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

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ClinicalTrials.gov Identifier: NCT01617967
Recruitment Status : Completed
First Posted : June 13, 2012
Results First Posted : November 21, 2018
Last Update Posted : November 21, 2018
Sponsor:
Information provided by (Responsible Party):
Alnylam Pharmaceuticals

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).

Condition or disease Intervention/treatment Phase
TTR-mediated Amyloidosis Drug: Patisiran Phase 2

Expanded Access : An investigational treatment associated with this study has been approved for sale to the public.   More info ...

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 29 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : May 2012
Actual Primary Completion Date : October 2013
Actual Study Completion Date : January 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Amyloidosis

Arm Intervention/treatment
Experimental: Patisiran (ALN-TTR02)
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.
Drug: Patisiran
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.
Other Name: ALN-TTR02




Primary Outcome Measures :
  1. Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Study Drug Discontinuation [ Time Frame: Up to 56 days post first dose ]
    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 :
  1. Percentage Change From Baseline in Serum Transthyretin (TTR) Protein [ Time Frame: Baseline to Day 21/28 and Day 42/56 depending on dosing regimen (Q3W/Q4W) ]
    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.

  2. Pharmacokinetic Parameters of Patisiran - Area Under the Concentration Curve From Time 0 to Last Measurable Time Point (AUC0-last) [ 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) ]
    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.

  3. Pharmacokinetic Parameters of Patisiran - Maximum Observed Plasma Concentration (Cmax) [ 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) ]
    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.

  4. Pharmacokinetic Parameters of Patisiran - Beta Elimination Half-life (t1/2 Beta) [ 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 ]
    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.

  5. Pharmacokinetic Parameters of Patisiran - Systemic Clearance (CL) [ 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 ]
    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.

  6. Pharmacokinetic Parameters of Patisiran - Apparent Volume of Distribution at Steady State (Vss) [ 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 ]
    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.

  7. Pharmacokinetic Parameters of Patisiran - Renal Clearance (CLR) [ 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 ]
    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.



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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01617967


Locations
United States, Massachusetts
Clinical Trial Site
Boston, Massachusetts, United States
Brazil
Clinical Trial Site
Rio de Janeiro, Brazil
France
Clinical Trial Site
Le Kremlin-bicetre, France
Clinical Trial Site
Marseille Cedex, France
Germany
Clinical Trial Site
Munster, Germany
Portugal
Clinical Trial Site
Lisbon, Portugal
Clinical Trial Site
Porto, Portugal
Spain
Clinical Trial Site
Barcelona, Spain
Clinical Trial Site
Palma De Mallorca, Spain
Sweden
Clinical Trial Site
Umeå, Sweden
Sponsors and Collaborators
Alnylam Pharmaceuticals
Investigators
Study Director: Jared Gollob, MD Alnylam Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Alnylam Pharmaceuticals:
Statistical Analysis Plan  [PDF] July 23, 2013
Study Protocol  [PDF] January 16, 2013


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Alnylam Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01617967     History of Changes
Other Study ID Numbers: ALN-TTR02-002
2012-000467-24 ( EudraCT Number )
First Posted: June 13, 2012    Key Record Dates
Results First Posted: November 21, 2018
Last Update Posted: November 21, 2018
Last Verified: October 2018

Studies a U.S. FDA-regulated Drug Product: Yes

Keywords provided by Alnylam Pharmaceuticals:
RNAi therapeutic

Additional relevant MeSH terms:
Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases