A Study to Investigate the Interaction Between Givosiran and a 5-probe Drug Cocktail in Patients With Acute Intermittent Porphyria (AIP)

A Drug-Drug Interaction Study to Investigate the Effect of Givosiran on the Pharmacokinetics (PK) of Midazolam, Caffeine, Losartan, Omeprazole, and Dextromethorphan in Patients With Acute Intermittent Porphyria (AIP) Who Are Asymptomatic High Excreters (ASHE)

The purpose of this study is to evaluate the effect of givosiran on the pharmacokinetics of the 5-probe cocktail of midazolam, caffeine, losartan, omeprazole, and dextromethorphan, and their metabolites, in asymptomatic patients with Acute Intermittent Porphyria.

Study Overview

• Status: Completed
• Conditions: Porphyria, Acute Intermittent; Acute Intermittent Porphyria (AIP); Acute Hepatic Porphyria (AHP); Acute Porphyria
• Intervention / Treatment: Drug: Givosiran; Drug: 5-probe cocktail

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• Sweden
  • Stockholm, Sweden
    • Clinical Trial Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 18 to 65 years old
• Weight between 45kg and 110kg, inclusive, if male
• Weight between 45kg and 100 kg, inclusive, if female
• Diagnosis of acute intermittent porphyria (AIP)
• Elevated urine PBG level
• Not be pregnant or breast feeding, and must be willing to use a highly effective method of contraception

Exclusion Criteria:

• Clinically significant abnormal laboratory results
• Experienced an acute porphyria attack within past 12 months
• History of multiple drug allergies, intolerances or sensitivities
• History of recurrent pancreatitis
• Received an experimental drug, within 3 months of dosing
• Donated or lost an excessive amount of blood within 60 days of dosing

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Givosiran with 5-probe cocktail	Drug: Givosiran; single dose of givosiran by subcutaneous (sc) injection; Drug: 5-probe cocktail; includes midazolam, caffeine, losartan, omeprazole, and dextromethorphan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Profile of Pharmacokinetics (PK) of Cytochrome P450 (CYP) probe cocktail	Area under the concentration-time curve (AUC)	Days 1 and 36
Profile of Pharmacokinetics (PK) of Cytochrome P450 (CYP) probe cocktail	Maximum plasma concentration (Cmax)	Days 1 and 36

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Profile of Pharmacokinetics (PK) of Cytochrome P450 (CYP) probe cocktail metabolites	Area under the concentration-time curve (AUC)	Days 1 and 36
Profile of Pharmacokinetics (PK) of Cytochrome P450 (CYP) probe cocktail metabolites	Maximum plasma concentration (Cmax)	Days 1 and 36
Profile of Pharmacokinetics (PK) of Cytochrome P450 (CYP) probe cocktail	Terminal half-life (t1/2)	Days 1 and 36
Profile of Pharmacokinetics (PK) of Cytochrome P450 (CYP) probe cocktail	Volume of distribution (V/F)	Days 1 and 36
The pharmacodynamic (PD) effect of givosiran on urine levels of delta-aminolevulinic acid (ALA)		Days 1, 8, and 36
The pharmacodynamic (PD) effect of givosiran on urine levels of Porphobilinogen (PBG) in patients with AIP		Days 1, 8, and 36
Safety as evaluated by the proportion of subjects experiencing adverse events (AEs)		Day 1 - Day 92

Collaborators and Investigators

• Sponsor: Alnylam Pharmaceuticals
• Investigators: Study Director: Nader Najafian, MD, Alnylam Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): April 26, 2018
• Primary Completion (Actual): November 16, 2018
• Study Completion (Actual): January 10, 2019

Study Registration Dates

• First Submitted: April 13, 2018
• First Submitted That Met QC Criteria: April 13, 2018
• First Posted (Actual): April 23, 2018

Study Record Updates

• Last Update Posted (Actual): March 12, 2019
• Last Update Submitted That Met QC Criteria: March 10, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: RNAi therapeutic; Porphyria; Acute Hepatic Porphyria (AHP); Acute Intermittent Porphyria (AIP)
• Additional Relevant MeSH Terms: Digestive System Diseases; Metabolic Diseases; Skin Diseases; Liver Diseases; Genetic Diseases, Inborn; Skin Diseases, Genetic; Porphyrias, Hepatic; Porphyria, Erythropoietic; Porphyrias; Coproporphyria, Hereditary; Porphyria, Acute Intermittent
• Other Study ID Numbers: ALN-AS1-004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No