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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT03338816
Registration number
NCT03338816
Ethics application status
Date submitted
7/11/2017
Date registered
9/11/2017
Titles & IDs
Public title
ENVISION: A Study to Evaluate the Efficacy and Safety of Givosiran (ALN-AS1) in Patients With Acute Hepatic Porphyrias (AHP)
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Scientific 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
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Secondary ID [1]
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ALN-AS1-003
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Acute Hepatic Porphyria
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Acute Intermittent Porphyria
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Porphyria, Acute Intermittent
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Acute Porphyria
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Hereditary Coproporphyria (HCP)
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Variegate Porphyria (VP)
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ALA Dehydratase Deficient Porphyria (ADP)
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Condition category
Condition code
Metabolic and Endocrine
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Other metabolic disorders
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Human Genetics and Inherited Disorders
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Other human genetics and inherited disorders
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Oral and Gastrointestinal
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Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
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Skin
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Other skin conditions
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Intervention/exposure
Study type
Interventional(has expanded access)
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Description of intervention(s) / exposure
Treatment: Drugs - Givosiran
Treatment: Drugs - Placebo
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.
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.
Treatment: Drugs: Givosiran
Givosiran by SC
Treatment: Drugs: Placebo
Matching placebo (normal saline \[0.9% NaCl\]) by SC
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Annualized Rate of Porphyria Attacks in Participants With Acute Intermittent Porphyria (AIP)
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Assessment method [1]
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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.
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Timepoint [1]
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6 months
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Secondary outcome [1]
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The Pharmacodynamic (PD) Effect of Givosiran on Urine Levels of Delta-aminolevulinic Acid (ALA) in Participants With AIP
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Assessment method [1]
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The PD effect of givosiran was evaluated by spot urine ALA levels normalized to spot urine creatinine levels.
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Timepoint [1]
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3 and 6 months
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Secondary outcome [2]
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The PD Effect of Givosiran on Urine Levels of Porphobilinogen (PBG) in Participants With AIP
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Assessment method [2]
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The PD effect of givosiran was evaluated by spot urine PBG levels normalized to spot urine creatinine levels.
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Timepoint [2]
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6 months
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Secondary outcome [3]
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Annualized Rate of Hemin Administration in Participants With AIP
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Assessment method [3]
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Annualized rate of hemin doses was evaluated as annualized days of hemin use.
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Timepoint [3]
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6 months
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Secondary outcome [4]
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Annualized Rate of Porphyria Attacks in Participants With AHP
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Assessment method [4]
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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.
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Timepoint [4]
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6 months
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Secondary outcome [5]
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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
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Assessment method [5]
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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.
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Timepoint [5]
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Baseline and 6 months
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Secondary outcome [6]
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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
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Assessment method [6]
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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.
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Timepoint [6]
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Baseline and 6 months
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Secondary outcome [7]
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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
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Assessment method [7]
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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.
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Timepoint [7]
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Baseline and 6 months
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Secondary outcome [8]
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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
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Assessment method [8]
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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.
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Timepoint [8]
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Baseline and 6 months
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Secondary outcome [9]
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AUC of the Change From Baseline in Weekly Mean Score Daily Worst Nausea Score as Measured by NRS in Participants With AIP
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Assessment method [9]
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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.
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Timepoint [9]
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Baseline and 6 months
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Secondary outcome [10]
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Average Change From Baseline in Weekly Mean Score Daily Worst Nausea Score as Measured by NRS in Participants With AIP
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Assessment method [10]
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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.
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Timepoint [10]
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Baseline and 6 months
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Secondary outcome [11]
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Change From Baseline in the Physical Component Summary (PCS) of the 12-Item Short Form Survey (SF-12) in Participants With AIP
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Assessment method [11]
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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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Timepoint [11]
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Baseline and 6 months
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Eligibility
Key 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
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Minimum age
12
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
16/11/2017
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
31/05/2021
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Sample size
Target
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Accrual to date
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Final
94
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Recruitment in Australia
Recruitment state(s)
VIC
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Recruitment hospital [1]
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Clinical Trial Site - Parkville
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Recruitment hospital [2]
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Clinical Trial Site - Auchenflower
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Recruitment hospital [3]
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Clinical Trial Site - Camperdown
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Recruitment postcode(s) [1]
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3050 - Parkville
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Recruitment postcode(s) [2]
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4066 - Auchenflower
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Recruitment postcode(s) [3]
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2050 - Camperdown
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Recruitment outside Australia
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United States of America
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Arkansas
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United States of America
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California
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United States of America
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Massachusetts
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United States of America
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Michigan
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New York
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United States of America
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North Carolina
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United States of America
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Pennsylvania
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Texas
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Utah
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United States of America
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Washington
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Bulgaria
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Sofia
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Canada
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Edmonton
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Denmark
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Odense
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Helsinki
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France
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Paris
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Germany
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Chemnitz
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Germany
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Italy
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Modena
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Hamamatsu
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Japan
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Iizuka
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Japan
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Tokyo
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Korea, Republic of
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Seoul
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Mexico
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Mexico City
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Netherlands
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Rotterdam
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Poland
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Warsaw
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Barcelona
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Spain
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El Palmar
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Spain
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Pamplona
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Sweden
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Stockholm
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Taiwan
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Taichung
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Taiwan
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Taipei city
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Taiwan
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Taoyuan city
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United Kingdom
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London
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
Alnylam Pharmaceuticals
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Address
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Ethics approval
Ethics application status
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Summary
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).
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Trial website
https://clinicaltrials.gov/study/NCT03338816
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Trial related presentations / 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.
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Public notes
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Contacts
Principal investigator
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Medical Director
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Address
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Alnylam Pharmaceuticals
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Contact person for public queries
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Contact person for scientific queries
Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
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.
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When will data be available (start and end dates)?
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Available to whom?
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Available for what types of analyses?
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How or where can data be obtained?
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What supporting documents are/will be available?
No Supporting Document Provided
Type
Other Details
Attachment
Study protocol
https://cdn.clinicaltrials.gov/large-docs/16/NCT03338816/Prot_002.pdf
Statistical analysis plan
https://cdn.clinicaltrials.gov/large-docs/16/NCT03338816/SAP_003.pdf
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results are available at
https://clinicaltrials.gov/study/NCT03338816