symptoms of the disease (e.g., sensory, motor, or autonomic neuropathy) that are at least mild to moderate in severity.
3. Body mass index (BMI) of 17–33 kg/m2.
4. Karnofsky performance status of 60% or greater.
5. Absolute neutrophil count (ANC) ≥1500 cells/mm³,
platelet count ≥100,000 cells/mm³, and hemoglobin ≥10 g/dL.
6. Adequate liver function, demonstrated by an aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 x the upper limit of normal (ULN), total bilirubin within normal limits, albumin >3 g/dL, international normalized ratio (INR) ≤1.2.
7. Adequate renal function: serum creatinine ≤1.5 x ULN.
8. Seronegative for hepatitis B virus (HBV) and hepatitis C virus (HCV).
9. Women of child-bearing potential must have a negative pregnancy test, cannot be breast feeding, and must be using two highly effective methods of contraception ( hormonal - oral, implantable, injectable, or transdermal contraceptives in conjunction with spermicide, condom, or diaphragm; mechanical - spermicide in conjunction with a barrier such as a condom or diaphragm; intrauterine device (IUD) in conjunction with spermicide or condom; or surgical sterilization of partner in conjunction with spermicide, condom, or diaphragm) prior to screening, throughout study participation, and for 1 month after ending study participation.
10. Males agree to use appropriate contraception throughout study participation and for 1 month after ending study participation.
11. Patient is willing and able to comply with protocol required visit schedule and visit requirements and provide written informed consent. |
|
E.4 | Principal exclusion criteria |
1. Pregnant or nursing.
2. Has had a liver transplant.
3. Has a known surgery planned during any point of the study period.
4. Has known human immunodeficiency virus (HIV) positive status.
5. Has a known or suspected systemic bacterial, viral, parasitic, or fungal infection.
6. Received an investigational agent, other than tafamidis or diflunisal, within 30 days prior to study drug administration.
7. Has a New York Heart Association heart failure classification >2.
8. Has unstable angina.
9. Has uncontrolled clinically significant cardiac arrhythmia.
10. Is considered unfit for the study by the Principal Investigator.
11. Had a prior severe reaction to a liposomal product.
12. Has known hypersensitivity to oligonucleotides.
13. Is an employee or family member of Alnylam, the CRO, or the clinical study site personnel. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
To evaluate the safety and tolerability of multiple doses of ALN-TTR02 including:
•assessment of adverse events (AEs),
•12 lead electrocardiograms (ECGs),
•cardiac monitoring (telemetry)
•arterial oxygen saturation (SaO2) using pulse oximetry,
•vital signs (blood pressure, pulse rate, oral body temperature and
respiratory rate),
•clinical laboratory safety tests (hematology, serum chemistry,
coagulation, urinalysis, liver function, lipid panel, thyroid function, complement factor Bb, cytokines, and
•physical examinations. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The review of AEs will be done at each visit from Day 0 through Day 56.
The other assessments will be carried out at specific timepoints between screening and D208, as descibed in the study schedule. |
|
E.5.2 | Secondary end point(s) |
PK profile of ALN-TTR02, including:
•plasma-concentration time profiles for ALN-18328 and the novel lipid components DLin-MC3-DMA and PEG2000-C-DMG.
PD effect of ALN-TTR02 on serum TTR, RBP and Vitamin A, including:
•serial assessment of serum concentrations of TTR, TTR mRNA, RBP and Vitamin A. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
ALN-18328, PEG2000-C-DMG and DLin-MC3-DMA concentrations will be determined at specified time points between D0 and D208, as described in the study schedule.
An assessment of the concentrations of serum TTR, TTR mRNA, RBP and Vitamin A will be determined at specified time points between screening and D208, as described in the study schedule. |
|
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 | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 9 |
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 |
Brazil |
France |
Germany |
Portugal |
Spain |
Sweden |
|
E.8.7 | Trial has a data monitoring committee | Yes |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |