Clinical trial NCT01406873
Conditions: Myotonic Dystrophy
Keywords: Myotonic Dystrophy Myotonic Dystrophy Type 1 (DM1) Muscular Dystrophy Mexiletine
Sponsor: University of Rochester
Start date: 2011-06-01; Completion date: 2017-03-01
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to investigate the effects of mexiletine treatment for 6 months on ambulation, myotonia, muscle function and strength, pain, gastrointestinal functioning, cardiac conduction, and quality of life in myotonic dystrophy type 1 (DM1).

Detailed description:
This study will provide data on the long term (6 months) safety and efficacy of mexiletine in:

* improving the distance participants are able to walk in six minutes;
* reducing myotonia;
* improving muscle strength;
* increasing lean muscle mass;
* decreasing musculoskeletal pain;
* improving gastrointestinal function and swallowing);
* improving functional abilities;
* decreasing cardiac arrhythmias; and
* improving disease-specific health related quality-of-life.

Arms: arm 1: 20 subjects will be randomized (assigned) to receive Mexiletine. Mexiletine is available on the market for the treatment of cardiac arrhythmias, but it is not currently approved for the treatment of myotonia or myotonic dystrophy. arm 2: 20 subjects will be randomized (assigned) to receive placebo (sugar pill). This control group is necessary to definitely establish the antimyotonic efficacy and safety of mexiletine.
Interventions: intervention 1: Mexiletine intervention 2: Placebo
Intervention descriptions: intervention 1: 150 mg/kg Mexiletine capsules taken by mouth, three times daily for 6 months intervention 2: 150 mg/kg placebo capsules taken by mouth, three times daily for 6 months

Protocol documents:
Prot_SAP_000.pdf: 
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STUDY PROTOCOL 
 
A Randomized, Placebo Controlled, Clinical Efficacy Trial of Mexiletine for 
Myotonic Dystrophy Type-1 (DM1). 
 
 
 


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A Randomized, Placebo Controlled, Clinical Efficacy Trial of Mexiletine for 
Myotonic Dystrophy Type-1 (DM1). 
  
RESEARCH PLAN 
 
A.  SPECIFIC AIMS: 
 
To evaluate the efficacy, tolerability, and safety of mexiletine in DM1 we will 
perform a six month, randomized, double-blind, trial of mexiletine (150 mg three 
times daily, n=20) vs. placebo (n=20) in ambulatory DM1 patients and pursue the 
Aims listed below.  
 
Primary Aim:  
• To determine if mexiletine (150 mg three times daily) improves six minute walk 
distances after 3 and 6 months of treatment.   
 
Secondary Aims:  
• To monitor the safety and tolerability of 6 months of mexiletine therapy. 
• To determine if mexiletine decreases myotonia (measured by relaxation time 
following maximum voluntary isometric contraction of the finger flexor muscles, 
eg. maximum hand grip) 
• To assess if 6 months of mexiletine improves grip strength, timed function tests 
(6 minute walk, time to arise from a chair and walk 30 feet, vital capacity), muscle 
mass (Dual Energy X-ray Absorptiometry (DEXA) scans), swallowing time (100 
ml of water), hand dexterity (Purdue Peg Board Test) and patient reported pain 
and gastrointestinal function. 
• To determine if mexiletine decreases the degree of cardiac conduction 
irregularities as measured by serial 24-hour Holter monitoring.  
• To assess if 6 months of mexiletine improves the health-related quality-of-life of 
patients as measured by a novel disease-specific DM1 quality-of-life instrument 
and generic quality-of-life instruments. 
  
APPROPRIATENESS FOR ORPHAN PRODUCT DEVELOPMENT GRANT 
PROGRAM: 
    
This study is being considered for funding by the FDA Orphan Product Development 
Grant Program.  It is appropriate for this program for the following reasons: 
 
 
 
1) Myotonic dystrophy type-1 is an orphan disease.  The prevalence of DM1 is 
approximately one out of every 10,000 people worldwide.1  Based on this estimate, 
there are fewer than 100,000 cases of DM1 in the United States.  Additional reports 
confirm the rarity of this disease noting prevalence of DM1 ranging from 2.4/100,000 in 
Northern Ireland, 5.5/100,000 in West Germany, and 4.9/100,000 in Switzerland. 2-4 
 
2) Mexiletine is available on the market for the treatment of cardiac arrhythmias, but it is 
not currently approved for the treatment of myotonia or myotonic dystrophy. 


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3) This study will provide data on the long term (6 months) safety and efficacy of 
mexiletine in: a) improving the distance participants are able to walk in six minutes; b) 
reducing myotonia; c) improving muscle strength; d) increasing lean muscle mass; e) 
decreasing musculoskeletal pain; f) improving gastrointestinal function and swallowing); 
g) improving functional abilities; h) decreasing cardiac arrhythmias; and, i) improving 
disease-specific health related quality-of-life as measured by a novel multi-domain 
instrument.  
 
If the safety and long term effectiveness of mexiletine is demonstrated, we anticipate 
that these results may lead to the approval of mexiletine as an orphan therapy for DM1. 
 
EVIDENCE FOR SUFFICIENT AVAILABILITY OF STUDY DRUG: 
 
Mexiletine is available by prescription for its approved indication as a ventricular 
antiarrhythmic.   For the active treatment group in this trial we will purchase 
commercially available mexiletine from Cardinal Drugs.  The exact generic brand we 
purchase depends upon the availability and price at the time of purchase.  Once 
purchased all future doses of mexiletine will be prepared using the same manufacturer’s 
product.  Since mexiletine is a commercially available product we are confident that an 
adequate supply of mexiletine will be available from Cardinal Drug to complete the 
study. 
 
EVIDENCE FOR SUFFICIENT NUMBER OF ELIGIBLE PATIENTS:   
Recruitment for this trial of mexiletine will utilize multiple sources.  These include: a) The 
University of Rochester Muscular Dystrophy Association (MDA) Clinic; b) The University 
of Rochester Medical Center (URMC) Neuromuscular Disease Center; c) direct referral 
from our local and national neuromuscular colleagues; d) the URMC NIH funded 
Wellstone Muscular Dystrophy Cooperative Research Center (MDCRC) project entitled, 
“Pathogenesis and Progression of Myotonic Dystrophy”; e) by direct advertisement on 
the MDA and NIH clinical trial websites; and, f) by using the NIH sponsored National 
Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients 
and Family Members. 
We currently provide care to many hundreds of DM1 patients through our MDA Clinic 
and the URMC Neuromuscular Disease Center.  We have established a steady referral 
base from western New York State, the Albany area, the southern tier region (northern 
Pennsylvania and southern New York State), as well as from physicians from other 
states who are familiar with our research and experience in the clinical management of 
DM1 patients.  In addition to this ready source of patients we have an active waiting list 
of DM1 patients who wish to participate in our recently funded Wellstone Center project 
mentioned above, entitled, “Pathogenesis and Progression of Myotonic Dystrophy”.  
This is a multiyear study designed to record the progression of disease in 80 ambulatory 
DM1 patients all of whom satisfy the inclusion and exclusion criteria for the study 
described in this application.  In an effort to increase the diversity of the patients 


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recruited for the current proposed trial of mexiletine, we will directly advertise and recruit 
through several widely accessed national sites, most notably those provided through the 
NIH and MDA.  Lastly, we will recruit patients through the National Registry of Myotonic 
Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family 
Members.  This registry currently has over 580 active DM1 patients and is 
headquartered at the University of Rochester.  
 
   B. BACKGROUND AND SIGNIFICANCE: 
 
Myotonic Dystrophy type-1 (DM1) is the most common adult muscular dystrophy1 and is 
caused by an unstable, trinucleotide repeat expansion on chromosome19q13.3.1  DM1 
is a multisystem, autosomal dominant disorder and affects skeletal, cardiac and smooth 
muscle, the eyes, heart, brain, skin, reproductive organs, and gastrointestinal function of 
patients.5-8  Unfortunately, the pathomechanism of, and effective treatment for, muscle 
weakness and wasting remain unknown.  One of the other cardinal features of muscle 
dysfunction in DM1 is myotonia, a delay in relaxation following muscle contraction.  This 
myotonia occurs in both skeletal and smooth muscle.  Recent studies indicate that the 
myotonia in DM1 results primarily from a decreased production of functional chloride 
channel protein. 9-12 This marked deficiency in channel protein is due to abnormal 
splicing of chloride channel pre-mRNA, caused by sequestration of the nuclear 
regulatory protein, muscleblind, by the abnormally expanded mutant DM1mRNA that 
accumulates in the myonuclei. 13-17  Myotonia may contribute to muscle pain, difficulty 
with ambulation, trouble swallowing, gastrointestinal complaints, and possibly to the 
skeletal muscle weakness and wasting that afflicts DM1 patients.  To date there is no 
cure or approved therapeutic agent for DM1.  Care focuses on symptomatic 
management, use of assistive devices for ambulation and breathing, and monitoring of 
cardiac conduction with the use of pacemaker treatment as needed. 1 
 
Mexiletine hydrochloride is a promising therapy for myotonic dystrophy.  Mexiletine has 
been used for over 35 years by cardiologists as a treatment for cardiac arrhythmias. 18  
In addition to being an effective antiarrhythmic, mexiletine has reduced myotonia in 
patients with non-dystrophic myotonia and with DM1 (n=9). 19  Previous case reports 
and our more recent FDA funded 7 week, double-blind, randomized, placebo controlled, 
crossover trial at the University of Rochester have strongly supported the use of 
mexiletine as an effective antimyotonia drug in DM1. 20-22   During the University of 
Rochester study, two standard antimyotonic dosages were tested, 150 mg TID and 200 
mg TID.  This study demonstrated that these dosages were able to significantly reduce 
the amount of clinical myotonia while being safe both safe and well tolerated. 22 In 
addition, the 150 mg TID dose produced a statistically significant improvement in hand 
strength. 22  A copy of our recent manuscript reporting results of this FDA funded 7 week 
trial is provided in Appendix A.   Despite the promising results of this study, a long-term, 
placebo controled, randomized clinical trial to definitely establish the antimyotonic 
efficacy and safety of mexiletine has not yet been performed.  
 
The treatment trial described in this orphan product development grant and research 
protocol has the potential to: a) establish mexiletine as a safe, effective antimyotonia 


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therapy capable of improving ambulation in DM1; b) identify other therapeutic benefits 
of long-term mexiletine treatment in DM1; and, c) improve the overall quality of life and 
clinical care for these patients.  The schematic shown in Appendix B and at the start of 
the Methods summarizes the major elements of the trial.  These elements include 
recruitment, randomization, specific outcome measures and potential benefits that may 
occur to improve the care of patients with DM1. 
 
