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

NCT03338816 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: ALN-AS1-003
• Study Type: interventional
• Target: 94
• Locations: 18 countries
• Sites: 36

Brief Summary

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).

Conditions

Acute Hepatic Porphyria; Acute Intermittent Porphyria; Porphyria, Acute Intermittent; Acute Porphyria; Hereditary Coproporphyria (HCP); Variegate Porphyria (VP); ALA Dehydratase Deficient Porphyria (ADP)

Keywords

Acute Intermittent Porphyria (AIP); Acute Hepatic Porphyria (AHP); Hereditary Coproporphyria (HCP); Variegate Porphyria (VP); ALA dehydratase deficient porphyria (ADP) (ALAD); RNAi therapeutic; Porphyria

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (11)

• The Pharmacodynamic (PD) Effect of Givosiran on Urine Levels of Delta-aminolevulinic Acid (ALA) in Participants With AIP

  3 and 6 months

• The PD Effect of Givosiran on Urine Levels of Porphobilinogen (PBG) in Participants With AIP

  6 months

• Annualized Rate of Hemin Administration in Participants With AIP

  6 months

• Annualized Rate of Porphyria Attacks in Participants With AHP

  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

  Baseline and 6 months

Study Arms (2)

Givosiran/Givosiran

EXPERIMENTAL

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; Drug: Placebo

Placebo/Givosiran

PLACEBO COMPARATOR

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; Drug: Placebo

Interventions

Givosiran DRUG

Givosiran by SC

Also known as: ALN-AS1, GIVLAARI

Givosiran/Givosiran; Placebo/Givosiran

Placebo DRUG

Matching placebo (normal saline \[0.9% NaCl\]) by SC

Givosiran/Givosiran; Placebo/Givosiran

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥ 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Alnylam Pharmaceuticals: lead

Study Sites (36)

Clinical Trial Site

Little Rock, Arkansas, 72205, United States

Location

Clinical Trial Site

San Francisco, California, 94143, United States

Location

Clinical Trial Site

Boston, Massachusetts, 02114, United States

Location

Clinical Trial Site

Ann Arbor, Michigan, 48109, United States

Location

Clinical Trial Site

New York, New York, 10029, United States

Location

Clinical Trial Site

Winston-Salem, North Carolina, 27157, United States

Location

Clinical Trial Site

Philadelphia, Pennsylvania, 19107, United States

Location

Clinical Trial Site

Galveston, Texas, 77555, United States

Location

Clinical Trial Site

Salt Lake City, Utah, 84112, United States

Location

Clinical Trial Site

Seattle, Washington, 98195, United States

Location

Clinical Trial Site

Parkville, Victoria, 3050, Australia

Location

Clinical Trial Site

Auchenflower, 4066, Australia

Location

Clinical Trial Site

Camperdown, 2050, Australia

Location

Clinical Trial Site

Sofia, 1431, Bulgaria

Location

Clinical Trial Site

Edmonton, T6G 2R3, Canada

Location

Clinical Trial Site

Odense, 5000, Denmark

Location

Clinical Trial Site

Helsinki, 00290, Finland

Location

Clinical Trial Site

Paris, 75877, France

Location

Clinical Trial Site

Chemnitz, 09116, Germany

Location

Clinical Trial Site

Munich, 80331, Germany

Location

Clinical Trial Site

Modena, 41124, Italy

Location

Clinical Trial Site

Hamamatsu, 430-0929, Japan

Location

Clinical Trial Site

Iizuka, 820-8505, Japan

Location

Clinical Trial Site

Tokyo, 108-0073, Japan

Location

Clinical Trial Site

Mexico City, 04530, Mexico

Location

Clinical Trial Site

Rotterdam, 3015, Netherlands

Location

Clinical Trial Site

Warsaw, 02-776, Poland

Location

Clinical Trial Site

Seoul, 05030, South Korea

Location

Clinical Trial Site

Barcelona, 08036, Spain

Location

Clinical Trial Site

El Palmar, 30120, Spain

Location

Clinical Trial Site

Pamplona, 31008, Spain

Location

Clinical Trial Site

Stockholm, 171 76, Sweden

Location

Clinical Trial Site

Taichung, 40705, Taiwan

Location

Clinical Trial Site

Taipei, 10002, Taiwan

Location

Clinical Trial Site

Taoyuan, 33305, Taiwan

Location

Clinical Trial Site

London, SE5 9RS, United Kingdom

Location

Related Publications (5)

• Badri P, Kolachana K, Duong A, Lasko M, Nandi T, Mehrotra N, Robbie GJ. Platform Assessment of Concentration-QTc Relationship Across GalNAc-siRNA Molecules. Clin Pharmacokinet. 2025 Dec 12. doi: 10.1007/s40262-025-01606-0. Online ahead of print.

  PMID: 41388232 DERIVED

• Lee MJ, Kuo HC, Chou LN, Sweetser MT, Wang JD. A randomized, placebo-controlled study of givosiran in patients with acute hepatic porphyrias (ENVISION): Final (36-month) analysis of the Taiwan Cohort. J Formos Med Assoc. 2024 Jun;123(6):679-686. doi: 10.1016/j.jfma.2023.10.016. Epub 2023 Dec 2.

  PMID: 38044204 DERIVED

• Kuter DJ, Bonkovsky HL, Monroy S, Ross G, Guillen-Navarro E, Cappellini MD, Minder AE, Hother-Nielsen O, Ventura P, Jia G, Sweetser MT, Thapar M; ENVISION Investigators. Efficacy and safety of givosiran for acute hepatic porphyria: Final results of the randomized phase III ENVISION trial. J Hepatol. 2023 Nov;79(5):1150-1158. doi: 10.1016/j.jhep.2023.06.013. Epub 2023 Jul 20.

  PMID: 37479139 DERIVED

• 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.

  PMID: 36028858 DERIVED

• 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.

  PMID: 32521132 DERIVED

MeSH Terms

Conditions

Coproporphyria, Hereditary; Porphyria, Acute Intermittent; Porphyria, Variegate; Porphyrias

Interventions

givosiran

Condition Hierarchy (Ancestors)

Porphyrias, Hepatic; Liver Diseases; Digestive System Diseases; Skin Diseases, Genetic; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin Diseases; Skin and Connective Tissue Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Results Point of Contact

• Title: Chief Medical Officer
• Organization: Alnylam Pharmaceuticals Inc

Clinicaltrials@alnylam.com

866-330-0326

Study Officials

• Medical Director

  Alnylam Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: November 7, 2017
• First Posted: November 9, 2017
• Study Start: November 16, 2017
• Primary Completion: January 31, 2019
• Study Completion: May 31, 2021
• Last Updated: April 22, 2024
• Results First Posted: February 11, 2020

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will share

Locations

CA (1); NL (1); PL (1); JP (3); AU (3); GB (1); SE (1); DE (2); FR (1); FI (1); DK (1); KR (1); ME (1); ES (3); US (10); TW (3); BU (1); IT (1)