CAD106 2203 primary manuscript – supplementary material 29 November 2016
Active Aβ immunotherapy CAD106 in Alzheimer’s disease:
aphase2b study
SUPPLEMENTARY SECTION
Supplementary Table 1
Inclusion and exclusion criteria.
Inclusion criteria1. Written informed consent was obtained according to local requirements for obtaining consent in patients with mild AD. An additional written informed consent was obtained from all patients who participated in the PET substudy.
2. Male and female patients <85 years of age. In addition, patients had to be ≥50 years of age to participate in the PET substudy.
3. Female patients without childbearing potential (post-menopausal or surgically sterilized).
• If sterilized, female patients were surgically sterilized ≥6 months prior to screening. Surgical sterilization procedures were supported with clinical documentation made available to the Novartis Monitor and noted in the Relevant Medical History/Current Medical Conditions section of the electronic case report form.
OR:
• Postmenopausal women had no regular menstrual bleeding for ≥1 year prior to inclusion as documented in the patient’s records.
4. Diagnosis of dementia of the Alzheimer’s type according to the DSM-IV criteria.
5. Patients who satisfied the criteria for a clinical diagnosis of probable AD established by a
Work Group of the NINCDS-ADRDA.
6. Mild AD was confirmed by a MMSE score of 20–26 (both inclusive) at screening, and either untreated or on stable dose of cholinesterase inhibitor and/or other AD treatment over the last 4 weeks prior to the clinical assessments.
7. Sufficient education to be able to read, write, and communicate effectively during the premorbid state (e.g., completion of ≥6 years of regular schooling or sustained employment).
8. Cooperative, willing to complete all aspects and attend all visits of the study including lumbar puncture/CSF samplings (primarily for safety reasons), and capable of doing so, either alone or with the aid of a responsible caregiver.
9. Residing with someone in the community throughout the study or, if living alone, who had daily contact with a primary caregiver.
10. Primary caregiver was present and willing to assent in writing to accept responsibility for assessing the condition of the patient throughout the study, and for providing input to safety and tolerability assessments in accordance with all protocol requirements.
Exclusion criteria
Exclusion criteria related to CNS
1. Any medical or neurological condition, other than AD, that contributed significantly to the
patient’s dementia (e.g., abnormal thyroid function tests, Vitamin B12 or folate deficiency, post-traumatic conditions, Huntington’s disease, Parkinson’s disease, Lyme’s disease, syphilis, HIV, dementia), including any CSF and/or brain MRI findings at screening.
2. History in the past 2 years or current diagnosis of CNS inflammation as indicated by:
• either MRI findings indicative of meningoencephalitis or another concurrent disease
(according to central reader evaluation at screening and clinical judgment);
• or signs of inflammation in CSF as defined by clinical judgment. In most cases, in a
CSF sample not contaminated by blood, this was shown by >5 leukocytes/μL).
3. Evidence of vascular dementia or other cerebrovascular disease, assessed to be of clinical significance by either investigator or MRI central reader, defined as any of the following:
• ≥1 large infarct (>2cm) or ≥2 lacunar infarcts (<2cm); or
• confluent white matter lesions, considered likely to contribute to patients’ dementia; or
• intracranial aneurysms or hemorrhages, except for up to one cerebral microhemorrhage, defined as a focal T2* hypointensity <1 cm or a superficial hemosiderosis; or
NB. If an MRI machine with field strength >1.5 T was used, up to two microhemorrhages were acceptable.
• Hachinski score of >4 at screening, or any transitory ischemic attack or unexplained loss of consciousness in the past year.
4. DSM-IV diagnosis of major depression and/or any other DSM-IV Axis 1 diagnosis that may have interfered with the evaluation of the patient’s response to study medication, including other primary neurodegenerative dementia, schizophrenia, or bipolar disorder.
5. Current diagnosis of an active, uncontrolled seizure disorder.
Exclusion criteria related to other medical conditions
6. Any advanced, severe, progressive, or unstable disease that could interfere with the safety, tolerability, and pharmacodynamics assessments and/or with the antibody titer response in the study or put the patient at special risk (e.g., indication for anticoagulant therapies, Hepatitis B or C, HIV).
