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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

Tracking Information
First Submitted Date  ICMJE June 7, 2012
First Posted Date  ICMJE June 13, 2012
Results First Submitted Date  ICMJE August 30, 2018
Results First Posted Date  ICMJE November 21, 2018
Last Update Posted Date November 21, 2018
Study Start Date  ICMJE May 2012
Actual Primary Completion Date October 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 23, 2018)
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).
Original Primary Outcome Measures  ICMJE
 (submitted: June 11, 2012)
Safety and tolerability in ATTR patients [ Time Frame: Up to 56 Days ]
The proportion of subjects experiencing adverse events (AEs), serious adverse events (SAEs) and study drug discontinuation
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 23, 2018)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 11, 2012)
  • Pharmacokinetics (PK) of ALN-TTR02 [ Time Frame: Up to 208 days ]
    Cmax, Area Under Curve, Tmax
  • Serum transthyretin (TTR) protein [ Time Frame: Up to 208 days ]
    Determination of % Lowering to pretreatment/Baseline Levels
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Tolerability of Patisiran (ALN-TTR02) in Transthyretin (TTR) Amyloidosis
Official Title  ICMJE 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
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).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE TTR-mediated Amyloidosis
Intervention  ICMJE 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
Study Arms  ICMJE 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.
Intervention: Drug: Patisiran
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 22, 2014)
29
Original Estimated Enrollment  ICMJE
 (submitted: June 11, 2012)
20
Actual Study Completion Date  ICMJE January 2014
Actual Primary Completion Date October 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Brazil,   France,   Germany,   Portugal,   Spain,   Sweden,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01617967
Other Study ID Numbers  ICMJE ALN-TTR02-002
2012-000467-24 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Alnylam Pharmaceuticals
Study Sponsor  ICMJE Alnylam Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Jared Gollob, MD Alnylam Pharmaceuticals
PRS Account Alnylam Pharmaceuticals
Verification Date October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP