Expedition 3 Trial

Achaia Taltoan, Mercer University College of Pharmacy

Alzheimer’s disease (AD) involves the development of extracellular amyloid beta (Aβ) plaques and intracellular fibrous tangles of tau protein. [1] The Aβ hypothesis postulates that overproduction or reduced clearance of Aβ from the cerebrum leads to formation of Aβ plaques, resulting in the cognitive deficits of Alzheimer’s disease. [1] Solanezumab is a humanized G1 monoclonal antibody that binds to Aβ peptides to increase clearance from the brain.[2] The Expedition and Expedition 2 trials evaluated the use of solanezumab in mild to moderate Alzheimer’s disease; pooled secondary analyses demonstrated a significant improvement in functional and cognitive decline in mild Alzheimer’s disease patients.[3] The Expedition 3 trial seeks to clarify the findings of the previous Expedition trials through limiting the population to mild Alzheimer’s disease patients.

Trial of solanezumab for mild dementia due to Alzheimer’s disease
Design Double-blind, multinational, phase III, randomized, placebo-controlled trial; N= 2,192
Objective To investigate the effect of solanezumab on cognitive decline in patients with mild Alzheimer’s disease
Study Groups Solanezumab 400mg (n= 1,057), placebo (n= 1,072)
Methods Inclusion Criteria

·       55-90 years old

·       Met National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorders Association diagnostic criteria for probable Alzheimer’s disease

·       MMSE score of 20-26 at screening visit

·       Geriatric Depression Scale score of ≤ 6

·       Magnetic resonance imaging (MRI) or computerized tomography (CT) scan within two years not conflicting with AD diagnosis

·       Florbetapir positron emission tomography (PET) scan or cerebrospinal fluid (CSF) result consistent with the presence of amyloid pathology at screening

Exclusion Criteria

·       No reliable caregiver in contact with patient >10 hours per week

·       History of serious infectious disease affecting brain, chronic alcohol abuse, substance/drug dependence or head trauma resulting in protracted loss of consciousness within 5 years of screening

·       Acetylcholinesterase inhibitor, memantine and/or other AD therapy < 4 months or < 2 months of stable therapy

·       Used medication affecting central nervous system outside AD<4 weeks

Patients were randomized to receive intravenous solanezumab 400mg or placebo every four weeks for 76 weeks. Patients maintained acetylcholinesterase inhibitors, memantine, and other non-pharmacological treatments for AD concomitantly with study medications.  The patients were administered the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-cog14) and Alzheimer’s Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL) 12, 28 40,52, 64, and 80 weeks after baseline; as well as the Mini-Mental State Examination (MMSE), the Functional Activities Questionnaire (FAQ), and the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB). The CDR-SB was administered only at baseline and final study visit. Plasma Aβ1-40 and Aβ1-42 levels, CSF samples, and Florbetapir PET scans were taken at baseline, and genetic testing for the APOEε4 genotype was collected in patients where allowed by law. Patients who completed the treatment period could progress to an open arm extension study. Follow up period was six months with telephone or mail contact.  Analyses were conducted based on the intention to treat principle. Fisher’s exact test and Pearson’s chi-square test was used for trial group comparisons of categorical data. Secondary outcomes were not analyzed for statistical significance.

Duration July 2013-February 2017 (date retrieved from clinicaltrials.gov)
Primary Outcome Measure The change in score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14) from baseline to 80 weeks

 

Baseline Characteristics  

Table 1 Characteristics of the patients at baseline

Characteristic Placebo

(n= 1072)

Solanezumab

(n= 1057)

p-value
Age (year) 73.3±8.0 72.2±7.8 0.07
Female sex (%) 58.9% 56.8% 0.34
Race (%)      
White 90.7% 90.5%  
Black 1.9% 1.4%  
Asian 7.2% 7.7%  
Multiple or other 0.2% 0.3%  
APOEε4 allele (%) 66.3% 69.3% 0.14
Education 13.7±3.8 13.7±3.7 0.91
Duration since symptom onset (year) 4.3±2.6 4.2±2.5 0.41
Duration since diagnosis 1.6±1.7 1.5±1.6 0.13
Acetylcholinesterase inhibitor or memantine use (%) 79.9% 77.8% 0.24
ADAS-cog14   score 29.7±8.5 28.9±8.3 0.02
ADCS-iADL score 45.4±8.1 45.6±7.9 0.44
MMSE score 22.6±2.9 22.8±2.8 0.12
FAQ score 10.6±7.1 10.3±6.8 0.36
CDR-SB score 3.9±2.0 3.9±1.9 0.54
Results Table 2 Primary and key secondary outcomes

