Primary:Evaluate the effect of subcutaneous (SC) givosiran (ALN-AS1), compared to placebo, on the rate of porphyria attacks requiring hospitalization, urgent healthcare visit, or intravenous (IV) hemin administration at home in patients with acute…
ID
Source
Brief title
Condition
- Chromosomal abnormalities, gene alterations and gene variants
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary
Annualized rate of porphyria attacks requiring hospitalization, urgent
healthcare visit, or home hemin administration during the 6-month double-blind
treatment period.
Secondary outcome
Secondary
All secondary endpoints will be measured over the 6-month double-blind
treatment period
*Percentage change from baseline in urinary ALA levels
*Percentage change from baseline in urinary PBG levels
*Annualized number of administered hemin doses
*Attack-free days (days without porphyria attacks requiring hospitalization,
urgent healthcare visit or home hemin administration)
*Daily worst pain score as measured by Brief Pain Inventory-Short Form (BPI-SF)
numeric rating scale (NRS)
*Daily worst nausea score as measured by NRS
*Daily worst fatigue score as measured by Brief Fatigue Inventory - Short Form
(BFI-SF) NRS
*Change from baseline in the Physical Component Summary (PCS) of the 12-item
Short-Form Health Survey (SF-12)
Background summary
The acute hepatic porphyrias (AHPs) are a family of rare, serious and
life-threatening metabolic disorders predominantly caused by a genetic mutation
in one of the 8 enzymes responsible for heme synthesis.
Over 75% of acute porphyria attacks require urgent medical care and/or
hospitalization or intravenous hemin. Patients are initially treated with
supportive care and intravenous (IV) glucose, analgesics and antiemetics, along
with the removal of known precipitating triggers, such as certain medications
or dieting. Pain relief typically requires opioids until porphyria-specific
therapy takes effect. In patients with moderate to severe attacks, or who fail
to respond to supportive measures, treatment with IV hemin is used. After 2 to
5 days of hemin treatment, urinary ALA and PBG levels approach normalization
accompanied by improvement in attack symptoms. However, in some patients
attacks can last several weeks, requiring prolonged hemin use and
hospitalization. Hemin administration can result in significant acute side
effects such as severe headache, nausea, flu-like symptoms, fatigue and
thrombophlebitis. There are no approved treatments for the prevention of acute
attacks of hepatic porphyria, and there is little evidence published on how
best to manage AHP patients with recurrent attacks.
AHP is associated with significant morbidity and mortality, and negatively
affects activities of daily living as well as the quality of life of patients.
There is a clear unmet need for novel therapeutics with favorable safety
profiles that effectively and durably decrease the frequency of debilitating
attacks, diminish the chronic symptoms in between attacks, and improve
patients* quality of life.
Based on the available nonclinical and clinical data, givosiran, administered
subcutaneously as a once-monthly dose regimen, may be able to offer
dose-dependent, potent and sustained suppression of ALAS1, thereby decreasing
the accumulation of the neurotoxic heme intermediates ALA and PBG. This may, in
turn, potentially prevent the occurrence of acute porphyria attacks, as well as
potentially ameliorate chronic porphyria symptoms that patients experience
between attacks, including pain, nausea and fatigue.
