ENVISION: A Study to Evaluate the Efficacy and Safety of Givosiran (ALN-AS1) in Patients With Acute Hepatic Porphyrias (AHP)

May 31, 2022 updated by: Alnylam Pharmaceuticals

ENVISION: A Phase 3 Randomized, Double-blind, Placebo-Controlled Multicenter Study With an Open-label Extension to Evaluate the Efficacy and Safety of Givosiran in Patients With Acute Hepatic Porphyrias

The purpose of this study is to evaluate the effect of subcutaneous givosiran (ALN-AS1), compared to placebo, on the rate of porphyria attacks in patients with Acute Hepatic Porphyrias (AHP).

Study Overview

Study Type

Interventional

Enrollment (Actual)

94

Phase

  • Phase 3

Expanded Access

No longer available outside the clinical trial. See expanded access record.

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Auchenflower, Australia, 4066
        • Clinical Trial Site
      • Camperdown, Australia, 2050
        • Clinical Trial Site
    • Victoria
      • Parkville, Victoria, Australia, 3050
        • Clinical Trial Site
      • Sofia, Bulgaria, 1431
        • Clinical Trial Site
      • Edmonton, Canada, T6G 2R3
        • Clinical Trial Site
      • Odense, Denmark, 5000
        • Clinical Trial Site
      • Helsinki, Finland, 00290
        • Clinical Trial Site
      • Paris, France, 75877
        • Clinical Trial Site
      • Chemnitz, Germany, 09116
        • Clinical Trial Site
      • Munich, Germany, 80331
        • Clinical Trial Site
      • Modena, Italy, 41124
        • Clinical Trial Site
      • Hamamatsu, Japan, 430-0929
        • Clinical Trial Site
      • Iizuka, Japan, 820-8505
        • Clinical Trial Site
      • Tokyo, Japan, 108-0073
        • Clinical Trial Site
      • Seoul, Korea, Republic of, 05030
        • Clinical Trial Site
      • Mexico City, Mexico, 04530
        • Clinical Trial Site
      • Rotterdam, Netherlands, 3015
        • Clinical Trial Site
      • Warsaw, Poland, 02-776
        • Clinical Trial Site
      • Barcelona, Spain, 08036
        • Clinical Trial Site
      • El Palmar, Spain, 30120
        • Clinical Trial Site
      • Pamplona, Spain, 31008
        • Clinical Trial Site
      • Stockholm, Sweden, 171 76
        • Clinical Trial Site
      • Taichung, Taiwan, 40705
        • Clinical Trial Site
      • Taipei city, Taiwan, 10002
        • Clinical Trial Site
      • Taoyuan city, Taiwan, 33305
        • Clinical Trial Site
      • London, United Kingdom, SE5 9RS
        • Clinical Trial Site
    • Arkansas
      • Little Rock, Arkansas, United States, 72205
        • Clinical Trial Site
    • California
      • San Francisco, California, United States, 94143
        • Clinical Trial Site
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Clinical Trial Site
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • Clinical Trial Site
    • New York
      • New York, New York, United States, 10029
        • Clinical Trial Site
    • North Carolina
      • Winston-Salem, North Carolina, United States, 27157
        • Clinical Trial Site
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19107
        • Clinical Trial Site
    • Texas
      • Galveston, Texas, United States, 77555
        • Clinical Trial Site
    • Utah
      • Salt Lake City, Utah, United States, 84112
        • Clinical Trial Site
    • Washington
      • Seattle, Washington, United States, 98195
        • Clinical Trial Site

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

10 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • ≥ 12 years of age
  • Diagnosed with Acute Hepatic Porphyria (Acute Intermittent Porphyria, Hereditary Corproporhyria, Variegate Porphyria, aminolevulinic acid (ALA) dehydratase deficient porphyria)
  • Elevated urinary or plasma porphobilinogen (PBG) or ALA values within the past year,
  • Have active disease, with at least 2 documented porphyria attacks within the last 6 months
  • Willing to discontinue or not initiate the use of prophylactic hemin throughout the study.
  • Women of child bearing potential must have a negative serum pregnancy test, not be nursing, and use acceptable contraception

Exclusion Criteria:

  • Clinically significant abnormal laboratory results
  • Anticipated liver transplantation
  • History of multiple drug allergies or intolerance to subcutaneous injections
  • Active HIV, hepatitis C virus, or hepatitis B virus infection(s)
  • History of recurrent pancreatitis

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Givosiran/Givosiran
Givosiran 2.5 mg/kg administered subcutaneously (SC), monthly (QM), for 6 months during the 6-Month Double-blind (DB) Period, followed by givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM for 29 months during the Open-label Extension (OLE) Period.
Givosiran by SC
Other Names:
  • ALN-AS1
  • GIVLAARI
Matching placebo (normal saline [0.9% NaCl]) by SC
Placebo Comparator: Placebo/Givosiran
Matching placebo (normal saline [0.9% NaCl]) was administered SC, QM, for 6 months during the 6-Month DB Period, followed by givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM for 29 months during the OLE period.
Givosiran by SC
Other Names:
  • ALN-AS1
  • GIVLAARI
Matching placebo (normal saline [0.9% NaCl]) by SC

