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

TTR-mediated Amyloidosis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01617967
• Other study ID #: ALN-TTR02-002
• Secondary ID: 2012-000467-24
• Status: Completed
• Phase: Phase 2
• Start date: May 2012
• Est. completion date: January 2014

Study information

• Verified date: October 2018
• Source: Alnylam Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 29
• Est. completion date: January 2014
• Est. primary completion date: October 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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.

Related Conditions & MeSH terms

• Amyloidosis
• TTR-mediated Amyloidosis

Intervention

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.

Locations

Country	Name	City	State
Brazil	Clinical Trial Site	Rio de Janeiro
France	Clinical Trial Site	Le Kremlin-bicetre
France	Clinical Trial Site	Marseille Cedex
Germany	Clinical Trial Site	Munster
Portugal	Clinical Trial Site	Lisbon
Portugal	Clinical Trial Site	Porto
Spain	Clinical Trial Site	Barcelona
Spain	Clinical Trial Site	Palma De Mallorca
Sweden	Clinical Trial Site	Umeå
United States	Clinical Trial Site	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Alnylam Pharmaceuticals

Countries where clinical trial is conducted

United States,  Brazil,  France,  Germany,  Portugal,  Spain,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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).	Up to 56 days post first dose
Secondary	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.	Baseline to Day 21/28 and Day 42/56 depending on dosing regimen (Q3W/Q4W)
Secondary	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.	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)
Secondary	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.	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)
Secondary	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.	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
Secondary	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.	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
Secondary	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.	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
Secondary	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.	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