   Potentially Treatable Symptoms of DM1: 
    
Patients with DM1 often develop progressive distal muscle weakness in the legs, 
forearms, and hands which invariably leads to functional disability. 23,24  Along with the 
weakness of leg muscles, myotonic muscle stiffness (myotonia), especially in the ankle 
stabilizing muscles, contributes to gait instability and falls.  In a 2009 qualitative study of 
relevant issues in DM1, “difficulty with ambulation” was the most frequently mentioned 
life-altering symptom by DM1 patients.24a  It is possible that a reduction in myotonia will 
have a profound effect on patient ambulation.  Lower extremity myotonia often impairs 
muscle contraction speed and stability and is a potentially treatable aspect of gait 
impairment.  Although prior therapies have failed to improve muscle weakness and 
wasting in DM1, there have been several small investigations that have suggested a 
beneficial effect from various treatments that ameliorate myotonia. 19,22,25-33  Of these, a 
short course (7 weeks) of mexiletine has been shown to have a statistically significant 
benefit on reducing DM1 myotonia.22   
 
Antimyotonia therapy with mexiletine may also exert a beneficial effect on 
cardiorespiratory and gastrointestinal function.  Isolated reports have suggested that 
untreated myotonia in DM1 may contribute to tachypnea, dyspnea, fecal incontinence, 
and chronic pain. 29-31,34  It is possible that a therapy that minimizes myotonia over a 
period of months or longer may also reduce the severity of these symptoms. 29,31 
 
Tongue and pharyngeal muscle myotonia hamper swallowing and may lead to 
aspiration of saliva, atelectasis of the lung, and pneumonia.  Such myotonia along with 
pharyngeal weakness may aggravate or precipitate obstructive sleep apnea.  It has 
been hypothesized that mexiletine may effectively reduce myotonia in tongue and 
pharyngeal muscles.  If true, mexiletine may also reduce the pulmonary complications 
that occur in DM1 patients.  To evaluate these potential effects of myotonia in DM1 we 
have included serial assessments of swallowing and pulmonary function as secondary 
endpoint measures in this clinical trial. 
 
Musculoskeletal pain is another common complaint in patients with DM1.  It occurs in up 
to 64% of all patients. 35  Generalized muscle pain is thought to be a directly related to 
the myotonic stiffness in limb and axial muscles of patients with DM1.  In 2008, Jensen 
and colleagues systematically studied the nature and scope of chronic pain in patients 
with DM1 and facioscapulohumeral dystrophy. 35  As part of this study they identified six 
patients who took mexiletine for chronic pain.  On average, these six patients 
experienced a relief of 3.91 (0 = no relief and 10 = complete relief).  These data are 
consistent with the hypothesis that antimyotonia therapy with mexiletine ameliorates 


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musculoskeletal pain.  The report by Jensen and colleagues also agrees with our 
anecdotal observations in the DM1 patients that we follow in our Neuromuscular 
Disease Center Clinic who receive antimyotonia therapy with mexiletine and report 
better control of their musculoskeletal pain.  To evaluate the benefit of mexiletine in the 
control of musculoskeletal pain we have included serial measurements of patient 
reported pain (modified Chronic Pain Scale, Brief Pain Inventory, and pain subdomain 
of our DM1-specific health-related quality-of-life instrument) in this trial. 
 
Cardiac arrhythmias are a frequent occurrence in myotonic dystrophy.  It has been 
estimated that up to 1/3 of DM1 patients may eventually die from the effects of a cardiac 
arrhythmia.35a  The exact mechanisms by which myotonic dystrophy exerts an effect on 
cardiac muscle and interferes with cardiac conduction remains unknown; however, it is 
possible that mexiletine (a class IB antiarrhythmic medication) may exert some positive 
cardiac effects on this population.   Modern ECG Holter monitoring is a comprehensive 
tool for investigating factors that might contribute to the mechanism of sudden cardiac 
death (SCD) in myotonic dystrophy. SCD may occur as a result of a complex interplay 
of numerous factors among which myocardial ischemia is the most common underlying 
condition.35b, 35c Events leading to a fatal event can be precipitated or influenced by 
abnormalities or transient changes in the autonomic control of the cardiovascular 
system as well as transient or progressive disruption of cardiovascular homeostasis. 
Holter recording will allow us to evaluate heart rate variability [HRV] parameters 
reflecting the status of the autonomic nervous system controlling the heart and will help 
to illustrate the relationship between parasympathetic and sympathetic components of 
this system. Heart rate turbulence  complements HRV analysis by providing insight into 
the baroreflex sensitivity component of central regulation of the cardiovascular system.  
 
The association between decreased variability of RR intervals recorded in 24-hour 
Holter monitoring and increased mortality was demonstrated in numerous 
studies.35d,35e,35f,35g,35h They indicate that depressed HRV is associated with all-cause 
and cardiac mortality. A study of 127 patients from the CHF-STAT trial showed that the 
standard deviation of NN-intervals (SDNN) <65 ms was significantly associated with all-
cause mortality and showed a borderline significance for predicting SCD.35e Also, in the 
UK-Heart study a significant association was made between low SDNN and all-cause 
mortality and mortality from progressive heart failure.35f 
 
For our mexiletine study we have added the use of serial 24-hour Holter assessments to 
better assess the effects mexiletine has on myotonic dystrophy cardiac conduction 
patterns.  All patients will receive three studies; one at baseline, one at three months, 
and one at the completion of the study.  We have consulted our colleagues in cardiology 
in making this addition to the protocol. They have indicated that based upon their 
experience there is no reason to include invasive monitoring techniques, such as, 
cardiac pacing in the ongoing assessment and monitoring of the study participants.  
They feel that such invasive testing has its own risks, is uncomfortable for patients, and 
is not indicated given our past findings of the safety of mexiletine in our 7, week double-
blind crossover studies of 150 mg and 200 mg dosages given three times daily.22  Our 
colleagues have wondered if there may have been therapeutic anti-arrhythmic benefit 


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from treatment with Mexiletine. For that reason we have included that question in our 
secondary aims for this proposal.  
 
Clinical Experience of Using Mexiletine for Myotonia: 
   
Despite the need for additional controlled studies, clinicians have been extensively 
utilizing mexiletine as a therapeutic agent in certain neuromuscular disorders.  In the 
routine care of patients with different forms of non-dystrophic as well as those with 
dystrophic myotonic disorders followed in our Neuromuscular Disease Center Clinic we 
have frequently chosen mexiletine as the treatment of choice to control myotonia.  We 
use mexiletine to treat patients with rare sodium channel diseases, such as, 
paramyotonia congenita and myotonia fluctuans, and in chloride channel diseases, such 
as, autosomal dominant Thomsens disease and autosomal recessive generalized 
myotonia.  The total number of patients with these disorders under our care receiving 
mexiletine exceeds thirty, and all have tolerated this medication with only mild or no side 
effects.  Most have experienced significant lessening of myotonic stiffness and have 
been able to resume sports activities, work in a cold environment, and handle stressful 
situations without an exacerbation of their myotonia.  We have used mexiletine to treat 
these patients with non-dystrophic myotonic disorders for over fifteen years, and we 
have noticed no loss of efficacy and no unexpected complications of therapy.   
 
More recently, over the past seven years, we have initiated mexiletine treatment in 
selected patients with DM1 to control some of their skeletal and smooth muscle 
complications which have been exacerbated by their myotonia.  The inability to open 
their hands, locking of the jaw, gastrointestinal hypomotility (sometimes requiring 
hospitalization), and severe muscle pain – especially in the upper back, posterior 
shoulder, and neck regions – are complaints in our DM1 patients that we and our 
patients attribute to myotonia.  We have found that mexiletine is extremely helpful in the 
treatment of these complaints, and our DM1 patients with these problems have 
responded with benefit to our prescribed treatment with mexiletine.  Eight patients have 
received mexiletine for periods varying from ten weeks to three years to treat these 
complaints.  One of the most severely affected patients is a woman with congenital DM1 
who had a history of episodic locking of her jaw for periods of 24-48 hours and who on 
other occasions had intermittent bouts of pseudo-obstruction of the intestine requiring 
several hospitalizations.  Since the initiation of mexiletine this patient has had a marked 
reduction in her problems with poor gastrointestinal motility, reduced her abdominal 
complaints, had no episodes of jaw locking, and has improved her hand dexterity.   
 
Four other DM1 clinic patients have received mexiletine to assist in the treatment of 
disabling pain.  These patients have all had amelioration of their discomfort and have 
also had an associated, remarkable decrease in their grip and percussion myotonia. 
 
Despite this encouraging anecdotal evidence, a systematic placebo controlled trial is 
essential to further determine the true benefit of mexiletine for DM1 patients.     
 
The University of Rochester’s Experience in Therapeutic Trials in DM1: 


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In the recent past we have used the methods described in this proposal to evaluate 
ambulation, myotonia, and muscle function in patients with DM1.  We have found that 
patients are comfortable with these procedures and that the measurements are reliable 
in assessing the efficacy of treatment with testosterone, recombinant human growth 
hormone, insulin-like growth factor 1, as well as mexiletine. 25,32,36  In other studies we 
have found that the measurements of grip myotonia using our methodology helps to 
quantitate and to describe a particular type of variable myotonia in a specific type of 
sodium channel myotonia, myotonia fluctuans. 37,38 Our methods for measuring whole 
body muscle strength and function have proven useful in several types of adult 
muscular dystrophy.  Recent studies in our Center have shown that maximum voluntary 
isometric contraction force is reliable, and is useful in evaluating the response of 
patients with facioscapulohumeral muscular dystrophy to treatment. 39-41   Furthermore, 
our primary outcome measure, the six minute walk, has been shown to be reliable, 
feasible, and relevant to the DM1 population.41a, 36   
 
Through our previous studies (including the FDA funded trial of mexiletine, past NIH 
funded investigations of metabolic alterations in DM1, previous MDA funded pilot study 
of DHEA in DM1 and recently completed NIH – MDA funded trial of IPLEX insulin-like 
growth factor-1 (IGF-1) complexed with IGF-1 binding protein 3 for DM1) we have 
demonstrated that we have the necessary equipment, the expertise, and practical day 
to day experience with the methods proposed to accomplish our study aims.   
 
C. PRELIMINARY STUDIES: 
 
Previous Mexiletine Trials and Reports:    
 
In 2007 our University of Rochester Neuromuscular Disease Center group gave oral 
presentations of results from the FDA funded, short-term, seven week, double-blind, 
randomized, crossover trial of DM1 patients and in 2010 published the full report. 22 
[Appendix A]   In this study, two sequential, randomized, double-blind, placebo-
controlled, crossover investigations of mexiletine (mexiletine 150mg three times daily 
vs. placebo; mexiletine 200mg three times daily vs. placebo TID) were carried out.  
Each study involved 20 moderately affected patients with DM1.  The inclusion and 
exclusion criteria for that study are identical to those in the study proposed in this FDA 
grant and research protocol.  Patients were randomized to receive seven weeks of 
treatment followed by seven weeks of placebo; or, seven weeks of placebo followed by 
seven weeks of treatment.  A four to six week washout period separated the active 
treatment and placebo arms of the trials.  Both dosages of mexiletine (150 mg and 200 
mg) were well tolerated, safe, and effective in reducing isometric grip relaxation time 
(p<.05) following seven weeks of treatment.  Side effects were minimal for both doses, 
and there was no worsening of first-degree heart block or bundle branch block in any 
patient with these conduction disturbances.  Although both dosages significantly 
improved myotonia, there was not an additional benefit to the higher 200 mg three times 
daily dose over the 150 mg three times daily dose, suggesting a plateau effect.  
Furthermore, the lower dose produced a statistically significant increase in peak grip 


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force not demonstrated at the higher dosage. [Appendix A].  The data obtained from this 
study was utilized to select the 150 mg TID dose for our study.  Although limited in 
duration, our prior seven week trials of mexiletine have demonstrated the short term 
safety, tolerability, and potential benefit of antimyotonia therapy with mexiletine in DM1.  
Prior to this University of Rochester crossover trial of mexiletine, there had been several 
small case reports suggesting a beneficial effect of mexiletine and other antimyotonia 
medications for different myotonic conditions.  Although these studies also reported 
encouraging results, all had significant limitations regarding their time frame, clinical 
design, and selected study populations.   
 
