Background and rationale

Amyotrophic lateral sclerosis (ALS) is a highly heterogenous disease, with a clinical presentation and progression varying significantly between patients. Marked variability is seen with respect to age of onset, site of onset, relative degree of upper (UMN) and lower motor neuron (LMN) involvement, cognitive impairment, and genetic abnormalities. The presentation is complicated by ALS’ disease spectrum with frontotemporal dementia (FTD) and its clinical overlap with primary lateral sclerosis (PLS) and progressive muscular atrophy (PMA) [1–3]. Phenotypic heterogeneity in ALS is likely underpinned by different pathogenic mechanisms [4,5], perhaps contributing to why so many ALS clinical trials have failed [6].

There is a general consensus in the field that a precision medicine approach, which considers an individual’s genotype and phenotype, will be required to effectively treat ALS [7,8]. To this end, groups are exploring methods to stratify patients into homogeneous subgroups. Genetic stratification in ALS has provided specific targets for drug development, spawning clinical trials with gene therapy approaches. Tofersen, a recently FDA-approved antisense oligonucleotide designed to downregulate SOD1 [9,10] is an example of such an approach that has shown benefit in the specific group of patients with a mutation in the SOD1 gene. However, precision medicine becomes more complex with non-genetic forms of ALS, which account for approximately 90% of cases of ALS [11].

Major infrastructures have been developed to support ALS clinical trials, share clinical datasets, and establish biospecimen repositories in order to advance the understanding of ALS. In a recent review, 22 registries and collaborative efforts were noted across North America, South America, Europe, and Asia [12]. Shared clinical databases enhance the coordination of resources and data analyses while biorepositories help ensure standardization and quality controls. These infrastructures provide critical resources to the research community. Examples of large ALS platforms collecting biological materials from people with ALS include Answer ALS, AMBRoSIA and CReATE [13]. These platforms also differ in their objectives, scope and protocols.

A major challenge in ALS research is to obtain comprehensive and longitudinal characterization of disease phenotype beyond basic clinical characteristics such as age, sex, time from symptom onset, region of onset, ALS Functional Rating Scale-Revised (ALSFRS-R) score, and respiratory vital capacity measurements. Linking genetic data and other biosamples to such thorough characterization would also be a key asset, though it is an additional challenge in ALS research. Meeting these challenges would allow a thorough, quantitative examination of the phenotypic and temporal heterogeneity in ALS, and would promote advances in biomarker discovery.

The Comprehensive Analysis Platform to Understand, Remedy and Eliminate ALS (CAPTURE ALS), is a Canadian open science research platform that was designed in response to the need to robustly characterize ALS heterogeneity, understand ALS biology and develop biomarkers. The study protocol presented here was developed largely on that used by the Canadian ALS Neuroimaging Consortium (CALSNIC) [14]. CALSNIC, which was founded by the same group, yielded two observational studies (CALSNIC-1 and CALSNIC-2) that acquired multimodal neuroimaging, neurological, neuropsychological, and speech data from over 250 ALS patients and 200 healthy controls. As the first multi-center, prospective, longitudinal neuroimaging study in ALS, CALSNIC used these unique datasets to develop and evaluate advanced MRI-based biomarkers that delineate biological heterogeneity, track disease progression and predict survival [15–20]. CAPTURE ALS expanded upon the CALSNIC study protocol to yield the most comprehensive clinical dataset linked to biological samples ever attempted in the field. Added in the CAPTURE ALS protocol is the collection of biosamples, for which standard operating procedures (SOPs) were developed under the guidance of and support of consortia preceding CAPTURE ALS, in particular the Northeast Amyotrophic Lateral Sclerosis Consortium (NEALS). Consultations with collaborators and other consortia were made to optimize CAPTURE ALS’ interoperability with materials of other consortia. To further ensure the protocol’s implementation, CAPTURE ALS incorporates the voices of people affected by ALS, and therefore created a Participant Partner Advisory Council (PPAC), which advises on the protocol and any proposed changes.

