Clinical Trial Results:
Phase II, Multicenter, Open-Label, Single Arm Study to Evaluate the Pharmacodynamic Effects of Once Weekly Administration of Gantenerumab in Participants with Early (Prodromal to Mild) Alzheimer’s Disease.
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Summary
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EudraCT number |
2020-001384-87 |
Trial protocol |
GB DE BE FR IT |
Global end of trial date |
15 Mar 2023
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Results information
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Results version number |
v2(current) |
This version publication date |
13 Apr 2024
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First version publication date |
26 Jan 2024
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
WN29722
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04592341 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
F. Hoffmann-La Roche AG
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Sponsor organisation address |
Grenzacherstrasse 124, Basel, Switzerland, CH-4070
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Public contact |
F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
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Scientific contact |
F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
15 Mar 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
15 Mar 2023
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The main objective of this trial was to evaluate the pharmacodynamic (PD) effect of a once a week (Q1W) dosing regimen of gantenerumab on brain amyloid load as determined by positron emission tomography (PET) imaging in participants with early (prodromal to mild) AD
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Protection of trial subjects |
All study participants were required to read and sign an Informed Consent Form (ICF).
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
19 Nov 2020
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 39
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Country: Number of subjects enrolled |
Belgium: 14
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Country: Number of subjects enrolled |
Germany: 30
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Country: Number of subjects enrolled |
Spain: 30
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Country: Number of subjects enrolled |
France: 11
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Country: Number of subjects enrolled |
United Kingdom: 19
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Country: Number of subjects enrolled |
Italy: 20
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Country: Number of subjects enrolled |
Poland: 29
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Worldwide total number of subjects |
192
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EEA total number of subjects |
134
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
44
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From 65 to 84 years |
148
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85 years and over |
0
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Recruitment
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Recruitment details |
Participants took part in this study at 33 investigative centers in the United States, Poland, Spain, Belgium, France, Germany, Italy, and the United Kingdom from 18 November 2020 up to 15 March 2023. | ||||||||||||||||||||||
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Pre-assignment
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Screening details |
This was a single-arm study and all participants received gantenerumab according to predefined universal up-titration scheme. Data was collected and reported in single arm for each participant who started treatment as specified and either completed or discontinued study. | ||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||
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Arms
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Arm title
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Gantenerumab | ||||||||||||||||||||||
Arm description |
Participants received gantenerumab, subcutaneous (SC) injections with gradual up-titration starting at a dose of 120 milligrams (mg), every four weeks (Q4W) on Day 1, Week 4, and Week 8, then 255 mg, Q4W on Weeks 12, 16, and 20, and then 255 mg every 2 weeks (Q2W) for 12 weeks (Weeks 24, 26, 28, 30, 32, and 34), followed by 255 mg every week (Q1W) up to Week 104 (Weeks 36 to 104). | ||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||
Investigational medicinal product name |
Gantenerumab
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Investigational medicinal product code |
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Other name |
RO4909832
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Gantenerumab was administered by SC injection, at a dose of 120 mg Q4W (Day 1, Week 4, and Week 8), then 255 mg Q4W (Weeks 12, 16, and 20), and then 255 mg Q2W for 12 weeks (Weeks 24, 26, 28, 30, 32, and 34), followed by the target dose of 255 mg Q1W (Weeks 36 to 104).
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Baseline characteristics reporting groups
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Reporting group title |
Gantenerumab
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Reporting group description |
Participants received gantenerumab, subcutaneous (SC) injections with gradual up-titration starting at a dose of 120 milligrams (mg), every four weeks (Q4W) on Day 1, Week 4, and Week 8, then 255 mg, Q4W on Weeks 12, 16, and 20, and then 255 mg every 2 weeks (Q2W) for 12 weeks (Weeks 24, 26, 28, 30, 32, and 34), followed by 255 mg every week (Q1W) up to Week 104 (Weeks 36 to 104). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Gantenerumab
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Reporting group description |
Participants received gantenerumab, subcutaneous (SC) injections with gradual up-titration starting at a dose of 120 milligrams (mg), every four weeks (Q4W) on Day 1, Week 4, and Week 8, then 255 mg, Q4W on Weeks 12, 16, and 20, and then 255 mg every 2 weeks (Q2W) for 12 weeks (Weeks 24, 26, 28, 30, 32, and 34), followed by 255 mg every week (Q1W) up to Week 104 (Weeks 36 to 104). | ||
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End point title |
Change from Baseline in Brain Amyloid Load at Week 104 as Measured by [18F] Florbetaben Positron Emission Tomography (PET) Scan [1] | ||||||||||||