Study objective
Primary:
Evaluate the effect of subcutaneous (SC) givosiran (ALN-AS1), compared to
placebo, on the rate of porphyria attacks requiring hospitalization, urgent
healthcare visit, or intravenous (IV) hemin administration at home in patients
with acute intermittent porphyria (AIP)
Secondary:
*Evaluate the effect of givosiran, compared to placebo, on urinary
aminolevulinic acid (ALA) levels in patients with AIP
*Evaluate the effect of givosiran, compared to placebo, on urinary
porphobilinogen (PBG) levels in patients with AIP
*Evaluate the effect of givosiran, compared to placebo, on hemin usage in
patients with AIP
*Evaluate the effect of givosiran, compared to placebo, on the rate of
porphyria attacks requiring hospitalization, urgent healthcare visit, or IV
hemin administration at home in patients with any AHP
*Evaluate the effect of givosiran, compared to placebo, in patients with AIP on
the symptoms of pain, nausea and fatigue
*Evaluate the effect of givosiran, compared to placebo, in patients with AIP on
the physical Component Summary (PCS) of the 12-item Short-Form health survey
(SF-12)
*Evaluate the safety and tolerability of givosiran in patients with any AHP
Exploratory:
_Evaluate the effects of givosiran, compared to placebo, in patients with AIP
and in patients with any AHP over the 6-month treatment period on:
__Rate of all porphyria attacks (requiring hospitalization, urgent healthcare
visit, IV hemin administration at home, or treatment at home without IV hemin)
__Urinary aminolevulinic acid synthase (ALAS1) messenger RNA (mRNA) levels
__Analgesic usage
__Additional quality of life (QOL) measures, including missed days of
work/school
*Assess the within-patients treatment effect of givosiran during the open-label
extension (OLE) period in patients with AIP and in patients with any AHP who
had previously been randomized to placebo treatment
*Assess the long-term treatment effect of givosiran in patients with AIP and in
patients with any AHP
*characterize the pharmacokinetics (PK) and assess the antidrug antibodies
(ADA) of givosiran in patients with any AHP
Study design
This is a 2-part multicenter, multinational Phase 3 study designed to evaluate
the efficacy and safety of givosiran in adults and adolescents (*12 years of
age) with a documented diagnosis of AIP. The efficacy and safety of givosiran
will also be investigated in the other AHPs types, including Hereditary
Coproporphyria (HCP), Variegate Porphyria (VP) and ALA dehydratase deficient
porphyria (ADP).
Patients who are on hemin prophylaxis prior to enrollment will be eligible to
participate if they meet the attack entry criteria. In this study, patients may
be given hemin for the treatment of acute attacks if clinically indicated, but
may not use hemin prophylactically. Hemin prophylaxis is not permitted in this
study because givosiran is intended as monotherapy to prevent attacks and the
regular co-administration of hemin could confound efficacy and safety signals
related to givosiran.
in the first part of the study, consenting (and assenting, where applicable)
patients who meet all eligibility criteria will be randomized in a 1:1 ratio to
receive 2.5mg/kg givosiran or placebo monthly for a 6-month treatment period
(double blind); both givosiran and placebo will be administered subcutaneously.
Randomization into treatment groups will be stratified at study entry by AHP
type (AIP [with mutation in the HMBS gene] versus HCP, VP, ADP, or any AHP
without identified mutation in a porphyria-related gene); all patients in the
AIP group will be further stratified by each patient's use of hemin prophylaxis
regimen at the time of screening and by each patient's historical annualized
attack rate. Patients on a hemin prophylaxis regimen prior to study entry will
be stratified by their historical annualized attack rate: <7 attacks versus *7
attacks in the past 12 months. Patients who were not on a hemin prophylaxis
regimen prior to study entry will be stratified by their historical annualized
attack rate: <12 attacks versus *12 attacks in the past 12 months.
No additional stratification factors will be considered for patients with HCP,
VP, ADP or any AHP without identified mutation in a porphyria-related gene.
During the 6-month treatment period, patients will undergo efficacy and safety
assessments every 2 weeks for the first month and monthly thereafter. After
month 6 visit procedures are completed in the treatment period, patients from
both the givosiran and placebo arms will begin the second part of the study,
the OLE period during which they will be treated with givosiran for up to 30
months.
