Dementia with Lewy Bodies Drug Therapies in Clinical Trials: Systematic Review up to 2022

Two known relevant scoping reviews on different neurodegenerative diseases published in the last two years were used as a starting point to identify the most extensive clinical trial databases and search strategies [12, 13]. For this systematic review, we used data on RCTs of drug therapies from three international registries: (1) the US National Library of Medicine of the National Institutes of Health (NIH) clinical research registry ClinicalTrials.gov, (2) the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT/clinicaltrialsregister.eu), and (3) the International Clinical Trials Registry Platform (ICTRP) operated by the World Health Organization (WHO).

To generate our dataset of drug trials, the search strategy was adapted for each of the search engines using pre-defined search fields with no time restrictions. Study protocols from RCTs for DLB on phases 1–3 and funded by NIH, industry, other US Federal agencies or any other (individual, university, organizations) were included. RCTs that included other diagnostic groups in addition to DLB were also considered in this review. All non-pharmacological, observational studies, phase 4, or phase 1 in healthy subjects, were excluded from our final dataset. Two independent reviewers (C.A. and M.C.G) examined each phase of the review (screening, eligibility, and inclusion and exclusion criteria). The index date for this review was September 27, 2022. Ethics committee approval was not required for this study. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

If a trial was classified as phase 1/2 or phase 2/3, we included the study in the lower of the two phases in our analyses (for example, a phase 1/2 was considered phase 1). We then extracted key trial characteristics: clinical trial title, source registry, trial number, classification into symptomatic or DMT, primary outcome measure, use of biomarkers as inclusion criteria and/or outcome measures (excluding safety biomarkers), start date, study completion date, actual end date, if completed, active or ongoing (recruiting, active/not recruiting), withdrawn, not recruiting, not yet recruiting, terminated or pending status; cause of termination, duration of treatment exposure in weeks, number of subjects planned for enrollment, number of subjects enrolled if completed or terminated; additional diagnostic groups, stage of the disease, global distribution, sponsorship, whether the agent was repurposed, or used an adaptive design. To identify a MoA, the common Alzheimer's Disease Research Ontology (CADRO) classification of the National Institute on Aging and the Alzheimer’s Association, International Alzheimer’s and Related Dementias Research Portfolio (iadrp.nia.nih.gov) was used. CADRO identifies disease processes of neurodegenerative disorders, and we identified a target process of each drug. If the agent has more than one MoA, we searched the literature to identify the action of the drug currently viewed as dominant. Each trial/protocol in our dataset was first defined as symptomatic therapy or novel DMT. We arbitrarily distinguished between "symptomatic" and "DMT" drugs, considering whether the drug's purpose was improvement in cognitive, motor, sleep, or neuropsychiatric symptoms without intending to affect the biological causes of cell death. By contrast, "disease modifiers" claimed to change the biology of the disease and/or provide neuroprotection. As reported in previous scoping reviews, we divided DMTs into biologics (i.e., vaccines, monoclonal antibodies, gene therapies, among others) and small molecules (oral treatments that are < 500 Daltons in molecular weight) [12]. Disease stage classification included the following categories: prodromal, dementia stages (mild, moderate, and severe), and combination of prodromal and dementia stages. Repurposed drugs were defined when an established compound was investigated for a new therapeutic indication [14]. Approved indication was defined searching in PubMed and using FDA, and EMA databases. Global distribution was based on trials performed in North America (United States and Canada), Latin America, Europe, Asia, Africa, Middle East, and/or Oceania. Lastly, sponsor was defined in accordance to the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use E6 as “an individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial” [15].

A detailed description of the methodology used in this systematic review can be found in the Supplementary material.

