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

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

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.

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: GDC-0134; Drug: Rabeprazole; Drug: Placebo; Drug: Midazolam; Drug: Caffeine

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3A 2B4
      • MUCH - Montreal Neurological Institute & Hospital
• Netherlands
  • Utrecht, Netherlands, 3508 GA
    • UMC Utrecht
• United States
  • California
    • San Francisco, California, United States, 94115
      • Forbes Norris Mda/als Ctr; Research Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Hospital - Florida
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • The Emory ALS Clinic
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • North Carolina
    • Raleigh, North Carolina, United States, 27612
      • Wake Research Associates
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • New Orleans Center for Clinical Research

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SAD Stage: GDC-0134; 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; GDC-0134 capsule will be administered orally at various doses, depending on the cohort and treatment period.; Drug: Rabeprazole; Rabeprazole 20 mg twice daily orally
Placebo Comparator: SAD Stage: Placebo; 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: Rabeprazole; Rabeprazole 20 mg twice daily orally; Drug: Placebo; Placebo matching to GDC-0134
Experimental: MAD Stage: GDC-0134; 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; GDC-0134 capsule will be administered orally at various doses, depending on the cohort and treatment period.; Drug: Midazolam; 2mg of liquid formulation of midazolam orally; Drug: Caffeine; 100 mg tablet or solution of caffeine orally
Placebo Comparator: MAD Stage: Placebo; 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; Placebo matching to GDC-0134; Drug: Midazolam; 2mg of liquid formulation of midazolam orally; Drug: Caffeine; 100 mg tablet or solution of caffeine orally
Other: Open-Label Safety Expansion (OSE); Participants will receive GDC-0134 at a dose determined by the corresponding MAD cohort.	Drug: GDC-0134; GDC-0134 capsule will be administered orally at various doses, depending on the cohort and treatment period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Genentech, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2016
• Primary Completion (Actual): March 16, 2020
• Study Completion (Actual): March 16, 2020

Study Registration Dates

• First Submitted: January 7, 2016
• First Submitted That Met QC Criteria: January 13, 2016
• First Posted (Estimate): January 14, 2016

Study Record Updates

• Last Update Posted (Actual): August 6, 2020
• Last Update Submitted That Met QC Criteria: August 4, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Purinergic Antagonists; Purinergic Agents; Gastrointestinal Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Midazolam; Rabeprazole; Caffeine
• Other Study ID Numbers: GN29823; 2017-002931-41 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes