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

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

• Status: Completed
• Conditions: Acute Hepatic Porphyria; Acute Intermittent Porphyria; Porphyria, Acute Intermittent; Acute Porphyria; Hereditary Coproporphyria (HCP); Variegate Porphyria (VP); ALA Dehydratase Deficient Porphyria (ADP)
• Intervention / Treatment: Drug: Givosiran; Drug: Placebo

• 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

Study Locations

• Australia
  • Auchenflower, Australia, 4066
    • Clinical Trial Site
  • Camperdown, Australia, 2050
    • Clinical Trial Site
  • Victoria
    • Parkville, Victoria, Australia, 3050
      • Clinical Trial Site
• Bulgaria
  • Sofia, Bulgaria, 1431
    • Clinical Trial Site
• Canada
  • Edmonton, Canada, T6G 2R3
    • Clinical Trial Site
• Denmark
  • Odense, Denmark, 5000
    • Clinical Trial Site
• Finland
  • Helsinki, Finland, 00290
    • Clinical Trial Site
• France
  • Paris, France, 75877
    • Clinical Trial Site
• Germany
  • Chemnitz, Germany, 09116
    • Clinical Trial Site
  • Munich, Germany, 80331
    • Clinical Trial Site
• Italy
  • Modena, Italy, 41124
    • Clinical Trial Site
• Japan
  • Hamamatsu, Japan, 430-0929
    • Clinical Trial Site
  • Iizuka, Japan, 820-8505
    • Clinical Trial Site
  • Tokyo, Japan, 108-0073
    • Clinical Trial Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 05030
    • Clinical Trial Site
• Mexico
  • Mexico City, Mexico, 04530
    • Clinical Trial Site
• Netherlands
  • Rotterdam, Netherlands, 3015
    • Clinical Trial Site
• Poland
  • Warsaw, Poland, 02-776
    • Clinical Trial Site
• Spain
  • Barcelona, Spain, 08036
    • Clinical Trial Site
  • El Palmar, Spain, 30120
    • Clinical Trial Site
  • Pamplona, Spain, 31008
    • Clinical Trial Site
• Sweden
  • Stockholm, Sweden, 171 76
    • Clinical Trial Site
• Taiwan
  • Taichung, Taiwan, 40705
    • Clinical Trial Site
  • Taipei city, Taiwan, 10002
    • Clinical Trial Site
  • Taoyuan city, Taiwan, 33305
    • Clinical Trial Site
• United Kingdom
  • London, United Kingdom, SE5 9RS
    • Clinical Trial Site
• United States
  • 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

Eligibility Criteria

• Ages Eligible for Study: 8 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

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

How is the study designed?

Design Details

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

Number of Arms

2

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.	Drug: Givosiran; Givosiran by SC; Other Names: ALN-AS1; GIVLAARI; Drug: Placebo; 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.	Drug: Givosiran; Givosiran by SC; Other Names: ALN-AS1; GIVLAARI; Drug: Placebo; 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)	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	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	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	Annualized rate of hemin doses was evaluated as annualized days of hemin use.	6 months
Annualized Rate of Porphyria Attacks in Participants With AHP	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	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	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	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	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	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	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	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

• Sponsor: Alnylam Pharmaceuticals
• Investigators: Study Director: Medical Director, Alnylam Pharmaceuticals

Publications and helpful links

General Publications

• Wang B, Ventura P, Takase KI, Thapar M, Cassiman D, Kubisch I, Liu S, Sweetser MT, Balwani M. Disease burden in patients with acute hepatic porphyria: experience from the phase 3 ENVISION study. Orphanet J Rare Dis. 2022 Aug 26;17(1):327. doi: 10.1186/s13023-022-02463-x.
• Balwani M, Sardh E, Ventura P, Peiro PA, Rees DC, Stolzel U, Bissell DM, Bonkovsky HL, Windyga J, Anderson KE, Parker C, Silver SM, Keel SB, Wang JD, Stein PE, Harper P, Vassiliou D, Wang B, Phillips J, Ivanova A, Langendonk JG, Kauppinen R, Minder E, Horie Y, Penz C, Chen J, Liu S, Ko JJ, Sweetser MT, Garg P, Vaishnaw A, Kim JB, Simon AR, Gouya L; ENVISION Investigators. Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria. N Engl J Med. 2020 Jun 11;382(24):2289-2301. doi: 10.1056/NEJMoa1913147.

Study record dates

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): April 22, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: RNAi therapeutic; Porphyria; Acute Hepatic Porphyria (AHP); Acute Intermittent Porphyria (AIP); Hereditary Coproporphyria (HCP); Variegate Porphyria (VP); ALA dehydratase deficient porphyria (ADP) (ALAD)
• Additional Relevant MeSH Terms: Digestive System Diseases; Metabolic Diseases; Skin Diseases; Liver Diseases; Genetic Diseases, Inborn; Skin Diseases, Genetic; Porphyrias, Hepatic; Porphyria, Erythropoietic; Porphyrias; Coproporphyria, Hereditary; Porphyria, Acute Intermittent; Porphyria, Variegate
• Other Study ID Numbers: ALN-AS1-003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Access to Anonymized individual participant data that support these results is made available 12 months after study completion and not less than 12 months after the product and indication have been approved in the US and/or the EU.

Data will be provided contingent upon the approval of a research proposal and the execution of a data sharing agreement. Requests for access to data can be submitted via the website www.vivli.org.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No