A Study of GDC-0134 to Determine Initial Safety, Tolerability, and Pharmacokinetic Parameters in Participants With Amyotrophic Lateral Sclerosis

Study Overview
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Brief Summary
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This first-in-human, double-blind, placebo-controlled Phase I study will be conducted in participants with amyotrophic lateral sclerosis (ALS) to explore safety, tolerability, and pharmacokinetic (PK) properties of GDC-0134. It will include three components: a Single-Ascending-Dose (SAD) stage, a Multiple-Ascending-Dose (MAD) stage, and an Open-Label Safety Expansion (OSE) stage.

Official Title
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A Phase I, Double-Blind, Randomized, Placebo-Controlled, Multicenter, Single- and Multiple-Ascending-Dose Study to Determine Initial Safety, Tolerability, and Pharmacokinetics of GDC-0134 in Patients With Amyotrophic Lateral Sclerosis

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: GDC-0134
* Drug: Placebo
* Drug: Rabeprazole
* Drug: Midazolam
* Drug: Caffeine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants with a diagnosis of possible, laboratory-supported probable, probable, or definite ALS according to modified El Escorial criteria Upright forced vital capacity of at least 50 percent (%) Ability to fast from food for 8 hours prior to dosing and 2 hours after dosing Exclusion Criteria: Currently taking riluzole unless on a stable dose for the 3 months prior to Day -1 and without current liver enzyme or liver function abnormalities Currently taking edaravone unless after completion of at least the second 14-day drug-treatment period, as long as Day 1 occurs during a drug-free period at least 24 hours after the last edaravone dose and at least 5 days prior to the first dose of the next cycle Positive for hepatitis C antibody, hepatitis B surface antigen, or human immunodeficiency virus (HIV) antibody Clinically significant thrombocytopenia Currently taking nutritional/herbal supplements, except for over-the-counter vitamins that are within Recommended Dietary Allowance (RDA), unless discontinued at least 7 days prior to Day -1, except upon approval of both the investigator and Sponsor For participants participating in a designated drug-drug interaction (DDI) cohort in the MAD stage of the study, who require midazolam/caffeine administration: known allergy, religious prohibition, or other condition limiting midazolam or caffeine administration

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAD Stage: GDC-0134<br>Participants in multiple cohorts and treatment periods will receive single doses of GDC-0134 oral capsules under fed/fasting conditions. To study the effect of proton pump inhibitor (PPI) medication rabeprazole on PK properties of GDC-0134, few participants may receive rabeprazole 20 milligrams (mg). | Drug: GDC-0134<br>* GDC-0134 capsule will be administered orally at various doses, depending on the cohort and treatment period.<br>Drug: Rabeprazole<br>* Rabeprazole 20 mg twice daily orally<br>|
| Placebo Comparator: SAD Stage: Placebo<br>Participants in multiple cohorts and treatment periods will receive placebo matching to GDC-0134 under fed/fasting conditions. Few participants may receive rabeprazole 20 mg. | Drug: Placebo<br>* Placebo matching to GDC-0134<br>Drug: Rabeprazole<br>* Rabeprazole 20 mg twice daily orally<br>|
| Experimental: MAD Stage: GDC-0134<br>Participants will receive multiple doses of GDC-0134 for 28 days. To study the interactions between GDC-0134 and other drugs, some participants may receive single doses of midazolam and caffeine at various time points. | Drug: GDC-0134<br>* GDC-0134 capsule will be administered orally at various doses, depending on the cohort and treatment period.<br>Drug: Midazolam<br>* 2mg of liquid formulation of midazolam orally<br>Drug: Caffeine<br>* 100 mg tablet or solution of caffeine orally<br>|
| Placebo Comparator: MAD Stage: Placebo<br>Participants will receive placebo matching to GDC-0134 for 28 days. To study the interactions between GDC-0134 and other drugs, some participants may receive single doses of midazolam and caffeine at various time points. | Drug: Placebo<br>* Placebo matching to GDC-0134<br>Drug: Midazolam<br>* 2mg of liquid formulation of midazolam orally<br>Drug: Caffeine<br>* 100 mg tablet or solution of caffeine orally<br>|
| Other: Open-Label Safety Expansion (OSE)<br>Participants will receive GDC-0134 at a dose determined by the corresponding MAD cohort. | Drug: GDC-0134<br>* GDC-0134 capsule will be administered orally at various doses, depending on the cohort and treatment period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events (AEs) |  | From randomization up to approximately 48 months | 
| Percentage of Participants With Clinically Significant Laboratory Abnormalities |  | From randomization up to approximately 48 months | 
| Percentage of Participants With Clinically Significant Vital Signs Abnormalities |  | From randomization up to approximately 48 months | 
| Percentage of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities |  | From randomization up to approximately 48 months | 
| Percentage of Participants With Clinically Significant Abnormalities in Physical Examination Findings |  | From randomization up to approximately 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) of GDC-0134 |  | From Day 1 up to 28 days after last dose | 
| Time to Maximum Plasma Concentration (tmax) of GDC-0134 |  | From Day 1 up to 28 days after last dose | 
| Area Under the Plasma Concentration Versus Time Curve (AUC) of GDC-0134 |  | From Day 1 up to 28 days after last dose | 
| Apparent Clearance (CL/F) of GDC-0134 |  | From Day 1 up to 28 days after last dose | 
| Apparent Terminal Volume of Distribution (Vz/F) of GDC-0134 |  | From Day 1 up to 28 days after last dose | 
| Apparent Terminal Half-Life (t1/2) of GDC-0134 |  | From Day 1 up to 28 days after last dose | 
| PK-Dose Proportionality of GDC-0134 as Assessed With Cmax and AUC |  | From Day 1 up to 28 days after last dose | 
| Accumulation Ratio of GDC-0134 |  | From Day 1 up to 28 days after last dose | 
| Dose Normalized Cmax (Cmax/Dose) of GDC-0134 |  | From Day 1 up to 28 days after last dose | 
| Dose Normalized AUC (AUC/Dose) of GDC-0134 |  | From Day 1 up to 28 days after last dose | 
| t1/2 of Midazolam |  | From Day -1 up to 28 days after last dose | 
| t1/2 of 1-Hydroxymidazolam (Metabolite of Midazolam) |  | From Day -1 up to 28 days after last dose | 
| t1/2 of Caffeine |  | From Day -1 up to 28 days after last dose | 
| t1/2 of Paraxanthine (Metabolite of Caffeine) |  | From Day -1 up to 28 days after last dose |