The datasets and biospecimens acquired through CAPTURE ALS are housed at the Clinical Biological Imaging and Genetic (C-BIG) Repository [21], whose technical, physical, ethical and legal framework was leveraged to permit sharing through open science with the global research community.

Objectives

CAPTURE ALS is a long-term research platform, with the overarching objective of advancing the understanding of ALS and defining its clinical heterogeneity. By making datasets available for researchers globally, the platform will facilitate investigations into the fundamental molecular alterations underlying ALS, foster the discovery of new biomarkers, and allow tissue- and fluid-based translational research to develop new treatments for ALS and related disorders. This will be achieved using a multidisciplinary approach. There are three specific aims:

1. Characterize people affected by ALS and related motor neuron diseases (MNDs), and healthy controls with deep clinical phenotyping, neuroimaging, speech analyses, whole genome sequencing, and multisource analyses.
2. Develop a de-identified database and biosample repository linked to detailed clinical information, that will be a resource for the Canadian and international scientific communities.
3. Develop and implement an inclusive, transparent, structured patient engagement strategy to be active throughout all stages of CAPTURE ALS.

Study design

The CAPTURE ALS research platform operates a prospective, longitudinal study enrolling people living with ALS (or related diseases) and healthy controls. It is a multi-center study that is currently recruiting at 4 Canadian ALS multidisciplinary clinics at the University of Alberta (Edmonton, Alberta), McGill University (Montreal, Quebec), Université Laval (Quebec City, Quebec) and the University of Toronto (Toronto, Ontario). A fifth site at the Centre hospitalier de l’université de Montréal is being onboarded. CAPTURE ALS follows best practices for Patient Oriented Research, as outlined by CIHR/SPOR [22,23].

Participant engagement

Patient engagement can facilitate recruitment and retention [24,25], but more importantly, it is the key to improving the relevance, feasibility, impact, and efficiency of research and can improve patient outcomes [26–28]. CAPTURE ALS is designed to incorporate the voices of people affected by ALS, including those living with ALS, their loved ones, friends, and communities. The PPAC holds regular meetings, providing ongoing input on study needs and challenges including input on research priorities and strategies for participant recruitment. One person living with ALS and one caregiver from each CAPTURE ALS site, as well as 1–3 representatives from the ALS Canada Ambassadors Program participate as PPAC members. Members have an anticipated term of 1–2 years with opportunities for longer participation. In addition to the PPAC, CAPTURE ALS’ participant engagement strategy includes a “Participant Experience Questionnaire”. This questionnaire is included in the study protocol and schedule of procedures for all participants. At the end of the last study visit, participants have the option to complete an online questionnaire to provide the research team with feedback on their overall experience as CAPTURE ALS research participants. The aim is to better understand research participation from the perspective of participants, and to explore how this experience can be improved for future ALS studies.

Study population

There are two main study populations in CAPTURE ALS. The first is the affected group that includes people living with ALS, a related MND (such as PLS or PMA), and presymptomatic individuals with a known ALS mutation. Affected participants are permitted to be enrolled in another clinical trial in parallel to their participation in CAPTURE ALS. Few inclusion/exclusion criteria are employed to ensure that the true heterogeneity in the ALS population is captured. Since the goal is to understand the different presentations of the disease across a spectrum, individuals with ALS meeting any designation of the revised El Escorial criteria [29], are eligible to participate. The second group is healthy controls. The inclusion and exclusion criteria for patients and controls are outlined under study procedures. In addition to affected participants and controls, caregivers have the opportunity to participate in CAPTURE ALS by consenting to complete behavioral assessment questionnaires.

Ethics

CAPTURE ALS is conducted in accordance with the Good Clinical Practice guidelines of the International Council for Harmonisation [30] and the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS2) [31]. Each site has received research ethics board (REB) approval from their respective institutional ethics committees to recruit participants. The consent provided by participants enables broad secondary use of their de-identified and coded data/materials for research on ALS, related diseases, and other neurological diseases as well as comparative research on other human diseases and conditions by both academia and industry in Canada and globally.

