Behaviors and Mental Disorders

All Conditions

Neoplasms

Nervous System Diseases

Rare Diseases

Cognitive Dysfunction

Brain Neoplasms

Cognition Disorders

Neurocognitive Disorders

Mental Disorders

Psychotic Disorders

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Brain Tumor, Childhood

Central Nervous System Depressants

Psychotropic Drugs

All Drugs and Chemicals

Lithium Carbonate

Antidepressive Agents

Enzyme Inhibitors

Lithionit 42 mg (lithium sulphate, 6 mmol), start dose 1x1, then slow dose escalation using therapeutic drug monitoring (TDI) to establish a target serum level of 0.5-1.0 mmol/liter.

Identical looking placebo (white round tablet, 10 mm diameter) will be dose escalated and monitored the same way as lithium, with sham values guiding the dosing.

Lithium

White round tablet, 10 mm. Identical to experimental drug (lithium)

Placebo

Klas Blomgren, MD, Professor

Gustaf Hellspong, MD, PhD Student

Gustaf Hellspong, MD

Klas Blomgren, MD, professor

Randomized, placebo-controlled, double-blinded, parallel group clinical trial to investigate if 6 months of oral lithium tablets (S-lithium 0,5-1,0 mmol/l) will prevent cognitive decline after brain radiotherapy in pediatric brain tumor survivors.

Primary outcome measure is Processing Speed Index (PSI) 2 years after start of study treatment.

Late-appearing cognitive side effects after brain radiotherapy is a potential disabling condition in pediatric brain tumor survivors. It can have profound negative effects on education, career options and quality of life. There is no current interventional drug treatment to prevent this intellectual impairment after brain tumor treatment.

Primary objective:

To assess the efficacy of lithium treatment (up to 7 years) after brain radiotherapy (both whole brain and focal) for central nervous system malignancy in preventing late-appearing cognitive processing speed impairment in children aged 5 or older.

Secondary objectives:

* To assess the efficacy of lithium treatment through evaluation of other neuropsychological/quality of life test scores.
* To assess the efficacy of lithium treatment through evaluation of radiological findings after lithium treatment using Magnetic Resonance Imaging (MRI) of the brain.

Exploratory objectives:

To explore the feasibility, safety and tolerability of lithium treatment in this patient group, using side effect forms/adverse events (AE) reporting and laboratory measures.

Randomization is based on whether or not the study participant had received radiotherapy to the whole brain (CSI) or only part of it (focal irradiation). Within each of these two arms there is a predetermined block randomization with a 2:1 lithium:placebo ratio.

Identical-looking placebo is used. S-lithium levels are masked by using a separate lab service and sham values for placebo group.

Lithium Treatment to Prevent Cognitive Impairment After Brain Radiotherapy

* Number of potentially eligible patients identified
* Number of patients screened
* Number of patients randomized
* Number of patients completing the study per protocol
* Number of patients terminating study during IMP treatment period (6 months).
* Number of patients terminating study during follow-up period (up 5 years post IMP treatment)

* Description of reason why eligle patient declined screening
* Description of reason why screened patient was not randomized/included
* Description of reason(s) for early study termination.

Duration of IMP treatment, measured in total number of days where IMP was taken

* Numbers of IMP dose reductions
* Number of IMP temporary stops

* Descriptions of reason(s) for IMP dose reductions
* Descriptions of reason(s) for IMP temporary stops
* Descriptions of reason(s) for IMP premature (before per protocol) permanent stop.

* Number of target serum concentration measurements within target range (0.5-1.0 mmol/liter) divided by total number of measurements.
* Number of target serum concentration measurements above target range (0.5-1.0 mmol/liter) divided by total number of measurments
* Number of target serum concentration measurements below target range (0.5-1.0 mmol/liter) divided by total number of measurments

Number of participants with treatment-related adverse events as assessed by CTCAE v5.0.

Cognitive processing speed. Normed score min 45, max 155. Higher = better.

* Verbal Comprehension Index (VCI)
* Visual Spatial Index (VSI)
* Fluid Reasoning Index (FRI)
* Working Memory Index (WMI)

Normed score min 45, max 155. Higher = better.

