Histaminergic Basis of Fatigue in Multiple Sclerosis

The purpose of this research study is to identify a way to improve the feeling of exhaustion that patients might experience because of Multiple Sclerosis (MS).

Study Overview

• Status: Withdrawn
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Drug: L-Histidine; Drug: Lodosyn; Drug: Placebo

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion and Exclusion Criteria

For Healthy (Normal) Participants

Inclusion Criteria:

• Male or female subjects between the ages of 18 and 60
• In good physical health without a history of chronic illness and considered generally healthy.

Exclusion Criteria:

• Adults unable to give informed consent due to cognitive impairment or mental disorders.
• Children below the age of consent
• Pregnant women (if the pregnancy test is positive during any stage of the study, subject will be removed from it)
• Prisoners
• Chronic untreated disorders like hypertension, diabetes, hyperlipidemia, depression, hypothyroidism etc., that could confound or interfere with the proposed therapy in the view of the PI are excluded. Stable treated above conditions are not exclusionary.
• Known chronic fatigue syndrome
• Blood disorders or coagulopathy
• Chronic allergies or history of asthma.
• Using antihistamines, bronchodilators or H2 blockers for hyperacidity
• Using medications for sleep, or known sleep disorders
• Any medication or condition deemed unsuitable by the PI. If necessary, subjects should wash out such medications for a duration of at least 5 half-lives.
• All medications prescribed and over the counter, should be approved by the PI during the duration of the trial.

For Multiple Sclerosis Participants

Inclusion Criteria:

• Established Multiple Sclerosis by McDonald Criteria - 2010 Revision or McDonald Criteria 2017. Relapsing-Remitting and progressive forms of MS are eligible
• Severe fatigue that has lasted greater than 6 months
• Clinically stable on a current therapy with any Disease Modifying Therapies (DMT)
• Fatigue Severity Score of >/= 4.0 will qualify as long as all other inclusion/exclusion criteria is met.

Exclusion Criteria:

• Adults unable to give informed consent due to cognitive impairment or mental disorders.
• Children below the age of consent
• Pregnant women (if the pregnancy test is positive during any stage of the study, subject will be removed from it)
• Prisoners
• Systemic disorders known to cause fatigue such as severe anemia, infections, chronic systemic infectious or inflammatory disorders, including known autoimmune disorders. (allowed as long is not present. Subject might qualify as per discretion of the Principal Investigator)
• Chronic fatigue syndrome
• Hypothyroidism (If treated and/or controlled subject might qualify as per discretion of the Principal Investigator)
• Systemic malignancy. Remote history of a malignancy is not a contraindication.
• Undergoing chemotherapy
• Depression (If treated and/or controlled subject might qualify as per discretion of the Principal Investigator)
• Sleep disorders including narcolepsy, excessive day-time sleep. (If treated and/or controlled subject might qualify as per discretion of the Principal Investigator)
• Ongoing substance abuse
• Excessive consumption of coffee or over-the-counter stimulants. Use of caffeine is not exclusionary but subjects are instructed to not change the use for the duration of the study.
• Concomitant medications of amantadine, methylphenidate, amphetamines, pemoline, barbiturates, tizanidine, MonoAmine Oxidase (MAO) inhibitors, benzodiazepines, barbiturates, tricyclic antidepressants, antihistamines, H2 blockers for Gastroesophageal reflux disease (GERD), Selective Serotonin Reuptake Inhibitor (SSRIs) and any other medication that in the opinion of the PI should be excluded. If used and approved by the PI at study entry, any change for the duration of the study is not permitted.
• Patients who were using modafinil for treatment of fatigues prior to the study may participate but will be required to undergo a washout of five half-lives prior to entry into the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PK/PD Group; Participants in the Pharmacokinetic (PK)/pharmacodynamic (PD) Group will receive L-Histidine and Lodosyn daily for 7 consecutive days.	Drug: L-Histidine; 1000 mg capsules taken by mouth (PO) twice daily (BID).; Other Names: Histamine; Drug: Lodosyn; 50 mg capsules taken PO BID.
Placebo Comparator: L-Histidine and Lodosyn followed by Placebo Group; Participants in this group will receive L-Histidine and Lodosyn daily for 2 consecutive weeks followed by Placebo for an additional 2 consecutive weeks with a 1-week wash-out period in between.	Drug: L-Histidine; 1000 mg capsules taken by mouth (PO) twice daily (BID).; Other Names: Histamine; Drug: Lodosyn; 50 mg capsules taken PO BID.; Drug: Placebo; Microcrystalline cellulose (placebo) 1000 mg capsules taken by mouth (PO) twice daily (BID).
Experimental: Placebo followed by L-Histidine and Lodosyn Group; Participants in this group will receive Placebo daily for 2 consecutive weeks followed by L-Histidine and Lodosyn for an additional 2 consecutive weeks with a 1 week wash out period in between.	Drug: L-Histidine; 1000 mg capsules taken by mouth (PO) twice daily (BID).; Other Names: Histamine; Drug: Lodosyn; 50 mg capsules taken PO BID.; Drug: Placebo; Microcrystalline cellulose (placebo) 1000 mg capsules taken by mouth (PO) twice daily (BID).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events	Adverse events will be evaluated by treating physician.	Up to 5 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy as measured by FSS scores	Efficacy will be reported as the number of participants that dropped one point or more from their baseline Fatigue Severity Scale (FSS) scores. FSS is a 9-item questionnaire with questions related to how fatigue interferes with certain activities according to a self-reported scale. Each of the items are scored on a 7 point scale with 1 = strongly disagree and 7 = strongly agree.	Up to 5 weeks
Efficacy as measured by MFIS Scores	Modified Fatigue Impact Scale (MFIS) is a scale is used to measure fatigue with the total score ranging from 0 to 84 with 0 being the best possible score and 84 being the worst score.	Up to 5 weeks
Efficacy as measured by the VAS scores	The Visual Analog Scale (VAS) allows participants to rate their health on a 20 cm vertical with a higher number indicating better outcomes.	Up to 5 weeks
Efficacy as measured by the MSQOL Scores	Multiple Sclerosis Quality of Life (MSQOL) has a total score ranging from 0 to 100 with a higher score indicating a better quality of life.	Up to 5 weeks

Collaborators and Investigators

• Sponsor: University of Miami
• Investigators: Principal Investigator: Kottil Rammohan, MD, University of Miami

Study record dates

Study Major Dates

• Study Start (Anticipated): January 1, 2022
• Primary Completion (Anticipated): October 30, 2022
• Study Completion (Anticipated): October 30, 2022

Study Registration Dates

• First Submitted: February 18, 2021
• First Submitted That Met QC Criteria: February 18, 2021
• First Posted (Actual): February 21, 2021

Study Record Updates

• Last Update Posted (Actual): July 29, 2021
• Last Update Submitted That Met QC Criteria: July 22, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Fatigue; Histamine
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Fatigue; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Histamine Agents; Histamine Agonists; Histamine
• Other Study ID Numbers: 20201550

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• 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