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Histaminergic Basis of Central Fatigue in Multiple Sclerosis - A Novel Approach

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03266965
Recruitment Status : Completed
First Posted : August 30, 2017
Last Update Posted : October 8, 2020
Sponsor:
Collaborator:
United States Department of Defense
Information provided by (Responsible Party):
Kottil W. Rammohan, University of Miami

Brief Summary:
The histaminergic system is phylogenetically one of the oldest parts of the nervous system but it is a relatively recent discovery. It is involved with several vegetative functions like sleep, attention and learning, feeding and satiety, working memory, cognition, depression, and most of all arousal and energy

Condition or disease Intervention/treatment Phase
Multiple Sclerosis Drug: Carbidopa Dietary Supplement: L-Histidine Phase 1

Detailed Description:
  1. Establish in an open label clinical trial the tolerability and safety of various doses of l-histidine and lodosyn that may increase levels of l-histidine and histamine in the serum and cerebrospinal fluid (CSF).
  2. Perform pharmacokinetic studies in serum and CSF of study subjects the levels of l-histidine and histamine after treatment with various combination of l-histidine and lodosyn.
  3. Preliminary information will also be collected on the effects of this intervention on alleviation of fatigue.

The findings from this study go beyond the effects of histamine on fatigue. If central histamine can be increased by the strategy outlined above, a number of other vegetative hypothalamic functions intricately associated with fatigue including sleep, cognition and satiety need to be examined in MS patients in future studies.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Histaminergic Basis of Central Fatigue in Multiple Sclerosis - A Novel Approach
Actual Study Start Date : March 23, 2018
Actual Primary Completion Date : August 7, 2020
Actual Study Completion Date : August 7, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Histidine Intervention Group
A total of 15 subjects will be recruited in batches of 5 until completed 15 subjects in the trial. If a subject withdraws the trial, the study will continue and enrolling subjects until 15 of them complete the trial. The subject composition (MS patient/Normal subject) 4 MS and 1 normal will be tested on a dose of L-Histidine 250 mg plus Lodosyn 50 mg BID for seven days. If there are no safety concerns, the next 5 patients will be recruited 4 MS and 1 normal to test the dose of 500 mg with Lodosyn 50 mg bid for seven days. If there are no safety concerns, then L-histidine 1,000 mg plus Lodosyn (Carbidopa) 50 mg bid will be tested in the next 5 subjects 4 MS and 1 normal for seven days.
Drug: Carbidopa
All subjects will receive a fixed dose of 50mg of Lodosyn twice daily.
Other Name: Lodosyn

Dietary Supplement: L-Histidine
Sequential Dose Escalation of 250mg to 500mg to 1000mg twice daily.




Primary Outcome Measures :
  1. Number of adverse events experienced by participants. [ Time Frame: 30 days ]
    All adverse and serious adverse events reported during the study will be analyzed and tabulated. No quantitative statistical analysis will be performed. The primary goal of this study is to establish that this intervention is safe and possibly effective.


Secondary Outcome Measures :
  1. Change extent of fatigue. [ Time Frame: Screening(0 day), baseline(15 days) and final visit(30 days) ]
    At the conclusion of the study, each individual would have completed a screening and baseline visit without any intervention and two weekly visits during intervention with the study medications. The two evaluations off drug will be compared to the two evaluations on drug. A drop of the Fatigue Severity Scale (FSS) score by 1 point or more will be considered a response. Once the information is converted into a binary function of response / no response, the data is amenable to conditional logistic regression analysis.

  2. Change in Quality of life. [ Time Frame: Screening(0 day), baseline(15 days) and final visit(30 days) ]
    Multiple Sclerosis Quality of Life (MSQOL) scales will be used to measure the change in Quality of Life. Based on the scale, there will be a 0 to 100 with a higher score indicating a higher quality of life.

  3. Change of fatigue impact scale. [ Time Frame: Screening(0 day), baseline(15 days) and final visit(30 days) ]
    Modified Fatigue Impact Scale (MFIS) scale will be used to evaluate the physical, cognitive and psychosocial scores. The score ranges from 0 to 84 with a lower score, lower side effects of fatigue.

  4. Change of visual pain. [ Time Frame: Screening(0 day), baseline(15 days) and final visit(30 days) ]
    Visual analogue scale to evaluate the pain by using a numerical scale for 0 to 10 with a lower score, less visual pain.

  5. Change of daytime sleepiness. [ Time Frame: Screening(0 day), baseline(15 days) and final visit(30 days) ]
    Epworth sleep scale to rate the probability of falling asleep during daytime on a scale of 0 to 24 with a lower score the lower the symptoms of sleepness.

  6. Change of hunger sensitivity. [ Time Frame: Screening(0 day), baseline(15 days) and final visit(30 days) ]
    Hunger Satiety Scale to determine the extent of hunger and fullness by using a 1 to 10 score range with a higher score indicating a higher hunger sensitivity.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria for Healthy Volunteers:

  1. Male or female subjects between the ages of 18 and 60 will be eligible.
  2. Subjects should be in good physical health without history of chronic illness and should be generally considered healthy.
  3. Spouses or caregivers of patients with MS would be encouraged to participate.

Inclusion Criteria for Patients with Multiple Sclerosis (MS):

  1. Patients with MS regardless of the disease type, who experience severe fatigue will be eligible to participate.
  2. Fatigue Severity Score of >/= 4.0 will qualify as long as all other inclusion / exclusion criteria are met.
  3. Established MS by McDonald Criteria - 2010 Revision (24). Relapse Remitting (RR) and progressive forms of MS are eligible
  4. Severe fatigue that has lasted greater than 6 months
  5. Clinically stable on a current therapy with any Disease Modifying Therapy (DMT)

Exclusion Criteria for Healthy Volunteers:

  1. Adults unable to give informed consent due to cognitive impairment or mental disorders.
  2. Children below the age of consent
  3. Pregnant women
  4. Prisoners
  5. History of chronic disorders like hypertension, diabetes, hyperlipidemia, depression, hypothyroidism etc. that require chronic treatment
  6. Known chronic fatigue syndrome
  7. Blood disorders or coagulopathy
  8. Chronic allergies or history of asthma.
  9. Using antihistamines, bronchodilators or H2 blockers for hyperacidity
  10. Using medications for sleep, or known sleep disorders
  11. Any medication or condition deemed unsuitable by the PI

Exclusion Criteria for Patients with Multiple Sclerosis (MS):

  1. Adults unable to give informed consent due to cognitive impairment or mental disorders.
  2. Children below the age of consent
  3. Pregnant women
  4. Prisoners
  5. Systemic disorders known to cause fatigue such as severe anemia, infections, chronic systemic infectious or inflammatory disorders, including known autoimmune disorders.
  6. Chronic fatigue syndrome
  7. Hypothyroidism
  8. Systemic malignancy
  9. Undergoing chemotherapy
  10. Depression
  11. Sleep disorders including narcolepsy, excessive day-time sleep.
  12. History of substance abuse
  13. Excessive consumption of coffee or over-the-counter stimulants
  14. Concomitant medications of amantadine, methylphenidate, amphetamines, pemoline, barbiturates, tizanidine, Monoamine oxidase inhibitor (MAO) inhibitors, benzodiazepines, barbiturates, tricyclic antidepressants, antihistamines, H2 blockers for gastro-esophageal reflux disease (GERD), selective serotonin reuptake inhibitors (SSRIs) and any other medication that in the opinion of the PI should be excluded.
  15. Patients who were using modafinil for treatment of fatigues prior to the study may participate but will be required to undergo a washout of 2 weeks prior to entry into the trial.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03266965


Locations
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United States, Florida
University of Miami
Miami, Florida, United States, 33136
Sponsors and Collaborators
University of Miami
United States Department of Defense
Investigators
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Principal Investigator: Kottil Rammohan, MD University of Miami
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Responsible Party: Kottil W. Rammohan, Professor Of Clinical Neurology, University of Miami
ClinicalTrials.gov Identifier: NCT03266965    
Other Study ID Numbers: 20161186
W81XWH-16-1-0462 ( Other Grant/Funding Number: Department of Defense )
First Posted: August 30, 2017    Key Record Dates
Last Update Posted: October 8, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Kottil W. Rammohan, University of Miami:
Fatigue
Histamine
Additional relevant MeSH terms:
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Multiple Sclerosis
Sclerosis
Fatigue
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Carbidopa
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Aromatic Amino Acid Decarboxylase Inhibitors
Enzyme Inhibitors