A Clinical Drug-Drug Interaction (DDI) Study With Omaveloxolone

Study Overview
=================
Brief Summary
-----------------
This study will assess the potential for clinical drug-drug interactions between omaveloxolone and a number of substrates and inhibitors of metabolic enzymes and drug transporters.

Detailed Description
-----------------
This study was previously posted by Reata Pharmaceuticals. In September 2023, sponsorship of the trial was transferred to Biogen.

Official Title
-----------------
A Phase 1, Open-Label, 4-Part, Drug-Drug Interaction Study With Omaveloxolone in Healthy Subjects

Conditions
-----------------
Healthy Adult Subjects

Intervention / Treatment
-----------------
* Drug: Omaveloxolone
* Drug: Midazolam oral solution
* Drug: Repaglinide 1 MG
* Drug: MetFORMIN 500 Mg Oral Tablet
* Drug: Rosuvastatin
* Drug: Digoxin tablet
* Drug: Gemfibrozil Tablets
* Drug: Itraconazole capsule
* Drug: Verapamil Pill


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects must satisfy all of the following criteria at the Screening Visit unless otherwise stated: Males or females, of any race, between 18 and 55 years of age, inclusive. Body mass index between 18.0 and 32.0 kg/m2, inclusive, and a total body weight >50 kg. In good health. Females will not be pregnant or lactating, and females of childbearing potential and males will agree to use contraception. Able to comprehend and willing to sign an ICF and to abide by the study restrictions. Exclusion Criteria: Subjects will be excluded from the study if they satisfy any of the following criteria at the Screening visit, unless otherwise stated: Significant history or clinical manifestation of any major system disorder, as determined by the investigator (or designee). History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the investigator (or designee). History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs (cholecystectomy will not be allowed; uncomplicated appendectomy and hernia repair will be allowed). History of alcoholism or drug/chemical abuse within 2 years prior to Check in (Day 1). Abnormal laboratory values considered clinically significant by the investigator Clinically significant abnormal 12 lead ECGs Personal history of unexplained syncopal events, or family history of long QT syndrome or sudden unexplained death in a young person. Pulse rate <50 bpm or systolic blood pressure <110 mmHg. Alcohol consumption of >21 units per week for males and >14 units for females. Positive urine drug screen or positive alcohol breath test result or positive urine drug screen. Positive hepatitis panel and/or positive human immunodeficiency virus test. Participation in a clinical study involving administration of an investigational drug (new chemical entity) in the past 30 days prior to dosing or 5 half lives (if known), whichever is longer, prior to dosing. Use or intend to use any medications/products known to alter drug absorption, metabolism, or elimination processes, including St. John's wort, within 30 days prior to dosing, unless deemed acceptable by the investigator (or designee). Have previously completed or withdrawn from this study or any other study investigating omaveloxolone, and have previously received the investigational product. Subjects who, in the opinion of the investigator (or designee), should not participate in this study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Omaveloxolone and Multiple Drugs (Part 1)<br>Single oral doses of 2 mg midazolam, 1 mg repaglinide, 500 mg metformin, and a 10 mg rosuvastatin/0.25 mg digoxin cocktail on Days 1, 2, 3, and 5, respectively, and 18, 19, 20, and 22, respectively. Oral doses of 150 mg omaveloxolone on Days 12 to 27 | Drug: Omaveloxolone<br>* 50 mg capsules<br>* Other names: RTA 408;Drug: Midazolam oral solution<br>* 2 mg/mL oral solution<br>Drug: Repaglinide 1 MG<br>* 1 mg tablet<br>Drug: MetFORMIN 500 Mg Oral Tablet<br>* 500 mg tablet<br>Drug: Rosuvastatin<br>* 10 mg tablet<br>Drug: Digoxin tablet<br>* 0.25 mg tablet<br>|
| Experimental: Omaveloxolone & Gemfibrozil (Part 2)<br>Single oral doses of 150 mg omaveloxolone on Days 1 and 13. Oral doses of 600 mg gemfibrozil (twice daily) on Days 10 to 18 | Drug: Omaveloxolone<br>* 50 mg capsules<br>* Other names: RTA 408;Drug: Gemfibrozil Tablets<br>* 600 mg tablet<br>|
| Experimental: Omaveloxolone and Itraconazole (Part 3)<br>Single oral doses of 150 mg omaveloxolone on Days 1 and 13. Oral doses of 200 mg itraconazole on Days 10 to 18. | Drug: Omaveloxolone<br>* 50 mg capsules<br>* Other names: RTA 408;Drug: Itraconazole capsule<br>* 100 mg capsule<br>|
| Experimental: Omaveloxolone and Verapamil (Part 4)<br>Single oral doses of 150 mg omaveloxolone on Days 1 and 13. Oral doses of 120 mg verapamil on Days 10 to 18. | Drug: Omaveloxolone<br>* 50 mg capsules<br>* Other names: RTA 408;Drug: Verapamil Pill<br>* 120 mg tablet<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 - Maximum concentration (Cmax) of probe drugs co-administered with omaveloxolone (midazolam, repaglinide, metformin, rosuvastatin, and digoxin) | Pharmacokinetics will be assessed by blood sampling for midazolam, repaglinide, metformin, rosuvastatin, and digoxin to determine maximum observed concentration (Cmax). | 28 days | 
| Part 1 - Area under the plasma concentration-time curve of (AUC) for probe drugs co-administered with omaveloxolone (midazolam, repaglinide, metformin, rosuvastatin, and digoxin) | Pharmacokinetics will be assessed by blood sampling for midazolam, repaglinide, metformin, rosuvastatin, and digoxin to determine area under the curve (AUC). | 28 days | 
| Part 2 - Maximum concentration (Cmax) of omaveloxolone | Pharmacokinetics will be assessed by blood sampling for omaveloxolone to determine maximum observed concentration (Cmax). | 23 days | 
| Part 2 - Area under the omaveloxolone concentration-time curve (AUC) | Pharmacokinetics will be assessed by blood sampling for omaveloxolone to determine area under the curve (AUC). | 23 days | 
| Part 3 - Maximum concentration (Cmax) of omaveloxolone | Pharmacokinetics will be assessed by blood sampling for omaveloxolone to determine maximum observed concentration (Cmax). | 23 days | 
| Part 3 - Area under the omaveloxolone concentration-time curve (AUC) | Pharmacokinetics will be assessed by blood sampling for omaveloxolone to determine area under the curve (AUC). | 28 days | 
| Part 4 - Maximum concentration (Cmax) of omaveloxolone | Pharmacokinetics will be assessed by blood sampling for omaveloxolone to determine maximum observed concentration (Cmax). | 23 days | 
| Part 4 - Area under the omaveloxolone concentration-time curve (AUC) | Pharmacokinetics will be assessed by blood sampling for omaveloxolone to determine area under the curve (AUC). | 28 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
RTA 408, RTA 408 capsules, omaveloxolone, omaveloxolone capsules, DDI