To our knowledge the first report of mexiletine use for muscle myotonia was in 1983.  At 
that time, a French group gave mexiletine (400 mg/day) to a patient with myotonia 
congenita (a non-dystrophic myotonic disorder) with reports of marked improvement 
measured by ergometric bicycle testing.20  The patient had previously failed a trial of 
other antimyotonia drugs including carbamazepine and diphenylhydantoin.  Other 
reports have described dramatic clinical and electromyographic improvement in 
mexiletine treated infants with myotonia congenita and electrical myotonia.21  
Mexiletine has also been previously tested in other rare myotonic disorders, such as, 
the hereditary sodium and chloride channel non-dystrophic myotonic disorders. 42,43  
Kwiecinski and colleagues reported a beneficial effect of mexiletine in reducing 
myotonia in nine DM1 patients, nine patients with autosomal dominant Thomsens 
disease, and 12 patients with recessive generalized myotonia. 19  During this treatment 
trial the efficacy of phenytoin, disopyramide, mexiletine, and tocainide was compared to 
placebo.  These researchers concluded that mexiletine and tocainide displayed the 
most potent antimyotonia activity and that mexiletine was safe at both 400mg and 
600mg per day dosages. 19  These same investigators indicated that despite similar 
beneficial effects of tocainide on myotonia in DM1 patients. the tendency of tocainide to 
cause bone marrow suppression has precluded its acceptability for the long term 
treatment of myotonia and made mexiletine the therapeutic agent of choice. 19,44,45  
 
A recent Cochrane review concluded that none of the ‘currently published’ treatment 
trials for myotonia reported as of 2006, were of high enough quality to conclude that any 
available drug for the treatment of myotonia is effective and safe. 46  For example, 
although the 1992 report by Kwiecinski and colleagues19 provides an important step 
forward in recognizing the antimyotonic properties of mexiletine, it had some significant 
deficiencies: short duration (4 weeks), a heterogeneous patient group with 3 different 
forms of chloride channel myotonia, a single blind study design, an inscrutable 
randomization process in which different numbers of patients were assigned to different 
study drugs, and incompletely validated methods to measure myotonia.  Ultimately, 
these types of study limitations, not their observed results, have limited the widespread 
acceptance of mexiletine as a treatment for patients with DM1. 
 
In addition to reducing myotonia in muscles that control grip and stability of the ankles , 
mexiletine may have important beneficial effects on whole body musculature (both 
skeletal and smooth muscle) in DM1 patients.  Mexiletine has been reported to have 
reversed fecal incontinence in one patient and tocainide (a lidocaine-like drug similar to 


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mexiletine) has been shown to eliminate both dyspnea and tachypnea in a DM1 patient 
with a history of severe dyspnea requiring hospitalization. 29,31  Although anecdotal, such 
benefits may be secondary to the antimyotonic effect that lidocaine-like drugs have on 
skeletal and smooth muscle.  A long-term trial of mexiletine, such as the one described 
in this protocol, is needed to establish not only safety and efficacy in reducing myotonia 
in specific limb muscles but also to determine if mexiletine can ameliorate whole body 
symptoms.  As part of our clinical trial, we will measure not only clinical myotonia, but 
also potentially related, additional outcome measures, such as, strength, 
gastrointestinal function, pulmonary function, swallowing function, muscle mass, timed 
testing of ambulation, hand dexterity, and quality-of-life.  
 
Our research design in this FDA grant and research protocol has built upon the 
encouraging results of previous treatment trials.  As a part of our research plan we will: 
a) extend the duration of treatment with mexiletine; b) use the most effective, tolerated 
dose of mexiletine (150 mg three times daily); c) perform a traditional placebo controlled 
trial of treatment; and d) evaluate multiple outcome measures, focusing on those with 
highest relevance to patients with DM1. 
 
The opportunity is now at hand to perform a carefully controlled, double blind, long-term, 
randomized treatment trial of mexiletine vs. placebo in DM1.  There is currently clinical 
equipoise in the medical community regarding which therapeutic agents (if any) should 
be used in the DM1 population.  This study will determine the efficacy, tolerability, and 
safety of 6 months of treatment with mexiletine (vs. placebo) in DM1.  It is our belief that 
this study will finally break the medical community’s equipoise and potentially establish 
mexiletine as an orphan drug for DM1. 
 
 


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D. RESEARCH DESIGN AND METHODS: 
 
TRIAL DESIGN: 
 
SCHEMATIC SUMMARY OF MEXILETINE TREATMENT IN DM1 
 
40 DM1 Patients
20 DM1 Patients
1) Muscle Myotonia
2) Muscle Strength
3) Lean Muscle Mass
4) Gastrointestinal Function
5) Swallowing Ability
6) Time to Rise from Chair
7) Purdue Peg Board Time
8) Time to Walk 30 Feet
9) Forced Vital Capacity
10) SF-36
11) Safety
12) Tolerability
13) Cardiac Function
14) Ambulation
15) Quality-of-Life
16) Pain
Randomization
Patient outcome 
measures
Improved 
Patient Care
Potential 
Designation of the 
First Therapeutic 
Agent for DM1
Insight into DM1 
Disease 
Progression
Potential FDA 
Orphan Drug 
Approval for 
Mexiletine
Benefits of Trial
Insight into 
Longterm Effects 
of Mexiletine in 
DM1
Adjustement of 
Current Standard 
of Care 
Potential 
Implementation of 
Mexiletine for 
Other 
Neuromuscular 
Disorders
20 DM1 Patients
The Study of Mexiletine vs. Placebo for Myotonic Dystrophy Type-1 (DM1)
DM1: Myotonic Dystrophy Type-1
Mexiletine 150 mg 
TID
Placebo TID
6 month of 
therapy
 
 
This FDA Orphan Product Development Project proposes a double-blind, randomized, 
placebo-controlled, six month clinical trial of the efficacy and safety of mexiletine (150 
mg three times daily) for the treatment of moderately affected ambulatory patients with 
DM1.  Twenty patients will be randomized to receive treatment while another 20 
patients will receive placebo.  Patients will be randomized in a 1:1 ratio to receive either 
mexiletine (150 mg three times daily) or placebo.  The primary outcome measure will be 
the assessment of ambulation by six minute walk time.  Secondary outcome measures 
will include: a) grip myotonia as determined by relaxation time following maximum 
voluntary isometric contraction of the finger flexor muscles; b) muscle strength; c) 
change in lean muscle mass; d) pain measurement using the Brief Pain Inventory and a 


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modified Chronic Pain Scale; e) Gastrointestinal function measured by two 
gastrointestinal questionnaires; f) The ability to swallow as measured by a timed 
swallowing test with water; g) physical function as measured by the time to rise form a 
chair, Purdue Peg Board Score, time to walk 30 feet, six minute walk, and SF-36; and, 
h) pulmonary function (measured by serial determinations of forced vital capacity); i) 
change in Holter monitor data from baseline; and j) patient relevance as measured by a 
novel disease-specific health-related quality-of-life instrument designed specifically as 
an clinical outcome measure for the DM1 population.   
 
During the trial of treatment with mexiletine, all patients will receive careful safety 
monitoring, including serial EKGs, laboratory testing, three in-person evaluations on the 
University of Rochester NIH funded Clinical Translational Sciences Institute sponsored 
Clinical Research Center, and phone calls to assess for any side effects or problems 
with the study medications, to encourage adherence to the treatment regimen, and to 
grade musculoskeletal pain.  Below is a more detailed description of the study design 
and the outcome measures. 
 
Rationale for Design: 
 
A randomized, double-blind, placebo-controlled approach was selected based on its 
efficacy, simplicity, widespread acceptance, and power to compare the efficacy of 
mexiletine vs. placebo in our study population.     
 
Study Population: 
 
Our decision to select patients with DM1 for our investigation has occurred for several 
reasons.  DM1 is an orphan disease and is appropriate for the Orphan Product 
Development Grant Program.  Published estimates of the prevalence of DM1 in 
European-American populations range, for example, from 2.4 per 100,000 in Northern 
Ireland to 5.5 per 100,000 in West Germany. 2,4   A study from Switzerland, that carefully 
attempted to obtain complete ascertainment of all cases, has reported a prevalence of 
4.9 per 100,000. 3  A general estimate of the prevalence of DM1 in populations 
Americans is approximately 10 per 100,000 and indicates a total prevalence of less than 
100,000 patients with DM in the United States. 1   
 
In addition, DM1 has clinical and laboratory features that permit careful assessment of 
symptoms.  Patients often have easily identified clinical signs of myotonia, and, as 
mentioned previously, myotonia may play an important contributory role in their 
symptoms.  For example, myotonia may have an additive effect with weakness to 
decrease dexterity in performing certain movements with the hands (e.g., compromising 
employment opportunities).  Myotonia may contribute to muscle spasm and pain in the 
posterior neck and low back (e.g., further compromising employment opportunities). 34  It 
may hamper swallowing and breathing (e.g., increasing the risk of life threatening 
illness), and it may worsen already compromised gastrointestinal motility. 23,24,29,30  
Myotonia may also exaggerate difficulties with agility, balance, and ambulation caused 
by progressive weakness (increase the risk of falls and associated injuries).  


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Demonstration that an effective antimyotonia treatment improves one or more of these 
clinical problems will provide an opportunity to improve the quality of care of these 
patients and extend their productive life span. 
 
One of the benefits of studying DM1 patients is that the diagnosis can be definitively 
established.  DM1 is an autosomal dominantly inherited disease and it results from an 
unstable trinucleotide repeat, [CTG]n, expansion in the DM gene on chromosome 19. 5-7  
The gene defect is well characterized and a specific diagnostic test using leukocyte 
DNA analysis is available to identify the abnormal enlargement of the [CTG]n repeat and 
to identify affected individuals. 47  The availability of a standard diagnostic test for DM1 
assures us that all the patients in our study population have a family history DM1.   
 
There will be 40 subjects with myotonic dystrophy between 18-80 years of age enrolled 
for this clinical trial.  Up to 60 patients will be screened for this trial until accrual of 40 
patients is met. Every effort will be made to insure that the study population reflects the 
makeup of the general population, including women and minorities, from which it is 
drawn.   
 
For over 30 years in our Neuromuscular Disease Center we have provided care to a 
large population of DM1 patients, and over the past 25 years we have carried out 
clinical investigations to clarify the pathomechanism of the muscle wasting that occurs 
in these patients.  We have also performed multiple therapeutic trials in subgroups of 
these DM1 patients. 25-32  At present we have a funded NIH study to investigate the 
disease progression of DM1.  This study has provided us with access to many patients 
from our local area and from other regions of the United States.  It is possible that these 
patients may also wish to participate in our therapeutic trial.  We also have access to 
over 580 DM1 patients through the National Registry of Myotonic Dystrophy Patients.  
We anticipate having no significant difficulty in recruiting the required number of patients 
for this trial.   
 