From a total of 412 clinical trials registered as of September 27, 2022, we selected 40 clinical trials. ClinicalTrials.gov has the largest number of registered trials, where we found 154 studies for screening. On EudraCT/clinicaltrialsregister.eu, we found 33 studies for screening (18 not found on clinicaltrials.gov), and, on the ICTPR registry, we found 225 studies for screening (88 not found on ClinicalTrials.gov) (Supplementary Fig. 1). The trials investigated 25 agents: 17.5% in phase 3 (7 studies), 77.5% in phase 2 (31 studies), and 5% in phase 1 (2 studies) (Table 1). Most of the trials investigated symptomatic agents: 75% versus 25% DMTs (number of agents: 30 versus 10) (Fig. 1). More than half of these clinical trials have been completed with 9 remaining active (Fig. 2).

The 30 clinical trials for symptomatic treatment included: 15 (50%) clinical trials for cognitive enhancers, 7 (23.3%) for neuropsychiatric and behavioral symptoms, 5 (16.7%) addressing motor symptoms, and 3 (10%) for sleep disturbances and rapid eye movement (REM) sleep behavior disorder (RBD). All DMTs were classified as small molecules.

We found 7 phase 3 clinical trials, all of them for symptomatic treatment: 3 (43%) cognitive enhancers, 3 (43%) for neuropsychiatric and behavioral symptoms, and 1 (14%) for motor symptoms. According to the CADRO classification of mechanisms of action, most of the drugs in phase 3 clinical trials target neurotransmitter receptors (6 out of 7; 86%), and there was 1 (14%) multi-target agent. All the agents in this phase were repurposed (Table 2).

In terms of disease stage, phase 3 clinical trials in DLB have included all dementia stages (mild, moderate, and severe: 4 clinical trials, 57%) and mild to moderate dementia stage (3 clinical trials, 43%).

Six of the seven clinical trials in this phase have been completed (86%), and there is one clinical trial currently recruiting (14%).

The clinical trials completed have investigated donepezil, galantamine, pimavanserin, zonisamide, and yokukansan. The clinical trial currently recruiting is investigating memantine’s effect on overall health and functioning as an add-on treatment to a cholinesterase inhibitor (ICTPR: ISRCTN79794378).

The 6 completed clinical trials enrolled a total of 970 participants (we found 1 study with unpublished results that planned to enroll 60 patients). The clinical trial currently recruiting plans to enroll 372 patients. The mean total of participants planned for enrollment in phase 3 clinical trials was 196 (range 50–372).

The mean treatment duration was 27 weeks (range 4–52): for cognitive enhancers the mean treatment exposure was 43 weeks (range 24–52), for neuropsychiatric symptoms the mean was 15 weeks (range 4–38), and the clinical trial investigating motor symptoms had 12 weeks of treatment exposure.

The clinical outcome measures used in phase 3 clinical trials were Mini-Mental State Examination (MMSE) and Cognitive Drug Research Assessment System (COGDRAS) for cognition; Neuropsychiatric Inventory (NPI-12) for neuropsychiatric symptoms, Alzheimer’s Disease Cooperative Study: Clinical Global Impression of Change (ADCS-CGIC) for clinical global change, and Unified Parkinson's Disease Rating Scale (UPDRS) part III total score for motor symptoms.

One clinical trial included fluorodeoxyglucose (FDG) positron emission tomography (PET) as an outcome measure, and none of the phase 3 clinical trials used biomarkers as inclusion criteria (Table 3).

We found 31 phase 2 clinical trials: 23 (74.2%) symptomatic and 8 (25.8%) DMTs (Table 4).

There were 12 (38.7%) clinical trials for cognitive enhancers, 4 (12.9%) for neuropsychiatric and behavioral symptoms, 4 (12.9%) for motor symptoms, and 3 (9.7%) for sleep disturbances and RBD. All DMTs investigated were small molecules.

CADRO mechanisms of both symptomatic and DMT clinical trials included neurotransmitter receptors (19; 61.3%), synaptic plasticity and neuroprotection (4; 12.9%), proteostasis and proteinopathies (4; 12.9%), multi-target (1; 3.2%), growth factor and hormones (1; 3.2%), oxidative stress (1; 3.2%), and 1 unknown target (1; 3.2%). Sixteen (51.6%) agents in phase 2 clinical trials were repurposed.