7. History or current diagnosis of an active autoimmune disease (e.g., psoriasis, rheumatoid
arthritis, Crohn’s disease, systemic lupus erythematosus, Type I diabetes mellitus,
Hashimoto thyroiditis).
8. Evidence of systemic inflammation as shown by e.g., an elevated C-reactive protein above normal range at screening or fever (i.e., axillary body temperature ≥38°C
[100.4°F]) before dosing on the day of first injection, as measured at the site).
NB. In case of positive findings at screening that were considered to be due to a known
transient condition (e.g., common cold, urinary tract infection), the randomization could be postponed until findings have normalized.
9. Coronary heart disease as shown by:
• history of myocardial infarction or coronary stent placement within the preceding year,
or
• current diagnosis of unstable angina pectoris or atherosclerotic coronary artery disease of clinical significance.
10. Symptomatic heart failure fulfilling the criteria of New York Heart Association Category>II or known left ventricular dysfunction with left ventricular ejection fraction <45%, or any other severe or unstable cardiovascular disease.
11. Vital signs outside of the following ranges at screening and baseline evaluations (as
measured after ≥3 minutes resting in the supine position):
• systolic blood pressure: 95–165 mmHg
• diastolic blood pressure: 50–95 mmHg
12. A QTc value ≥500 msec on the screening electrocardiogram assessed by the central electrocardiogram reader using either Bazett or Fridericia formula, whichever was the highest.
13. History of malignancy of any organ system, treated or untreated, within the past 5 years
whether or not there was evidence of local recurrence or metastases. However, localized
tumors not requiring systemic chemo- or radiotherapy were permitted.
Exclusion criteria related to other therapies/substances
NB. In case of treatment with medications listed in criteria 14 to 18 during the specified timeframe, the patient could be re-screened at a later point:
14. Treatment in the 4 weeks prior to first injection with:
• any investigational drug,
• any drug or treatment known for their potential to cause major organ system toxicity,
i.e., drugs that require monitoring of a specific organ (e.g., clozapine, tamoxifen)
• parenteral immunoglobulin preparation, blood products, and/or plasma derivates
• anticoagulants (e.g., coumadin) or antiplatelet agents (e.g., clopidogrel). However,
acetylsalicylic acid ≤325 mg/day was permitted.
15. Treatment in the 2 weeks prior to first injection with:
• any other immunization (e.g., influenza vaccination)
• systemic antibiotic or antiviral therapy.
16. Initiation or change in dose of current treatment in the 4 weeks prior to clinical
assessments during screening with:
• cholinesterase-inhibitors and/or other AD treatment
• psychotropic medication, with the exception of mild hypnotic drugs (e.g., zolpidem,
zopiclone, oxazepam, midazolam), and low doses of neuroleptic drugs (e.g., ≤2mg
risperidone),
• non-anticholinergic antidepressant (e.g., selective serotonin reuptake inhibitors),
serotonin–norepinephrine reuptake inhibitors, noradrenergic and specific
serotonergic antidepressants
• centrally acting anticholinergic drugs including tricyclic and tetracyclic antidepressants
• peripheral anticholinergics (e.g., oxybutynin).
17. Prior participation in any other AD immunotherapy study receiving active treatment.
18. History in the past 5 years or current treatment with immunosuppressive drugs (including chronic systemic steroids, cancer chemotherapy/radiotherapy). However, local application of steroids (e.g., local injections, external steroid application, and inhalation) or <4-week systemic treatment were permitted.
19. History of alcohol or drug abuse within the last 2 years and/or current alcohol/drug abuse that could jeopardize patients’ participation in the study.
Exclusion criteria related to study procedures
20. Contraindication to MRI investigations (including hypersensitivity or contraindication to
gadolinium-diethylenetriaminepentaacetic acid, claustrophobia, selected metals
in the body).
21. Donation or loss of >400 mL of blood within 8 weeks prior to first injection.
22. Contraindication to lumbar puncture, e.g., platelet count <100000 /μL or any other finding.
23. Any disability that could have prevented the patient from completing all study
requirements (e.g., blindness, deafness, severe language difficulty).