Patient Selection: 
 
Myotonic dystrophy type-1 patients of both genders will be recruited for this study.  All 
NIH guidelines regarding gender and minority inclusion will be followed.  Issues 
regarding human subjects are discussed in the section identified as Human Subjects.   
 
All patients must fulfill the following inclusion criteria to participate in the study:   
1) Age 18 years or older and less than or equal to 80 years old. 
2) Have a diagnosis of myotonic dystrophy type 1 and a 1st degree family member with 
a positive DNA test for myotonic dystrophy type 1 
3) Have delayed relaxation of grip of one second or more following a maximum 
voluntary isometric contraction using our standard Jamar grip ergometer. 
4) Have sufficient finger flexor strength to grasp the handle of the ergometer used to 
measure myotonia. 
5) Have sufficient strength to swallow. 


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6) Be able to walk independently 30 feet and to walk continuously for more than six 
minutes (cane, walker, orthoses allowed) at a distance over 100 meters. 
7) Have a reliable method of birth control (if a female subject of child bearing potential). 
8) Able to swallow an appropriately sized capsule. 
 
Patients with one or more of the following criteria will be excluded from participation 
in the study: 
1) Known allergy to mexiletine. 
2) Treatment with mexiletine within past 8 weeks. 
3) Second or third degree heart block, atrial flutter, atrial fibrillation, ventricular 
arrhythmias, or is receiving medication for treatment of a cardiac arrhythmia. 
4) Receiving another antimyotonia drug. 
5) Liver or kidney disease requiring ongoing treatment. 
6) Have a seizure disorder. 
7) Are pregnant or lactating. 
8) Had severe depression within 3 months of randomization or a history of suicide 
ideation. Physicians review current medications and clinical assessments of primary 
care physicians and coordinate  participation in the study with them. If the primary care 
doctor is not comfortable including assessments of cognitive or emotional state (i.e. 
severe depression) we will not include them in the study until they satisfy all of the 
inclusion criteria. We always share laboratory data and significant findings with the 
primary care doctor and any other care providers with permission of the subject. 
9) History of non-compliance with other therapies. 
10) Have any one of the following medical conditions: uncontrolled diabetes mellitus, 
congestive heart failure, symptomatic cardiomyopathy, symptomatic coronary artery 
disease, cancer other than skin cancer less than five years previously, multiple 
sclerosis, or other serious medical illness. 
11) Have any of the following conditions on routine blood screening: WBC <3000, 
platelets <100,000, hematocrit <30%, symptomatic liver disease, BUN >30mg%. 
12) Drug or alcohol abuse within 3 months of enrollment. 
13) Coexistence of another neuromuscular disease. 
14) Is unable to give informed consent. 
15) Severe arthritis or other medical condition (besides DM1) that would significantly 
impact ambulation. 
 
Study Time Line and Procedures: 
 
Patients will receive three in-person evaluations during this study.  An outline of the 
testing that will take place during these visits is provided in Schedule 1 (attached). 
 
Baseline Screening: 
 
A baseline evaluation will determine the eligibility of each recruited individual to 
participate in the study.  At this visit consent will be obtained, and measurements of 
height, weight, blood pressure, pulse, urinalysis, and electrocardiogram will be 
performed.  A blood specimen will be drawn for: complete blood count and differential 


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cell count, serum sodium, chloride, potassium, bicarbonate, calcium, phosphorus, total 
protein, glucose, blood urea nitrogen, prothrombin time, partial thromboplastin time, 
creatinine, thyroid stimulating hormone, T3, T4, gamma glutamyl transferase, aspartate 
aminotransferase, and lactic dehydrogenase. A pregnancy test will be given to women 
of childbearing potential.   
 
Patients will be required to have had a 24 hour Holter monitor study performed within 2 
months, or prior to their initial screening visit. The Holter monitoring assessment will 
occur through collaboration with our study cardiologist, Dr. [REDACTED], who is 
reviewing the resting electrocardiograms and 24 hour Holter monitoring results on each 
of the study participants.  Patients will come to the University of Rochester Medical 
Center > 36 hours before their scheduled Clinical Research Center [CRC] visit for out-
patient electrode placement and attachment of the Holter recording equipment.  The 
Holter equipment and electrode removal will occur at the time of admission of the 
participant to the CRC.  Rapid review of the tracing will occur to allow a determination of 
their eligibility after all the initial baseline screening is performed to assure that the 
patient satisfies the inclusion and exclusion criteria for participation in the trial of 
mexiletine.  The out of town participants will stay in a hotel close to the University of 
Rochester Medical Center during the period before their CRC admission.  The 
application of the Holter monitor will occur as noted above as an out-patient procedure 
that will be coordinated through our cardiology group, including Drs. [REDACTED] and 
[REDACTED] (cardiologists), [REDACTED] (ECG Core Lab Manager) and 
[REDACTED] (Technician).   
 
Past medical history will be collected by the study coordinator and a physical exam will 
be completed by one of the investigators.  If an individual patient meets the inclusion 
criteria and has none of the exclusion criteria, that patient will be enrolled and their 
inpatient evaluation continued.  If recruited individuals do not meet the inclusion criteria 
or have one or more exclusion criteria, they will not be eligible to participate and will not 
continue in the study.         
 
Screening Evaluations:  
  
 
• Review of the study procedures/consent review: Upon arrival at the CRC, the 
information in the screening consent form will be reviewed with the patient in 
detail.  The patient will be provided with an opportunity to ask any additional 
questions prior to starting the study procedures scheduled for the day.   
 
• Standard blood testing.  Up to 4 tablespoons of blood will be taken from a vein in 
the participants arm. This blood will be used for routine laboratory testing listed 
above and in the schedule.  A pregnancy test will also be performed for women 
of childbearing potential. 
 
• A urine sample will be collected a urinalysis will be performed.  Height, weight, 
and vital signs will be recorded. 


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• A standard 12 lead electrocardiogram (ECG) test will be performed.   
 
• A study doctor will perform a physical examination and medical history. Medical 
records will be reviewed.  
 
• A 6-minute walk test (6MWT) will be performed under the supervision of a trained 
physical therapist. Blood pressure, heart rate, breathing rate, and oxygen 
saturation will be recorded before and after this test. 
 
• A swallowing evaluation will be conducted to determine the ability of the patient 
to swallow pills with water. 
 
• Myotonia testing.  For this testing we will have the patient grasp a handle that is 
connected to a computer.  The patient will squeeze the handle as strongly as 
they can for 3 seconds and then relax.  The time required for the patient’s hand 
to relax will be recorded by the computer and be used to measure the patient’s 
hand myotonia.  To find out if repeated muscle contractions shorten the time 
required for grip to relax (warm-up effect) a similar test will be performed.  With 
the right hand patients will grasp onto the handle.  They will squeeze the handle 
as strongly as they can for 3 seconds and then relax for 10 seconds.  They will 
repeat this five times. This series of grip exercises will be repeated for a total of 3 
sets.  Each set will be separated by a 10 minute rest period.   
   
• Placement of a 12-lead 24-hour Holter monitor test. The patient will come to the 
University of Rochester Clinical Research Center (CRC) and a technician from 
the Cardiology Group working on this project will work with the CRC nursing staff 
to set up the Holter monitor.  Patients will not require this testing if they have had 
a Holter monitor within 2 months.  This testing can be done before or after the 
above screening procedures and after the screening consent form has been 
reviewed and signed. 
 
 
Potential Enrollment: All screening information will be reviewed by the PI to determine 
subject eligibility.  If a patient satisfies all the inclusion and exclusion criteria, the patient 
will be invited to participate in the research study and a consent form for the treatment 
trial (attached) will be reviewed with them.  If the patient decides to participate in the 
clinical trial the patient will undergo the following: 
 
      I. 
Continuation of the Screening/Baseline Visit at the University of Rochester 
Clinical Research Center (CRC).  This visit will take two days.  During this 
visit a series of evaluations will be carried out to determine how the patient 
is affected by myotonic dystrophy.  An additional aspect of the 
Screening/Baseline Visit is that the patient will be started and monitored 
on the study drug (either mexiletine or placebo). 
 


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II. 
Follow-up visits to the CRC 3 months and 6 months after the 
Screening/Baseline Visit.  During these visits many of the same 
evaluations from the Screening/Baseline Visit will be repeated to 
determine how the patient’s condition has changed over time. 
 
      III. 
Telephone evaluations.  The patient will receive a telephone call about 
every two weeks while they are enrolled in the study, except for the weeks 
when they come to the CRC for a study visit. The study coordinator will 
telephone the patient to check on any side effects that may occur and 
make sure that the study medication is being taken as directed.  The 
coordinator will also ask each patient about their pain level during these 
phone calls. 
 
A schedule of procedures and assessments for this project is outlined in schedule 1 (Appendix 
C). 
 
Description of study procedures: 
 
The Screening/Baseline Visit of the study will take place over two consecutive days on 
the CRC.  On Day 1 the patient will be admitted to the Clinical Research Center (CRC) 
for an overnight stay.     
  
Screening/Baseline Visit Day 1 - The activities during the first day will take all day 
(about 4 hours in the morning and 3 hours in the afternoon).  These activities include 
the screening evaluations listed above as well as the procedures outlined below.  
• Review of the study procedures/consent review: Upon arrival at the CRC, the 
information in the treatment consent form will be reviewed with the patient in 
detail.  The patient will be provided with an opportunity to ask any additional 
questions they may have prior to starting the study procedures scheduled for the 
day.  
• An assessment of the patient’s ability to swallow.  A swallowing evaluation will be 
conducted to determine the time it takes for the patient to swallow water. 
• The patient’s muscle strength will be tested in several ways by a physical 
therapist using hand grading and a myometer.  The patient’s force vital capacity 
will be checked. The patient will be timed as they get up from a chair and walk 30 
feet and perform a Purdue Peg Board test and Jebsen-Taylor Hand function 
tests. The patient will be asked to pinch a piece of equipment with their fingers to 
measure their pinch strength.  
• Each patient will be given a standard lunch on the CRC. 
• They will be asked to complete a series of questionnaires to find out how 
myotonic dystrophy impacts upon the patient’s life and daily activities.  These 
include the following questionnaires: Upper Extremity Functional Index, myotonia 
visual analog scale, Medical Outcome Short Form Health Survey (SF 36), 
Epworth Sleepiness Scale, an Individualized Neuromuscular Quality of Life 


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Questionnaire (INQoL), two gastrointestinal function questionnaires, a chronic 
pain scale and brief pain inventories, and a DM1 specific Health related quality of 
life questionnaire (MDHI). Additionally, patients will be asked to complete an 
assessment of the usability and relevance of some of these questionnaires (i.e., 
SF-36, INQoL, and MDHI).  
• Each patient will receive a standard dinner on the CRC.  
• After all of the baseline assessments are completed, each patient will receive the 
first dose of study medication (mexiletine or placebo) with dinner. The patient will 
stay overnight on the CRC.   
 
Screening/Baseline Visit Day 2 - The activities during the second day will take 
approximately 4.5 hours to complete. The procedures described for Day 2 will begin on 
the Clinical Research Center (CRC) in the morning at 7:30AM.  
 