Outcome Raw score at baseline Raw score at 80 weeks Least-squares mean change at 80 weeks Estimated Difference at 80 weeks (95%CI) p-value
Primary Outcome
  Placebo Solanezumab Placebo Solanezumab Placebo Solanezumab    
ADAS-cog14  score 29.70±8.50 28.87±8.26 36.11±14.27 35.09±13.28 7.44±0.36 6.65±0.36 0.80(-1.73-0.14)

 

0.10
Secondary Outcomes
MMSE score 22.62±2.89 22.81±2.77 19.09±5.56 19.62±5.30 -3.66±0.16 -3.17±0.15 0.49

(0.10-0.88)

 
ADCS-iADL score 45.37±8.14 45.60±7.93 39.01±11.86 39.83±11.41 -7.17±0.32 -6.17±0.32 1.00

(0.17-1.83)

 
ADCS-ADL score 66.69±9.15 676.02±8.67 59.00±14.61 60.20±13.52 -8.77±0.39 -7.42±0.39 1.35

(0.33-2.37)

 
FAQ score 10.60±7.11 10.31±6.81 15.73±8.10 15.35±8.24 5.57±0.21 5.17±0.21 -0.40 (-0.93-0.13)  
CDR-SB score 3.93±1.95 3.88±1.90 6.02±3.38 5.72±3.18 2.21±0.11 1.87±0.10 -0.34

(-0.57- -0.11)

 
iADRS score 105.70±13.95 106.73±13.47 93.04±23.71 94.81±22.15 -14.59±0.54 -12.92±0.53 1.68

(0.29-3.06)

 
Adverse Events Common Adverse Events: (Solanezumab vs. placebo, n%)

Nasopharyngitis:8.4% vs. 7.5%

Headache: 8.3% vs. 8.2%

Nausea: 5.3% vs. 4.3%

 

Serious Adverse Events: (Solanezumab vs. placebo, n%)

Death: 0.9% vs. 1.6%

Atrial fibrillation: 0.5% vs. 0.8%

Urinary tract infection: 0.2% vs. 0.7%

 

Percentage that Discontinued due to Adverse Events: (Solanezumab vs. placebo, n%) 4.5% vs. 3.6%
Study Author Conclusions Solanezumab 400 mg administered every 4 weeks did not significantly affect cognitive decline in mild Alzheimer’s disease patients.

 

The primary outcomes were changed before the study was executed from ADAS-Cog14 and ADCS-iADL to the ADAS-Cog14  alone. [4] The ADAS-Cog14 primarily assesses cognitive function while the ADCS-iADL evaluates the functional ability of dementia patients. [5] This appears to be a rational decision because recent evidence suggests cognitive decline precedes functional decline in dementia patients. [6] It would have been beneficial to assess the CSF levels of solanezumab to evaluate whether enough drug penetrated the blood brain barrier to affect the Ab concentrations. Overall, this trial does not support the use of solanezumab 400 mg in mild dementia patients.

 

References

[1] Hyman BT, Phelps CH, Beach TG, et al. National institute on aging-Alzheimer’s association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement. 2012;8(1):1-13.

[2] Honig LS, Vellas B, Woodward M, et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med. 2018;378(4):321-330.

[3] Siemers ER, Sundell KL, Carlson C, et al. Phase 3 solanezumab trials: secondary outcomes in mild Alzheimer’s disease patients. Alzheimers Dement. 2016; 12:110-20.

[4] Lilly Announces Change to Primary Endpoint of EXPEDITION3 Study. Eli Lily and Company. https://investor.lilly.com/releasedetail.cfm?ReleaseID=960661. Accessed January 31, 2018.

[5] Wessels AM, Siemers ER, Yu P, et al. A combined measure of cognition and function for clinical trials: the integrated Alzheimer’s disease rating scale (iADRS). J Prev Alzheimers Dis. 2015;2(4):227-241.

[6] Liu-Seifert H, Siemers ER, Price K, et al. Cognitive impairment precedes and predicts functional impairment in mild Alzheimer’s disease. J Alzheimers Dis. 2015;47(1):205-14.

 

 

 

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