Clinical trial NCT02035605: A Phase 1 Study of an Investigational Drug, ALN-AT3SC, in Healthy Volunteers and Hemophilia A or B Patients
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hemophilia A
Hemophilia B
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2014-01-14
Enrollment: 51
Sex: MALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: 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 outcomes:
measure: The pharmacokinetics (PK) of ALN-AT3SC as characterized by plasma PK profiles and urine samples.
timeFrame: 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
measure: The pharmacodynamic (PD) effect of ALN-AT3SC, evaluated by Plasma AT levels.
timeFrame: 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
measure: The pharmacodynamic (PD) effect of ALN-AT3SC, evaluated by Plasma TG.
timeFrame: 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
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: Clinical Trial Site
state: Pennsylvania
city: Plovdiv
country: Bulgaria
facility: Clinical Trial Site
city: Sofia
country: Bulgaria
facility: Clinical Trial Site
city: Varna
country: Bulgaria
facility: Clinical Trial Site
city: Kirov
country: Russian Federation
facility: Clinical Trial Site
city: Moscow
country: Russian Federation
facility: Clinical Trial Site
city: St. Petersburg
country: Russian Federation
facility: Clinical Trial Site
city: St. Gallen
country: Switzerland
facility: Clinical Trial Site
city: Zurich
country: Switzerland
facility: Clinical Trial Site
city: Glasgow
country: United Kingdom
facility: Clinical Trial Site
city: London
country: United Kingdom
facility: Clinical Trial Site
city: London
country: United Kingdom
facility: Clinical Trial Site
city: Manchester
country: United Kingdom
facility: Clinical Trial Site
city: Truro
country: United Kingdom
facility: Clinical Trial Site
Study officials:
affiliation: Alnylam Pharmaceuticals
name: Kate Madigan, MD
role: STUDY_DIRECTOR
References:
citation: 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.