• Each patient will be given a second dose of study medication with their breakfast. 
The amount of muscle tissue, fat tissue, and bone in the body will be measured using 
dual energy X-ray absorptiometry (DEXA).  The DEXA machine will scan over the 
patient’s body while they lie still for about 15 minutes.  The DEXA scan involves 
radiation exposure which is less than one day’s worth of exposure to natural 
background radiation. 
• Video-recording of Hand Opening Time.  The dominant wrist and hand are 
placed on a bedside table with the forearm fully supinated.  The participant is 
asked to open the hand after making a tight fist for 3-5 seconds.  A digital video 
recording is made of the hand opening.  The video field of view only includes the 
participant’s forearm and hand.  The time required for hand opening, which often 
ranges from 3 to 20 seconds in individuals with DM1, is determined by blinded 
review of the video recording.  The procedure is carried out three times over 30 
minutes.   
• Each patient will be given a third dose of study medication with their lunch. 
• Up to 4 tablespoons of blood will be taken from a vein in the patient’s arm.  This 
blood will be used for routine laboratory testing listed in the schedule.  The level 
of mexiletine in the blood will also be measured.  
• An electrocardiogram will be performed and reviewed by a physician in real-time. 
• The study coordinator will give each patient bottles containing a three month 
supply of study medication.  Each patient will also be given a diary to record the 
amount of medication taken each day and any side effects that they may 
experience.  The coordinator will go over instructions for taking the study 
medication and completing the medication diaries. At the 3 and 6 months follow-
up visits patients will be asked to return the study medication bottles, any unused 
study medication, and completed diaries. 
 
Itinerary of Follow-up Visits: (Month 3 and Month 6)           
 


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The evaluations of patients at their Month 3 and Month 6 Visits will be similar to those 
performed at their Screening/Baseline Visit with the exception that a DEXA scan will 
only be performed at Screening/Baseline and at Month 6.  Holter monitoring will occur 
within the week immediately before the CRC admissions at Month 3 and Month 6, and 
the procedure for placement of the Holter recording equipment and electrode placement 
will use the same standard procedure described above and routinely used by our 
cardiology consultant group at the University of Rochester Medical Center.   
 
On the Month 3 and Month 6 follow-up visits, the patient will complete the following 
study procedures following an overnight fast.  The patient will be supplied with a 
standard breakfast after the blood draw. 
  
• An electrocardiogram will be performed. 
• The patient will have up to 4 tablespoons of blood drawn, and if the patient is a 
female of childbearing potential, a pregnancy test will be done.  A urine sample 
will be collected to test kidney function.  
• A study doctor will perform a history and physical examination; height, weight 
and vitals will be recorded.   
• A study doctor and study coordinator will discuss any side effects that the patient 
may have experienced and any recent changes in medications.  
• An assessment of the 6-minute walk test (6MWT) will be performed.  
• A swallowing evaluation will be conducted. 
• Myotonia, functional, and strength testing will be performed (as described 
above).  
• A standard lunch will be given on the CRC. 
• A DEXA study will be performed (six month only). 
• Questionnaires will be completed (Upper Extremity Functional Index, myotonia 
visual analog scale, Medical Outcome Short Form Health Survey (SF 36), 
Epworth Sleepiness Scale, an Individualized Neuromuscular Quality of Life 
Questionnaire (INQoL), two gastrointestinal function questionnaires, chronic pain 
scale and brief pain inventories, and a DM1 specific Health related quality of life 
questionnaire (MDHI). Additionally, patients will be asked to complete an 
assessment of the usability and relevance of some of these questionnaires (i.e., 
SF-36, INQoL, and MDHI).  
• The study coordinator will collect medication bottles, unused medication and the 
patient’s diary. At the month 3 visit, the patient will be provided with a new supply 
of study medication and a patient diary. 
• The patient will receive a standard dinner on the CRC. 
 
Once all of these activities are completed, the visit will be finished and the patient 
will be discharged from the CRC.  
 
Diet: 
 


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During inpatient evaluations on the Clinical Research Center of the University of 
Rochester Medical Center (CRC) each participant will receive a constant diet that is 
designed in advance with the CRC dietitian.  The meals provided on Study Day 1 will be 
the identical to the meals provided on Study Day 2.  Each meal will be given at the 
same time (8AM, 12:30PM, and 6:00PM) on both Study Days 1 and 2.  During both 
study days participants will only consume the research diet provided and will not 
perform vigorous physical exertion other than that required for the muscle strength 
testing in the research protocol.  This dietary control helps to avoid changes in hormonal 
regulation of potassium balance that might exert a significant influence on the degree of 
myotonia in study participants. 
 
Randomization: 
 
After eligibility has been confirmed and the treatment consent has been reviewed and 
signed, the patient will be randomized to one of two treatments (placebo or mexiletine) 
according to the randomization plan developed by the biostatistics programmer at the 
University of Rochester, under the supervision of the biostatistician (Dr. [REDACTED]).  
The randomization will include blocking to insure balance among the two treatment 
sequences after a certain number of patients have been enrolled.  Only Dr. 
[REDACTED] and the biostatistics programmer will be aware of the block size used.   
 
After the randomization plan has been generated by the biostatistics programmer, it will 
be sent to the pharmacy at the University of Rochester Medical Center where drug 
packaging and labeling will take place.  All drug will be labeled with a patient ID number.  
Only the biostatistics programmer and the pharmacist will have access to the treatment 
assignments, i.e., the link between the patient ID number and treatment.  The 
biostatistician (Dr. [REDACTED]) will remain blinded to treatment assignment.    
 
Drug will be assigned sequentially.  No patient will be dispensed study drug until after all 
baseline assessments have been completed.  The study coordinator will be required to 
check all baseline forms for completeness and verify eligibility criteria before calling the 
pharmacy to officially randomize a patient.  Enrollment will be documented on a case 
report form.   
 
The biostatistics programmer will also provide the study coordinator with a set of sealed 
emergency disclosure envelopes which will allow the investigator to become quickly 
unblinded to the patient’s treatment assignment in case of a medical emergency.  It is 
anticipated that such disclosure will not be necessary in this study.   
 
Study Drug, Dosage, and Compliance: 
 
Study Medication:  
Mexiletine is available by prescription for its approved indication as a ventricular 
antiarrhythmic.  In support of this research protocol the Investigational Drug Service 
(IDS) will supply both active and placebo products in a blinded fashion.   
 


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For the active treatment group commercially available mexiletine will be purchased from 
Cardinal Drugs and charged to the research grant.  The exact generic brand to be 
purchased is to be determined and will be based off of availability and price at the time 
of purchase.  Once purchased all future active doses will be prepared using the same 
manufacturer’s product.   
 
To blind the active product the IDS will over-encapsulate the commercial product by 
placing each capsule inside a larger empty opaque capsule.  The placebo product will 
consist of a placebo capsule (size 3 capsule containing 240mg of lactose powder USP) 
placed inside the same type of larger opaque capsule. 
 
Rationale for dosage:   
Mexiletine has an established pharmacokinetics and side effect profile and it is already 
approved as an alternative treatment for symptomatic ventricular arrhythmias. 48-53 
Previous research has established that serum concentrations of mexiletine exceeding 
1.5 to 2 mcg/ml are associated with an increased risk of toxic side effects and a 
standard assay of the serum level of mexiletine is available. 48-53  This information 
provides assurance that the present study design has utilized an appropriate dosage, 
an appropriate approach to monitoring of potential adverse events related to the 
treatment, and has appropriate precautions to monitor the patients.  The availability of a 
serum assay for mexiletine is another advantage in this investigation because the 
measurements of serum levels of mexiletine included in the protocol will help to 
determine if the concentrations achieved are in the therapeutic range, if there is any 
correlation between the serum level and its antimyotonia efficacy, and if the patients are 
taking the medication.  The fact that much higher doses of mexiletine have been used to 
treat pain in patients with diabetic neuropathy without producing serious toxicity gives 
additional assurance that mexiletine in the dose set forth in this proposal (mexiletine 
150 mg three times daily) is not only appropriate, based upon previous research in DM1 
patients, but is also well within the safe therapeutic range for this medication. 19,22,54,55 
We also have considerable anecdotal experience in using mexiletine to control 
myotonia in patients with various myotonic diseases, and feel that the dosage of 
mexiletine in this protocol will be well tolerated by most DM1 patients.  Lastly, the 
mexiletine dose of 150 mg three times daily in this protocol was selected over a higher 
dose of 200 mg three times daily based upon data from our FDA funded 7 week, 
double-blind, crossover trials of mexiletine that demonstrated that this lower dose of 
mexiletine had a slightly greater clinical efficacy in increasing hand grip peak force while 
demonstrating a similar effect in reducing myotonia. 22   
 
Compliance:   
Participants will be asked to return the study medication bottle at each follow-up visit [ 
Month 3 and Month 6].  In addition, study subjects will be supplied with compliance 
diaries to record their compliance with taking the study medication.  In addition, the 
study coordinator will contact each participant at about 2 week intervals during the trial 
to assess side effects and pain, and will encourage each study subject to adhere to the 
treatment regimen. 
 


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Withdrawal/ Discontinuation/ Dosage Reduction: 
 
Patients will have the option of withdrawing from the study at any time.  Patients may 
also be withdrawn because of an inability to comply with study procedures (e.g., 
because of significant surgery or medical illness).  If a patient experiences intolerable 
adverse events, the dosage may be reduced by one level (e.g. from three times a day 
dosing to twice a day dosing).  Patients who experience intolerable adverse events 
requiring withdrawal of study medication or who require treatment with exclusionary 
medications will continue to be followed according to the protocol, if the patient is 
willing.  Primary statistical analyses will be performed according to the intention-to-treat 
principle and will utilize all patient data collected. 
 
All patient withdrawals, dosage reductions, treatment discontinuations, and treatment 
with exclusionary medications will be carefully documented on case report forms. 
 
In case of a medical emergency, the principal investigator will contact the pharmacy and 
become unblinded to the patient’s treatment assignment.  
 
Coordination of Patient Care Following the Completion of the Study Protocol: 
At the completion of the study all patients will be tapered off the study drug/placebo over 
a one week period.  We will provide each patient’s primary care physician and/or 
neurologist a detailed summary of the patient’s current health status and will coordinate 
with them any questions regarding management of their patient including the potential 
use of mexiletine therapy. 
Study Testing Procedures: 
 
Evaluation of safety and tolerability: 
Adverse side effects will be monitored during each CRC visit (Baseline, Month 3, Month 
6) and during telephone calls at about 2 week intervals during the intervening weeks of 
the trial.  The adverse effects of mexiletine observed most commonly include: dizziness, 
lightheadedness, nervousness, nausea, vomiting, or upset stomach, diarrhea, 
constipation, trembling, shaking of hands, blurred vision, tiredness, or weakness.  More 
serious side effects, which are less common include: irregular heart beat, chest pain, 
shortness of breath, trouble breathing, skin rash, severe itching, or hives.   
 
If there are more serious side effects, the principal investigator will be notified. The 
principal investigator will contact the patient and determine if it is necessary to have the 
patient reduce the dosage of treatment agent of to stop it. The principal investigator will 
also determine if an urgent evaluation of the patient is necessary. These medical plans 
and any related change in care will be coordinated with the primary care physician of 
the patient. If necessary, the code will be broken to determine if the patient is receiving 
placebo or mexiletine treatment.  
 
