Ketamine for Multiple Sclerosis Fatigue

Study Overview
=================
Brief Summary
-----------------
The proposed study is a single-center, phase II, randomized, double-blind, parallel-group, active-placebo-controlled trial of intravenous low-dose ketamine in patients with MS fatigue.

Official Title
-----------------
Low-Dose Ketamine Infusion for the Treatment of Multiple Sclerosis Fatigue (INKLING-MS)

Conditions
-----------------
Multiple Sclerosis Fatigue

Intervention / Treatment
-----------------
* Drug: Ketamine
* Drug: Midazolam


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject must be a man or woman, 18 to 65 years of age, inclusive. Subject must be medically stable based on physical examination, medical history, and vital signs Subject must meet McDonald 2017 diagnostic criteria for multiple sclerosis based on the PI review of the medical records Subject must complain from fatigue as one of their main symptoms and have a screening MFIS score equal or higher than the cutoff based on gender, age, and education displayed in Table-226 Subject must be ambulatory (able to walk at least 20 feet using bilateral assistance) Subject must have internet and email access and ability to use a computer or tablet or smartphone Subjects that are currently taking medication for alleviating fatigue (such as amantadine, modafinil and armodafinil, and amphetamine-like psychostimulants) at Screening are eligible to participate unless the medication is one of the disallowed therapies (Table 3). Subjects taking a fatigue medication at the Screening visit must have been receiving a stable dose for at least four weeks before the Screening visit and be willing to continue the medication at the same dose for the duration of the study. Exclusion Criteria: BDI-II score of more than 29 (indicating severe depression) Having a known clear cause for secondary fatigue, such as untreated sleep apnea, untreated hypothyroidism, chronic liver disease, history of moderate to severe anemia (hemoglobin concentration of less than 9 gr/dl in men or less than 8 gr/dl in women). Neurodegenerative disorders other than relapsing or progressive MS Breastfeeding or pregnant History of coronary artery disease or congestive heart failure Uncontrolled hypertension at Screening (history of high blood pressure and screening systolic blood pressure >160 or diastolic blood pressure>100) History of severe liver disease, including cirrhosis Terminal medical conditions Currently treated for active malignancy Alcohol or substance abuse in the past year (except marijuana or other cannabinoids) A history of intolerance or allergic or anaphylactic reaction to ketamine or midazolam Clinically unstable medical or psychiatric disorders that require acute treatment as determined by the PI History of severe or untreated coronary artery disease or history of congestive heart failure History of prior ischemic or hemorrhagic stroke and cerebral vascular aneurysms. History of recurrent seizures or epilepsy Taking any disallowed therapy(ies), as noted in the protocol.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketamine-Ketamine<br>Participants in this arm will receive two infusions of ketamine four weeks apart. | Drug: Ketamine<br>* Infusion of ketamine 0.5 mg/kg over 40 minutes<br>|
| Experimental: Ketamine-Midazolam<br>Participants in this arm will receive one infusion of ketamine followed four weeks later by an infusion of midazolam. | Drug: Ketamine<br>* Infusion of ketamine 0.5 mg/kg over 40 minutes<br>Drug: Midazolam<br>* Infusion of midazolam 0.05 mg/kg over 40 minutes<br>|
| Experimental: Midazolam-Ketamine<br>Participants in this arm will receive one infusion of midazolam followed four weeks later by an infusion of ketamine. | Drug: Ketamine<br>* Infusion of ketamine 0.5 mg/kg over 40 minutes<br>Drug: Midazolam<br>* Infusion of midazolam 0.05 mg/kg over 40 minutes<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Fatigue Impact Scale (MFIS) Score | The total score of the MFIS ranges from 0 to 84. Higher scores denote more severe fatigue. | Baseline (infusion visit) through four weeks after the infusion. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fatigue Severity Scale (FSS) | The total score of the FSS ranges from 1 to 7. Higher scores denote more severe fatigue. | Baseline (infusion visit) through four weeks after the infusion. | 
| Epworth Sleepiness Scale (ESS) | The total score of the ESS ranges from 0 to 24. Higher scores denote more severe sleepiness. | Baseline (infusion visit) through four weeks after the infusion. | 
| Beck Depression Inventory-II (BDI-II) | The total score of the BDI-IIranges from 0 to 63. Higher scores denote more severe depression. | Baseline (infusion visit) through four weeks after the infusion. |