Hereditary Hemorrhagic Telangiectasia
Conditions
Keywords
siRNA, RNAi therapeutic, Plasminogen, PLG, HHT, Osler-Weber-Rendu, epistaxis
Brief summary
The purpose of this study is to: * evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of ALN-6400 in healthy volunteers * evaluate the efficacy, safety, tolerability and PD of multiple doses of ALN-6400 in adult patients with HHT
Interventions
DRUGALN-6400
ALN-6400 will be administered subcutaneously (SC)
DRUGPlacebo
Placebo will be administered subcutaneously (SC)
Sponsors
Alnylam Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
- Part A: * Is a healthy adult volunteer Part B: * Is an adult patient with a clinical diagnosis of HHT
Exclusion criteria
- Part A: * Has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> upper limit of normal (ULN) * Has known human immunodeficiency virus (HIV) infection; or known current or chronic hepatitis C virus or hepatitis B virus infection * Has an estimated glomerular filtration (eGFR) of \<90 mL/min/1.73m\^2 at screening Part B: * Has ALT or AST \>2×ULN * Has total bilirubin \>1.5×ULN * Has eGFR of \<30 mL/min/1.73m\^2 at screening Parts A and B: * Is not willing to comply with the contraceptive requirements during the study period Note: other protocol defined inclusion /
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part A: Frequency of Adverse Events | Up to Week 36 |
| Part B: Frequency of Adverse Events | Up to Week 96 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Concentrations of ALN-6400 in Plasma | Predose and up to 2 days postdose | — |
| Part A: Change from Baseline in Plasminogen (PLG) in Plasma Protein Levels | Predose and up to Week 36 postdose | — |
| Part B: Change from Baseline in Plasminogen (PLG) in Plasma Protein Levels | Screening and up to Week 96 postdose | — |
| Part A: Change from Baseline in Plasminogen (PLG) in Plasma Activity Levels | Predose and up to Week 36 postdose | — |
| Part B: Change from Baseline in Plasminogen (PLG) in Plasma Activity Levels | Part B: Screening and up to Week 96 postdose | — |
| Part B: Change from Baseline in Intensity-adjusted Epistaxis Duration | Baseline up to Week 96 | Intensity-adjusted epistaxis duration will be assessed using a daily patient epistaxis diary. |
| Part B: Change from Baseline in Epistaxis Severity Score (ESS) Scale | Baseline up to Week 96 | Validated bleeding scale in HHT scored between 0-10, higher scores indicate worse bleeding. |
| Part B: Change from Baseline in Epistaxis Duration | Baseline up to Week 96 | Epistaxis duration will be assessed using a daily patient epistaxis diary. |
| Part B: Change from Baseline in Epistaxis Frequency | Baseline up to Week 96 | Epistaxis frequency will be assessed using a daily patient epistaxis diary. |
| Part B: Change from Baseline in Epistaxis Intensity | Baseline up to Week 96 | Epistaxis intensity will be assessed using a daily patient epistaxis diary. |
| Part B: Change from Baseline in Epistaxis-free Days per Month | Baseline up to Week 96 | Epistaxis-free days per month will be assessed using a daily patient epistaxis diary. |
| Part B: Change from Baseline in Hematologic Support Score (HSS) | Baseline up to Week 96 | The HSS is a quantitative tool designed to longitudinally assess the red blood cells (RBC) and iron supplementation needs of patients with HHT and other chronic bleeding disorders. |
| Part B: Change from Baseline in Iron Infusions | Baseline up to Week 96 | — |
| Part B: Change from Baseline in Red Blood Cell (RBC) Infusions | Baseline up to Week 96 | — |
| Part B: Change from Baseline in Hemoglobin | Baseline up to Week 96 | — |
| Part B: Change from Baseline in Quality of Life Patient-reported Outcomes (QoL/PRO) assessed by Nasal Outcome Score for Epistaxis in Hereditary Hemorrhagic Telangiectasia (NOSE HHT) Score | Baseline up to Week 84 | HHT-specific QoL/PRO will be assessed using the NOSE HHT score. The NOSE HHT is a 29-item patient-reported, clinically validated outcome measure, with total scores ranging continuously from 0 to 4 with higher scores indicating worse scores. |
| Part B: Change from Baseline in QoL/PRO assessed by Modified Patient Global Impression of Severity (mPGI-S) Score | Baseline up to Week 84 | HHT-specific QoL/PRO will be assessed using the mPGI-S. The patient will respond to a single question, providing their global impression of change in their overall status and epistaxis experience. |
Countries
Australia, Canada, France, Germany, Spain, United States
Contacts
STUDY_DIRECTORMedical Director
Alnylam Pharmaceuticals
Outcome results
None listed