EIP19-NFD-401

WITHIN SUBJECT CROSSOVER STUDY OF COGNITIVE EFFECTS OF NEFLAMAPIMOD IN EARLY-STAGE HUNTINGTON DISEASE

Terminated

SPONSOR

EIP Pharma Inc

PARTICIPANTS

16

The main purpose of EIP19-NFD-401 is to determine whether a drug called Neflamapimod can improve cognitive functions (planning, memory etc) in patients with early-stage Huntington’s disease (HD). The drug is taken orally. In the study 16 patients will receive the drug for 10 weeks and then be given placebo for 10 weeks or vice versa. Neither the doctor nor the patient knows in which period they get the active drug or the placebo. The effect will be tested with different cognitive tests. Neflamapimod target an enzyme in the brain called p38 alpha. The aim is to reduce expression of the enzyme in neurons and enable the cells to function better. The drug has proven promising effect in animal tests and it is also currently being tested on patients with Alzheimers Disease. 

Study terminated (Due to the long delay because of COVID-19 and results from another study suggesting a higher dose may be more beneficial, EIP Pharma decided on October 15th, 2020, to end the trial prematurely.)

Ages Eligible for Study:

30 Years to 70 Years (Adult, Older Adult)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Inclusion Criteria

  • Men and women age 30 to 70 years, inclusive.
  • Willing and able to provide informed consent.
  • Must have genetically confirmed HD and identified cognitive deficits
    • Stage 1, as defined by Unified Huntington’s Disease Rating Scale (UHDRS) Total Functional Capacity (TFC) score >10, and,
    • CANTAB Paired Associate Learning Total Adjusted Error Score of >16.
  •  
  • Normal or corrected eye sight and auditory abilities, sufficient to perform all aspects of the cognitive and functional assessments.
  • No history of learning difficulties that may interfere with the subject’s ability to complete the cognitive tests.

Exclusion Criteria

  • A profile of impairment that is not consistent with Huntington’s disease (HD).
  • Diagnosis of any other ongoing central nervous system condition other than HD, including, but not limited to, vascular dementia, dementia with Lewy bodies, and Parkinson’s disease.
  • Suicidality, defined as active suicidal thoughts within 6 months before Screening or at Baseline, defined as answering yes to items 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS), or history of suicide attempt in previous 2 years, or, in the Investigator’s opinion, at serious risk of suicide.
  • Ongoing major and active psychiatric disorder, moderate to severe depressive symptoms, and or other concurrent medical condition that, in the opinion of the Investigator, might compromise safety and/or compliance with study requirements.
  • Diagnosis of alcohol or drug abuse within the previous 2 years.
  • Poorly controlled clinically significant medical illness, such as hypertension (blood pressure >180 mmHg systolic or 100 mmHg diastolic); myocardial infarction within 6 months; uncompensated congestive heart failure or other significant cardiovascular, pulmonary, renal, liver, infectious disease, immune disorder, or metabolic/endocrine disorders or other disease that would preclude treatment with p38 mitogen activated protein (MAP) kinase inhibitor and/or assessment of drug safety and efficacy.
  • Anemia with a hemoglobin ≤10 g/dL, clinically significant thyroid function abnormality, electrolyte abnormalities.
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 × the upper limit of normal (ULN), total bilirubin >1.5 × ULN, and/or International Normalized Ratio (INR) >1.5.
  • Known human immunodeficiency virus; or active hepatitis B or hepatitis C virus infection; evidence of active or latent tuberculosis.
  • Subject participated in a study of an investigational drug less than 3 months or 5 half-lives of an investigational drug, whichever is longer, before enrollment in this study.
  • History of previous neurosurgery to the brain.
  • Female subjects who are pregnant or breast-feeding.
  • Male subjects with female partners of child-bearing potential who are unwilling or unable to adhere to contraception requirements specified in the protocol (see Section 5.8).
  • Female subjects who have not reached menopause or have not had a hysterectomy or bilateral oophorectomy/salpingo-oophorectomy and are not willing or unable to adhere to contraceptive requirements specified in the protocol (see Section 5.8).
  • Requires concomitant use of cytochrome P450 (CYP) 3A4 inhibitors or anti-tumor necrosis factor-alpha therapies during study participation.
  • Known allergy to any ingredient of the trial medication or placebo.

COUNTRIES

UNITED KINGDOM

TRIAL SITE:
John Van Geest Centre for Brain Repair
Address: Cambridge, United Kingdom

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phenoptype

Phenotype refers to an individual’s observable traits, such as height, eye color and blood type. A person’s phenotype is determined by both their genomic makeup (genotype) and environmental factors.

