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A Phase 1/2 Study of an Investigational Drug, ALN-CC5, in Healthy Adult Volunteers and Patients With PNH

Primary Purpose

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
ALN-CC5
Sterile Normal Saline (0.9% NaCl)
Sponsored by
Alnylam Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Paroxysmal Nocturnal Hemoglobinuria (PNH) focused on measuring PNH, RNAi therapeutic

Eligibility Criteria

18 Years - 45 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Adequate complete blood counts, liver and renal function
  • 12-lead electrocardiogram (ECG) within normal limits
  • Female subjects of child bearing potential agreeing to use a protocol specified method of contraception
  • Male subjects agreeing to use protocol specified methods of contraception
  • Willing to provide written informed consent and willing to comply with study requirements

Exclusion Criteria:

  • Any uncontrolled or serious disease, or any medical or surgical condition, that may interfere with participation in the clinical study and/or put the subject at significant risk
  • Received an investigational agent within 90 days before the first dose of study drug or are in follow-up of another clinical study
  • History of multiple drug allergies or intolerance to subcutaneous injection
  • Parts A and B of the study: Used prescription medications within 14 days or 7 half-lives of administration of the first dose of study drug.
  • History of meningococcal infection

Sites / Locations

  • Clinical Trial Site
  • Clinical Trial Site
  • Covance Clinical Research Unit
  • Richmond Pharmacology

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

ALN-CC5

Sterile Normal Saline (0.9% NaCl)

Arm Description

Outcomes

Primary Outcome Measures

Number of Participants With Adverse Events
Adverse events were reported for single-ascending doses (SAD) or multiple ascending doses (MAD) of ALN-CC5 when administered to healthy adult subjects and of multiple doses (MD) in patients with paroxysmal nocturnal hemoglobinuria (PNH)

Secondary Outcome Measures

Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP)
Complement activity was measured in serum samples collected at timepoints throughout the study using the CAP ELISA assay. Percentage reduction was calculated relative to baseline levels. A positive value indicates a reduction in CAP from baseline.
Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP)
Complement activity was measured in serum samples collected at time points throughout the study using the CCP ELISA assay. Percentage reduction was calculated relative to baseline levels. A positive value indicates a reduction in CCP from baseline.
Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels
Total C5 protein levels were measured in serum samples collected at time points throughout the study using a mass spectrometry-based method. Percentage reduction was calculated relative to baseline levels. A positive value indicates a reduction in C5 protein level from baseline.
Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (25-mer)
Maximum observed plasma concentration (Cmax) of ALN-CC5 (cemdisiran) 25-mer.
Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (23-mer)
Maximum observed plasma concentration (Cmax) of ALN-CC5 (cemdisiran) 23-mer.
Pharmacokinetic (PK) Effect of ALN-CC5: T Max (25-mer)
Time of maximum observed plasma concentration (T max) of ALN-CC5 (cemdisiran) 25-mer.
Pharmacokinetic (PK) Effect of ALN-CC5: T Max (23-mer)
Time of maximum observed plasma concentration (T max) of ALN-CC5 (cemdisiran) 23-mer.
Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (25-mer)
Area under the plasma concentration-time curve over the dosing interval zero to time (AUC 0-t) of ALN-CC5 (cemdisiran) 25-mer.
Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (23-mer)
Area under the plasma concentration-time curve over the dosing interval zero to time (AUC 0-t) of ALN-CC5 (cemdisiran) 23-mer.

Full Information

First Posted
January 23, 2015
Last Updated
March 17, 2020
Sponsor
Alnylam Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT02352493
Brief Title
A Phase 1/2 Study of an Investigational Drug, ALN-CC5, in Healthy Adult Volunteers and Patients With PNH
Official Title
A Phase 1/2 Single-ascending and Multiple-ascending Dose, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of Subcutaneously Administered ALN-CC5 in Healthy Adult Volunteers and Patients With Paroxysmal Nocturnal Hemoglobinuria
Study Type
Interventional

2. Study Status

Record Verification Date
March 2020
Overall Recruitment Status
Completed
Study Start Date
January 2015 (undefined)
Primary Completion Date
April 2016 (Actual)
Study Completion Date
August 2017 (Actual)

3. Sponsor/Collaborators

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

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of ALN-CC5 in healthy adult volunteers and subjects with PNH

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Keywords
PNH, RNAi therapeutic