24. Patients who were declared mentally incompetent (i.e., who require an appointed legal
representative as determined by applicable country/state law).
Exclusion criteria related to PET substudy
25. Contraindication to PET scan investigations.
26. Participation in PET or nuclear medicine investigations in the previous year.
27. Intolerance to previous PET scans; i.e., previous hypersensitivity reactions to any PET
ligand or imaging agent or failure to participate in and comply with previous PET scans.
No additional exclusions were applied by the investigator, in order to ensure that no
additional bias was introduced with regard to the population of all eligible patients.
Abbreviations: AD, Alzheimer’s disease; CNS, central nervous system; CSF, cerebrospinal fluid; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition; MMSE, Mini Mental State Examination; MRI, magnetic resonance imaging; NINCDS-ADRDA, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association; PET, positron emission tomography.
Supplementary Table 2
Summary of serious adverse events (SAF).
n (%)* / CAD106 150 μg (n=69) / CAD106 450 μg (n=37) / CAD106 total(n=106) / Placebo
(n=15)
Acute myocardial infarction / 1 (1.4) / 0 / 1 (0.9) / 0
Atrial fibrillation / 1 (1.4) / 0 / 1 (0.9) / 0
Chest pain / 1 (1.4) / 1 (2.7) / 2 (1.9) / 0
Non-cardiac chest pain / 1 (1.4) / 0 / 1 (0.9) / 0
Cholelithiasis / 2 (2.9) / 0 / 2 (1.9) / 0
Cholecystitis acute / 1 (1.4) / 0 / 1 (0.9) / 0
Lobar pneumonia / 2 (2.9) / 0 / 2 (1.9) / 0
Clostridium difficile colitis / 1 (1.4) / 0 / 1 (0.9) / 0
Sepsis / 1 (1.4) / 0 / 1 (0.9) / 0
Device related infection / 0 / 1 (2.7) / 1 (0.9) / 0
Meniscus lesion / 1 (1.4) / 0 / 1 (0.9) / 0
Subdural hematoma / 0 / 1 (2.7) / 1 (0.9) / 0
Subdural hemorrhage / 0 / 1 (2.7) / 1 (0.9) / 0
Ankle fracture / 0 / 1 (2.7) / 1 (0.9) / 0
Diabetes mellitus / 0 / 2 (5.4) / 2 (1.9) / 0
Hypoglycemia / 0 / 1 (2.7) / 1 (0.9) / 0
Osteoarthritis / 1 (1.4) / 0 / 1 (0.9) / 0
Arthralgia / 1 (1.4) / 1 (2.7) / 2 (1.9) / 0
Arthropathy / 0 / 1 (2.7) / 1 (0.9) / 0
Mesothelioma malignant / 1 (1.4) / 0 / 1 (0.9) / 0
Laryngeal cancer / 0 / 1 (2.7) / 1 (0.9) / 0
Syncope / 2 (2.9) / 0 / 2 (1.9) / 0
Ischemic cerebral infarction / 1 (1.4) / 0 / 1 (0.9) / 0
Dementia Alzheimer’s type / 0 / 1 (2.7) / 1 (0.9) / 0
Encephalopathy / 0 / 1 (2.7) / 1 (0.9) / 0
Cerebral hemorrhage / 0 / 1 (2.7) / 1 (0.9) / 0
Subarachnoid hemorrhage / 0 / 1 (2.7) / 1 (0.9) / 0
Migraine / 0 / 1 (2.7) / 1 (0.9) / 0
Headache / 0 / 1 (2.7) / 1 (0.9) / 0
Aggression / 1 (1.4) / 0 / 1 (0.9) / 1 (6.7)
Delusion / 1 (1.4) / 0 / 1 (0.9) / 0
Acute psychosis / 1 (1.4) / 0 / 1 (0.9) / 0
Agitation / 0 / 0 / 0 / 1 (6.7)
Renal failure acute / 1 (1.4) / 0 / 1 (0.9) / 0
Pleural effusion / 0 / 1 (2.7) / 1 (0.9) / 0
Respiratory failure / 0 / 1 (2.7) / 1 (0.9) / 0
Dermatitis allergic / 1 (1.4) / 0 / 1 (0.9) / 0
Aortic aneurysm / 1 (1.4) / 0 / 1 (0.9) / 0
Hypertension / 0 / 1 (2.7) / 1 (0.9) / 0
*Patients may have experienced more than one serious adverse event. Patients with multiple occurrences of the same serious adverse event are counted once under that treatment category.