Additional details regarding the evaluation of the safety and tolerability of this 
medication are provided in the human subjects section of this application.  


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Description of Efficacy Measures: 
 
As described in the section on Rationale for the Study, the effects of myotonia on 
patient function can be profound.  Mexiletine has the potential to ameliorate many 
symptoms attributed to myotonia (FIGURE 1).  Below is a description of the outcome 
measures we will utilize to help determine the effect of mexiletine on patient health. 
 
PRIMARY MEASURE OF EFFICACY: 
 
6 Minute Walk - Evaluation of Gait & Endurance: 
 
The primary outcome measure for this study will be the distance patients can walk 
during a 6 minute period (6-minute walk test).  Ambulation has been identified as one of 
the most important and relevant symptoms in DM1. 36 The six minute walk has been 
shown to be a reliable and feasible mechanism for testing DM1 patient ambulation and 
endurance.41a  Our Neuromuscular Disease Center has extensive experience safely 
utilizing this measure and has used this measure in clinical trials.  All patients will be 
timed and monitored under the close supervision by a clinical evaluator during the 
implementation of this clinical test.    
 
Protocol For 6 - Minute Walk Test (6MWT) 
 
The 6MWT will be used to assess changes in mobility, strength and endurance in the 
DM1 patients participating in this long term trial of mexiletine versus placebo. The 
guidelines published by The American Thoracic Society42b will be used for administering 
this test.  The object of the test is for the subject to walk as far as possible in 6 minutes.  
The subject will rate their baseline dyspnea and overall fatigue using the Borg scale 
before and after the test. Blood pressure, respiratory rate, heart rate and oxygen 
saturation will be measured before and after the test. The clinical evaluator supervising 
and monitoring this procedure will record the use of any braces, canes or assistive 
devices. The 6WMT will be performed in a long, straight, hard surfaced corridor in our 
CRC that is about 20 meters. Once the participant reaches the end of the corridor they 
will pivot, continue back along the corridor, and continue back and forth until 6 minutes 
is over. The subject may slow down, stop or rest as necessary.  The distance walked 
during 6 minutes at screening will help determine a subject’s eligibility. Throughout the 
study, the same corridor of the CRC will be used for all of the 6MWTs. 
42b 
 
 
 
 
 
 
 
 


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FIGURE 1: 
 
Myotonic 
Dystrophy Type-1
Myotonic 
Dystrophy Type-2
Myotonic 
Dystrophy Type-1
Myotonia
Thomsen’s 
Disease
Fluctuating 
Myotonia 
Congenita
Myotonia Levior
Becker’s Disease
Paramyotonia 
Congenita
Hyperkalemic 
Periodic Paralysis
Myotonia 
Fluctuans
Myotonia 
Permanens
Muscle Pain
Muscle Weakness
Muscle Atrophy
Gastrointestinal 
Dysfunction
Respiratory 
Dysfunction
Decreased 
Functionality
Increased 
Disability
Reduced Quality 
of Life
Potential Mexiletine 
Shielding
Potential Mexiletine 
Shielding
Patient Symptoms
The Implications of Myotonia on Patient Health
Difficulty Walking
 


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SECONDARY MEASURES OF EFFICACY: 
 
Evaluation of Myotonia: 
 
Two procedures will be used to obtain serial measurements of myotonia in each 
participant.  They are: 1) The measurement of maximum isometric voluntary contraction 
force and relaxation time; and, 2) Video-recording of Hand Opening Time.  Given its 
overall reliability and sensitivity, data from the maximum isometric voluntary contraction 
and relaxation time measurement will be utilized as the primary outcome measurement.  
Details regarding these procedures for determining myotonia are provided below. 
 
1. Maximum Isometric Voluntary Contraction Force and Relaxation Time Measurement 
of Myotonia: 
Maximum isometric contraction force of the long finger flexors and the subsequent 
relaxation time (myotonia) will be measured using a highly reliable technique we have 
utilized for a number of years. 38,56,57  The testing will use the right arm.  Patients will be 
seated while the right arm is flexed to 90o at the elbow and the forearm neutral.  With 
the palm up the 2nd, 3rd, 4th, and 5th fingers are flexed in their distal portions to hold to 
the grip handle.  The hand is strapped securely to prevent movement during contraction 
and during relaxation.  This configuration of hand and force transducer has eliminated 
the variability in measuring isometric grip myotonia that we had previous observed using 
a hand dynamometer without maintaining the hand and fingers in fixed position. 58 The 
output from the transducer is played out on an oscilloscope for the patient to watch and 
recorded on diskette for computerized analysis of the relaxation time. 
To determine the grip myotonia in resting forearm muscle, each participant will squeeze 
with a maximum grip for three seconds then relax until force returns to baseline.  The 
time required for relaxation following this initial maximum isometric contraction will be 
used to calculate the degree of myotonia.  To determine if repeated muscle contractions 
shorten the time required for full muscle relaxation, e.g., warm-up, a series of three 
maximum voluntary contractions (MVC) will be made each for three seconds duration 
with each of these contractions followed by a ten second period of rest.  Following the 
final contraction, the time required for the force to return to baseline will be used to 
measure the effect of warm-up on myotonia.  The measurement of warm-up will be 
made by comparing relaxation time for the initial maximum isometric voluntary 
contraction to the relaxation time following the final contraction in the series of five 
contractions used to evaluate warm up exercise.   
 
Myotonia will be assessed by the time required for the force to fall from 90% of 
maximum voluntary contraction force to 5%, a measurement we have found most 
reliable to assess myotonia. 22,38,57 The change in this time with treatment will serve as 
the primary outcome for this clinical trial.  Each participant will perform three sets of 
hand grip exercises using our standard grip myotonia measurement protocol. 56,57  Each 
set will be separated by a 10 minute rest period.  During this rest period the opposite 
hand will undergo brief myotonia testing using the repetitive stimulation protocol 
described below. 


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2.Video-recording of Hand Opening Time.  The dominant wrist and hand are placed on 
a bedside table with the forearm fully supinated.  The participant is asked to open the 
hand after making a tight fist for 3-5 seconds.  A digital video recording is made of the 
hand opening.  The video field of view only includes the participant’s forearm and hand.  
The time required for hand opening, which often ranges from 3 to 20 seconds in 
individuals with DM1, is determined by blinded review of the video recording.  The 
procedure is carried out three times over 30 minutes.   
 
Evaluation of Muscle Strength:   
Muscle strength will serve as a secondary outcome measure.  Evaluation of muscle 
weakness will be carried out by blinded clinical evaluators and will include quantitative 
myometry, and manual muscle testing (MMT).  These tests will occur at the baseline 
evaluation, at three months, and at the completion of the trial of mexiletine (six months).  
A brief description of the muscle strength testing is provided below. 
 
1. Quantitative Myometry (QMT):  
Maximum Voluntary Isometric Contraction Testing (MVICT) of the limb muscles will be 
performed using the Quantitative Muscle Assessment (QMA) system designed by 
Computer Source, Atlanta, GA.  This system uses an adjustable cuff to attach the 
patient's arm or leg to an inelastic strap that is connected to a force transducer with a 
load of 0.5 to 1,000 Newtons.  The clinical evaluator is a trained physical therapist with 
previous experience in clinical trials.  Photographs and written instructions illustrating 
patient position, strap placement, examiner fixation, and common substitutions will be 
used by the evaluators to ensure standardization of testing.  Each muscle will be tested 
twice while the patient is encouraged by the evaluator to exert maximal effort.   The 
maximum force generated by the patient will be recorded for each trial, and the 
maximum over the two trials will be used as the final measurement for each muscle.  
Measurements resulting from this method of testing have been shown to be reliable and 
valid in several neuromuscular diseases. 39,61  Seven muscle groups will be tested 
bilaterally (shoulder abductors, biceps, triceps, quadriceps, hamstrings, ankle flexors 
and hand grip) for a total of twelve muscle groups.  These particular muscles were 
chosen because they show excellent test-retest reliability in neuromuscular patients and 
normal volunteers and they reflect the distribution of muscle involvement in myotonic 
dystrophy.  If myotonia exerts a deleterious effect on muscle strength, we anticipate that 
the above QMA assessment will have the greatest sensitivity to detect this influence.  
The QMA assessment will serve as our primary measure of strength for our analysis of 
the effect of mexiletine on muscle strength.   
 
2. Manual Muscle Testing:  
Manual muscle testing will be performed on each of 26 muscle groups (shoulder 
abductors, elbow flexors, wrist flexors, wrist extensors, hip flexors, knee extensors, hip 
extensors, knee flexors, hip abductors, elbow extensors, ankle dorsiflexors, and plantar 
flexors on the right and left plus neck extensor and neck flexors). The muscles will be 
tested in various positions including sitting, supine, prone, and side-lying and each 
graded on a modification of the Medical Research Council (MRC) scale of 0-5.  


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Measurements resulting from this method of testing have been shown to be reliable and 
valid in many neuromuscular diseases, as well as being sensitive to detect the 
beneficial effects of treatment in clinical trials of neuromuscular disease. 62,63  
 
The Measurement of Lean Muscle Mass: 
 
Lean muscle mass (LMM) will be measured via Dual Energy X-Ray Absorptiometry 
(DEXA).  DEXA uses a very small amount of x-ray energy (0.5 to 1.0 mREM vs. 20-30 
mREM for a chest x-ray) to measure body composition and it is an easily performed 
safe method.   Lean muscle mass is composed predominantly of muscle.  The other 
contributors to lean muscle mass are relatively constant, and as a result the DEXA 
technique provides a reliable estimate of true muscle mass.  DEXA measured lean 
muscle mass in neuromuscular patients is highly correlated with urinary creatinine 
excretion (Ucr).   Measurement of Ucr excretion has until now been the standard 
method for estimation of muscle mass.  However, valid measurement of UCr requires 
subjects to be on a meat free diet and to carefully collect urine for 72 hrs.  Even under 
carefully supervised conditions, the day to day variability in Ucr excretion is much 
greater.  In the present investigations DEXA provides a more practical approach and 
has been utilized previously in multiple myotonic dystrophy clinical trials as an outcome 
measure. 22,36 Moreover, each scan requires only 20-30 minutes to perform.   DEXA will 
be performed at baseline and after six months of therapy.  
 
Pain Measurement: 
 
During our study we will serially measure pain intensity and duration using a modified 
Chronic Pain Scale and a Brief Pain Inventory.  The Chronic Pain Scale is a 10 point 
rating scale with 0 symbolizing “no pain” and 10 representing pain “as bad as could be”.  
This scale will be modified for clinical trial use by adjusting its timescale to represent 
symptoms over the prior week as opposed to the prior six months.  Documentation of 
the patient reported score of their musculoskeletal pain from 0 to 10 will be made by the 
study coordinator at two week intervals during her regular telephone calls to each 
patient to assess safety, side effects and any other problems the patient reports. 
 
The Brief Pain Inventory is a 9 item scale designed to measure the interference pain 
has with patient daily activities.  These scales were selected based on their validity, 
simplicity, ability to detect change in pain with treatment, patient relevance, reliability, 
test-retest scores, and their previous use in pain studies of the myotonic dystrophy 
population.35,64-66  These scales will be given to patients at baseline, 3, and 6 months to 
measure patient assessed pain while on mexiletine or placebo. 
 