Status and timeline of the study

CAPTURE ALS launched at the University of Alberta with the first study visit of the first affected participant in March 2022. Recruitment at the other three sites initiated over the course of the following year. Recruitment is ongoing. This is a long-term research platform with no restrictions on sample size or timeframe beyond those permitted by available funds. The current funding permits recruitment of 120 affected participants and 50 healthy control participants. Sites will continue to submit the annual renewal for the study at their REB until the target recruitment numbers are reached, or as long as funds are available to continue study visits. Recruitment is expected to be completed in December 2026, and data collection in December 2027.

Study procedure

Eligibility criteria

Data collection

All study investigators, research coordinators, and other study personnel are required to undergo documented training on the study protocol and have an up-to-date Good Clinical Practice certificate. CAPTURE ALS SOPs were created for specific tasks in the protocol. Study personnel delegated to perform these tasks must have reviewed the relevant SOP and have it documented on the training log prior to performing the task. A full list of the SOPs can be found in Supporting Information.

All participants undergo deep clinical phenotyping, neurocognitive testing, multimodal neuroimaging, speech analysis, and multisource biospecimen collection and analyses. These assessments are described under Primary Outcomes. Affected participants have study visits at Month 0 (baseline), Month 4, Month 8, and Month 12. Control participants have two study visits: Month 0 (baseline) and Month 8. Both affected and control participants must pass a screening visit, which can be combined with the baseline visit to reduce participant burden. Study procedures performed at each visit are summarized in Table 1 for affected participants and Table 2 for control participants. Compared to affected participants, control participants do not undergo neurological examinations, ALSFRS-R, Forced Vital Capacity (FVC), Frontal Systems Behavior Scale (FrSBe) and the ALS Assessment Questionnaire Short Form (ALSAQ-5).

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 1. Schedule of study procedures for affected participants.

https://doi.org/10.1371/journal.pone.0332430.t001

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 2. Schedule of study procedures for control participants.

https://doi.org/10.1371/journal.pone.0332430.t002

Primary outcomes

The following clinical assessments are performed to undergo deep phenotyping

Neuroimaging.

One of the major features that sets CAPTURE ALS apart from other international ALS initiatives is the collection of longitudinal brain imaging data using MRI on all participants. Brain imaging has provided insights into pathology and pathophysiological mechanisms in vivo in both symptomatic and presymptomatic individuals with ALS. The CAPTURE ALS neuroimaging protocol is derived and adapted from those used in CALSNIC-1 and CALSNIC-2 [14], as shown in Table 3. CALSNIC studies demonstrated the ability to monitor the progression of neurodegeneration using imaging metrics over an observation interval of 4−8 months [15,17,19], and that clinical heterogeneity (disease progression rate, UMN burden) is associated with MRI measures of cerebral pathology [16,18,20]. The harmonization across all 3 studies enables their integration and pooling of data. The multimodal protocol assesses structure (T1-weighted (T1w)), microstructure (diffusion tensor imaging (DTI)), neurochemistry (magnetic resonance spectroscopy (MRS)), resting state function (rs-fMRI), iron deposition (susceptibility weighted imaging (SWI)), blood flow (arterial spin labeling (ASL)), and co-existing pathology (fluid-attenuated inversion recovery (FLAIR)). All of these modalities have shown sensitivity to change in ALS compared to healthy controls in prior studies. Single voxel MRS of the motor cortex (MC) and prefrontal cortex (PFC) was performed in CALSNIC-1 but not done in CALSNIC-2; in CAPTURE ALS, the MC is probed, but the frontal voxel was not retained due to lower metabolite ratio precision from that region accompanied by a lack of robust cross-sectional and longitudinal change [61].

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 3. Imaging protocol across studies.

https://doi.org/10.1371/journal.pone.0332430.t003

Sequence parameters are dependent on the MRI system (Siemens, GE, Philips) operating at the site. Some parameters are common across all systems. As examples, constants across respective sequences and MRI systems are image resolution, the number of DTI b-values and diffusion directions, and the number of volumes in rs-fMRI [14].

