A Phase 1 Study of Givosiran (ALN-AS1) in Patients With Acute Intermittent Porphyria (AIP)

• ClinicalTrials.gov Identifier: NCT02452372
• Recruitment Status: Completed
• First Posted: May 22, 2015
• Last Update Posted: June 14, 2018
• Sponsor: Alnylam Pharmaceuticals
• Information provided by (Responsible Party): Alnylam Pharmaceuticals

Tracking Information

• First Submitted Date: May 19, 2015
• First Posted Date: May 22, 2015
• Last Update Posted Date: June 14, 2018
• Actual Study Start Date: May 6, 2015
• Actual Primary Completion Date: September 6, 2017 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: February 8, 2018): The safety of givosiran evaluated by the proportion of subjects experiencing adverse events (AEs), serious adverse events (SAEs), and AEs leading to study drug discontinuation [ Time Frame: Part A (SAD phase): through day 42; Part B (MAD) phase: through Day 70; Part C (MD) phase: through Day 168 ]
• Original Primary Outcome Measures (submitted: May 20, 2015): The safety of ALN-AS1 evaluated by the proportion of subjects experiencing adverse events (AEs), serious adverse events (SAEs), and AEs leading to study drug discontinuation [ Time Frame: Part A (SAD phase): through day 42; Part B (MAD) phase: through Day 70; Part C (MD) phase: through Day 126 ]

Current Secondary Outcome Measures (submitted: February 8, 2018)

• Profile of Pharmacokinetics (PK) of givosiran [ Time Frame: Part A (SAD) phase: predose - 42 days post-dose; Part B (MAD) phase: predose - 70 days post-dose; Part C (MD) phase: predose - 168 days post-dose ]
  Cmax
• Profile of Pharmacokinetics (PK) of givosiran [ Time Frame: Part A (SAD) phase: predose - 42 days post-dose; Part B (MAD) phase: predose - 70 days post-dose; Part C (MD) phase: predose - 168 days post-dose ]
  tmax
• Profile of Pharmacokinetics (PK) of givosiran [ Time Frame: Part A (SAD) phase: predose - 42 days post-dose; Part B (MAD) phase: predose - 70 days post-dose; Part C (MD) phase: predose - 168 days post-dose ]
  AUC
• Profile of Pharmacokinetics (PK) of givosiran [ Time Frame: Part A (SAD) phase: predose - 42 days post-dose; Part B (MAD) phase: predose - 70 days post-dose; Part C (MD) phase: predose - 168 days post-dose ]
  t1/2
• The change in delta-aminolevulinic acid (ALA) from baseline [ Time Frame: Part A (SAD) phase: screening - 42 days post-dose; Part B (MAD) phase: screening - 70 days post-dose; Part C (MD) phase: screening - 168 days post-dose ]
• The change in Porphobilinogen (PBG) from baseline [ Time Frame: Part A (SAD) phase: screening - 42 days post-dose; Part B (MAD) phase: screening - 70 days post-dose; Part C (MD) phase: screening - 168 days post-dose ]

Original Secondary Outcome Measures (submitted: May 20, 2015)

• Profile of Pharmacokinetics (PK) of ALN-AS1 [ Time Frame: Part A (SAD) phase: predose - 42 days post-dose; Part B (MAD) phase: predose - 70 days post-dose; Part C (MD) phase: predose - 126 days post-dose ]
  Cmax, tmax, AUC, t1/2
• The change in delta-aminolevulinic acid (ALA) and Porphobilinogen (PBG) from baseline [ Time Frame: Part A (SAD) phase: screening - 42 days post-dose; Part B (MAD) phase: screening - 70 days post-dose; Part C (MD) phase: screening - 126 days post-dose ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase 1 Study of Givosiran (ALN-AS1) in Patients With Acute Intermittent Porphyria (AIP)
• Official Title: A Phase 1, Single-ascending Dose, Multiple-ascending Dose, and Multi-dose Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of Subcutaneously Administered ALN AS1 in Patients With Acute Intermittent Porphyria (AIP)
• Brief Summary: The purpose of this study is to evaluate the safety and tolerability of givosiran (ALN-AS1) in AIP patients as well as to characterize pharmacokinetics (PK) and pharmacodynamics (PD) of ALN-AS1 in AIP patients.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Participant); Primary Purpose: Treatment
• Condition: Acute Intermittent Porphyria

Intervention

• Drug: givosiran (ALN-AS1)
  Single or multiple doses of ALN-AS1 by subcutaneous (sc) injection
• Drug: Sterile Normal Saline (0.9% NaCl)
  calculated volume to match active comparator

Study Arms

• Active Comparator: givosiran (ALN-AS1)
  Intervention: Drug: givosiran (ALN-AS1)
• Placebo Comparator: Sterile Normal Saline (0.9% NaCl)
  Intervention: Drug: Sterile Normal Saline (0.9% NaCl)

• Publications *: Sardh E, Harper P, Balwani M, Stein P, Rees D, Bissell DM, Desnick R, Parker C, Phillips J, Bonkovsky HL, Vassiliou D, Penz C, Chan-Daniels A, He Q, Querbes W, Fitzgerald K, Kim JB, Garg P, Vaishnaw A, Simon AR, Anderson KE. Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria. N Engl J Med. 2019 Feb 7;380(6):549-558. doi: 10.1056/NEJMoa1807838.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 7, 2017): 40
• Original Estimated Enrollment (submitted: May 20, 2015): 48
• Actual Study Completion Date: September 6, 2017
• Actual Primary Completion Date: September 6, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Parts A and B

Inclusion Criteria:

• Diagnosis of AIP
• Urine PBG at Screening indicating patient is a high excreter
• No clinically significant health concerns
• Women of child bearing potential must have a negative pregnancy test, not be nursing, and use effective contraception
• Willing to provide written informed consent and willing to comply with study requirements.

Exclusion Criteria:

• Porphyria attack within 6 months of screening
• Started a new prescription medication within 3 months of screening
• Clinically significant abnormal laboratory results
• 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

Part C

Inclusion Criteria:

• Diagnosis of AIP
• Patient experienced a porphyria attack or was taking medication to prevent attacks recently
• No clinically significant health concerns
• Women of child bearing potential must have a negative pregnancy test, not be nursing, and use effective contraception
• Willing to provide written informed consent and willing to comply with study requirements.

Exclusion Criteria:

• Stared a new prescription medication within 3 months of screening
• Clinically significant abnormal laboratory results
• 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT02452372
• Other Study ID Numbers: ALN-AS1-001
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Alnylam Pharmaceuticals
• Original Responsible Party: Same as current
• Current Study Sponsor: Alnylam Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Amy Simon, MD; Alnylam Pharmaceuticals

• PRS Account: Alnylam Pharmaceuticals
• Verification Date: June 2018