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Safety and Tolerability of Patisiran (ALN-TTR02) in Transthyretin (TTR) Amyloidosis

Primary Purpose

TTR-mediated Amyloidosis

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Patisiran
Sponsored by
Alnylam Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for TTR-mediated Amyloidosis focused on measuring RNAi therapeutic

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Body mass index must be between 17 kg/m^2 and ≤ 33 kg/m^2;
  • Women of child-bearing potential must have a negative pregnancy test, cannot be breast feeding, and must use appropriate contraception;
  • Males agree to use appropriate contraception;
  • Diagnosis of TTR amyloidosis;
  • Adequate blood counts, liver and renal function;
  • Willing to give written informed consent and are willing to comply with the study requirements.

Exclusion Criteria:

  • Known human immunodeficiency virus (HIV) positive status or known or suspected systemic bacterial, viral, parasitic, or fungal infection;
  • Received an investigational agent, other than tafamidis or diflunisal, within 30 days prior to first dose study drug administration;
  • Prior liver transplant;
  • Poor cardiac function;
  • Considered unfit for the study by the Principal Investigator;
  • Employee or family member of the sponsor or the clinical study site personnel.

Sites / Locations

  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site
  • Clinical Trial Site

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Patisiran (ALN-TTR02)

Arm Description

Two administrations of patisiran will be administered once every 4 weeks [Q4W]) in 4 sequential cohorts with escalating doses followed by optional cohorts with an alternative dosing regimen (once every 3 weeks [Q3W]), and an alternative premedication regimen.

Outcomes

Primary Outcome Measures

Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Study Drug Discontinuation
The number of participants experiencing at least one adverse event (AE), at least one serious adverse event (SAE) and study drug discontinuation (due to any reason).

Secondary Outcome Measures

Percentage Change From Baseline in Serum Transthyretin (TTR) Protein
Percentage change of TTR relative to pretreatment/baseline levels is reported. For arms with a dosing regimen of Q4W TTR protein samples were measured on Days 28 and 56. For the arms with a dosing regimen of Q3W TTR protein samples were measured on Days 21 and 42.
Pharmacokinetic Parameters of Patisiran - Area Under the Concentration Curve From Time 0 to Last Measurable Time Point (AUC0-last)
Pharmacokinetic profiles for patisiran (ALN-TTR02) were determined based on dosage and dosing frequency only, not premedication regimens. For arms with a dosing regimen of Q4W PK samples were taken on Days 0 and 28. For the arm with a dosing regimen of Q3W PK samples were taken on Days 0 and 21.
Pharmacokinetic Parameters of Patisiran - Maximum Observed Plasma Concentration (Cmax)
Pharmacokinetic profiles for patisiran (ALN-TTR02) were determined based on dosage and dosing frequency only, not premedication regimens. For arms with a dosing regimen of Q4W PK samples were taken on Days 0 and 28. For the arm with a dosing regimen of Q3W PK samples were taken on Days 0 and 21.
Pharmacokinetic Parameters of Patisiran - Beta Elimination Half-life (t1/2 Beta)
Pharmacokinetic profiles for patisiran were determined based on dosage and dosing frequency only, not premedication regimens. For arms with a dosing regimen of Q4W PK samples were taken on Days 0 and 28. For the arm with a dosing regimen of Q3W PK samples were taken on Days 0 and 21.
Pharmacokinetic Parameters of Patisiran - Systemic Clearance (CL)
Pharmacokinetic profiles for patisiran were determined based on dosage and dosing frequency only, not premedication regimens. For arms with a dosing regimen of Q4W PK samples were taken on Days 0 and 28. For the arm with a dosing regimen of Q3W PK samples were taken on Days 0 and 21.
Pharmacokinetic Parameters of Patisiran - Apparent Volume of Distribution at Steady State (Vss)
Pharmacokinetic profiles for patisiran were determined based on dosage and dosing frequency only, not premedication regimens. For arms with a dosing regimen of Q4W PK samples were taken on Days 0 and 28. For the arm with a dosing regimen of Q3W PK samples were taken on Days 0 and 21.
Pharmacokinetic Parameters of Patisiran - Renal Clearance (CLR)
Pharmacokinetic profiles for patisiran were determined based on dosage and dosing frequency only, not premedication regimens. For arms with a dosing regimen of Q4W PK samples were taken on Days 0 and 28. For the arm with a dosing regimen of Q3W PK samples were taken on Days 0 and 21.