The Measurement of Gastrointestinal Function: 
 
Gastrointestinal function will be measured using the Irritable Bowel Syndrome Impact 
Scale (IBS-IS), and the Gastrointestinal Symptom Rating Scale modified for use in 
patients with IBS (GSRS-IBS). Both of these scales have been previously tested and 
utilized to monitor and track myotonic dystrophy gastrointestinal symptoms during a 


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treatment trial. 36 The GSRS-IBS is a 13 question scale (point range 1-7 for each 
question) which measures pain, bloating constipation, diarrhea and satiety symptoms 
over the preceding 7 days.  The questionnaire has been validated against current 
health-related quality of life questionnaires.  The Irritable Bowel Syndrome Impact Scale 
(IBS-IS) is a 26 question scale (point range 1-7 for each question) which measures 
modalities in fatigue, daily activities, sleep, emotions, and eating habits.  It was 
developed specifically for use in clinical trials and validated against the GSRS-IBS, SF-
36, Visceral Sensitivity Index, and hospital anxiety and depression scale.  Both of these 
questionnaires can be completed in less than 10 minutes.  These scales were selected 
based on their question content and the significant symptomatic overlap between 
myotonic dystrophy gastrointestinal symptoms and irritable bowel syndrome.  These 
scales will be given to patients at baseline, 3 months, and at 6 months. 
 
The Measurement of Swallowing Function:   
 
In order to test patient dysphagia and myotonia of the tongue and pharyngeal muscles 
we have included a timed testing of swallowing.  This test was previously piloted in our 
FDA funded initial 7 week, double-blind crossover trials of mexiletine and found to be an 
effective, safe, and well tolerated procedure to evaluate dysphagia. 22 The swallowing 
testing will occur immediately before eating breakfast during all three in–person 
evaluations (baseline, 3 & 6 month CRC visits).  Each participant will drink 100ml of 
water as fast as they can without choking.  The time will be kept with a stopwatch and 
will begin with the first swallow and conclude with completion of the final swallow.  As 
part of the screening visit, a patient will also be asked to demonstrate their ability to 
swallow a placebo pill with water.  At the conclusion of this study the change in 
swallowing times will be compared across treatment groups. 
 
Measurement of Cardiac Conduction Defects: 
 
The data obtained from Holter recordings will provide 24 hour circadian data in addition 
to basic autonomic electrocardiographic tone parameters at baseline and at Month 3 
and Month 6 on therapy with mexiletine (and placebo) in the DM1 patients participating 
in this research protocol. DM1 has a tendency for lower blood pressure and alters 
peripheral vasomotor control that may affect heart rate adaptation to positional changes. 
Information from the dairy used in the Holter monitoring protocol may provide important 
clinical management information about potential benefits that mexiletine may exert on 
cardiovascular function as well as on skeletal muscle relaxation.  Potential correction or 
modulation of the chloride channel dysfunction that occurs in DM1 by mexiletine may 
alter/improve peripheral vasomotor control and parasympathetic tone in the study 
participants.  Ventricular arrhythmia data including ventricular ectopy counts, 
nonsustained ventricular tachycardia number of events and duration over a circadian 
time period of one day may provide greater insight into any proarrhythmic or 
antiarrhythmic effects of mexiletine therapy in this disease. While the current study 
design is not powered to answer questions about the possible beneficial effect of 
mexiletine on the heart in DM1, the findings on Holter monitoring may encourage 
subsequent investigations to explore such a possibility. 


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Serial 24-hour Holter monitors will be utilized during this study to determine if there are 
any effects of mexiletine on cardiac conduction patterns.  Each study will be analyzed 
by a cardiologist with specific training in the interpretation of the findings on Holter 
monitoring.  Measured variables  include: 1) heart rate variability; 2) number of 
premature ventricular contractions during a 24 hour period; 3) QTc intervals; 4) average 
heart rate; 5) presence or absence of atrial arrhythmias; 6) presence or absence of non-
sustained ventricular arrhythmias; 7) duration of non-sustained ventricular tachycardia 
(if present); and, 8) presence or absence of AV block progression.  If any significant 
abnormalities are observed by the cardiologist reviewing the results of the Holter 
monitoring, the independent medical monitor and PI of the study will be notified 
immediately.  In addition to the important analysis of Holter findings during the CRC 
admissions of each study participant, at the completion of our study biostatistical 
analyses will be performed on the Holter monitoring data to compare baseline to Month 
3 and Month 6 findings in each individual receiving mexiletine and placebo to search for 
trends in our findings that suggest a beneficial or non-beneficial effect of mexiletine 
compared to the variations that occur in similar patients with DM1 receiving placebo.  
 
We will utilize the below ECG data collection and review template (see Figure 2) that 
will be used in the data collection and analysis for the study and will be available to the 
members of the DSMB for their review.  Our staff will enter the appropriate information 
on each participant’s electrophysiology and this information will be charted longitudinally 
throughout the study.  This format for the analysis of ECG data has been used by 
investigators in other studies.  It provides both a numerical/statistical and graphical 
representation of trends in various ECG and Holter variables in a timeline.  Abrupt 
changes as well as potential clinically significant trends in the ECG parameters of an 
individual participant will be detected.  Abnormal values will be highlighted for the DSMB 
for rapid initial review. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 2 A sample template for the basic electrocardiographic data to be 
collected.  This data will also be graphically represented for each subject. 
 
Our DSMB will be organized to help monitor these data and will include a 
cardiologist (Dr. [REDACTED]), a biostatistician (Dr. [REDACTED]), and a 
neurologist (Dr. [REDACTED]) with DSMB experience.  None of the members of 
the DSMB have active collaborations with the investigators on this grant and 
none are members of the specific subspecialty units of which the investigators 
are faculty members.   
 
The criteria for DSMB intervention will consist of three levels: 
 
Level One- Abnormality noted. Possible normal variation. Clinically non-
significant. 
 
Level Two- Abnormality noted. Potential clinical significance. Requires further 
review and decision by DSMB. 
 
Level Three- Critical Value. Clinically significant and immediate intervention 
required. 


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Any Level Three occurrence will warrant a temporary stoppage of study 
medication use for an individual patient until an expedited DSMB determination 
can be made.  
 
Figure 3 below lists possible observable cardiac findings via ECG or Holter 
monitoring and each event’s required DSMB action. 
 
Figure 3: Required DSMB interventions for possible cardiac events. 
Data Category 
Variable 
DSMB Intervention Level 
ECG 
1 degree AV block 
1 
ECG 
2nd Type 1 
2 
ECG 
2nd type 2 
3 
ECG 
3rd degree AV block 
3 
ECG 
Sinus tachycardia 
1 
ECG 
Sinus bradycardia 
2 
ECG 
New Bundle branch block 
2 
ECG 
QRS widening>50% 
3 
ECG 
QTc>500msec 
3 
Holter Monitoring 
PVC frequency Increase 
2 
Holter Monitoring 
Nonsustained VT Increase 
2 
Holter Monitoring 
Sustained VT 
3 
Clinical Symptom 
Syncope/unresponsiveness 
3 
 
      
Functional Testing: 
 
In addition to the six minute walk, three timed functional tests have been selected for 
serial testing.  The tests include: placement of pegs in a Purdue peg board for 30 
seconds with dominant hand (number placed), the time to walk 30 feet, and time 
required to “rise up from a chair.”  These tests reflect specific functional impairments 
that occur in patients with DM1, specifically:  hand weakness (especially finger flexors) 
and gait impairment due to quadriceps stiffness and weakness and cardiorespiratory 
functional limitations due to myotonic stiffness and weakness.  In addition to these tests, 
forced vital capacity and serial SF-36 evaluations will be performed at all inpatient visits.  
Forced vital capacity directly reflects respiratory function while the SF-36 is a widely 
studied, 36 question, generic health survey index designed to measure functional health 
and well-being.  
 
DM1-Specific Patient Reported Health-Related Quality-of-Life: 
 
There is an increasing need to demonstrate that potential new treatments being 
evaluated in therapeutic trials have relevance to patients. To meet this need, over the 
last two years we have been developing a disease-specific patient reported outcome 
instrument to measure health related quality-of-life of DM1 patients for use during 
therapeutic trials.  To date, this research has led to the identification, transcription, and 
coding of over 1100 DM1 patient quotes regarding the highest-impact, most relevant 


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issues and symptoms for DM1 patients.  Under the guidance of the NIH funded 
PROMIS (Patient-Reported Outcomes Measurement Information System) and Neuro-
Qol networks we will soon have a DM1-specific patient reported instrument capable of 
measuring health-related quality-of-life for this population.  This 
instrument/questionnaire will directly represent the issues of highest importance to 
patients with DM1; as identified and validated by several hundred DM1 patients.  The 
completion and development of this instrument was carefully planned to abide by the 
FDA’s recommendations for PRO instrument use during clinical trials.[Patrick et al, 
2007]  Using a patient validated question set this instrument has the capability to 
measure patient-relevant DM1-specific quality-of-life.  In addition, this instrument will be 
able to measure and tract subdomains of DM1-specific quality-of-life.  These 
subdomains include 1) ambulation; 2) problems with hands or arms; 3) inability to do 
activities; 4) fatigue; 5) pain, 6) gastrointestinal issues; 7) impaired sleep; 8) emotional 
issues; 9) cognitive issues; 10) decreased satisfaction in social situations; 11) 
decreased performance in social situation; 12) myotonia; 13) breathing difficulties; 14) 
choking issues; and 15) issues related to medicine side effects.  A draft version of this 
instrument is included in the application.   
 
Independent Medical Monitor: 
Dr. [REDACTED], Professor of Neurology at the University of Rochester Medical Center 
and an international authority on therapeutic trials in neuromuscular disorders, will serve 
as the independent medical monitor for this study.  Dr. [REDACTED] will coordinate his 
assessments of the laboratory data with the Data Safety Monitoring Board (Dr. 
[REDACTED] will not serve as a board member of the Data Safety Monitoring Board) 
overseeing this study and will serve as resource member to that group. The 
independent medical monitor and the statistical programmer will be unblinded and will 
review laboratory data and side effects.  The independent medical monitor will work 
closely with the statistical programmer to identify any potential deleterious effects of 
mexiletine in our patients.  Concerns will be discussed as appropriate with the principal 
investigator.  When necessary the blind will be broken and appropriate medical 
treatment carried out.  Because of previous experience in the use of mexiletine, we do 
not anticipate any major adverse events that will require discontinuation of the study.  
Additional information regarding the safety monitoring of this study is provided in the 
Human Subjects Protection portion of this application.    
 
Data Management: 
 
Study forms, logs, databases, data entry screens, data audit trails, and secure daily 
computer backups have been developed.  The study coordinator will send all forms on a 
weekly basis to the data manager, who will supervise data entry and verification.  Forms 
relating to adverse events, dosage changes, randomization, terminations, will be faxed 
to the data manager.  Data from DEXA and MVICT measurements will be sent 
electronically.  The manager will track receipt of data and identify missing data.  
Immediately thereafter this data will be electronically transferred to the statistical 
programmer.  The study coordinator will notify the principal investigator and IRB and 
follow FDA stipulated guidelines to report any serious adverse events within 24 hours.  


