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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03338816
Recruitment Status : Active, not recruiting
First Posted : November 9, 2017
Results First Posted : February 11, 2020
Last Update Posted : May 12, 2020
Sponsor:
Information provided by (Responsible Party):
Alnylam Pharmaceuticals

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 available outside the clinical trial.   More info ...

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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
Estimated Study Completion Date : May 2021


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




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.



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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03338816


Locations
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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, Florida
Clinical Trial Site
Miami, Florida, United States, 33136
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
Belgium
Clinical Trial Site
Leuven, Belgium, 3000
Bulgaria
Clinical Trial Site
Sofia, Bulgaria, 1431
Canada
Clinical Trial Site
Edmonton, Canada, T6G 2R3
Clinical Trial Site
Montréal, Canada, H3A 2B4
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
Milano, Italy, 20122
Clinical Trial Site
Modena, Italy, 41124
Japan
Clinical Trial Site
Hamamatsu, Japan, 430-0929
Clinical Trial Site
Hiroshima, Japan, 734-8551
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
Switzerland
Clinical Trial Site
Zürich, Switzerland, 8063
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
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Study Director: Amy Simon, MD Alnylam Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Alnylam Pharmaceuticals:
Study Protocol  [PDF] May 28, 2019
Statistical Analysis Plan  [PDF] February 13, 2019

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Responsible Party: Alnylam Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03338816    
Other Study ID Numbers: ALN-AS1-003
First Posted: November 9, 2017    Key Record Dates
Results First Posted: February 11, 2020
Last Update Posted: May 12, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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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