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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03338816
Registration number
NCT03338816
Ethics application status
Date submitted
7/11/2017
Date registered
9/11/2017
Date last updated
22/04/2024
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
Country [1]
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United States of America
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State/province [1]
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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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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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United States of America
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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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Finland
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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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Munich
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Italy
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Modena
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Japan
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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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Spain
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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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State/province [33]
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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/ct2/show/NCT03338816
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Trial related presentations / publications
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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
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03338816
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