Supplementary Table 3
Incidence of local and systemicrelated reactions collected in the patient diary (SAF).
n (%) / CAD106 150 μg (n=69) / CAD106 450 μg without adjuvant (n=16) / CAD106 450 μg + Alum 450 μg(n=21) / Placebo
(n=15)
Local / 56 (81.2) / 14 (87.5) / 18 (85.7) / 6 (40.0)
Ecchymosis / 21 (30.4) / 6 (37.5) / 4 (19.0) / 1 (6.7)
Redness / 38 (55.1) / 10 (62.5) / 10 (47.6) / 3 (20.0)
Induration / 30 (43.5) / 10 (62.5) / 11 (52.4) / 4 (26.7)
Swelling / 39 (56.5) / 9 (56.3) / 10 (47.6) / 3 (20.0)
Pain / 49 (71.0) / 13 (81.3) / 17 (81.0) / 4 (26.7)
Systemic / 54 (78.3) / 15 (93.8) / 18 (85.7) / 8 (53.3)
Chills / 27 (39.1) / 11 (68.8) / 7 (33.3) / 1 (6.7)
Malaise / 30 (43.5) / 11 (68.8) / 12 (57.1) / 2 (13.3)
Myalgia / 35 (50.7) / 13 (81.3) / 12 (57.1) / 1 (6.7)
Arthralgia / 24 (34.8) / 7 (43.8) / 7 (33.3) / 1 (6.7)
Headache / 29 (42.0) / 8 (50.0) / 14 (66.7) / 6 (40.0)
Sweating / 19 (27.5) / 4 (25.0) / 9 (42.9) / 1 (6.7)
Fatigue / 36 (52.2) / 13 (81.3) / 11 (52.4) / 5 (33.3)
Fever / 12 (17.4) / 4 (25.0) / 1 (4.8) / 0
Abbreviations: Alum, aluminum hydroxide; SAF, safety analysis set.
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CAD106 2203 primary manuscript – supplementary material 29 November 2016
Supplementary Table 4
IFN-γ T-cell responses by treatment and visit (SAF). Aβ and Qβ-specific T-cell lymphocyte responses assessed by the numbers of cells secreting IFN-γ upon stimulation with Aβ1-6, Aβ1-42 or Qβ, as detected by enzyme-linked immunosorbent spot assay.
CAD total (n=106) / Placebo total (n=15)Parameter / Statistic / Baseline / Week 8 / Change / Baseline / Week 8 / Change
Aβ1-42 peptide / n / 104 / 15
Min / -15.4 / -36.2 / -76.4 / -2.7 / -3.9 / -313.9
Median / -0.49 / -0.73 / -0.32 / 0.00 / -0.91 / -0.67
Max / 327.5 / 396.0 / 68.5 / 315.2 / 289.9 / 5.6
Aβ1-6 peptide / n / 104 / 15
Min / -12.7 / -25.4 / -24.2 / -3.9 / -5.7 / -12.3
Median / -0.24 / -0.52 / -0.07 / 0.00 / -0.91 / 0.19
Max / 144.9 / 159.1 / 27.4 / 9.6 / 11.3 / 4.1
Qβ peptide pool / n / 100 / 15
Min / -2.6 / 1.2 / -127.4 / 1.8 / -2.4 / -252.1
Median / 32.11 / 85.99 / 35.13 / 38.70 / 32.11 / -2.45
Max / 435.1 / 530.2 / 330.7 / 316.0 / 211.4 / 147.1
T-cell response is defined as MEAN(antigen) - SD(antigen) - MEAN(medium control) + SD(medium control)
Abbreviations: Aβ, amyloid beta; IFN-γ, interferon gamma; Qβ, Q beta; SAF, safety analysis set; SD, standard deviation
Supplementary Table 5
Percentage change from baseline to Week 78 in global cortical region PET data by responder group (strong serological responders versus controls) and visit (BPAS)
SSRs (n=11) / Controls (n=4)Statistic / Baseline / Week 78 / Change / Baseline / Week 78 / Change
Mean / 1.47 / 1.45 / -1.23 / 1.38 / 1.40 / 1.44
SD / 0.189 / 0.172 / 5.805 / 0.192 / 0.214 / 5.229
Min / 1.2 / 1.2 / -9.6 / 1.1 / 1.2 / -5.6
Median / 1.47 / 1.49 / -1.54 / 1.40 / 1.41 / 2.42
Max / 1.8 / 1.7 / 9.6 / 1.6 / 1.6 / 6.6
Only patients with values at baseline and Week 78 are included.
