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

• ClinicalTrials.gov Identifier: NCT03338816
• Recruitment Status: Completed
• First Posted: November 9, 2017
• Results First Posted: February 11, 2020
• Last Update Posted: June 23, 2022
• Sponsor: Alnylam Pharmaceuticals
• Information provided by (Responsible Party): Alnylam Pharmaceuticals

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Acute Hepatic Porphyria; Acute Intermittent Porphyria; Porphyria, Acute Intermittent; Acute Porphyria; Hereditary Coproporphyria (HCP); Variegate Porphyria (VP); ALA Dehydratase Deficient Porphyria (ADP)	Drug: Givosiran; Drug: Placebo	Phase 3

Expanded Access : An investigational treatment associated with this study is no longer available outside the clinical trial.   More info ...

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 94 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: November 16, 2017
• Actual Primary Completion Date: January 31, 2019
• Actual Study Completion Date: May 31, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.

Eligibility Criteria

• Ages Eligible for Study: 12 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Arkansas

Clinical Trial Site

Little Rock, Arkansas, United States, 72205

United States, California

Clinical Trial Site

San Francisco, California, United States, 94143

United States, Massachusetts

Clinical Trial Site

Boston, Massachusetts, United States, 02114

United States, Michigan

Clinical Trial Site

Ann Arbor, Michigan, United States, 48109

United States, New York

Clinical Trial Site

New York, New York, United States, 10029

United States, North Carolina

Clinical Trial Site

Winston-Salem, North Carolina, United States, 27157

United States, Pennsylvania

Clinical Trial Site

Philadelphia, Pennsylvania, United States, 19107

United States, Texas

Clinical Trial Site

Galveston, Texas, United States, 77555

United States, Utah

Clinical Trial Site

Salt Lake City, Utah, United States, 84112

United States, Washington

Clinical Trial Site

Seattle, Washington, United States, 98195

Australia, Victoria

Clinical Trial Site

Parkville, Victoria, Australia, 3050

Australia

Clinical Trial Site

Auchenflower, Australia, 4066

Clinical Trial Site

Camperdown, Australia, 2050

Bulgaria

Clinical Trial Site

Sofia, Bulgaria, 1431

Canada

Clinical Trial Site

Edmonton, Canada, T6G 2R3

Denmark

Clinical Trial Site

Odense, Denmark, 5000

Finland

Clinical Trial Site

Helsinki, Finland, 00290

France

Clinical Trial Site

Paris, France, 75877

Germany

Clinical Trial Site

Chemnitz, Germany, 09116

Clinical Trial Site

Munich, Germany, 80331

Italy

Clinical Trial Site

Modena, Italy, 41124

Japan

Clinical Trial Site

Hamamatsu, Japan, 430-0929

Clinical Trial Site

Iizuka, Japan, 820-8505

Clinical Trial Site

Tokyo, Japan, 108-0073

Korea, Republic of

Clinical Trial Site

Seoul, Korea, Republic of, 05030

Mexico

Clinical Trial Site

Mexico City, Mexico, 04530

Netherlands

Clinical Trial Site

Rotterdam, Netherlands, 3015

Poland

Clinical Trial Site

Warsaw, Poland, 02-776

Spain

Clinical Trial Site

Barcelona, Spain, 08036

Clinical Trial Site

El Palmar, Spain, 30120

Clinical Trial Site

Pamplona, Spain, 31008

Sweden

Clinical Trial Site

Stockholm, Sweden, 171 76

Taiwan

Clinical Trial Site

Taichung, Taiwan, 40705

Clinical Trial Site

Taipei city, Taiwan, 10002

Clinical Trial Site

Taoyuan city, Taiwan, 33305

United Kingdom

Clinical Trial Site

London, United Kingdom, SE5 9RS

Sponsors and Collaborators

Alnylam Pharmaceuticals

Investigators

• Study Director: Medical Director; Alnylam Pharmaceuticals

  Study Documents (Full-Text)

Documents provided by Alnylam Pharmaceuticals:

Study Protocol  [PDF] March 29, 2021

Statistical Analysis Plan  [PDF] February 13, 2019

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Alnylam Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03338816
• Other Study ID Numbers: ALN-AS1-003
• First Posted: November 9, 2017
• Results First Posted: February 11, 2020
• Last Update Posted: June 23, 2022
• Last Verified: May 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Alnylam Pharmaceuticals:

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

Additional relevant MeSH terms:

Porphyria, Acute Intermittent; Porphyrias, Hepatic; Coproporphyria, Hereditary; Porphyria, Variegate; Porphyria, Erythropoietic; Porphyrias; Metabolic Diseases; Skin Diseases, Genetic; Genetic Diseases, Inborn; Skin Diseases; Liver Diseases; Digestive System Diseases