Table 3

Recommendations for future clinical trials in FTD spectrum disorders

ElementRecommendations and examples
DiagnosisInvestigators should clearly state if participants enrolled in the clinical trial have:

  • Clinical diagnosis according to current international consensus diagnostic criteria, such as:

    • Probable bvFTD according to Rascovsky 201130 criteria.

  • Molecular findings supportive of FTLD or absence of biomarkers suggestive of another diagnosis, such as:

    • Hypometabolism on PET scan suggestive of FTD.

    • Cerebral atrophy in frontotemporal regions suggestive of FTD.

    • Negative amyloid PET imaging.

  • Genetic diagnosis according to the presence of a known disease-causing mutation, such as:

    • Common gene mutations: C9orf72, GRN and MAPT.

    • Rare gene mutations: VCP, TARDBP, TIA1, TBK1, CCNF, FUS and CHMP2B.

  • Histopathological diagnosis, such as:

    • Subsequent autopsy confirmation of clinical diagnosis.


If participants have a molecular, genetic or histopathological diagnosis, it should be stated if participants are asymptomatic/presymptomatic or symptomatic.
The natural disease progression of enrolled participants should be carefully examined to determine whether it is slowly or rapidly progressing.
The presence of concomitant motor neuron disease should be reported.
Study designInnovative study design and methodology should be considered in order to maximise chance of capturing positive effects.

  • International multicentre trials should be prioritised, such as:

    • The GENFI cohort.

    • The LEFFTDS cohort.

    • The ARTFL cohort.

  • Platform trials, multi-interventional, multiarm trials should be considered, such as:

    • Multiple molecular targets.

    • Combination therapies.

    • Non-pharmacological intervention with pharmacological intervention.

  • Collaboration between the pharmaceutical industry, clinicians, clinical trial statisticians, statistical geneticists and bioinformaticians should be promoted.

  • Interventional trials in presymptomatic high-risk participants should be attempted.

  • Prespecified post-hoc analyses should be considered to find subgroup responders.


Interventions should be clearly defined as to whether they are preventive, disease-modifying and/or symptomatic in nature.
Eligibility criteriaInclusion and exclusion criteria should be clearly reported and justified. The following variables should be carefully addressed:

  • Minimum and maximum age limits should be justified.

  • Adequate sex representation should be sought by avoiding exclusion criteria that preferentially affect one sex over the other.

  • Significant cognitive impairment precluding randomisation should be carefully defined and justified.

  • Non-FTD cases should be excluded through the use of biomarkers such as CSF amyloid beta or amyloid PET imaging.

Outcome of interestInvestigators should clearly state outcomes of interest of the study and whether they pertain to:

  • Patient-centred and/or caregiver-centred outcomes, such as:

    • Quality of life.

    • Caregiver burden.

    • Autonomy/independency.

    • Risk of institutionalisation.

  • Surrogate outcomes, such as:

    • Brain atrophy on imaging.

    • Tau brain deposits on imaging.

    • Progranulin plasma level.

  • Symptomatology:

  • Cognitive outcomes, such as:

    • Frontal lobe functions.

    • Language.

  • Neuropsychiatric outcomes, such as:

    • Apathy and disinhibition.

    • Depression.

  • Motor outcomes, such as:

    • Speech.

    • Mobility.

    • Dystonia.


Patients, families and caregivers should be involved in the decision process of selecting and prioritising future clinical trials’ main goals.
Endpoint measure and effect assessmentSeveral accurate and validated tools and scales should be used, in combination with more commonly used clinical scales, in order to encompass disease heterogeneity, including global and specific scales:

  • Disease-specific scales, such as:

    • CDR-FTLD.

    • PSPRS.

  • Severity of symptoms and deficits:

  • Cognitive scales.

    • General cognitive scales, such as DRS and MoCA.

    • Specific cognitive domain tools, such as:

      • Processing speed: Simple Reaction Time, Choice Reaction Time.

      • Attention and working memory: Forward Digit Span, Backward Digit Span.

      • Executive functioning: Stroop Task, Trail-Making Test, Verbal Fluency.

      • Language: Boston Naming Test, Western Aphasia Battery.

      • Social cognition: ToM tasks, Interpersonal Reactivity Index.

  • Neuropsychiatric scales, such as:

    • FBI.

    • NPI.

  • Motor measures, such as:

    • Time to being a wheelchair user.

    • Time to unintelligible speech.

    • UPDRS score.

Multidimensional patient and caregiver-reported measures should be included in the treatment effect assessment, including functional and quality of life scales.
Potential differential effect of the investigational drug should be sought in subgroup analysis or by including the following variables as covariates of interest:

  • Age.

  • Sex.

  • Genetic variants, such as:

    • MAPT H1 haplotype.

    • TMEM106B genotype.

  • Copathology.

  • Italicized items in the table represent examples.

  • ARTFL, Advancing Research and Treatment for Frontototemporal Lobar Degeneration; BvFTD, behavioural variant FTD; CDR-FTLD, Clinical Dementia Rating Scale-Frontotemporal Lobar Degeneration; CSF, cerebrospinal fluid; DRS, Dementia Rating Scale; FBI, Frontal Behavioural Inventory; FTD, frontotemporal dementia; FTLD, frontotemporal lobar degeneration; GENFI, Genetic Frontotemporal Dementia Initiative; LEFFTDS, Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects; MoCA, Montreal Cognitive Assessment; NNIPPS, Neuroprotection and Natural History in Parkinson Plus Syndromes; NPI, Neuropsychiatric Inventory; PET, positron-emission tomography; PSPRS, Progressive Supranuclear Palsy Rating Scale; ToM, theory of mind; UPDRS, Unified Parkinson’s Disease Rating Scale.