End point description |
Screening amyloid PET scan was considered baseline evaluation.Brain amyloid load was quantified in terms of Standardized Uptake Value Ratio (SUVR),defined as ratio of tracer uptake in cortical composite target region of interest(ROI)to tracer uptake in reference ROI.Composite region: frontal,parietal,temporal,posterior cingulate cortex,anterior cingulate cortex. Reference ROI (whole cerebellum) was represented by weighted average of Cerebellum Ventral,Cerebellum Dorsal (left/right), Cerebellar White Matter.SUVR linearly transformed to standardized Centiloid Scale (CL) using formula CL=175.6xSUVR-174.2.CL ranges from <0 to >100, anchor points are 0=high-certainty amyloid negative scan and 100=amount of global amyloid deposition found in typical AD scan. ITT population set participants were included. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
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End point type |
Primary
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End point timeframe |
Baseline, Week 104
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical comparison was planned. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Responses to Home Administration Questionnaire (HAQ) by Caregiver or Study Partner | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
HAQ comprised 4 items completed by study partner capturing confidence (Q1), convenience (Q2), ease of use (Q3), and overall satisfaction (Q4) with administering medication. Response options Q1: Not at all confident, somewhat confident, confident, very confident; Q2: Not at all convenient, somewhat convenient, convenient, very convenient; Q3: Not at all easy, somewhat easy, easy, very easy; Q4:Not at all satisfied, somewhat satisfied, satisfied, very satisfied. Opportunity for Home Dosing Safety-Evaluable Analysis Set (OH-SE) included all participants of the SE analysis set who did not discontinue the study drug before week (W) 26. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
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End point type |
Secondary
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End point timeframe |
Weeks 36, 52, 76, 104
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) | ||||||||||||
End point description |
AE: any untoward medical occurrence in participant administered pharmaceutical product, which does not necessarily have causal relationship with treatment. Any unfavorable, unintended sign, symptom, or disease temporally associated with use of medicinal product, whether or not considered related to it. SAE: any AE that was fatal, life threatening, required prolonged inpatient hospitalization, resulted in significant disability or resulted in a congenital anomaly to mother exposed to study treatment. This was a single-arm study and all participants received gantenerumab according to predefined universal up-titration scheme as follows: 120 mg Q4W (Day 1, Week (W) 4, and W8), then 255 mg Q4W (W 12, 16, and 20), then 255 mg Q2W for 12 weeks (W 24, 26, 28, 30, 32, and 34), followed by target dose of 255 mg Q1W (W 36 to 104). Data was collected and reported in single arm for each participant who started treatment as specified and either completed or discontinued study. Safety Evaluable set.
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End point type |
Secondary
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End point timeframe |
From day of first dose up to 16 weeks after the last dose (up to 120 weeks)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Participants With Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS) | ||||||||||||||||||||
End point description |
C-SSRS=assess lifetime suicidality of participant as well as any new instances of suicidality.Structured interview prompts recollection of suicidal ideation (intensity of ideation, behavior, & attempts with actual/potential lethality).Categories have binary responses (yes/no) & include Wish to be Dead; Non-specific Active Suicidal Thoughts; Active Suicidal Ideation with Any Methods(Not Plan)without Intent to Act; Active Suicidal Ideation with Some Intent to Act, without Specific Plan; Active Suicidal Ideation with Specific Plan and Intent, Preparatory Acts and Behavior; Aborted Attempt; Interrupted Attempt; Actual Attempt (non-fatal);Completed Suicide. Suicidal ideation/behavior indicated by yes answer to any of listed categories. Score 0=no suicide risk. Score 1 or higher= suicidal ideation or behavior. Categories with non-zero values are only reported.Safety Evaluable population was analyzed.Number of participants analyzed is number of participants with data available for analysis.
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End point type |
Secondary
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End point timeframe |
From day of first dose up to 16 weeks after the last dose (up to 120 weeks)
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Number of Participants with Amyloid-Related Imaging Abnormalities-Haemosiderin deposition (ARIA-H) Confirmed by Magnetic Resonance Imaging (MRI) | ||||||
End point description |
ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. ARIA-H (H for hemosiderosis) are small foci of signal loss observed on MRI sequences sensitive for paramagnetic tissue properties and comprise cerebral microbleeds (small foci of bleeding in the brain parenchyma) and leptomeningeal hemosiderosis (small foci of bleeding on the surface of the brain). These changes also occur sporadically in AD. MRI Safety-Evaluable Analysis Set included all participants of the SE analysis set who had at least one post-baseline MRI assessment.
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End point type |
Secondary
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End point timeframe |
From day of first dose up to 16 weeks after the last dose (up to 120 weeks)
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Participants with Amyloid-Related Imaging Abnormalities-Edema (ARIA-E) Confirmed by Magnetic Resonance Imaging (MRI) | ||||||
End point description |
ARIA are an identified risk with anti-amyloid antibodies, including gantenerumab. These changes can be identified on brain MRI. The occurrences of imaging abnormalities in vasogenic edema and sulcal effusions (ARIA-E) were evaluated. MRI Safety-Evaluable Analysis Set included all participants of the SE analysis set who had at least one post-baseline MRI assessment.