Most clinical trials included participants in mild to moderate dementia (19; 61.3%), followed by all dementia stages (6; 19.4%), prodromal and mild dementia stage (2; 6.5%), and prodromal/mild cognitive impairment stage (1; 3.2%). Three (9.7%) clinical trials did not provide this information.

Regarding clinical trial status, we found 15 (48.4%) completed, 7 (22.6%) recruiting, 3 (9.7%) withdrawn, 2 (6.5%) not recruiting, 2 (6.5%) pending status, 1 (3.2%) terminated, and 1 (3.2%) active not recruiting.

The agents investigated in the 8 active clinical trials are: CT1812 (σ-2 receptor modulator), vodobatinib (tyrosine kinase inhibitor), nilotinib (tyrosine kinase inhibitor), fosgonimeton (activates signaling via the hepatocyte growth factor (HGF)), ambroxol (increases lysosomal fraction and the enzymatic activity of glucocerebrosidase), NYX-458 (NMDA receptor modulator), ondansetron (selective antagonist of serotonin 5-HT3 receptors), and CST-103/CST-107 (CST-103: β-2 adrenoceptor agonist/CST-107: β blocker with minimal brain penetration).

A total of 1897 participants were enrolled in completed clinical trials (one clinical trial had missing information about the number of enrolled participants; their planned enrollment was 50 participants). Three participants were enrolled in a clinical trial that was terminated due to low subject recruitment and enrollment. Clinical trials currently recruiting plan to enroll 878 participants. The mean total of participants planned for enrollment in phase 2 clinical trials was 94 (range 20–340), with a mean duration of treatment exposure of 18 weeks (1 missing value) (range 4–92 weeks). For symptomatic treatment, the mean treatment exposure was 12 weeks (range 4–24, 1 missing value) with an average of 101 participants planned for enrollment, and for DMTs exposure was 36 weeks (range 12–92) with an average of 77 participants planned for enrollment.

The clinical measures used as primary outcomes in phase 2 clinical trials for evaluating cognition were Montreal Cognitive Assessment (MoCA), MMSE, Frontal Assessment Battery (FAB), Hasegawa Dementia Rating Scale, negative emotional bias in the Facial Expression Recognition Task (FERT), Trail Making Test (TMT), and the following composite scores: a study-specific neuropsychological test battery (NTB) that included assessment of attention, executive function, and visual learning; the continuity of attention (CoA) composite score of the Cognitive Drug Research Computerized Cognition Battery (CDR-CCB); and the Global Statistical Test (GTS) that combines scores from the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) and change in event-related potential (ERP) P300 latency. UPDRS part II, III and IV were used for motor symptoms; Clinician’s Interview-Based Impression of Change Plus caregiver input (CIBIC-Plus), Clinical Global Impression (CGI), and ADCS-CGIC were used for identifying clinical change; Geriatric Depression Scale and NPI were used for neuropsychiatric symptoms, the Japanese version of the Zarit Burden Interview (J-ZBI) for caregiver burden; the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) for daily function, and the Dementia Cognitive Fluctuation Scale (DCFS) was used for cognitive fluctuations.

Nine phase 2 clinical trials used the following biomarkers for inclusion criteria: Dopamine Transporter Single Photon Emission Computed Tomography (DaTSCAN), ¹²³iodine-myocardial scintigraphy (MIBG), polysomnography (PSG); whereas plasma Aβ42/40 ratio, cerebrospinal fluid (CSF) AD biomarkers, and genetic testing for Apolipoprotein E (APOE) and glucosylceramidase β (GBA) were used for stratification. Fifteen clinical trials included biomarkers as an outcome measure: plasma, CSF, amyloid PET neuroimaging, electroencephalogram (EEG), quantitative EEG (qEEG), PSG, video-PSG, MIBG, DaTSCAN, Magnetic Resonance Imaging (MRI), and digital biomarkers (actigraphy, Lilly trial App, Electronic Walkway Assessment, Mini Balance Evaluation Systems Test -Mini-BESTest-, and a digital wearable device called BioStamp) (Table 3).