Abbreviations: BPAS, biomarker positive analysis set; PET, positron emission tomography; SSRs, strong serological responders;SD, standard deviation
Supplementary Table 6
Summary statistics for volumetric MRI changes across selected brain regions in strong serological responders versus controls from baseline to week 78 (BPAS)
Whole brain volume (cm3) / Cerebral cortex volume (cm3) / Hippocampus volume (cm3) / Ventricle volume(cm3)SSRs / Controls / SSRs / Controls / SSRs / Controls / SSRs / Controls
N (Placebo, SR)* / 41 / 22 (6, 16) / 41 / 22 (6, 16) / 41 / 22 (6, 16) / 41 / 22 (6, 16)
LS mean change / -3.46% / -2.89% / -6.07% / -3.87% / -6.90% / -4.81% / 20.33% / 16.23%
Difference in LS mean change / -0.58 / -2.19 / -2.09 / 4.10
95% CI / (-1.64, 0.49) / (-3.79, -0.60) / (-5.30, 1.12) / (-0.22, 8.41)
p-value / 0.2863 / 0.0077 / 0.1983 / 0.0623
Correlation to AUC of IgG titers: Spearman coefficient (n)** / -0.04 (n=55) / -0.20 (n=55) / -0.04 (n=55) / 0.06 (n=55)
NB: MMRM for the change or percentage change from baseline in vMRIincluded factors for effects of responder group, the corresponding baseline value, visit, whole brain volume normalized on intracranial volume and age as well as interaction terms respondergroup*visit and baseline value*visit. The model was performed for all regions of interest (ROIs).
A total of n = 5 patients were SRs and excluded from the comparison (SSRs vs Controls). *Only for Controls: number of placebo and SR patients included in the control group. **Spearman correlation coefficient calculated for CAD106 treated patients of the BPAS.Abbreviations: BPAS, biomarker positive analysis set; SSRs, strong serological responders; vMRI, volumetric magnetic resonance imaging
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CAD106 2203 primary manuscript – supplementary material 29 November 2016
Supplementary Table 7
Change from baseline in Alzheimer’s disease CSF biomarkers at week 78 (BPAS).
Biomarker / Aβ1–40 / Aβ1–42 / Phospho-tau / Total-tauSSRs / Controls / SSRs / Controls / SSRs / Controls / SSRs / Controls
N (Placebo, SR)* / 17 / 8 (4, 4) / 17 / 8 (4, 4) / 17 / 8 (4, 4) / 17 / 8 (4, 4)
LS mean change / -1404 / -1359 / 234.3 / 288.3 / -3.22 / 2.50 / 9.16 / 39.51
Difference in LS mean change / -45.11 / -54.05 / -5.72 / -30.35
95% CI / ( -1246, 1155.6) / (-172.5, 64.39) / (-13.01, 1.57) / (-132.1, 71.38)
p-value / 0.9405 / 0.3659 / 0.1223 / 0.5538
Correlation to AUC of IgG titers: Spearman correlation coefficient (n)** / 0.08 (n=22) / -0.12 (n=22) / -0.15 (n=22) / 0.14 (n=22)
NB: MMRM for the change from baseline in CSF biomarkers included factors for effects of responder group, the corresponding baseline value, visit, as well as interaction terms responder group*visit and baseline value*visit.