Patients who crossed over to the OLE period prior to the implementation of
amendment 3 (ie, under amendment version 1 or 2) and are receiving a 2.5 mg/kg
once monthly givosiran dose will remain on that dose. Upon entry to the OLE
period under amendment version 3, patients will cross over to receive a 1.25
mg/kg once monthly dose of givosiran. After implementation of amendment 3 and
until implementation of amendment 5, patients assigned to the once monthly
1.25 mg/kg treatment group who experience inadequate disease control may be
allowed to have their monthly dose increased to 2.5 mg/kg starting at the Month
13 Study Visit (when 6 months of open-label givosiran dosing have been
completed at 1.25 mg/kg) based on discussion and agreement by the Investigator
and medical monitor, demonstration of tolerability to givosiran and fulfillment
of ALA and clinical activity criteria. Upon implementation of amendment 5, all
patients receiving 1.25 mg/kg givosiran once monthly who do not have ongoing
clinically relevant transaminase elevations will have their dose increased to
2.5 mg/kg givosiran once monthly based on tolerability alone, without any
criteria for ALA reduction or clinical activity.
For particular study visits, as specified in the Schedule of assessments, and
where applicable country and local regulations and infrastructure allow, study
procedures, including study drug administration, may be conducted by a
qualified home healthcare professional. Patients must demonstrate the ability
to tolerate doses of the study drug at the study center before dosing at a
location other than the study center is permitted. If the patient is unable to
come to the study site, and a visit by a home healthcare professional is not
possible due to circumstances related to the COVID-19 pandemic, givosiran may
be administered by the patient or the caregiver under the oversight of the
Investigator, and following consultation with the medical monitor, as allowed
by applicable country and local regulations.
Patients or caregivers will be provided with an electronic diary (eDiary) to
record severity of daily pain, nausea, and fatigue, as well as analgesic usage.
Potential porphyria attacks will be reported by patients and caregivers through
the eDiary when they occur; study centers will be notified when potential
porphyria attacks are reported in the eDiary. In instances when the eDiary is
not used to report potential porphyria attacks, study centers may be notified
by telephone by patients, caregivers, or other healthcare providers. All
potential porphyria attacks will be confirmed by the Investigator.
Intervention
Monthly Givosiran/Placebo 2.5mg/kg subcutaneously administered during the
blinded 6 month treatment period
Monthly Givosiran 1.25 mg/kg or 2.5mg/kg subcutaneously administered during the
open-label extension period.
Study burden and risks
41 visits to the study center (where applicable country and local regulations
and infrastructure allow, about 24 of the study visits can be performed by a
home healthcare professional)
Blinded 6-month treatment period:
- 6x physical examination
- 9x vital signs
- 1x Single 12-Lead ECG
- 3x Triplicate 12-Lead ECG
- 8x pregnancy test
- 9x Urine samples for ALA and PBG
- 3x Questionnaire of Life to fill out
- Daily Electronic Diary Entries
Monthly administration of the study drug/placebo (subcutaneously)
Open-Label Extension period (Month 6through Month 18):
- 5x physical examination
- 10x vital signs
- 1x Triplicate 12-Lead ECG
- 9x pregnancy test
- 10 urine samples for ALA en PBG
- 3x Questionnaire of Life to fill out
- first 6 months, daily Electronic Diary Entries, from month 13 on only when
potential attacks occur
Monthly administration of the study drug (subcutaneously)
Open-Label Extension period (Month 19 through End of Study):
- 4x physical examination
- 7x vital signs
- 2 Single 12-Lead ECG
- 13x pregnancy test
- 7x urine sample for ALA and PBG
- 3x Questionnaire of Life to fill out
- Electronic Diary Entries only when potential attacks occur
Monthly administration of study drug (subcutaneously) except during the visit
in month 36 (End of Study) and during the Safety FU visit.