We found 2 clinical trials in phase 1 investigating small molecules for DMT, which are not yet recruiting. One is investigating a CADRO mechanism classified as metabolism and bioenergetics, and the other one is testing a drug that targets proteostasis and proteinopathies. Both agents are repurposed: terazosin (α-1 adrenergic receptor blockers) and ambroxol (increases lysosomal fraction and the enzymatic activity of glucocerebrosidase) (Table 5).

These 2 clinical trials plan to enroll a total of 55 participants in mild to moderate dementia stages, and the mean total exposure will be 34 weeks (15 and 52 weeks).

MMSE for evaluating cognition will be used as the primary outcome measure in one clinical trial. Both phase 1 clinical trials will use biomarkers as outcomes: brain ATP measured by MRI spectroscopy, FDG-PET, serum ATP levels, CSF, plasma, global and regional MRI atrophy measures. One of these clinical trials requires DaTSCAN for inclusion (Table 3).

Detailed information about treatment exposure, number of subjects, and their contribution in person weeks in DLB clinical trials is presented in Supplementary Table 1. Completed clinical trials have recruited a total of 2867 participants (planned enrollment was 2539 patients). The average of DLB patients enrolled per completed clinical trials was 137 (2 clinical trials with missing data: 1 phase 2 clinical trial planned to enroll 50 participants, and 1 phase 3 clinical trial planned to enroll 60 participants). The mean duration of treatment exposure was 16 weeks (range 4–52) (Supplementary Table 1).

There are 9 (22.5%) ongoing clinical trials (8 recruiting and 1 active, not recruiting), that plan to enroll 1290 participants. Most of these trials are phase 2 (8, 88.9%).

Mild to moderate dementia was the most common disease stage of participants among all clinical trials (24; 60%), active (5; 55.6%), completed (16; 76.2%), symptomatic (16; 53.3%) and DMT (8; 80%) (Supplementary Table 2). Twenty-one (52.5%) clinical trials included DLB patients only, whereas the rest included DLB plus the following diagnostic groups: PD, PD dementia (PDD), RBD, multiple system atrophy (MSA), AD, vascular dementia, frontotemporal dementia (FTD), Huntington’s disease (HD), all causes of dementia and mild cognitive impairment (Supplementary table 3). Most of the 9 active clinical trials include DLB patients only (4; 44.4%), followed by DLB or PDD (3; 33.3%), DLB or PD (1; 11.1%) and DLB, PDD, PD associated with RBD, or mild cognitive impairment patients (1; 11.1%).

Most clinical trials have been conducted in 1 continent (33; 82.5%): 16 (40%) in North America, 13 (32.5%) in Asia, and 4 (10%) in Europe (Table 6). The same is true for completed and active clinical trials. Seventy-six percent (n = 16) of completed clinical trials have been conducted in 1 continent (Asia, Europe, or North America), 14.3% (n = 3) have been conducted in 2 continents (Europe and North America, or North America and Latin America), and 9.5% (n = 2) have been conducted in 3 continents (Asia, Europe, and North America; and Europe, North America, and Latin America). Active clinical trials are being conducted in 1 continent (7, 77,8%): Europe or America; or 2 continents (2, 22.2%): Europe and Oceania (Table 6). We did not find clinical trials performed in Africa or the Middle East.

Academic centers sponsored 52.5% (n = 21) of all clinical trials in DLB, biopharma industry sponsored 42.5% (n = 17), and public–private partnerships sponsored 5% (n = 2). Active clinical trials are being sponsored by academic centers (5; 55.6%), biopharma industry (3, 33.3%), and public private partnerships (1, 11.1%). Likewise, most clinical trials testing repurposed agents are conducted by academic centers. With regards to therapeutic purpose, half of the symptomatic treatment were sponsored by biopharma industry and most of the DMTs (7; 70%) by academic centers (Table 7).