Full Information

First Posted
June 7, 2012
Last Updated
October 23, 2018
Sponsor
Alnylam Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01617967
Brief Title
Safety and Tolerability of Patisiran (ALN-TTR02) in Transthyretin (TTR) Amyloidosis
Official Title
A Phase 2, Open-Label, Multi-Dose, Dose Escalation Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenous Infusions of ALN-TTR02 in Patients With TTR Amyloidosis
Study Type
Interventional

2. Study Status

Record Verification Date
October 2018
Overall Recruitment Status
Completed
Study Start Date
May 2012 (undefined)
Primary Completion Date
October 2013 (Actual)
Study Completion Date
January 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Alnylam Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Data Monitoring Committee
No

5. Study Description

Brief Summary
This was a multiple dose, dose escalation study designed to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of patisiran (ALN-TTR02) in participants with transthyretin (TTR) mediated amyloidosis (ATTR).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
TTR-mediated Amyloidosis
Keywords
RNAi therapeutic

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
29 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Patisiran (ALN-TTR02)
Arm Type
Experimental
Arm Description
Two administrations of patisiran will be administered once every 4 weeks [Q4W]) in 4 sequential cohorts with escalating doses followed by optional cohorts with an alternative dosing regimen (once every 3 weeks [Q3W]), and an alternative premedication regimen.
Intervention Type
Drug
Intervention Name(s)
Patisiran
Other Intervention Name(s)
ALN-TTR02
Intervention Description
Participants received a single dose of patisiran as an intravenous (IV) infusion on Day 0 and Day 28 (Q4W). Optional cohorts received an alternative dosing regimen (once every 3 weeks [Q3W]: Day 0 and Day 21) and an alternative premedication regimen.
Primary Outcome Measure Information:
Title
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Study Drug Discontinuation
Description
The number of participants experiencing at least one adverse event (AE), at least one serious adverse event (SAE) and study drug discontinuation (due to any reason).
Time Frame
Up to 56 days post first dose
Secondary Outcome Measure Information:
Title
Percentage Change From Baseline in Serum Transthyretin (TTR) Protein
Description
Percentage change of TTR relative to pretreatment/baseline levels is reported. For arms with a dosing regimen of Q4W TTR protein samples were measured on Days 28 and 56. For the arms with a dosing regimen of Q3W TTR protein samples were measured on Days 21 and 42.
Time Frame
Baseline to Day 21/28 and Day 42/56 depending on dosing regimen (Q3W/Q4W)
Title
Pharmacokinetic Parameters of Patisiran - Area Under the Concentration Curve From Time 0 to Last Measurable Time Point (AUC0-last)
Description
Pharmacokinetic profiles for patisiran (ALN-TTR02) were determined based on dosage and dosing frequency only, not premedication regimens. For arms with a dosing regimen of Q4W PK samples were taken on Days 0 and 28. For the arm with a dosing regimen of Q3W PK samples were taken on Days 0 and 21.
Time Frame
Predose, end of infusion and post-infusion at 5 minutes (min), 10 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 24 h and 48 h on Day 0 and Day 21/28 depending on dosing regimen (Q3W/Q4W)
Title
Pharmacokinetic Parameters of Patisiran - Maximum Observed Plasma Concentration (Cmax)
Description
Pharmacokinetic profiles for patisiran (ALN-TTR02) were determined based on dosage and dosing frequency only, not premedication regimens. For arms with a dosing regimen of Q4W PK samples were taken on Days 0 and 28. For the arm with a dosing regimen of Q3W PK samples were taken on Days 0 and 21.
Time Frame
Predose, end of infusion and post-infusion at 5 minutes (min), 10 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 24 h and 48 h on Day 0 and Day 21/28 depending on dosing regimen (Q3W/Q4W)
Title
Pharmacokinetic Parameters of Patisiran - Beta Elimination Half-life (t1/2 Beta)
Description
Pharmacokinetic profiles for patisiran were determined based on dosage and dosing frequency only, not premedication regimens. For arms with a dosing regimen of Q4W PK samples were taken on Days 0 and 28. For the arm with a dosing regimen of Q3W PK samples were taken on Days 0 and 21.
Time Frame
Predose, end of infusion and post-infusion at 5 minutes (min), 10 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 24 h and 48 h on Day 0 and Day 21/28 depending on dosing frequency
Title
Pharmacokinetic Parameters of Patisiran - Systemic Clearance (CL)
Description
Pharmacokinetic profiles for patisiran were determined based on dosage and dosing frequency only, not premedication regimens. For arms with a dosing regimen of Q4W PK samples were taken on Days 0 and 28. For the arm with a dosing regimen of Q3W PK samples were taken on Days 0 and 21.
Time Frame
Predose, end of infusion and post-infusion at 5 minutes (min), 10 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 24 h and 48 h on Day 0 and Day 21/28 depending on dosing frequency
Title
Pharmacokinetic Parameters of Patisiran - Apparent Volume of Distribution at Steady State (Vss)
Description
Pharmacokinetic profiles for patisiran were determined based on dosage and dosing frequency only, not premedication regimens. For arms with a dosing regimen of Q4W PK samples were taken on Days 0 and 28. For the arm with a dosing regimen of Q3W PK samples were taken on Days 0 and 21.
Time Frame
Predose, end of infusion and post-infusion at 5 minutes (min), 10 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 24 h and 48 h on Day 0 and Day 21/28 depending on dosing frequency
Title
Pharmacokinetic Parameters of Patisiran - Renal Clearance (CLR)
Description
Pharmacokinetic profiles for patisiran were determined based on dosage and dosing frequency only, not premedication regimens. For arms with a dosing regimen of Q4W PK samples were taken on Days 0 and 28. For the arm with a dosing regimen of Q3W PK samples were taken on Days 0 and 21.
Time Frame
Predose (within 1 h of planned dosing start) and post-infusion at 0-6 h (pooled) on Day 0 and Day 21/28 depending on dosing frequency

