Acute Hepatic Porphyrias (AHP) MedDRA version: 20.0 Level: PT Classification code 10036182 Term: Porphyria acute System Organ Class: 10010331 - Congenital, familial and genetic disorders MedDRA version: 20.0 Level: LLT Classification code 10036184 Term: Porphyria hepatic System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Sponsors
Alnylam Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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 =4× 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 hydroxymethylbilane synthase gene (HMBS; also referred to as the porphobilinogen 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 (=65 years) yes F.1.3.1 Number of subjects for this age range 15
Exclusion criteria
Exclusion criteria: 1. Any of the following laboratory parameter assessments at Screening: a. Alanine aminotransferase (ALT) >2×ULN b. Total bilirubin >1.5× ULN. Patients with elevated total bilirubin that is secondary to documented Gilbert’s syndrome are eligible if the total bilirubin is 1.5 (patients on an anticoagulant [eg, warfarin] with an INR< 3.5 will be allowed) 2. Estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73 m2 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 outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: • Evaluate the effect of subcutaneous (SC) givosiran, 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 Objective: • To evaluate the effect of givosiran, compared to placebo, on: o Urinary aminolevulinic acid (ALA) levels in patients with AIP o Urinary porphobilinogen (PBG) levels in patients with AIP o Hemin usage in patients with AIP o The rate of porphyria attacks requiring hospitalization, urgent healthcare visit, or IV hemin administration at home in patients with any AHP o In patients with AIP on the symptoms of pain, nausea, and fatigue o 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;Primary end point(s): • Annualized rate of porphyria attacks requiring hospitalization, urgent healthcare visit, or IV hemin administration at home in patients with AIP over the 6-month treatment period;Timepoint(s) of evaluation of this end point: Over the 6-month treatment period. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Urinary ALA in patients with AIP at 3 months • Urinary ALA in patients with AIP at 6 months • Urinary PBG in patients with AIP at 6 months • Annualized rate of administered hemin doses in patients with AIP over the 6-month treatment period • Annualized rate of porphyria attacks requiring hospitalization, urgent healthcare visit, or IV hemin administration at home in patients with any AHP over the 6-month treatment period • Daily worst pain score as measured by Brief Pain Inventory-Short Form (BPI-SF) numeric rating scale (NRS) in patients with AIP over the 6-month treatment period • Daily worst nausea score as measured by NRS in patients with AIP over the 6-month treatment period • Daily worst fatigue score as measured by Brief Fatigue Inventory-Short Form (BFI-SF) NRS in patients with AIP over the 6-month treatment period • Change from baseline in the PCS of the SF-12 in patients with AIP at 6 months Safety • Incidence, severity, seriousness, and relatedness of adverse events during the 6-month treatment period and in the OLE period;Timepoint(s) of evaluation of this end point: All secondary endpoints will be measured over the 6-month double-blind treatment period | — |
Countries
Australia, Belgium, Brazil, Bulgaria, Canada, Czech Republic, Denmark, Finland, France, Germany, Italy, Japan, Korea, Republic of, Mexico, Netherlands, Poland, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Contacts
Public ContactClinical Trials Hotline
Alnylam Pharmaceuticals, Inc.
Outcome results
None listed