Motor speed / manual dexterity. Unit: time in seconds to complete all pegs. Lower=better.

Visual motor integration. Normed score min 1, max 19. Higher = better.

Sustained attention. Multiple T-scores, min 0, max 80. Higher = better.

Executive function and inhibition, age 8 years and above. Normed score min 1, max 19. Higher = better.

Executive function and inhibition. Normed score min 1, max 19. Higher = better.

Executive function and inhibition, age below 8 years. Normed score min 1, max 19. Higher = better.

Health related quality of life. Score min 0, max 100. Higher=better.

Loneliness scale. Score min 3, max 9. Lower = better.

Psychosocial strengths and difficulties. Score min 0, max 40.

Executive function. Score min 20, max 80.

Rigshospitalet, Denmark

Region Stockholm

Symptoms and General Pathology

Immune System Diseases

Neoplasm Metastasis

Sclerosis

Multiple Sclerosis

Multiple Sclerosis, Chronic Progressive

Atrophy

Autoimmune Diseases

Demyelinating Autoimmune Diseases, CNS

Autoimmune Diseases of the Nervous System

Demyelinating Diseases

Neoplastic Processes

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

Channel Blockers

Natriuretic Agents

Anticonvulsants

Neuroprotective Agents

Amiloride

Fluoxetine

Riluzole

Selective Serotonin Reuptake Inhibitors

Serotonin

Neurotransmitter Agents

Cytochrome P-450 Enzyme Inhibitors

Excitatory Amino Acid Antagonists

Protective Agents

Diuretics

Sodium Channel Blockers

Diuretics, Potassium Sparing

Amiloride 5 mg twice per day (5 mg once per day for first 4 weeks) for 96 weeks

Riluzole 50 mg twice per day (50 mg once per day for first 4 weeks) for 96 weeks

Fluoxetine 20 mg twice per day (20 mg once per day for first 4 weeks) for 96 weeks

Matched placebo 1 capsule twice per day (1 capsule a day for first 4 weeks) for 96 weeks

Jeremy Chataway

Siddharthan Chandran

Multiple sclerosis (MS) is a disabling and progressive neurological disease that affects approximately 100,000 people in the UK. Many patients with MS experience two phases of disease; early MS (also called relapsing remitting MS, RRMS) and late MS (also called secondary progressive MS (SPMS). Early MS is due to inflammation of the nerves and the insulation (called myelin) that surrounds the nerves. Early MS is often characterised by periods of "attacks" interspersed with periods of "remission" with no or low disease symptoms. Late or progressive MS, which affects the majority of patients and typically emerges after 10-15 years of disease, results from actual nerve death (also called neurodegeneration). The progressive stage of disease results not in individual attacks but slow, cumulative and irreversible disability affecting walking, balance, vision, cognition, pain control, bladder and bowel function. Critically, and unlike early disease, there is no proven treatment for the late stage of MS. This is therefore an urgent and major unmet health need. MS-SMART directly addresses this need and will evaluate in this clinical trial three drugs (fluoxetine, riluzole or amiloride), all of which have shown some promise in MS, and in particular in SPMS. The trial is randomised and blinded. Randomisation means patients can get any one of the three active drugs or the inactive placebo/dummy; blinded means that neither patients nor the doctors will know which drug or placebo patients are receiving. Randomisation and blinding are standard approaches in clinical trials to ensure unbiased testing of drugs. All patients in MS-SMART will have periodic MRI (magnetic resonance imaging) brain scans and after 96 weeks these will be analysed. We will then compare the scans of each drug to the placebo or dummy to see if any of the drugs slow the rate of brain shrinkage that normally occurs in SPMS. This measured change in brain size is the primary (major) outcome of MS-SMART.

MS-SMART will test the efficacy and mechanism of action of three repurposed drugs (fluoxetine, riluzole and amiloride). All three drugs are in human use and have a good safety record. Critically for the purpose of MS-SMART they all have shown promise in early phase human MS clinical trials and target one or more of the pivotal neurodegenerative causing pathways implicated in SPMS. This is a Type B trial, as the IMPs are all in human use, have a good safety profile but are not currently used for this patient population.