Abbreviations: Aβ, amyloid beta; CSF, cerebrospinal fluid; CI, confidence interval; BPAS, biomarker positive analysis set; LS, least squares; SSR, strong serological responder.A total of n = 1 patient was a SR and excluded from the comparison (SSRs vs Controls). *Only for Controls: number of placebo and SR patients included in the control group. **Spearman correlation coefficient calculated for CAD106 treated patients of the BPAS.
Supplementary Table 8
Change from baseline in clinical scales at week 78 (BPAS).
ADAS-Cog 12 / ADCS-ADL(total score) / CDR SB / MMSE / NPI-Q
(total score)
SSRs / Controls / SSRs / Controls / SSRs / Controls / SSRs / Controls / SSRs / Controls
N (Placebo, SR)* / 38 / 13 (6, 7) / 40 / 14 (6, 8) / 40 / 13 (5, 8) / 39 / 14 (6, 8) / 40 / 13 (6, 7)
Baseline mean (SD) / 26.7 (8.44) / 22.2 (6.06) / 68.1 (7.43) / 66.5 (8.53) / 3.3 (1.52) / 3.5 (1.18) / 22.8 (2.32) / 23.4 (1.95) / 6.1 (6.26) / 14.2 (12.63)
Week 78 mean (SD) / 35.8 (12.40) / 28.0 (9.20) / 58.5 (16.15) / 60.8 (9.34) / 5.6 (2.87) / 5.2 (2.18) / 18.0 (4.72) / 21.6 (4.38) / 12.5 (12.00) / 14.7 (13.24)
Mean change (SD) / 9.0 (9.40) / 5.8 (6.94) / -9.63 (12.36) / -5.7 (6.34) / 2.3 (2.20) / 1.7 (1.80) / -4.8 (3.60) / -1.9 (3.28) / 6.3 (8.15) / 0.5 (10.59)
LS mean change / 9.83 / 8.40 / -11.2 / -10.0 / 2.76 / 2.02 / -4.93 / -2.91 / 6.65 / 2.57
Difference in LS mean change / 1.43 / -1.23 / 0.74 / -2.02 / 4.08
95% CI / ( -4.03, 6.89) / ( -8.46, 6.00) / ( -0.68, 2.16) / ( -4.06, 0.02) / ( -1.80, 9.96)
p-value / 0.6038 / 0.7354 / 0.3030 / 0.0522 / 0.1708
Correlation to AUC of IgG titers: Spearman coefficient (n)** / -0.05 (n=49) / -0.19 (n=52) / 0.09 (n=52) / -0.11 (n=51) / 0.13 (n=51)
NB: MMRM for the change or percentage change from baseline in clinical scales included factors for effects of responder group, the corresponding baseline value, educational status (number of years of formal education), region (USA/CAN, non-USA/CAN), visit, as well as interaction terms responder group*visit and baseline value*visit.
P values are uncorrected for multiple comparisons. A total of n = 5 patients were SRs and excluded from the comparison (SSRs vs Controls). *Only for Controls: number of placebo and SR patients included in the control group. **Spearman correlation coefficient calculated for all CAD106 treated patients of the BPAS. A positive difference in LS mean changeindicates a result in favor of active for MMSE and ACDS-ADL, and negative difference in LS mean changeindicates a result in favor of active for CDR SB, ADAS-Cog, and NPI-Q.
Abbreviations: ADAS-Cog 12, Alzheimer’s Disease Assessment Scale-Cognitive Subscale (including delayed recall); ADCSADL, Alzheimer’s disease Cooperative Study – Activities of Daily Living;AUC, area under the curve; BPAS, biomarker positive analysis set; CI, confidence interval; CDR SB, Clinical Dementia Rating scale Sum of Boxes; LS, least squares; MMSE, Mini Mental State Examination (NPI-Q);SD, standard deviation; SSR, strong serological responder.
