A Phase 1 Study of an Investigational Drug, ALN-AT3SC, in Healthy Volunteers and Hemophilia A or B Patients

A Phase 1 Single-ascending and Multiple-ascending Dose, Safety, Tolerability and Pharmacokinetics Study of Subcutaneously Administered ALN-AT3SC in Healthy Adult Volunteers and Hemophilia A or B Patients (Moderate or Severe Hemophilia)

The purpose of this study is to determine the safety, tolerability, and pharmacokinetics of ALN-AT3SC in healthy volunteers and Hemophilia A or B patients.

Study Overview

• Status: Completed
• Conditions: Hemophilia A; Hemophilia B
• Intervention / Treatment: Drug: Sterile Normal Saline (0.9% NaCl); Drug: ALN-AT3SC

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Phase 1

Contacts and Locations

Study Locations

• Bulgaria
  • Plovdiv, Bulgaria
    • Clinical Trial Site
  • Sofia, Bulgaria
    • Clinical Trial Site
  • Varna, Bulgaria
    • Clinical Trial Site
• Russian Federation
  • Kirov, Russian Federation
    • Clinical Trial Site
  • Moscow, Russian Federation
    • Clinical Trial Site
  • St. Petersburg, Russian Federation
    • Clinical Trial Site
• Switzerland
  • St. Gallen, Switzerland
    • Clinical Trial Site
  • Zurich, Switzerland
    • Clinical Trial Site
• United Kingdom
  • Glasgow, United Kingdom
    • Clinical Trial Site
  • London, United Kingdom, NW3 2QG
    • Clinical Trial Site
  • London, United Kingdom, SE1 1YR
    • Clinical Trial Site
  • Manchester, United Kingdom
    • Clinical Trial Site
  • Truro, United Kingdom
    • Clinical Trial Site
• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States
      • Clinical Trial Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

Part A (SAD phase) inclusion:

• Healthy adult males aged 18 to 40 years inclusive at Screening.
• Subjects with adequate complete blood counts and liver function tests.
• Willing to provide written informed consent and willing to comply with study requirements.

Part B & C (MAD & MD phase) inclusion:

• Adult male hemophilia patients aged 18 to 65 years inclusive at Screening.
• Patients with adequate complete blood counts and liver function tests.
• Patients with moderate or severe, clinically stable hemophilia A or B (Factor VIII or Factor IX ≤5%).
• Willing to provide written informed consent and willing to comply with study requirements

Part D (MD Phase in patients with inhibitors) Inclusion:

• Same as Parts B/C
• A Bethesda inhibitor assay > 0.6 BU/mL

Exclusion Criteria:

Part A (SAD phase) exclusion:

• Subjects with a personal history and/or family history of venous thromboembolism (VTE)
• Subjects with a known co-existing thrombophilic disorder
• Subjects with a history of multiple drug allergies or history of allergic reaction to an oligonucleotide or GalNAc.
• Subjects with a history of serious mental illness that includes, but is not limited to schizophrenia, bipolar disorder, severe depression requiring hospitalization or pharmacological intervention.
• Subjects who have a clinically relevant history or presence of cardiovascular, respiratory, gastrointestinal, renal, hematological, lymphatic, neurological, musculoskeletal, genitourinary, immunological including osteoarthritis and other inflammatory diseases, dermatological including rash, eczema, dermatitis, or connective tissue diseases or disorders.

Part B & C (MAD & MD phase) exclusion:

• Patients with a current serious mental illness that, in the judgment of the Investigator, may compromise patient safety, ability to participate in all study assessments, or study integrity.
• Patients who have a clinically relevant history or presence of cardiovascular, respiratory, gastrointestinal, renal, neurological, inflammatory or other diseases that in the judgment of the investigator precludes their participation in the study.
• Patients with a known co-existing thrombophilic disorder
• Patients with a history of multiple drug allergies or history of allergic reaction to an oligonucleotide or GalNAc.
• Patients who are known to be HIV positive and have a CD4 count <400 cells/μL

Part D (MD Phase in patients with inhibitors) exclusion:

• Same as Parts B/C
• Patients who are known to be HIV positive and have a CD4 count <200 cells/μL

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Sterile Normal Saline (0.9% NaCl)	Drug: Sterile Normal Saline (0.9% NaCl); Calculated volume to match active comparator
Active Comparator: ALN-AT3SC	Drug: ALN-AT3SC; Ascending doses of ALN-AT3SC by subcutaneous (sc) injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The safety of ALN-AT3SC evaluated by the proportion of subjects experiencing adverse events (AEs), serious adverse events (SAEs), dose-limiting toxicities (DLTs), and AEs leading to study drug discontinuation.	Part A (SAD phase): through day 56; Part B (MAD) phase: through Day 70; Part C (MD Phase) through Day 112; Part D (MD Phase in patients with inhibitors) through Day 112

Secondary Outcome Measures

Outcome Measure	Time Frame
The pharmacokinetics (PK) of ALN-AT3SC as characterized by plasma PK profiles and urine samples.	Part A (SAD) phase: through day 56; Part B (MAD) phase: through Day 70; Part C (MD Phase) through Day 112; Part D (MD Phase in patients with inhibitors) through Day 112
The pharmacodynamic (PD) effect of ALN-AT3SC, evaluated by Plasma AT levels.	Part A (SAD) phase: through day 56; Part B (MAD) phase: through Day 70; Part C (MD Phase) through Day 112; Part D (MD Phase in patients with inhibitors) through Day 112
The pharmacodynamic (PD) effect of ALN-AT3SC, evaluated by Plasma TG.	Part A (SAD) phase: through day 56; Part B (MAD) phase: through Day 70; Part C (MD Phase) through Day 112; Part D (MD Phase in patients with inhibitors) through Day 112

Collaborators and Investigators

• Sponsor: Sanofi
• Investigators: Study Director: Kate Madigan, MD, Alnylam Pharmaceuticals

Publications and helpful links

General Publications

• Pasi KJ, Rangarajan S, Georgiev P, Mant T, Creagh MD, Lissitchkov T, Bevan D, Austin S, Hay CR, Hegemann I, Kazmi R, Chowdary P, Gercheva-Kyuchukova L, Mamonov V, Timofeeva M, Soh CH, Garg P, Vaishnaw A, Akinc A, Sorensen B, Ragni MV. Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy. N Engl J Med. 2017 Aug 31;377(9):819-828. doi: 10.1056/NEJMoa1616569. Epub 2017 Jul 10.

Study record dates

Study Major Dates

• Study Start (Actual): January 20, 2014
• Primary Completion (Actual): July 20, 2017
• Study Completion (Actual): July 20, 2017

Study Registration Dates

• First Submitted: January 13, 2014
• First Submitted That Met QC Criteria: January 13, 2014
• First Posted (Estimate): January 14, 2014

Study Record Updates

• Last Update Posted (Actual): December 19, 2020
• Last Update Submitted That Met QC Criteria: December 16, 2020
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Blood Coagulation Disorders; Hemophilia A; Hemophilia B
• Other Study ID Numbers: ALN-AT3SC-001

Plan for Individual participant data (IPD)

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