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oxidative seres

an imbalance between unstable molecules called “free radicals” and protective “antioxidants” in your body

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Metabolism & bioenergetics

describe how your body turns food into fuel and uses that energy to live. 

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Small Molecule

a tiny chemical compound, much smaller than big biological structures like proteins, that can easily travel inside our cells to act as medicine (like aspirin or ibuprofen), a building block (like glucose), or a signaling tool in the body, often taken as pills because they’re easy to absorb and distribute

 

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Nucleic acid

(DNA and RNA) are the essential information-carrying molecules in all life, acting like blueprints that store and transmit genetic instructions for building and operating cells, directing everything from growth to protein production, and passing traits from parents to offspring.

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SNP-single nucleotide polymorphisms

a single-letter spelling difference in a gene. SNPs, pronounced ‘snips’, are common and most don’t change the function of the gene.

 
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at risk

You do not know if you carry the genetic mutation for HD gene 

 
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TFC-total functional capacity

A standardized rating scale for function in HD, used to assess capacity to work, handle finances, perform domestic chores and self-care tasks.
Scores range from 0 to 13, with higher scores indicating better functional capacity. 

 
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Double-blinded

 means that neither the participant nor the clinical trial doctor can choose or know the group the participant is in until the trial is over. This approach helps to prevent bias.

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Open label

A trial in which the patient and doctor know what drug is being used. Open label trials are susceptible to bias through placebo effects.

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Gene therapy

a technique that aims to treat or prevent diseases by modifying a person’s genes. It involves introducing, removing, or changing genetic material (DNA or RNA) within a patient’s cells.

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UHDRS- Unified Huntington Disease Rating Scale

A standardized neurological examination that aims to provide a uniform assessment of the clinical features of HD

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CAG repeat

The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD

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Wild-type

the opposite of ‘mutant’. Wild-type huntingtin, for example, is the ‘normal’, ‘healthy’ protein

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Tolerabilty

How well a person can handle a treatment without having serious or uncomfortable side effects.

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Striatum

Part of the brain that  coordinates multiple aspects of cognition, including both motor and action planning, decision-making, motivation, reinforcement, and reward system.

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Randomized allocation

A type of allocation strategy in which participants are assigned to the arms of a clinical trial by chance.

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Radioligand

a radioactive substance that binds to a specific target in the body, allowing visualization of that target’s distribution and activity

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Protein

Protein builds, maintains, and replaces the tissues in your body. The building blocks of life.

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Premanifest / Prodromal

Prior to onset or diagnosis of movement symptoms.

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Placebo

A placebo is a dummy medicine containing no active ingredients. The placebo effect is a psychological effect that causes people to feel better even if they’re taking a pill that doesn’t work.

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PK - Pharmacokinetics

The movement of drugs through the body

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PD - Pharmacodynamics

The body’s biological response to drugs

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PET scan

Positron emission tomography which produces detailed 3-dimensional images of the inside of the body.

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Neuron

Brain cells that store and transmit information

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MRI

Magentic resonance imaging: A technique using powerful magnetic fields to produce detailed images and visualizes the structure of organs, tissues, and bones 

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mHTT

Mutant huntingtin protein. The protein produced by the faulty HD gene.

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Manifest

after HD diagnosis, or when symptoms are already showing

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Longitudinal study

A study where each participant is looked at several times over a time period – unlike a cross-sectional study, where each participant is looked at only once

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HTT

one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15

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fMRI

functional MRI:As with MRI, a technique using powerful magnetic fields  but focusing on brain function by measuring and mapping changes in blood flow, revealing which areas of the brain are active during specific tasks or cognitive processes

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CSF - cerebrospinal fluid

A clear fluid produced by the brain, which surrounds and supports the brain and spinal cord.

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Efficacy

A measure of whether a treatment works or not

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ASO(Antisense oligonucleotides)

A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene

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Biomarker

a test of any kind – including blood tests, thinking tests and brain scans – that can measure or predict the progression of a disease like HD. Biomarkers may make clinical trials of new drugs quicker and more reliable

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BDNF

Brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD.

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Allele

one of the two copies of a gene

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Plasma

Liquid component of the blood.

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Gene

The basic unit of heredity passed from parent to child. Genes are made up of sequences of DNA and are arranged, one after another, at specific locations on chromosomes in the nucleus of cells.

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Phase

Clinical trial phases are different stages of research that assess the safety and effectiveness of a new medical treatment or intervention in humans.

Each phase has a specific goal and involves a different number of participants. Generally, there are 4 phases (I-IV), with Phase I focusing on safety and dosage, Phase II on efficacy and side effects, Phase III on comparing the new treatment with standard treatments, and Phase IV on long-term safety monitoring.