Supplementary Table 9
Summary statistics for volumetric MRI changes across selected brain regions from baseline to week 78 (FAS)
Whole brain volume (cm3) / Cerebral cortex volume (cm3)CAD106 / Placebo / CAD106 / Placebo
Baseline / Week 78 / Change / Baseline / Week 78 / Change / Baseline / Week 78 / Change / Baseline / Week 78 / Change
n / 81 / 8 / 81 / 8
Mean / 1036.26 / 1006.04 / -2.95 / 989.92 / 966.77 / -2.28 / 429.6 / 409.59 / -4.67 / 414.31 / 399.08 / -3.7
SD / 127.965 / 128.153 / 1.971 / 134.342 / 130.92 / 3.701 / 54.754 / 54.603 / 3.616 / 50.076 / 50.888 / 2.605
Median / 1047.13 / 1016.49 / -2.91 / 927.09 / 928.64 / -3.47 / 428.26 / 411.38 / -4.38 / 396.66 / 382.85 / -3.35
Range / 755.5–1417.9 / 727.2–1391.7 / -8.2–2.3 / 841.9–1198.5 / 814.7–1183.4 / -6.1–6.1 / 308.4–559.4 / 284.4–548.9 / -12.3–7.1 / 370.9–521.5 / 361.9–511.9 / -7.6–0.2
Hippocampus volume (cm3) / Ventricle volume (cm3)
CAD106 / Placebo / CAD106 / Placebo
Baseline / Week 78 / Change / Baseline / Week 78 / Change / Baseline / Week 78 / Change / Baseline / Week 78 / Change
n / 81 / 8 / 81 / 8
Mean / 6.69 / 6.31 / -5.85 / 6.51 / 6.3 / -2.04 / 50.63 / 59.27 / 18.11 / 51.19 / 59.06 / 14.45
SD / 1.18 / 1.225 / 5.536 / 0.958 / 0.608 / 12.296 / 20.595 / 22.745 / 10.598 / 23.595 / 27.953 / 8.351
Median / 6.65 / 6.31 / -5.98 / 6.59 / 6.26 / -5.04 / 48.56 / 57.05 / 15.25 / 44.2 / 53.66 / 11.21
Range / 3.1–9.7 / 3.3–9.1 / -20.8–12.1 / 4.5–7.7 / 5.6–7.2 / -13.7–27.2 / 15.7–111.9 / 19.3–127.2 / -3.3–47.9 / 24.3–95.5 / 26.9–106 / 4.7–29.1
NB: MMRM for the change or percentage change from baseline in PET included factors for effects of responder group, the corresponding baseline value, visit, and interaction terms treatment group*visit and baseline value*visit. The model for change from baseline in vMRI was also adjusted for whole brain volume normalized on intracranial volume and age and performed for all regions of interest (ROIs).
Abbreviations: FAS, full analysis set; vMRI, volumetric magnetic resonance imaging; SD, standard deviation.
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CAD106 2203 primary manuscript29 November 2016
Supplementary Table 10Summary statistics for change from baseline in Alzheimer’s disease CSF biomarkers at week 78 (FAS)
Aβ1–40 (pg/mL) / Aβ1–42 (pg/mL)CAD106 / Placebo / CAD106 / Placebo
Baseline / Week 78 / Change / Baseline / Week 78 / Change / Baseline / Week 78 / Change / Baseline / Week 78 / Change
n / 28 / 4 / 28 / 4
Mean / 5390.75 / 3755.36 / -1635.4 / 5370 / 3927.5 / -1442.5 / 396.07 / 696.11 / 300.04 / 372.25 / 594.5 / 222.25
SD / 3235.663 / 2149.209 / 3108.576 / 2929.016 / 1928.806 / 1909.963 / 252.052 / 454.936 / 325.74 / 89.875 / 192.883 / 113.948
Median / 5760 / 2730 / -1225 / 5280 / 3655 / -1550 / 312.5 / 608 / 298.5 / 363.5 / 629 / 265.5
Range / 651–11600 / 1570–11300 / -9030–3480 / 1880–9040 / 2170–6230 / -3300–630 / 0.0–1140 / 311.0–2660 / -344.0–1710 / 282.0–480 / 336.0–784 / 54.0–304
Phospho-tau (pg/mL) / Total-tau (pg/mL)
CAD106 / Placebo / CAD106 / Placebo
Baseline / Week 78 / Change / Baseline / Week 78 / Change / Baseline / Week 78 / Change / Baseline / Week 78 / Change
n / 28 / 4 / 28 / 4
Mean / 79.21 / 78.23 / -0.98 / 72.03 / 73.3 / 1.28 / 577.35 / 592.44 / 15.09 / 491.68 / 531.63 / 39.95
SD / 30.708 / 31.353 / 9.736 / 10.419 / 15.263 / 7.129 / 260.769 / 295.463 / 121.515 / 112.96 / 119.138 / 73.681
Median / 78.3 / 70.35 / -1.4 / 69.35 / 73.55 / -0.8 / 498.3 / 534.2 / -1.5 / 448.65 / 498.9 / 29.25
Range / 35.4–196.4 / 41.2–192 / -28.9–20.3 / 63.8–85.6 / 59.2–86.9 / -4.6–11.3 / 239.3–1492.5 / 238.9–1774.6 / -165.3–371.8 / 414.9–654.5 / 437.5–691.2 / -38.0–139.3
Abbreviations: Aβ, amyloid beta; CSF, cerebrospinal fluid; FAS, full analysis set; SD, standard deviation.