Biosample collection.

Biosamples of participants of CAPTURE ALS are collected every study visit as per standard procedures at each CAPTURE ALS site. These include blood collection for serum, plasma and RNA in all participants (Tables 4 and 5). Affected participants provide a baseline blood sample for peripheral blood mononuclear cell (PBMC) isolation, and whole blood for DNA isolation. Cerebrospinal fluid (CSF) collection is optional. All biosamples collected through CAPTURE ALS are stored in the C-BIG Repository at the Montreal Neurological Institute (MNI) for future research purposes. Depending on the sample type, some biospecimens are processed at the collecting site before being shipped to C-BIG Repository according to the CAPTURE ALS Biosampling SOP (S9 Appendix).

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 4. Schedule of blood collection for affected participants.

https://doi.org/10.1371/journal.pone.0332430.t004

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 5. Schedule of blood collection for control participants.

https://doi.org/10.1371/journal.pone.0332430.t005

Secondary outcomes

Data management

Each participant is assigned a study identification number at the time of informed consent by the research coordinator and is used on all source documents and database entries. The de-identified information collected in CAPTURE ALS is managed by the Longitudinal Online Research and Imaging System (LORIS). LORIS is a software platform used for managing data in multimodal studies. It was coded to meet the specific needs of CAPTURE ALS to manage the entire dataset, including the multimodal clinical assessments, imaging data, and biospecimen inventory details.

MRI scans are uploaded by the MRI technicians at each CAPTURE ALS site using a specialized MRI uploader that ensures data to be consistently captured and meet the standardized MRI protocol. Once an MRI scan is uploaded, it passes various parameter checks and flags any scan to the individual modality level to ensure MRI data are collected according to the predefined study protocols.

Clinical data entered in the LORIS database undergoes quality review at the central coordinating site (University of Alberta).

Progress

At the time of writing this paper, 118 participants had consented to participate in CAPTURE ALS (87 affected participants and 31 control participants). The mean age for male and female MND participants is 59 years old and 57 years old, respectively. For controls, it is 52 years old and 48 years old. In line with the literature [63], MND participants have a greater male-to-female ratio. The healthy controls exhibit a higher female-to-male ratio, a limitation that may be explained by male MND participants with female caregivers participating as healthy controls.

Regarding participant engagement, five people living with ALS and five caregivers are members of the PPAC. Since February 2021, 18 PPAC meetings have been held. Participant engagement webinars were initiated in March 2023; six have been held to date. The PPAC has contributed to governance documents, has provided their input on the study protocol and sub-studies, engagement webinar development and feedback surveys [64].

Dissemination

The CAPTURE ALS database and biobank are located at the MNI’s C-BIG Repository, which uses an open science framework. CAPTURE ALS is dedicated to offering an open science research platform. Those requesting CAPTURE ALS datasets and/or samples must have an ethics approved project aligned with the informed consent form of the CAPTURE ALS. There are increasing levels of access to data and materials available to researchers (https://captureals.ca):

1. Open Access: De-identified data with no risk of re-identification will be made publicly available. This will include summary data for example diagnosis, age and sex.
2. Registered Access: Researchers who register with CAPTURE ALS. These data include results of medical evaluations such as the ALSFRS-R, FVC and neurological examination.
3. Controlled Access: This includes all biological samples, MRI data, speech data, and data that have a higher risk of re-identification or are particularly sensitive (i.e., more personal information than data found through open or registered access). This level of access requires submission of a project description approved by the investigator’s Institutional Review Board (IRB) for review by CAPTURE ALS’s Tissue and Data Committee, and C-BIG Repository’s Tissue and Data Committee.

Researchers using the CAPTURE ALS dataset in C-BIG Repository are encouraged to return their results to CAPTURE ALS after publication, and to disseminate study results through peer-reviewed journal publications, posters, and conference presentations. Researchers requesting CAPTURE ALS registered and controlled access data are required to recognize the CAPTURE ALS database in published work.

