Combining Clemastine and Aerobic Exercise to Treat Cognitive Dysfunction in Schizophrenia by Targeting Myelin Plasticity

NCT06315972 | Not Yet Recruiting Phase 2

• 1 other identifier: 2022-000054-28
• Study Type: interventional
• Target: 90
• Locations: 0 countries
• Sites: N/A

Brief Summary

Schizophrenia (SZ) is a broad clinical entity characterized by different subjective symptoms,behavioural signs, and disease course. Research has pointed to numerous biological indicators tentatively associated with neurocognitive dysfunction, brain structural and neurochemical alterations. Cognitive deficits occur as early as the prodromal phase of the illness and significantly determine its outcome. Pathophysiologically, SZ is regarded as a disconnectome disorder in which frontal and temporal brain regions are functionally disconnected, which contributes substantially to the development of cognitive dysfunction. Impaired connectivity is related to synaptic (microconnectivity) and myelin (macroconnectivity) plasticity. With design-based stereology, a decreased number of oligodendrocytes (OLs) in the CA4 hippocampal subregion as the basis for disturbed myelination and impaired cognition, but also a decrease in the prefrontal cortex were observed. Animal studies demonstrated that clemastine enhances remyelination by increasing the differentiation of oligodendrocyte precursor cells (OPCs) and showed that aerobic exercise increases the rate of remyelination and proliferation of OPCs; this clinically meaningful effect of aerobic exercise is stronger in combination with clemastine. Furthermore, aerobic exercise improves everyday functioning, measured by the Global Assessment of Functioning (GAF) scale, and cognitive dysfunction in SZ and increases hippocampal volume, especially the volume in the hippocampal CA4 subregion. This regional volume change correlates negatively with global and cell-specific polygenic risk scores (PRSs), indicating that OPCs are involved in the genetic risk mechanisms and disturbed plasticity underlying SZ. In patients with multiple sclerosis, 90 days' administration of clemastine fumarate 10.72 mg/day, corresponding to clemastine 8 mg/day, significantly decreased the P100 latency delay of visual evoked potentials (VEPs) as a sign of myelin repair. In a bicentric, randomized, double-blind, controlled phase IIb clinical trial with a 2-arm parallel group design in patients with SZ, the study will compare the effects of aerobic exercise training plus clemastine vs. aerobic exercise training plus placebo over a period of 3 months on 1) everyday functioning and 2) working memory as primary outcomes.

Conditions

Schizophrenia

Outcome Measures

Primary Outcomes (2)

• change in Global Assessment of Functioning

  change in Global Assessment of Functioning (GAF) scores from the start of the intervention period (V1.1) to primary outcome visit after 90-93 days of treatment (V2).

  3 months

• change in working memory performance

  change in working memory performance assessed by the n-back test (2-back level, d-prime) from V1.1 to V2.

  3 months

Study Arms (2)

Experimental intervention

EXPERIMENTAL

Application of double-blind add-on clemastine at a dosage of 8 mg/day (morning: 4 mg; evening: 4 mg) + aerobic exercise training 50 min 3x/week over a period of 3 months

Drug: clemastine (8 mg/day)

Control intervention

PLACEBO COMPARATOR

Application of double-blind add-on placebo (morning and evening) + aerobic exercise training 50 min 3x/week

Drug: Placebo

Interventions

clemastine (8 mg/day) DRUG

add-on clemastine (8 mg/day) + aerobic exercise training

Experimental intervention

Placebo DRUG

add-on placebo + aerobic exercise training

Control intervention

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent obtained from the participant prior to performing any protocol-related procedures, including screening evaluations
• A DSM-V diagnosis of schizophrenia or schizophrenia-spectrum disorder according to MINI interview
• Age between 18 and 65 years EudraCT Number: 2022-000054-28 Confidential OligoTreat Study Protocol Version 2.0 06.09.2023 9 of 62
• Total Positive and Negative Syndrome Scale (PANSS) score ≤ 75 at V0
• Female participants with reproductive potential must have a negative beta- HCG serum pregnancy test as part of the screening visit
• Female participants with reproductive potential must have a negative serum pregnancy test within seven days prior to randomization
• Male participants and female participants who are not capable of bearing children or who use a method of contraception that is medically approved by the health authority of the respective country at screening

You may not qualify if:

• Patients who are unable to give informed consent
• Treatment-naïve schizophrenia defined as cumulative treatment with an antipsychotic agent lifetime for \<30 days
• Insufficient understanding of the German language
• Patients with primary active (moderate or severe) substance use disorder (other than nicotine) according to MINI interview (DSM-V): patients fulfilling early (\>3 months) or sustained (\>12 months) remission criteria and/or with low severity of substance use disorder according to MINI are eligible for the study
• Known clinically relevant CNS disorder(s), such as epilepsy or history of seizures
• Concomitant use of any other putative remyelinating therapy as determined by investigator
• Co-occurrent unstable somatic condition
• Known porphyria
• Known intolerance, allergy/contraindications to one of the study drugs or any of the excipients or other agents with similar chemical properties as the study drugs (such as other arylalkylamine antihistamines)
• Clinically relevant liver and/or renal impairment (serum creatinine \>1.5mg/dl or eGFR\<30 ml/min/1.73 m2 at screening, AST or ALT \> 2-times the upper limit of normal at screening)
• Current treatment with macrolide-antibiotics (such as erythromycin, clarithromycine) or azole-type antimycotics
• Clinically relevant cardiac comorbidities (i.e. Long QT-syndrome)
• Current hypokalaemia and/or clinically relevant hyponatraemia at screening
• Patient-reported hereditary galactose-intolerance and/or Lapp lactosedeficiency, lactose intolerance and/or glucose-galactose malabsorption
• Pregnancy or breast-feeding

Sponsors & Collaborators

• LMU Klinikum: lead

MeSH Terms

Conditions

Schizophrenia

Interventions

Clemastine

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: M.Sc.

Study Record Dates

• First Submitted: March 12, 2024
• First Posted: March 18, 2024
• Study Start: April 1, 2024
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): April 1, 2028
• Last Updated: March 20, 2024

Record last verified: 2024-03