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Body mass index must be between 17 kg/m^2 and ≤ 33 kg/m^2; Women of child-bearing potential must have a negative pregnancy test, cannot be breast feeding, and must use appropriate contraception; Males agree to use appropriate contraception; Diagnosis of TTR amyloidosis; Adequate blood counts, liver and renal function; Willing to give written informed consent and are willing to comply with the study requirements. Exclusion Criteria: Known human immunodeficiency virus (HIV) positive status or known or suspected systemic bacterial, viral, parasitic, or fungal infection; Received an investigational agent, other than tafamidis or diflunisal, within 30 days prior to first dose study drug administration; Prior liver transplant; Poor cardiac function; Considered unfit for the study by the Principal Investigator; Employee or family member of the sponsor or the clinical study site personnel.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jared Gollob, MD
Organizational Affiliation
Alnylam Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Clinical Trial Site
City
Boston
State/Province
Massachusetts
Country
United States
Facility Name
Clinical Trial Site
City
Rio de Janeiro
Country
Brazil
Facility Name
Clinical Trial Site
City
Le Kremlin-bicetre
Country
France
Facility Name
Clinical Trial Site
City
Marseille Cedex
Country
France
Facility Name
Clinical Trial Site
City
Munster
Country
Germany
Facility Name
Clinical Trial Site
City
Lisbon
Country
Portugal
Facility Name
Clinical Trial Site
City
Porto
Country
Portugal
Facility Name
Clinical Trial Site
City
Barcelona
Country
Spain
Facility Name
Clinical Trial Site
City
Palma De Mallorca
Country
Spain
Facility Name
Clinical Trial Site
City
Umeå
Country
Sweden

12. IPD Sharing Statement

Citations:
PubMed Identifier
26338094
Citation
Suhr OB, Coelho T, Buades J, Pouget J, Conceicao I, Berk J, Schmidt H, Waddington-Cruz M, Campistol JM, Bettencourt BR, Vaishnaw A, Gollob J, Adams D. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J Rare Dis. 2015 Sep 4;10:109. doi: 10.1186/s13023-015-0326-6.
Results Reference
derived

Learn more about this trial

Safety and Tolerability of Patisiran (ALN-TTR02) in Transthyretin (TTR) Amyloidosis

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