The major need for patients with established and progressive MS is neuroprotective or disease modifying treatments that will slow or even stop disease progression. This study will evaluate three highly promising putative neuroprotective drugs as well as comprehensively address several of the current knowledge gaps related to the understanding of neuroprotection and neurodegeneration in SPMS through MRI and CSF examination.

MS-SMART is a multicentre, multi-arm, double blind, placebo-controlled phase IIb randomised controlled trial. A total of 440 patients with SPMS, with an entry criteria of an EDSS score of 4.0-6.5 will be equally randomised to receive placebo or one of the three active agents (fluoxetine 20mg bd, amiloride 5mg bd or riluzole 50mg bd). Patients will be followed up for 96 weeks with outcome-data collected after 0, 24, 48 and 96 weeks. That is, the duration of the trial for a trial participant is 96 weeks (a telephone assessment at week 100, 4 weeks post completion will be conducted). This is standard practice for phase II trials in SPMS.

MS-SMART: Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial

A Multi-arm Phase IIB Randomised, Double Blind Placebo-controlled Clinical Trial Comparing the Efficacy of Three Neuroprotective Drugs in Secondary Progressive Multiple Sclerosis.

Persistent new T1 hypointense lesion count to assess neuroprotection in new lesions.

Grey matter volume change to assess cortical neuroprotection.

MR spectroscopy (MRS) to measure N-acetyl aspartate (reversal of neuronal mitochondrial dysfunction), myoinositol (prevention of glial cell inflammation) and glutamate (prevention of excitotoxicity).

Magnetic Transfer Ratio (MTR) to evaluate myelination.

Cervical cord imaging to assess cord neuroprotection.

Composite MRI/disability scores to increase sensitivity and study interaction of treatment mechanisms.

Quantification of Cerebrospinal fluid (CSF) neurofilament levels to measure neuroprotection.

Optical Coherence Tomography (OCT) measured Retinal Nerve Fibre Layer (RNFL) thickness as a measure of neuroprotection.

To establish whether a drug, from a panel of 3 leading candidate neuroprotective drugs, slows the rate of brain volume loss in SPMS over 96 weeks using MRI-derived percentage brain volume change (PBVC).

To establish that a multi-arm trial strategy is an efficient way of screening drugs in SPMS and can become the template for future work.

To explore any anti-inflammatory drug activity using the count of new and enlarging T2 lesions.

Examining for evidence of pseudo-atrophy (to ensure reliability of the primary outcome measure).

To examine the clinical effect of neuroprotection as measured by clinician - EDSS, MSFC, SDMT, SLCVA, relapse rate and patient reported outcome measures - MSIS29 v2, MSWS v2, Pain - NPRS and BPI and Fatigue - NFI.

To collect basic health economic data (EQ-5D) to inform future phase III trials.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Lithium Treatment to Prevent Cognitive Impairment After Brain Radiotherapy	NCT06051240	Cognitive Impai... Cognitive Decli... Radiotherapy Si... Radiotherapy; C... Brain Tumor Memory Impairme... Late Effect of ...	Lithium Placebo	5 Years -	Region Stockholm
Lithium Treatment to Prevent Cognitive Impairment After Brain Radiotherapy	NCT06051240	Cognitive Impai... Cognitive Decli... Radiotherapy Si... Radiotherapy; C... Brain Tumor Memory Impairme... Late Effect of ...	Lithium Placebo	5 Years -	Region Stockholm
Lithium Treatment to Prevent Cognitive Impairment After Brain Radiotherapy	NCT06051240	Cognitive Impai... Cognitive Decli... Radiotherapy Si... Radiotherapy; C... Brain Tumor Memory Impairme... Late Effect of ...	Lithium Placebo	5 Years -	Region Stockholm
MS-SMART: Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial	NCT01910259	Secondary Progr...	Amiloride Riluzole Fluoxetine Placebo	25 Years - 65 Years	University College, London

Spots Global Cancer Trial Database for neuroprotective