Supplementary Table 11Summary statistics for change from baseline in clinical scales at week 78 (FAS)
MMSE / CDR-SBCAD106 / Placebo / CAD106 / Placebo
Baseline / Week 78 / Change / Baseline / Week 78 / Change / Baseline / Week 78 / Change / Baseline / Week 78 / Change
n / 69 / 8 / 71 / 7
Mean / 23.2 / 19.7 / -3.5 / 22.6 / 19.1 / -3.5 / 3.42 / 5.34 / 1.92 / 3.71 / 5.71 / 2
SD / 2.21 / 5.1 / 3.83 / 2.26 / 5.72 / 4.17 / 1.474 / 2.724 / 2.083 / 1.577 / 2.27 / 1.633
Median / 24 / 20 / -4 / 22.5 / 20 / -3.5 / 3.5 / 5 / 1.5 / 4 / 6 / 2
Range / 20–26 / 4–30 / -18–4 / 20–26 / 10–29 / -10–3 / 0.5–7 / 0.5–13 / -1.0–8.5 / 0.5–5.5 / 2.5–9 / -0.5–4.5
ADAS-Cog / ADCS-ADL (Total)
CAD106 / Placebo / CAD106 / Placebo
Baseline / Week 78 / Change / Baseline / Week 78 / Change / Baseline / Week 78 / Change / Baseline / Week 78 / Change
n / 65 / 8 / 70 / 8
Mean / 25.2 / 31.8 / 6.6 / 25 / 32.1 / 7.1 / 67.6 / 60 / -7.5 / 68.1 / 61.3 / -6.9
SD / 7.68 / 12.65 / 9.23 / 7.43 / 10.59 / 8.25 / 8.35 / 14.56 / 10.83 / 6.2 / 10.14 / 5.3
Median / 25 / 32 / 6 / 25 / 31 / 8.5 / 70 / 64 / -4.5 / 68.5 / 63 / -8
Range / 11–44 / 4–71 / -21–28 / 14–35 / 15–50 / -6–19 / 45–78 / 21–78 / -43–10 / 59–76 / 45–74 / -14–3
NPI-Q (Total)
CAD106 / Placebo
Baseline / Week 78 / Change / Baseline / Week 78 / Change
n / 69 / 8
Mean / 7.4 / 12.6 / 5.2 / 12.3 / 14.9 / 2.6
SD / 8.3 / 13.17 / 9.6 / 14.49 / 14.89 / 9.8
Median / 4 / 9 / 3 / 7.5 / 13 / 3
Range / 0–40 / 0–53 / -17–36 / 0–42 / 0–41 / -16–18
Abbreviations: ADAS-Cog, Alzheimer’s Disease Assessment Scale-Cognitive Subscale (including delayed recall); ADCSADL, Alzheimer’s disease Cooperative Study – Activities of Daily Living; CDR SB, Clinical Dementia Rating scale Sum of Boxes; FAS, full analysis set; MMSE, Mini Mental State Examination: NPI-Q, Neuropsychiatric Inventory-Questionnaire; SD, standard deviation.
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CAD106 2203 primary manuscript29 November 2016
Supplementary Fig. 1
MRI FLAIR image from the patient with ARIA-E showing a hyperintense signal with effacement of the sulci in the right occipital lobe.