The CAPTURE ALS PPAC contributes to dissemination indirectly through its input on foundational documentation such as the CAPTURE ALS Charter, focus on patient-centered study processes, and response to study needs and challenges as identified by the CAPTURE ALS Executive Committee. Direct contributions include input on participant engagement webinars and co-authorship on a publication outlining lessons learned from CAPTURE ALS’ active participant engagement strategy [64].

Limitations

One of the challenges is the recruitment of a heterogeneous patient population and also the constraints posed by the longitudinal design. Due to the number of assessments included in the CAPTURE ALS protocol, recruitment can be challenging as people living with ALS may not have the time or energy for lengthy visits. To minimize participant fatigue and burden, the following adjustments are permitted: 1) screening and baseline visits may be combined, and 2) assessments can be carried over to an alternative day within window limits.

The MRI requirement can result in a selection bias towards individuals with milder disabilities and slower progression. The MRI is not mandatory after the baseline visit, allowing patients to continue their participation even if they can no longer tolerate the MRI scan due to disease progression so that data and biofluid sample collection can continue.

Other limitations include the likelihood of low numbers of participants with diagnoses of PLS, PMA, or presymptomatic cases. To some extent, the use of the El Escorial criteria to define ALS cases may contribute to this limitation. More recently developed criteria, such as the Gold Coast criteria, may broaden the phenotypic range of ALS in future studies and can identify ALS patients with higher sensitivity [65]. CAPTURE ALS remains important to providing comprehensive data regarding the phenotype of MNDs and may guide future dedicated studies to these less common MND presentations. The data collected in this study can be combined with that of other initiatives to assist in meeting thresholds required for meaningful analyses.

The CAPTURE ALS protocol does not include a peripheral electrophysiological measure or collection and banking of postmortem tissue. These could not be integrated into the protocol at launch due to funding restrictions.

CAPTURE ALS is among other international projects that seek to better understand ALS by collecting clinical, genetic, biomarker, neurophysiologic, and/or neuroimaging data [66–73]. Each project includes differences in its study questions, methodology, and inclusion criteria. Nonetheless, there would be advantages to being able to aggregate data between studies, in order to generate data with a large number of participants, representing the full breadth of ALS phenotypes and population diversity. Such data coordination efforts are likely to be a massive undertaking and may benefit from support from international ALS organizations to connect respective project coordinators to determine the feasibility of data harmonization.

Strengths

ALS is a rare disease with significant individual heterogeneity which makes studying the disease exceptionally challenging. Addressing the variability and heterogeneity will have implications for current therapeutic approaches. Thus, the CAPTURE ALS platform is designed to address the high variability and heterogeneity observed in ALS patients by providing the most comprehensive clinical picture of individuals living with ALS ever attempted in the field. The unique contributions of CAPTURE ALS include its open science framework and the inclusion of a PPAC by comparison to other large ALS platforms such as Answer ALS, AMBRoSIA, and CReATE among others. The CAPTURE ALS multidisciplinary platform also collects longitudinal MRI scans and detailed neurocognitive and speech data, which is unique, and links biosamples to these datasets. Such a comprehensive dataset is of invaluable significance and will also help understand the complex nature of ALS. This extensive data collection could lead to the identification of novel clinical-biological associations and the development of personalized predictive models for ALS.

Conclusion

CAPTURE ALS will provide researchers with robustly phenotyped biosamples and data for research exploring ALS biology and heterogeneity.

CAPTURE ALS has the benefit of using lessons learned from the preceding CALSNIC platform, which included standardized neuroimaging, neurocognitive and clinical collections across 9 centres. Lastly, the inclusion of a PPAC ensures that CAPTURE ALS is driving its objectives with the voices of people living with ALS.

Using an open science framework, CAPTURE ALS will provide a comprehensive clinical picture of the disease for the research community to better understand and study ALS. Conducting this observational longitudinal study will provide more insight into variability between people living with ALS and will make access to data easier for researchers to pursue initiatives to eliminate ALS.

Supporting information