A Study to Evaluate ALN-6400 in Healthy Volunteers and Patients With Hereditary Hemorrhagic Telangiectasia (HHT) (InsigHHT)

InsigHHT: A Phase 1/2, Randomized, Double-blind, Placebo-controlled, 2-part Study of the Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of Single Dose ALN-6400 in Adult Healthy Volunteers and Multiple Dose ALN-6400 in Adult Patients With Hereditary Hemorrhagic Telangiectasia (HHT)

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

Study Overview

• Status: Recruiting
• Conditions: Hereditary Hemorrhagic Telangiectasia
• Intervention / Treatment: Drug: ALN-6400; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Alnylam Clinical Trial Information Line; Phone Number: 1-877-ALNYLAM; Email: clinicaltrials@alnylam.com
• Study Contact Backup: Name: Alnylam Clinical Trial Information Line; Phone Number: 1-877-256-9526; Email: clinicaltrials@alnylam.com

Study Locations

• Australia
  • Camperdown, Australia, 2050
    • Recruiting
    • Clinical Trial Site
  • Parkville, Australia, 3050
    • Recruiting
    • Clinical Trial Site
• Canada
  • Mount Royal, Canada, H3P 3P1
    • Recruiting
    • Clinical Trial Site
  • Toronto, Canada, M5B 1W8
    • Recruiting
    • Clinical Trial Site
• France
  • Bordeaux, France, 33000
    • Recruiting
    • Clinical Trial Site
  • Bron, France, 69500
    • Recruiting
    • Clinical Trial Site
• Germany
  • Homburg, Germany, 66421
    • Recruiting
    • Clinical Trial Site
• Spain
  • L'Hospitalet de Llobregat, Spain, 8907
    • Recruiting
    • Clinical Trial Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Recruiting
      • Clinical Trial Site
  • California
    • Cypress, California, United States, 90630
      • Recruiting
      • Clinical Trial Site
  • Florida
    • Gainesville, Florida, United States, 32608
      • Recruiting
      • Clinical Trial Site
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Recruiting
      • Clinical Trial Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Clinical Trial Site
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Clinical Trial Site
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Clinical Trial Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • Recruiting
      • Clinical Trial Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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 / exclusion criteria apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Part A: Placebo; Participants will be administered a single dose of placebo.	Drug: Placebo; Placebo will be administered subcutaneously (SC)
Experimental: Part A: ALN-6400; Participants will be administered a single dose of ALN-6400.	Drug: ALN-6400; ALN-6400 will be administered subcutaneously (SC)
Experimental: Part B: ALN-6400; Participants will be administered multiple doses of ALN-6400.	Drug: ALN-6400; ALN-6400 will be administered subcutaneously (SC)
Placebo Comparator: Part B: Placebo; Participants will be administered multiple doses of placebo.	Drug: Placebo; Placebo will be administered subcutaneously (SC)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Part A: Frequency of Adverse Events	Up to Week 36
Part B: Frequency of Adverse Events	Up to Week 96

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Intensity-adjusted epistaxis duration will be assessed using a daily patient epistaxis diary.	Baseline up to Week 96
Part B: Change from Baseline in Epistaxis Severity Score (ESS) Scale	Validated bleeding scale in HHT scored between 0-10, higher scores indicate worse bleeding.	Baseline up to Week 96
Part B: Change from Baseline in Epistaxis Duration	Epistaxis duration will be assessed using a daily patient epistaxis diary.	Baseline up to Week 96
Part B: Change from Baseline in Epistaxis Frequency	Epistaxis frequency will be assessed using a daily patient epistaxis diary.	Baseline up to Week 96
Part B: Change from Baseline in Epistaxis Intensity	Epistaxis intensity will be assessed using a daily patient epistaxis diary.	Baseline up to Week 96
Part B: Change from Baseline in Epistaxis-free Days per Month	Epistaxis-free days per month will be assessed using a daily patient epistaxis diary.	Baseline up to Week 96
Part B: Change from Baseline in Hematologic Support Score (HSS)	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.	Baseline up to Week 96
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	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.	Baseline up to Week 84
Part B: Change from Baseline in QoL/PRO assessed by Modified Patient Global Impression of Severity (mPGI-S) Score	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.	Baseline up to Week 84

Collaborators and Investigators

• Sponsor: Alnylam Pharmaceuticals
• Investigators: Study Director: Medical Director, Alnylam Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): November 7, 2024
• Primary Completion (Estimated): January 5, 2028
• Study Completion (Estimated): June 22, 2028

Study Registration Dates

• First Submitted: October 24, 2024
• First Submitted That Met QC Criteria: October 24, 2024
• First Posted (Actual): October 26, 2024

Study Record Updates

• Last Update Posted (Actual): May 14, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: epistaxis; RNAi therapeutic; HHT; siRNA; Plasminogen; Osler-Weber-Rendu; PLG
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Respiratory Tract Diseases; Hemorrhage; Hematologic Diseases; Congenital Abnormalities; Nose Diseases; Otorhinolaryngologic Diseases; Signs and Symptoms, Respiratory; Cardiovascular Abnormalities; Hemostatic Disorders; Hemorrhagic Disorders; Vascular Malformations; Telangiectasis; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Hemic and Lymphatic Diseases; Epistaxis; Telangiectasia, Hereditary Hemorrhagic; Substandard Drugs; Pharmaceutical Preparations; Counterfeit Drugs
• Other Study ID Numbers: ALN-6400-001; 2025-522510-23-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Phase 2-4:

Access to Anonymized individual participant data that support these results is made available 12 months after study completion and not less than 12 months after the product and indication have been approved in the United States (US) and/or the European Union (EU).

Data will be provided contingent upon the approval of a research proposal and the execution of a data sharing agreement. Requests for access to data can be submitted via the website www.vivli.org.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes