Study of Pyridostigmine With Ondansetron in Subjects With Anti-AchR Positive Myasthenia Gravis

Study Overview
=================
Brief Summary
-----------------
This is a phase II, single center, randomized, double-blind, placebo-controlled, study in patients with a diagnosis of anti-AchR antibody positive myasthenia gravis.

Detailed Description
-----------------
Methodology: This is a phase II, single center, randomized, double-blind, placebo-controlled, study in patients with a diagnosis of anti-AchR antibody positive myasthenia gravis. Study Design: The clinical trial will be conducted over a 6-week treatment period. Group A: Patients currently taking pyridostigmine and experiencing pyridostigmine-related gastrointestinal (GI) adverse events (AEs) within the past 7 days Group B: Patients not currently taking pyridostigmine due to GI AEs or that had their dose reduced due to pyridostigmine related GI AEs Group A will be enrolled in the study and randomized to either the control (pyridostigmine+ placebo) or the test group (pyridostigmine + ondansetron) and treated for 6 weeks. Following enrolment, patients may (if needed) titrate up their pyridostigmine dose at the investigator's discretion each week to the highest dose deemed appropriate, tolerable and safe by the Investigator. Group B patients not currently taking pyridostigmine due to GI AEs will initiate pyridostigmine at a dose determined by the investigator based on the patient's history and may titrate as deemed tolerable and safe by Investigator during screening; patients on a reduced dose due to pyridostigmine related GI AEs may titrate pyridostigmine as deemed tolerable and safe by the investigator during screening. If patients in Group B experience GI AEs that fulfil enrolment criteria, along with all other inclusion/exclusion criteria, they will be enrolled into the study at that dose and randomized to either the control (pyridostigmine+ placebo) or the test group (pyridostigmine + ondansetron) and treated for 6 weeks. Following enrolment, patients may (if needed) titrate up their pyridostigmine dose at the investigator's discretion each week to the highest dose deemed appropriate, tolerable and safe by the Investigator.

Official Title
-----------------
A Phase II, Study to Evaluate the Safety and Tolerability of Pyridostigmine When Given With Ondansetron to Subjects With Anti-AchR Positive Myasthenia Gravis

Conditions
-----------------
Myasthenia Gravis

Intervention / Treatment
-----------------
* Drug: DAS-001


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: diagnosed with myasthenia gravis and who are currently taking pyridostigmine and experienced pyridostigmine-related GI side effects within the past 7 days. GSRS rating of at least Moderate discomfort on questions 5, 11, and 12. Subjects must be willing and able to complete a GI symptom diary within a consistent timeframe on a daily basis. Subjects must be able to tolerate a pyridostigmine dose of 30mg TID. Must be clinically stable in judgement of treating neurologists for past 3 months. Must have AchR antibody positive MG. Subjects must be able to swallow liquids. Subjects must be in good health as determined by their medical history, physical examination, vital signs, and laboratory tests. A subject with a medical abnormality may be included only if the investigator or designee considers that the abnormality will not introduce significant additional risk to the subject's health or interfere with study objectives. Subjects must have signed an informed consent form indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study and comply with the study procedures and restrictions. Exclusion Criteria: Key exclusion criteria: The criteria for exclusion of a subject from enrollment in the study are as follows: Any acute or chronic diseases which are associated with GI distress (such as nausea, vomiting, or diarrhea), which could interfere with the subjects' safety during the trial, expose them to undue risk, or interfere with the study objectives. History or presence of hepatic, or renal disease or other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs. History of substance abuse, known drug addiction, or positive test for drugs of abuse or alcohol. Patients currently using marijuana for any reason (medical or recreational). Known hypersensitivity to pyridostigmine, or to ondansetron or similar 5-HT3 serotonin receptor antagonists. ECG changes including QT interval prolongation and congenital long QT syndrome. Electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmia's or other medicinal products that lead to QT prolongation. Treatment with drugs affecting peripheral cholinergic transmission within 1 month of study entry (with the exception of pyridostigmine). Subjects unlikely to co-operate during the study, and/or be questionably compliant in the opinion of the investigator. Patients currently being treated with narcotics. Patients being treated with aminoglycoside antibiotics, which are contraindicated in myasthenia gravis. Patients unable to be contacted in case of an emergency. Intake of an investigational drug within 30 days of study entry. Pregnancy and women of childbearing potential not willing to follow the birth control requirements as described in the informed consent or breastfeeding. History or presence of obstructive pulmonary disease or urinary obstruction (contraindication for pyridostigmine). This use of selective serotonin reuptake inhibitors (SSRI's).

Ages Eligible for Study
-----------------
Minimum Age: 18 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: Single Group Assignment
Interventional Model Description: randomized to ondansetron + pyridostigmine or placebo+ pyridostigmine in a 3:1 ratio.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: treatment<br>ondansetron + pyridostigmine | Drug: DAS-001<br>* ondansetron + pyridostigmine<br>|
| Placebo Comparator: Placebo<br>placebo+ pyridostigmine | Drug: DAS-001<br>* ondansetron + pyridostigmine<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with change in the gastrointestinal (GI) side effects | difference in GI side effects as measured by the GSRS-self (Gastrointestinal System Rating Scale - self-administered) | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with change in the side effects | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 . Incidence and nature of adverse events | 6 weeks | 
| Number of participants with change in in physical examine | physical examination changes General appearance,Head, eyes, ears, nose, and throat, Respiratory, Cardiovascular, Musculoskeletal, Abdomen, Neurologic, Extremities, Dermatologic, Lymphatic) | 6 weeks | 
| Number of participants with change in in clinical laboratory evaluations | changes in clinical laboratory evaluations (Creatinine, Potassium(K+),Sodium (Na+) , Chloride (Cl-), Magnesium (Mg++), Calcium, Inorganic phosphate, Glucose, Urea,Bilirubin (Total) ,Bilirubin (direct), AST, ALT, GGT, Alkaline phosphatase, Total Protein, Albumin,Hematocrit Hemoglobin Platelet count Red blood cell (RBC) count WBC count WBC differential Mean cell volume (MCV) Mean cell hemoglobin (MCH) MCH concentration (MCHC) | 6 weeks | 
| Number of participants with change in Electrocardiography (ECG) | ECG (standard digital 12-lead in singlicate) | 6 weeks | 
| Plasma concentrations of pyridostigmine | Cmax | 6 weeks | 
| Plasma concentrations of ondansetron | Cmax | 6 weeks |