ENVISION: Givosiran in Patients with Acute Hepatic Porphyrias
Research type
Research Study
Full 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
IRAS ID
233692
Contact name
David Rees
Contact email
Sponsor organisation
Alnylam UK Limited
Eudract number
2017-002432-17
Clinicaltrials.gov Identifier
IND Number, 126094
Duration of Study in the UK
3 years, 11 months, 30 days
Research summary
Research Summary
Acute hepatic porphyrias (AHP) are rare diseases caused by a genetic defect in one of the enzymes responsible for the synthesis of haem in the liver. Haem is an important protein that plays a role in helping the liver to metabolise various foods and drugs.
This genetic defect causes a build-up of 2 substances that make haem, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). This build up causes injury to nerve cells and can cause porphyria attacks and symptoms in between attacks. Some people experience frequent attacks of severe stomach or back pain, nausea, vomiting, diarrhoea, muscle weakness, mental changes, seizures, and in some cases paralysis.
The drug in this trial, givosiran is thought to work by lowering the enzyme (called ALAS1) that makes PBG and ALA. It is believed givosiran will temporarily slow down the rate of ALAS1 synthesis. This means the liver might make less PBG and ALA, and this could help people with AHP by reducing injury to nerve cells which may improve their symptoms.
This study will evaluate the efficacy and safety of givosiran when given to patients with AHP compared to placebo. Participants will receive either givosiran or placebo during a 6 months period. They will have a 1 in 2 (50%) chance of receiving either givosiran or placebo during this period. After 6 months all patients will receive givosiran. Participants will take part for up to 38 monthsSummary of Results
The following study results are from the 6-month double-blind period (the treatment patients received is unknown to both patients and doctors).Did givosiran reduce the number of porphyria attacks compared to placebo?
At the beginning of the study, the participants in the placebo group and the givosiran group had a similar average number of porphyria attacks. After 6 months, participants in the givosiran group had fewer porphyria attacks compared to the participants in the placebo group. With givosiran treatment, the number of porphyria attacks per patient per month decreased over 6 months. For some participants, porphyria attacks stopped; for other participants, porphyria attacks occurred less often. For participants in the placebo group, the number of porphyria attacks per patient per month did not change throughout the 6 months.
Did givosiran reduce the amount of hemin used compared to placebo?
Givosiran group had an average of 4.7 days of hemin use. Placebo group had an average of 12.8 days of hemin use. Participants in the givosiran group needed hemin less often to treat porphyria attacks compared to participants in the placebo group.
Did givosiran reduce aminolevulinic acid (ALA) and porphobilinogen (PBG) levels compared to placebo?
Compared to the placebo group, the reduction of ALA and PBG levels towards normal levels occurred very quickly in the givosiran group and lasted for the entire 6-month period.
What did participants report about how their quality of life, daily activities, and overall health changed during the study?
These questions were exploratory and assessed using questionnaires: Short Form 12, Patient Global Impression of Change and Porphyria Patient Experience.
Short Form 12 (SF-12) Participants were asked at the beginning of the study and after 6 months to answer questions about their quality of life using the SF-12 assessment. Researchers then compared the average changes in SF-12 scores between givosiran and placebo groups. At the end of 6 months, participants in the givosiran group reported more improvement in their physical quality of life compared to the placebo group (a greater increase in the average change means more improvement).
Patient Global Impression of Change (PGIC), The PGIC is one question asking how a participant feels his/her overall health has improved since the start of the study. More participants in the givosiran group reported improvement in their overall status than participants in the placebo group.
Porphyria Patient Experience Questionnaire (PPEQ) was designed for the ENVISION study and includes 8 questions about the impact of Acute Hepatic Porphyria (AHP) symptoms on participants’ ability to function and their response to the study medication. More participants in the givosiran group reported improvements in daily activities compared to participants in the placebo group.What medical problems did the participants have during the study?
Study doctors record any medical problems (called “adverse events”) that participants have during a clinical study. Adverse events can be caused by AHP or another condition and/or disease, by another medication, or by chance. Sometimes the cause is unknown. Participants can have adverse events that are either related or not related to the study medication.
How many participants reported an adverse event (AE)?
In participants who received givosiran 43 out of 48 (90%) had at least one adverse event. In participants who received the placebo 37 out of 46 people (80%) had at least 1 adverse event.
How many participants experienced serious adverse events (SAEs)?
An adverse event is considered “serious” when it is life-threatening, causes lasting problems, or requires hospital care. Participants who received Givosiran reported 21% SAE (10 out of 48). In participants who received the placebo 9% SAEs were reported (4 out of 46). The serious adverse events that occurred in 2 or more participants were decreased kidney function and device related infection. One participant (1 in 46) in the givosiran group had a serious adverse event of increased liver enzymes and stopped taking givosiran.
REC name
London - Central Research Ethics Committee
REC reference
17/LO/1760
Date of REC Opinion
22 Nov 2017
REC opinion
Further Information Favourable Opinion