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
62 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ALN-CC5
Arm Type
Active Comparator
Arm Title
Sterile Normal Saline (0.9% NaCl)
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
ALN-CC5
Intervention Description
Single or multiple doses of ALN-CC5 by subcutaneous (sc) injection
Intervention Type
Drug
Intervention Name(s)
Sterile Normal Saline (0.9% NaCl)
Intervention Description
calculated volume to match active comparator
Primary Outcome Measure Information:
Title
Number of Participants With Adverse Events
Description
Adverse events were reported for single-ascending doses (SAD) or multiple ascending doses (MAD) of ALN-CC5 when administered to healthy adult subjects and of multiple doses (MD) in patients with paroxysmal nocturnal hemoglobinuria (PNH)
Time Frame
Part A: through day 658; Part B: through day 532; Part C: through day 280
Secondary Outcome Measure Information:
Title
Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Alternative Pathway (CAP)
Description
Complement activity was measured in serum samples collected at timepoints throughout the study using the CAP ELISA assay. Percentage reduction was calculated relative to baseline levels. A positive value indicates a reduction in CAP from baseline.
Time Frame
Part A: through day 70; Part B: through day 140; Part C: through day 140
Title
Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in Complement Classical Pathway (CCP)
Description
Complement activity was measured in serum samples collected at time points throughout the study using the CCP ELISA assay. Percentage reduction was calculated relative to baseline levels. A positive value indicates a reduction in CCP from baseline.
Time Frame
Part A: through day 70; Part B: through day 140; Part C: through day 140
Title
Pharmacodynamic (PD) Effect of ALN-CC5: Percentage Reduction From Baseline in C5 Protein Levels
Description
Total C5 protein levels were measured in serum samples collected at time points throughout the study using a mass spectrometry-based method. Percentage reduction was calculated relative to baseline levels. A positive value indicates a reduction in C5 protein level from baseline.
Time Frame
Part A: through day 70; Part B: through day 140; Part C: through day 140
Title
Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (25-mer)
Description
Maximum observed plasma concentration (Cmax) of ALN-CC5 (cemdisiran) 25-mer.
Time Frame
Part A: 0-48 hrs, Day 0; Part B (weekly dosing cohorts): 0-48 hrs, Day 28; Part B (biweekly, weekly/monthly/biweekly/monthly cohorts): 0-48 hrs, Day 84; Part C: 0- 24 hrs, Day 84
Title
Pharmacokinetic (PK) Effect of ALN-CC5: Cmax (23-mer)
Description
Maximum observed plasma concentration (Cmax) of ALN-CC5 (cemdisiran) 23-mer.
Time Frame
Part A: 0-48 hrs, Day 0; Part B (weekly dosing cohorts): 0-48 hrs, Day 28; Part B (biweekly, weekly/monthly/biweekly/monthly cohorts): 0-48 hrs, Day 84; Part C: 0- 24 hrs, Day 84
Title
Pharmacokinetic (PK) Effect of ALN-CC5: T Max (25-mer)
Description
Time of maximum observed plasma concentration (T max) of ALN-CC5 (cemdisiran) 25-mer.
Time Frame
Part A: 0-48 hrs, Day 0; Part B (weekly dosing cohorts): 0-48 hrs, Day 28; Part B (biweekly, weekly/monthly/biweekly/monthly cohorts): 0-48 hrs, Day 84; Part C: 0- 24 hrs, Day 84
Title
Pharmacokinetic (PK) Effect of ALN-CC5: T Max (23-mer)
Description
Time of maximum observed plasma concentration (T max) of ALN-CC5 (cemdisiran) 23-mer.
Time Frame
Part A: 0-48 hrs, Day 0; Part B (weekly dosing cohorts): 0-48 hrs, Day 28; Part B (biweekly, weekly/monthly/biweekly/monthly cohorts): 0-48 hrs, Day 84; Part C: 0- 24 hrs, Day 84
Title
Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (25-mer)
Description
Area under the plasma concentration-time curve over the dosing interval zero to time (AUC 0-t) of ALN-CC5 (cemdisiran) 25-mer.
Time Frame
Part A: 0-48 hrs, Day 0; Part B (weekly dosing cohorts): 0-48 hrs, Day 28; Part B (biweekly, weekly/monthly/biweekly/monthly cohorts): 0-48 hrs, Day 84; Part C: 0- 24 hrs, Day 84
Title
Pharmacokinetic (PK) Effect of ALN-CC5: AUC 0-t (23-mer)
Description
Area under the plasma concentration-time curve over the dosing interval zero to time (AUC 0-t) of ALN-CC5 (cemdisiran) 23-mer.
Time Frame
Part A: 0-48 hrs, Day 0; Part B (weekly dosing cohorts): 0-48 hrs, Day 28; Part B (biweekly, weekly/monthly/biweekly/monthly cohorts): 0-48 hrs, Day 84; Part C: 0- 24 hrs, Day 84

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Adequate complete blood counts, liver and renal function 12-lead electrocardiogram (ECG) within normal limits Female subjects of child bearing potential agreeing to use a protocol specified method of contraception Male subjects agreeing to use protocol specified methods of contraception Willing to provide written informed consent and willing to comply with study requirements Exclusion Criteria: Any uncontrolled or serious disease, or any medical or surgical condition, that may interfere with participation in the clinical study and/or put the subject at significant risk Received an investigational agent within 90 days before the first dose of study drug or are in follow-up of another clinical study History of multiple drug allergies or intolerance to subcutaneous injection Parts A and B of the study: Used prescription medications within 14 days or 7 half-lives of administration of the first dose of study drug. History of meningococcal infection
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nader Najafian, MD
Organizational Affiliation
Alnylam Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Clinical Trial Site
City
Barcelona
Country
Spain
Facility Name
Clinical Trial Site
City
Leeds
Country
United Kingdom
Facility Name
Covance Clinical Research Unit
City
Leeds
Country
United Kingdom
Facility Name
Richmond Pharmacology
City
London
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
33047216
Citation
Badri P, Jiang X, Borodovsky A, Najafian N, Kim J, Clausen VA, Goel V, Habtemariam B, Robbie GJ. Pharmacokinetic and Pharmacodynamic Properties of Cemdisiran, an RNAi Therapeutic Targeting Complement Component 5, in Healthy Subjects and Patients with Paroxysmal Nocturnal Hemoglobinuria. Clin Pharmacokinet. 2021 Mar;60(3):365-378. doi: 10.1007/s40262-020-00940-9. Erratum In: Clin Pharmacokinet. 2022 Jun;61(6):919.
Results Reference
derived

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A Phase 1/2 Study of an Investigational Drug, ALN-CC5, in Healthy Adult Volunteers and Patients With PNH

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