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Annualized Rate of Porphyria Attacks in Participants With Acute Intermittent Porphyria (AIP)
Time Frame: 6 months
Porphyria attacks were defined as meeting all of the following criteria: an acute episode of neurovisceral pain in the abdomen, back, chest, extremities and/or limbs, no other medically determined cause, and required treatment with intravenous (IV) dextrose or hemin, carbohydrates, or analgesics, or other medications such as antiemetics at a dose or frequency beyond the participant's usual daily porphyria management. The annualized rate of porphyria attacks is a composite endpoint which included porphyria attacks requiring hospitalization, urgent healthcare visit, or IV hemin administration at home.
6 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The Pharmacodynamic (PD) Effect of Givosiran on Urine Levels of Delta-aminolevulinic Acid (ALA) in Participants With AIP
Time Frame: 3 and 6 months
The PD effect of givosiran was evaluated by spot urine ALA levels normalized to spot urine creatinine levels.
3 and 6 months
The PD Effect of Givosiran on Urine Levels of Porphobilinogen (PBG) in Participants With AIP
Time Frame: 6 months
The PD effect of givosiran was evaluated by spot urine PBG levels normalized to spot urine creatinine levels.
6 months
Annualized Rate of Hemin Administration in Participants With AIP
Time Frame: 6 months
Annualized rate of hemin doses was evaluated as annualized days of hemin use.
6 months
Annualized Rate of Porphyria Attacks in Participants With AHP
Time Frame: 6 months
Porphyria attacks were defined as meeting all of the following criteria: an acute episode of neurovisceral pain in the abdomen, back, chest, extremities and/or limbs, no other medically determined cause, and required treatment with intravenous (IV) dextrose or hemin, carbohydrates, or analgesics, or other medications such as antiemetics at a dose or frequency beyond the participant's usual daily porphyria management. The annualized rate of porphyria attacks is a composite endpoint which included porphyria attacks requiring hospitalization, urgent healthcare visit, or IV hemin administration at home.
6 months
Area Under the Curve (AUC) of the Change From Baseline in Weekly Mean Score of Daily Worst Pain as Measured by the Brief Pain Inventory-Short Form (BPI-SF) Numeric Rating Scale (NRS) in Participants With AIP
Time Frame: Baseline and 6 months
Participants rated worst daily pain score in an eDiary using the 11-point BPI-SF NRS, in which 0=no pain and 10=worst pain. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the post baseline weekly mean score minus the baseline score. Lower scores indicate an improvement. The 6-month AUC was calculated based on change from baseline in weekly mean scores.
Baseline and 6 months
Average Change From Baseline in Weekly Mean Score of Daily Worst Pain as Measured by the Brief Pain Inventory-Short Form (BPI-SF) Numeric Rating Scale (NRS) in Participants With AIP
Time Frame: Baseline and 6 months
Participants rated worst daily pain score in an eDiary using the 11-point BPI-SF NRS, in which 0=no pain and 10=worst pain. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the postbaseline weekly mean score minus the baseline score. Lower scores indicate an improvement.
Baseline and 6 months
AUC of the Change From Baseline in Weekly Mean Score of Daily Worst Fatigue Score as Measured by the Brief Fatigue Inventory-Short Form (BFI-SF) NRS in Participants With AIP
Time Frame: Baseline and 6 months
Participants rated daily worst fatigue score in an eDiary using the 11-point BFI-SF NRS, in which 0=no fatigue and 10=worst fatigue. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the post baseline weekly mean score minus the baseline score. Lower scores indicate an improvement. The 6-month AUC was calculated based on change from baseline in weekly mean scores.
Baseline and 6 months
Average Change From Baseline in Weekly Mean Score of Daily Worst Fatigue Score as Measured by the Brief Fatigue Inventory-Short Form (BFI-SF) NRS in Participants With AIP
Time Frame: Baseline and 6 months
Participants rated daily worst fatigue score in an eDiary using the 11-point BFI-SF NRS, in which 0=no fatigue and 10=worst fatigue. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the postbaseline weekly mean score minus the baseline score. Lower scores indicate an improvement.
Baseline and 6 months
AUC of the Change From Baseline in Weekly Mean Score Daily Worst Nausea Score as Measured by NRS in Participants With AIP
Time Frame: Baseline and 6 months
Participants rated worst daily nausea score in an eDiary using an 11-point NRS, in which 0=no nausea and 10=worst nausea. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the postbaseline weekly mean score minus the baseline score. Lower scores indicate an improvement. The 6-month AUC was calculated based on change from baseline in weekly mean scores.
Baseline and 6 months
Average Change From Baseline in Weekly Mean Score Daily Worst Nausea Score as Measured by NRS in Participants With AIP
Time Frame: Baseline and 6 months
Participants rated worst daily nausea score in an eDiary using an 11-point NRS, in which 0=no nausea and 10=worst nausea. Daily eDiary entries were averaged into a weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the postbaseline weekly mean score minus the baseline score. Lower scores indicate an improvement.
Baseline and 6 months
Change From Baseline in the Physical Component Summary (PCS) of the 12-Item Short Form Survey (SF-12) in Participants With AIP
Time Frame: Baseline and 6 months
The SF-12 is a survey designed for use in patients with multiple chronic conditions. This 12-item scale can be used to assess the physical and mental health of respondents. 10 of the 12 questions are answered on a 5 point likert scale and 2 are answered on a 3 point likert scale. The questions are then scored and weighted into 2 subscales, physical health and mental health. Respondents can have a score that ranges from 0-100 with 100 being the best score and indicating high physical or mental health. A 3 point change in SF-12 score reflects a meaningful difference. A higher score indicates improvement.
Baseline and 6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 16, 2017

Primary Completion (Actual)

January 31, 2019

Study Completion (Actual)

May 31, 2021

Study Registration Dates

First Submitted

November 7, 2017

First Submitted That Met QC Criteria

November 7, 2017

First Posted (Actual)

November 9, 2017

Study Record Updates

Last Update Posted (Actual)

June 23, 2022

Last Update Submitted That Met QC Criteria

May 31, 2022

Last Verified

May 1, 2022

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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