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End point type |
Secondary
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End point timeframe |
From day of first dose up to 16 weeks after the last dose (up to 120 weeks)
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Participants with Injection-Site Reactions (ISR) | ||||||
End point description |
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product or other protocol-imposed intervention, regardless of attribution. Injection reactions (local and systemic) were defined as AEs that occured during or within 24 hours after study drug administration that were judged to be related to the study drug injection. Safety Evaluable population included all participants enrolled who received at least one dose of study treatment, whether prematurely withdrawn from the study or not.
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End point type |
Secondary
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End point timeframe |
From day of first dose up to 16 weeks after the last dose (up to 120 weeks)
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| No statistical analyses for this end point | |||||||
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End point title |
Change in Brain Amyloid Based on Different Dosing Frequency | ||||||||
End point description |
The change from baseline at Week 52 using the once-weekly dosing frequency was analysed using the centiloid scale. 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 scan. The range of centiloid values can be below 0 (negative) and greater than 100. ITT population set, included all enrolled participants (i.e., who gave informed consent, did not fail screening, and had at least one Amyloid PET scan with a valid quantitative measurement performed with either florbetaben or flutemetamol), whether or not the participant received the assigned treatment. Overall number analyzed is the number of participants with data available for analysis.
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End point type |
Secondary
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End point timeframe |
Baseline up to Week 52
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Participants With Treatment-emergent Anti-Drug Antibodies to Gantenerumab | ||||||||
End point description |
A participant with an ADA assay result from at least one post-baseline sample was defined as a post-baseline evaluable participant. Treatment Emergent ADA was defined as a participant with a negative or missing baseline ADA result(s) and at least one positive post-baseline ADA result, or a participant with a positive ADA result at baseline who has at least one post-baseline titer results with at least a >2.5-fold increase in titer compared to baseline greater than the baseline titer result. Safety Evaluable population included all participants enrolled who received at least one dose of study treatment, whether prematurely withdrawn from the study or not. Overall number analyzed is the number of participants with an ADA assay result from at least one post-baseline sample.
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End point type |
Secondary
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End point timeframe |
From day of first dose up to 16 weeks after the last dose (up to 120 weeks)
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| No statistical analyses for this end point | |||||||||
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End point title |
Plasma Concentration of Subcutaneous (SC) Gantenerumab at specified timepoints | ||||||||||||||||||
End point description |
PK evaluable population included only participants that received the previous 6, 4, 6 or 6 planned doses at weeks 24, 36, 52 and 76, respectively. Overall number analyzed was the number of participants with data available for analysis. Number Analyzed was the number of participants with data available for analyses at the specified timepoint.
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End point type |
Secondary
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End point timeframe |
Day 4 of Week 1, Week 24, 36, 52, and 76
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| No statistical analyses for this end point | |||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From day of first dose up to 16 weeks after the last dose (up to 120 weeks)
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Adverse event reporting additional description |
Safety Evaluable population. This was single-arm study and all participants received gantenerumab according to predefined universal up-titration scheme. Data was collected and reported in single arm for each participant who started treatment as specified and either completed or discontinued study.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.1
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Reporting groups
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Reporting group title |
GANTENERUMAB
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Reporting group description |
Participants received gantenerumab, SC injections with gradual up-titration starting at a dose of 120 mg, Q4W on Day 1, Week 4, and Week 8, then 255 mg, Q4W on Weeks 12, 16, and 20, and then 255 mg Q2W for 12 weeks (Weeks 24, 26, 28, 30, 32, and 34), followed by 255 mg Q1W up to Week 104 (Weeks 36 to 104). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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17 Nov 2021 |
• The planned sample size (approximately 150 participants) was corrected to the
final sample size of 192 participants.
• Language were added to clarify that adverse events associated with a special
situation that also qualify as adverse events of special interest should be reported
within 24 hours. |
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16 May 2022 |
• The study was updated to include the optional 2-year extension. The schedule
of assessments until Week 103 remains unchanged and the benefit-risk profile of
gantenerumab remains unchanged.
• The secondary and biomarker endpoints was updated to include a
change from baseline to Week 208.
• The change from baseline up to Week 208 in deposited amyloid as measured
by brain amyloid PET centiloid levels was added as an exploratory
biomarker endpoint.
• The change from baseline to Week 208 was included for the exploratory
efficacy scales and home administration questionnaire.
• The Medical Monitor was changed, and the Medical Monitor contact information was deleted from Emergency Medical Contacts to avoid the inclusion of outdated telephone numbers in the protocol. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| None reported | |||||||