Risk: Possible side effects of the study drug and study procedures
Third Street 300
Cambridge MA 02142
US
Third Street 300
Cambridge MA 02142
US
Listed location countries
Age
Inclusion criteria
Each patient must meet all of the following inclusion criteria to be eligible
for enrollment in the study:
1. Age *12 years
2. Documented diagnosis of AIP, HCP, VP or ADP based on clinical features (eg.
acute attacks of abdominal, back, chest, extremities and/or limb pain), at
least one documented urinary or plasma PBG or ALA value *4x upper limit of
normal (ULN) within the past year prior to Screening, and one of the following:
* documented genetic evidence of mutation in a porphyria-related gene, defined
as any of the following: _AIP: mutation in the hydroxmethylbilane synthase gene
(HMBS; also referred to as the porphobilibnogen deaminase [PBGD] gene); _HCP:
mutation in the coporphyrinogen oxidase (CPOX) gene; _VP: mutation in the
protoporphyrinogen oxidase (PPOX) gene; _ADP: mutation in the aminolevulinic
acid dehydratase (ALAD) homozygous or compound heterozygous genes
*Or if the results of a patient's genetic testing do not identify a mutation in
a porphyria-related gene (<5% of cases), a patient may be eligible for the
study if they have both clinical features and diagnostic biochemical criteria
consistent with AHP
3. Have active disease, with at least 2 porphyria attacks requiring
hospitalization, urgent healthcare visit or treatment with IV hemin at home
within the 6 months prior to screening
4. willing to discontinue and/or not initiate use of prophylactic hemin at the
time of screening and for the duration of the study
5. have adequate venous access for study sample collection as judged by the
investigator
6. be willing to comply with the contraceptive requirements during the study
period
7. be willing and able to comply with the study requirements and to provide
written informed consent and assent in the case of patients under the age of
legal consent, per local and national requirements
Exclusion criteria
Each patient must not meet any of the following exclusion criteria to be
eligible for enrollment in the study:
1. Any of the following laboratory parameter assessments at Screening:
* Alanine aminotransferase (ALT) >2xULN
* Total bilirubin >&.5xULN. Patients with elevated total bilirubin that is
secondary to documented Gilbert's syndrome are eligible if the total bilirubin
is <2xULN
* International normalized ratio (INR)>1.5 (patients on an anticoagulant [eg.
warfarin] with an INR<3.5 will be allowed)
2. Estimated Glomerular Filtration Rate (eGFR) <30mL/min/1.73m² using the
Modification of Diet in Renal Disease (MDRD) formula
3. on an active liver transplantation waiting list, or anticipated to undergo
liver transplantation during the blinded study treatment period
4. History of multiple drug allergies or history of allergic reaction to an
oligonucleotide or to N-acetylgalactosamine (GalNAc)
5. History of intolerance to subcutaneous injection(s)
6. Known active HIV infection; or evidence of current or chronic hepatitis C
virus (HCV) or hepatitis B virus (HBV) infection
7. Currently enrolled in another investigational device or drug study, or less
than 30 days or 5 half-lives (whichever is longer) since ending another
investigational device or drug study(s), or receiving other investigational
agent(s)
8. Females who are pregnant, breast-feeding, or planning to become pregnant
during the study
9. Any condition (eg. medical concern or alcohol or substance abuse), which in
the opinion of the Investigator, would make the patient unsuitable for dosing
or which could interfere with the study compliance, the patient's safety and/or
the patient's participation in the 6-month treatment period of the study. This
includes significant active and poorly controlled (unstable) cardiovascular,
neurologic, gastrointestinal, endocrine, renal or psychiatric disorders
unrelated to porphyria identified by key laboratory abnormalities or medical
history
10. History of recurrent pancreatitis, or acute pancreatitis with disease
activity within the past 12 months prior to screening
11. Has planned elective major surgery scheduled to occur during the study
12. History of serious infection within one month prior to screening
13. Had a malignancy within 5 years prior to screening, except for basal or
squamous cell carcinoma of the skin, cervical in-situ carcinoma, or breast
ductal carcinoma, that has been successfully treated
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-002432-17-NL |
| ClinicalTrials.gov | NCT03338816 |
| CCMO | NL63599.000.17 |