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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 : November 16, 2020
Sponsor:
Information provided by (Responsible Party):
Alnylam Pharmaceuticals

Tracking Information
First Submitted Date  ICMJE November 7, 2017
First Posted Date  ICMJE November 9, 2017
Results First Submitted Date  ICMJE January 30, 2020
Results First Posted Date  ICMJE February 11, 2020
Last Update Posted Date November 16, 2020
Actual Study Start Date  ICMJE November 16, 2017
Actual Primary Completion Date January 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 30, 2020)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 7, 2017)
The annualized rate of porphyria attacks in patients with AIP. [ Time Frame: at 6 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 30, 2020)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 7, 2017)
  • The pharmacodynamic (PD) effect of Givosiran on urine levels of delta-aminolevulinic acid (ALA) in patients with AIP. [ Time Frame: at 3 and 6 months ]
  • The pharmacodynamic (PD) effect of Givosiran on urine levels of Porphobilinogen (PBG) in patients with AIP. [ Time Frame: at 6 months ]
  • Annualized rate of hemin administrations in AIP patients. [ Time Frame: through month 6 ]
  • Annualized rate of porphyria attacks in patients with AHP. [ Time Frame: through month 6 ]
  • Pain as measured by a numeric rating scale. [ Time Frame: through month 6 ]
  • Nausea as measured by a numeric rating scale. [ Time Frame: through month 6 ]
  • Fatigue as measured by a numeric rating scale. [ Time Frame: through month 6 ]
  • Change from baseline in the Physical Component Summary of the 12-Item Short Form Survey (SF-12). [ Time Frame: through month 6 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE ENVISION: A Study to Evaluate the Efficacy and Safety of Givosiran (ALN-AS1) in Patients With Acute Hepatic Porphyrias (AHP)
Official Title  ICMJE 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
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).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Hepatic Porphyria
  • Acute Intermittent Porphyria
  • Porphyria, Acute Intermittent
  • Acute Porphyria
  • Hereditary Coproporphyria (HCP)
  • Variegate Porphyria (VP)
  • ALA Dehydratase Deficient Porphyria (ADP)
Intervention  ICMJE
  • Drug: Givosiran
    Givosiran by SC
    Other Names:
    • ALN-AS1
    • GIVLAARI
  • Drug: Placebo
    Matching placebo (normal saline [0.9% NaCl]) by SC
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Givosiran
    • Drug: Placebo
  • 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.
    Interventions:
    • Drug: Givosiran
    • Drug: Placebo
Publications * Balwani M, Sardh E, Ventura P, Peiró PA, Rees DC, Stölzel 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: October 5, 2018)
94
Original Estimated Enrollment  ICMJE
 (submitted: November 7, 2017)
74
Estimated Study Completion Date  ICMJE May 2021
Actual Primary Completion Date January 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Bulgaria,   Canada,   Denmark,   Finland,   France,   Germany,   Italy,   Japan,   Korea, Republic of,   Mexico,   Netherlands,   Poland,   Spain,   Sweden,   Taiwan,   United Kingdom,   United States
Removed Location Countries Belgium,   Switzerland
 
Administrative Information
NCT Number  ICMJE NCT03338816
Other Study ID Numbers  ICMJE ALN-AS1-003
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Alnylam Pharmaceuticals
Study Sponsor  ICMJE Alnylam Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Alnylam Pharmaceuticals
PRS Account Alnylam Pharmaceuticals
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP