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A Study of Gantenerumab in Participants With Mild Alzheimer Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02051608
Recruitment Status : Completed
First Posted : January 31, 2014
Results First Posted : June 16, 2022
Last Update Posted : February 10, 2023
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Description
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Brief Summary:

Part 1 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study will evaluate the efficacy and safety of gantenerumab in participants with mild Alzheimer disease. Participants will be randomized to receive either gantenerumab subcutaneously every 4 weeks or placebo subcutaneously every 4 weeks. Approved Alzheimer medication is allowed if on stable dose for 3 months prior to screening. Part 2 is an open-label extension (OLE).

A positron emission tomography (PET) imaging substudy will be conducted within the main study. Eligible participants who provide separate informed consent will undergo PET imaging scans using the radioligand florbetapir as a pharmacodynamic measure of changes in brain amyloid load over time.


Condition or disease Intervention/treatment Phase
Alzheimer's Disease Drug: Placebo Drug: Gantenerumab Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 389 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase III, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Efficacy and Safety Study of Gantenerumab in Patients With Mild Alzheimer's Disease; Part II: Open-Label Extension For Participating Patients
Actual Study Start Date : March 27, 2014
Actual Primary Completion Date : April 16, 2021
Actual Study Completion Date : April 16, 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Placebo Comparator: Part 1 (Double Blind treatment): Placebo
Participants received matching placebo by subcutaneous (SC) injection every 4 weeks (Q4W) up to 100 weeks during Part 1 of the study.
 Drug: Placebo
Participants received Placebo SC injection Q4W.
Experimental: Part 1 (Double Blind treatment): Gantenerumab
Participants received 105 mg Gantenerumab by SC injection Q4W for 24 weeks and if eligible 225 mg SC injection Q4W from weeks 28-100 during Part 1 of the study.
 Drug: Gantenerumab
Participants received Gantenerumab at 105 mg , 225 mg, or at doses up to 1200 mg SC injection Q4W.
Placebo Comparator: Part 2 (Open-Label Extension [OLE] treatment): Placebo switched to Gantenerumab Up to 1200 mg
Participants who had received Placebo in Part 1, received Gantenerumab at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.
 Drug: Placebo
Participants received Placebo SC injection Q4W.
Experimental: Part 2 (OLE treatment): Gantenerumab up to 1200 mg
Participants who had received Gantenerumab in Part 1, received treatment at doses up to 1200 mg by SC injection Q4W for up to 2 years. Additionally, participants were given the option to continue receiving open-label gantenerumab treatment for 3 years.
 Drug: Gantenerumab
Participants received Gantenerumab at 105 mg , 225 mg, or at doses up to 1200 mg SC injection Q4W.


Outcome Measures
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Primary Outcome Measures :
  1. Part 2: Percentage of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) [ Time Frame: First dose up to 4 weeks after the last dose of study drug (up to 249 weeks) ]
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. SAE is any adverse event that is fatal or which requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity or causes congenital anomaly/birth defect or results in a significant medical event in the investigator's judgment.

  2. Part 2: Percentage of Participants With Treatment Emergent Anti-Drug Antibodies (ADAs) [ Time Frame: First dose up to last dose (Baseline up to until maximum 5 years) ]
    Participants were considered positive or negative for ADA based on their baseline and post-baseline sample results. The number and percentage of participants with confirmed positive ADA levels were determined for participants previously (in part 1) on Gantenerumab and Placebo. The prevalence of ADA at baseline was calculated as the percentage of participants with confirmed positive ADA levels at baseline relative to the total number of participants with a sample available at baseline. The incidence of treatment-emergent ADAs was determined as the percentage of participants with confirmed post-baseline positive ADAs relative to the total number of participants that had at least one post-baseline sample available for ADA analysis.

  3. Part 2: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment [ Time Frame: First dose up to 4 weeks after the last dose in OLE (Up to approximately 249 weeks) ]
    Percentage of participants with adverse events leading to discontinuation from treatment were reported.


Secondary Outcome Measures :
  1. Part 1: Percentage of Participants With AEs, SAEs [ Time Frame: First dose up to last dose (Up to approximately 152 weeks) ]
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. A serious adverse event is any adverse event that is fatal or which requires or prolongs inpatient hospitalization or results in persistent or significant disability/incapacity or causes congenital anomaly/birth defect or results in a significant medical event in the investigator's judgment.

  2. Part 1: Percentage of Participants With Treatment Emergent ADAs [ Time Frame: First dose up to last dose (Up to approximately 152 weeks) ]
    Participants were considered positive or negative for ADA based on their baseline and post-baseline sample results. The number and percentage of participants with confirmed positive ADA levels were determined for participants previously (in part 1) on Gantenerumab and Placebo. The prevalence of ADA at baseline was calculated as the percentage of participants with confirmed positive ADA levels at baseline relative to the total number of participants with a sample available at baseline. The incidence of treatment-emergent ADAs was determined as the percentage of participants with confirmed post-baseline positive ADAs relative to the total number of participants that had at least one post-baseline sample available for ADA analysis.

  3. Part 1: Gantenerumab Plasma Concentration at Multiple Timepoints [ Time Frame: Pre-dose: Weeks 4, 8, 12, 24, 48, 72 and Post dose: Day 4 ]
  4. Part 1: Percentage of Participants With Adverse Events Leading to Discontinuation of Treatment [ Time Frame: First dose up to last dose (Up to approximately 152 weeks) ]
    Percentage of participants with adverse events leading to discontinuation from treatment were reported.

  5. Part 2: Percent Change From Baseline in Hippocampal Volume at Week 104 [ Time Frame: Baseline (Part 1 screening), Week 104 ]
    Change from baseline in hippocampal right volume (HRV) and hippocampal left volume (HLV) were analyzed at Week 104 using magnetic resonance imaging.

  6. Part 2: Percent Change From Baseline in Whole Brain Volume at Week 104 [ Time Frame: Baseline (Part 1 screening), Week 104 ]
    Change from baseline brain volume were analyzed at Week 104 using magnetic resonance imaging.

  7. Part 2: Percent Change From Baseline in Cortical Thickness at Week 104 [ Time Frame: Baseline (Part 1 screening), Week 104 ]
    Change from baseline in cortical thickness were analyzed at Week 104 using magnetic resonance imaging.

  8. Part 2: Ventricular Volume as Measured by MRI at Week 104 [ Time Frame: Part 2: Week 104 ]
    Ventricular volume were analyzed at Week 104 using magnetic resonance imaging.

  9. Part 2: Gantenerumab Plasma Concentration at Multiple Timepoints [ Time Frame: Pre-dose: Weeks 104, 116, 156, 208; Post-dose: Weeks 53, 101 ]
  10. Part 2: Change From Baseline in Brain Amyloid Load at Week 156 in a Subset of Participants [ Time Frame: Baseline, Week 156 ]
    Brain amyloid load over time was assessed using a Florbetapir [F18] injection, a positron emission tomography (PET) radioligand selective to amyloid. Analysis was conducted in a subset of participants who signed consent to participate in the PET substudy. Amyloid PET burden was measured in a composite region of interest (ROI) by using standardized uptake value ratio (SUVR) mapped to the centiloid scale. The composite region was composed of the following six bilateral regions: frontal lobe, parietal lobe, temporal lobe, posterior cingulate cortex, anterior cingulate cortex. The reference region used to normalize the composite region was the cerebellar cortex. SUVR is ratio of tracer uptake in each of cingulate, frontal, parietal and temporal cortexes relative to cerebellum. The centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition found in a typical AD scans.


Other Outcome Measures:
  1. Part 1: Mean Change From Baseline in Alzheimer's Disease Activity Scale-Cognitive Subscale 13 (ADAS-Cog13) Scores at Week 104 [ Time Frame: Baseline, Week 104 ]
  2. Part 1: Mean Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Scores at Week 104 [ Time Frame: Baseline, Week 104 ]
  3. Part 1: Percentage Change From Baseline in Total Tau (T-tau) in CSF at Week 104 [ Time Frame: Baseline, Week 104 ]
  4. Part 1: Percentage Change From Baseline in Abeta 1-42 Levels in CSF at Week 104 [ Time Frame: Baseline, Week 104 ]
  5. Part 1: Percentage Change From Baseline in Phosphorylated Tau [P-tau] in CSF at Week 104 [ Time Frame: Baseline, Week 104 ]
  6. Part 1: Percent Change From Baseline in Hippocampal Volume at Week 104 [ Time Frame: Baseline, Week 104 ]
  7. Part 1: Percent Change From Baseline in Whole Brain Volume at Week 104 [ Time Frame: Baseline, Week 104 ]
  8. Part 1: Percent Change From Baseline in Cortical Thickness at Week 104 [ Time Frame: Baseline, Week 104 ]
  9. Part 1: Ventricular Volume as Measured by MRI at Week 104 [ Time Frame: Baseline, Week 104 ]
  10. Part 1: Change From Baseline in Clinical Dementia Rating Global Score (CDR-GS) at Week 104 [ Time Frame: Baseline, Week 104 ]
  11. Part 1: Change From Baseline in CDR Sum of Boxes (SB) at Week 104 [ Time Frame: Baseline, Week 104 ]
  12. Part 1: Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Week 104 [ Time Frame: Baseline, Week 104 ]
  13. Part 1: Change From Baseline in NPI Domain Score at Week 104 [ Time Frame: Baseline, Week 104 ]
  14. Part 1: Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Week 104 [ Time Frame: Baseline, Week 104 ]
  15. Part 1: Change From Baseline in Alzheimer's Dementia (QoL-AD) Global Score at Week 104 [ Time Frame: Baseline, Week 104 ]
  16. Part 1: Change From Baseline in Symptom Guide Facilitated (GAS) at Week 104 [ Time Frame: Baseline, Week 104 ]
  17. Part 1: Change From Baseline in Dependence Scale (DS) at Week 104 [ Time Frame: Baseline, Week 104 ]
  18. Part 1: Change From Baseline in Resource Utilization Dementia-Lite (RUD - Lite) Scale at Week 104 [ Time Frame: Baseline, Week 104 ]
  19. Part 1: Change From Baseline in Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD) at Week 104 [ Time Frame: Baseline, Week 104 ]
  20. Part 1: Time to Clinical Decline [ Time Frame: Baseline up to Week 104 ]
  21. Part 1: Change From Baseline in Clinical Composite Score (Prespecified Items From The ADAS-Cog, MMSE, and CDR) at Week 104 [ Time Frame: Baseline, Week 104 ]
  22. Part 1: Percentage of Participants With ADAS-Cog Response [ Time Frame: Baseline up to Week 152 ]

Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   50 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Clinical diagnosis of probable mild Alzheimer disease (AD) based on National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria or major NCD based whether or not receiving AD approved medication
  • Cerebral spinal fluid (CSF) result consistent with the presence of amyloid pathology
  • Availability of a person ('caregiver') who in the investigator's judgment has frequent and sufficient contact with the participant, and is able to provide accurate information regarding the participant's cognitive and functional abilities
  • Fluency in the language of the tests used at the study site
  • Willingness and ability to complete all aspects of the study
  • Adequate visual and auditory acuity, in the investigator's judgment, sufficient to perform the neuropsychological testing (eye glasses and hearing aids are permitted)
  • If currently receiving approved medications for AD, the dosing regimen must have been stable for 3 months prior to screening
  • Agreement not to participate in other research studies for the duration of this trial and its associated substudies

PART 2 - All participants who have been randomized and are actively participating in the study are eligible for Part 2

Exclusion Criteria:

  • Dementia or neurocognitive disorder (NCD) due to a condition other than AD, including, but not limited to, frontotemporal dementia, Parkinson disease, dementia with Lewy bodies, Huntington disease, or vascular dementia
  • History or presence of clinically evident vascular disease potentially affecting the brain that in the opinion of the investigator has the potential to affect cognitive function
  • History or presence of stroke within the past 2 years or documented history of transient ischemic attack within the last 12 months
  • History or presence of systemic autoimmune disorders potentially causing progressive neurologic disease with associated cognitive deficits
  • History of schizophrenia, schizoaffective disorder, or bipolar disorder
  • Alcohol and/or substance use disorder (according to the DSM-5) within the past 2 years (nicotine use is allowed)
  • History or presence of atrial fibrillation
  • Within the last 2 years, unstable or clinically significant cardiovascular disease (e.g., myocardial infarction, angina pectoris, cardiac failure New York Heart Association Class II or higher)
  • Uncontrolled hypertension
  • Chronic kidney disease
  • Impaired hepatic function

PET imaging substudy, in addition to above:

- Prior participation in other research study or clinical care within the last year such that the total radiation exposure would exceed the local or national annual limits

Part 2 Participants who have been discontinued from the study

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02051608


Locations
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Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Layout table for investigator information
Study Director: Clinical Trials Hoffmann-La Roche
  Study Documents (Full-Text)

Documents provided by Hoffmann-La Roche:
Study Protocol  [PDF] February 28, 2020
Statistical Analysis Plan  [PDF] May 31, 2021

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02051608    
Other Study ID Numbers: WN28745
2013-003390-95 ( EudraCT Number )
First Posted: January 31, 2014    Key Record Dates
Results First Posted: June 16, 2022
Last Update Posted: February 10, 2023
Last Verified: February 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
 Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders