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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Acute Intermittent Porphyria (AIP), Acute Hepatic Porphyria (AHP), Porphyria, Acute Intermittent, Acute Porphyria

Intervention / Treatment
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* Drug: Givosiran
* Drug: 5-probe cocktail


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RNAi therapeutic, Porphyria, Acute Hepatic Porphyria (AHP), Acute Intermittent Porphyria (AIP)