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All paper copies will be kept in locked cabinets.  Additional information regarding the 
data monitoring of this study is provided in the Human Subjects Protection portion of 
this application.   Some patients may simultaneously participate in the University of 
Rochester Pathogenesis and Progression in Myotonic Dystrophy Study (RSRB 24971, 
CRC 1259).  In such cases data sharing may take place to minimize redundancy in 
functional or laboratory testing. 
 
Statistical Analyses: 
 
The primary outcome variable in this clinical trial will be the change from baseline to 
Month 6 in the mean distance walked during the six minute walk test.  Using historical 
six minute walk test data in the DM1 population, we will have 80% power to detect a 
group mean change of 183 feet in distance walked over six minutes. The primary 
statistical analysis will involve fitting a repeated measures analysis of covariance model 
with treatment group as the factor of interest and the baseline value of the outcome 
variable as a covariate.  The model will also include terms for month (categorical) and 
the interaction between treatment group and month.  An unstructured covariance 
pattern will be used for model fitting.  This model will be used to determine a 95% 
confidence interval for the adjusted mexiletine – placebo difference in mean response 
(treatment effect) at Month 6.  Confidence intervals for treatment effects at Month 3, as 
well as averaged over Months 3 and 6, can also be obtained using this model; these will 
be considered to be secondary analyses. 
 
If clinically important differences are found between the groups at baseline, particularly 
with regard to important variables such as age, gender, and years since symptom 
onset, the primary analyses will be repeated after statistically adjusting for these 
differences.  These sensitivity analyses will be considered to be secondary, however. 
 
The underlying assumptions of the analysis of covariance model will be thoroughly 
checked (e.g., normality, linearity), including analyses of residuals.  Remedial measures 
(e.g., transformations, use of nonparametric methods) will be taken if serious violations 
of these assumptions are detected. 
 
The primary analyses will be performed according to the intention-to-treat principle and 
will include all randomized subjects.  Every effort will be made to retain subjects in this 
study and to collect all data at every visit.  If a subject cannot tolerate or refuses to 
continue taking study medication, we will continue to follow and evaluate that subject if 
he/she is willing.  If a subject drops out, attempts will be made to bring the subject in for 
a final evaluation.  Compliance with trial procedures, dropouts/dropins, and reasons for 
subject withdrawal will be carefully tracked throughout the study.  The repeated 
measures analysis of covariance model above uses maximum likelihood to estimate the 
parameters of interest (treatment effects) using available data from all subjects.  A key 
assumption underlying this analysis is that the missing data are “missing at random” 
(MAR), i.e., the probability that responses are missing for a subject depends only on the 
set of observed data for that subject and not on the specific missing values that were 
not obtained. 67 


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An alternative approach that will be used to deal with missing data in this setting, as a 
secondary (confirmatory) analysis, is multiple imputation.  This will be applied using a 
regression-based imputation model. 68  For subjects with complete data up to a particular 
visit, a multiple regression model will be fit that includes the outcome at that visit as the 
dependent variable and outcomes at previous visits and treatment group as 
independent variables.  Separate models will be similarly constructed for each visit.  
Using these regression models, a missing value for a subject at a particular visit will be 
imputed as a draw from the predictive distribution given the outcomes at previous visits 
(some possibly imputed) and treatment group of the subject. 68 This will be done 
sequentially starting with the Month 3 visit.  This process will be repeated 100 times, 
resulting in 100 complete analysis data sets.  The analyses will be performed separately 
for each of the 100 complete analysis data sets, and the results will be combined into 
one multiple imputation inference (estimated treatment effect and associated confidence 
interval and p-value). 68,69  This strategy is appropriate for data sets that have a 
monotone missing pattern.  If the data set does not precisely have this pattern, the 
monotone data augmentation method using Markov-Chain Monte-Carlo70,71 will be used 
to impute the small amount of missing data that is required to make the missing data 
pattern monotone before applying the multiple imputation algorithm described above.  
This approach to imputation should be superior to other strategies such as carrying 
forward the last available observation, which often yields unrealistic imputed values.  
Also, the use of multiple imputation avoids the problem of artificially increasing power 
through data imputation associated with single-imputation methods because it accounts 
for the uncertainty associated with the imputation. 67, 69 
 
Analysis of the Secondary Outcome Variables for Efficacy: 
 
The secondary outcome variables for efficacy include: relaxation following maximum 
voluntary isometric contraction of the long finger flexors, repetitive stimulation relaxation 
time, rapid hand contraction and extension time, composite MVICT score derived by 
averaging the standardized (normalized) scores across the 10 individual muscles40, grip 
strength derived by averaging the strength scores over the left and right hands, average 
MMT score derived by averaging the individual MMT scores across the 26 individual 
muscles40, DEXA lean body mass, Modified Chronic Pain Scale scores, Brief Pain 
Inventory scores, holter monitor findings, IBS-IS scores, GSRS-IBS score, swallowing 
times, Purdue pegboard score, time to rise from a chair, time to walk 30 feet, Holter 
monitor data, SF-36 scores, and disease-specific health-related quality-of-life scores.  
These variables will be analyzed as described above for the primary outcome variable 
using repeated measures analysis of covariance, with the baseline value of the outcome 
variable used as a covariate.  Again, depending on the nature of the outcome variable, 
data transformation or the use of nonparametric statistical methods may be required for 
analysis. 
 
Analysis of Safety Outcomes and Subject Disposition: 
 


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Adverse events will be tabulated by treatment group, severity, and perceived 
relationship to study drug.  For each adverse event (AE), the treatment groups will be 
compared regarding the occurrence of at least one event using Fisher's exact tests.  
The comparisons will be repeated excluding all mild symptoms.  Particular attention will 
be paid to AEs known to be associated with mexiletine in previous studies.  Individual 
AEs will be listed, with particular attention paid to serious AEs.  Laboratory test 
abnormalities will be similarly analyzed, whether or not they are judged to be clinically 
significant (classified as AEs). 
 
Continuous measures of safety (vital signs, EKG results, laboratory test results) will be 
analyzed descriptively.  Formal analyses may be performed using methods similar to 
those described above for the primary outcome variable (repeated measures analysis of 
covariance). 
 
The frequency of and reasons for subject withdrawal, dosage reduction, and premature 
withdrawal of study drug will be summarized by treatment group.  The compliance data 
(amount of unused drug returned, compliance diaries) will be summarized by treatment 
group and visit, as will dosage level of study drug.  Guessed treatment from the 
blindness questionnaire will be tabulated by actual treatment separately for subjects and 
the investigator.  Chi-square tests will be used to determine whether or not the 
proportion of subjects who guess that the subject received mexiletine treatment differ 
among the actual treatment groups.  The investigator’s guesses will be similarly 
analyzed.   Additional information regarding adverse event assessment and processing 
is provided in the Human Subjects Protection portion of this application.    
 
Sample Size Considerations: 
 
The primary outcome variable in this clinical trial will be the change from baseline to 
Month 6 in the mean distance walked during the six minute walk test.  Using historical 
six minute walk test data in the DM1 population, we will have 80% power to detect a 
group mean change of 183 feet in distance walked over six minutes.  This is based on a 
sample size of 18 per group (increased to 20 to account for the possibility of a 10% 
withdrawal rate), and a standard deviation of 190 feet. A two-sample T-Test Power 
Analysis is provided in Appendix A.   
 
An important secondary outcome variable is the change from baseline to Month 6 in the 
time for relaxation of grip force following maximum voluntary isometric contraction of the 
long finger flexors.   
This will be operationally defined as the time required to go from 90% of MVC to 5% of 
MVC averaged over three trials.  In our randomized cross-over trials of mexiletine 150 
mg three times daily and 200 mg three times daily, relaxation time from 90% to 5% of 
MVC was found to be the most sensitive measure of myotonia in terms of detecting a 
benefit of mexiletine.  In the 18 subjects who completed the trial of 200 mg TID, the 
mean (± standard deviation) change (mexiletine – placebo) in this outcome was -1.34 ± 
1.42 seconds.  These data suggest that a sample size of 20 subjects per group will 


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provide 82% power to detect a group difference in mean response of -1.3 seconds in 
the proposed trial, using a t-test and a significance level of 5% (two-tailed). 
 
Another important secondary outcome variable is the change from baseline to Month 6 
in grip strength, averaged over the left and right hands.  In our pilot randomized trial of 
troglitazone, grip strength data were available from 17 of the 20 randomized subjects at 
baseline and Month 8.  The mean change averaged over both hands was -0.93 kg 
(reflecting mean changes of -1.32 kg in the left hand and -0.53 kg in the right hand) and 
the standard deviation of the changes was approximately 2.5 kg.  Similar results were 
obtained at the Month 4 visit.  These data suggest that a sample size of 20 subjects per 
group will provide 80% power to detect a group difference in mean response of 2.3 kg in 
the proposed trial, using a t-test and a significance level of 5% (two-tailed). 
 
The sample size will be increased as necessary to achieve a final group of 20 DM1 
patients in both the mexiletine and placebo treatment groups.  We anticipate that there 
may be a 10% rate of subject withdrawal based upon our recently completed FDA 
funded, 7 week, double-blind crossover trial of mexiletine in DM1 [Appendix A]. 
 
E. HUMAN SUBJECTS 
 
Monitoring and Human Subjects Protection 
 
Risks to Human Subjects 
 
1. Human Subject Involvement: 
Ambulatory moderately affected DM1 patients between the ages of eighteen and eighty 
will be evaluated during this clinical trial.  The inclusion/ exclusion criteria are listed in 
the patient selection section above.   
 
Nonambulatory patients have been excluded because in our experience the majority of 
non-ambulatory patients have advanced weakness in the arms and legs, especially in 
the flexors of the fingers and the intrinsic hand muscles.  Such severe weakness will 
prevent this group of patients from participating in the assessment of myotonia (grip 
myotonia testing, repeated rapid contraction and extension of the fingers). These 
patients are also unable to perform 6 minute walk testing which is the primary end point 
used to assess efficacy of treatment for this study.   
 
2. Sources of Research Material: 
The sources of our research material are the data collected from the history and 
physical examination of each patient, and from the results of 6 minute walk testing, 
myotonia testing, muscle testing, blood and urine specimen analyses.  The material is 
solely for research purposes.  Patients will be asked to give permission for investigators 
to examine existing medical records and to determine their eligibility.   
 
All data forms will contain the initials of each study subject and their assigned study 
number.   


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3. Potential Risks:  
The risk category of this study is greater than minimal.   
 
Mexiletine is approved by the FDA as an alternative treatment for symptomatic 
ventricular arrhythmias. The dosage selected for use in this study is in the low 
therapeutic range.  Toxic side effects of mexiletine occur with greater frequency at 
higher dosages required to control arrhythmias and neuropathic pain. 52-55  These 
dosages are typically two to three times higher than the dosages used in the present 
study.  Patients taking these higher dosages of mexiletine (600-3200 mg/day) have a 
significantly increased incidence of upper gastrointestinal distress, 41%, 
lightheadedness and tremor, 12.5%.72  These symptoms are dose related, generally not 
serious, and disappear after dose reduction or discontinuation of treatment.  No patient 
in our study will receive a dose of mexiletine greater than 450 mg a day.  
 
A recent study which included 9 patients with DM1 has demonstrated that the relatively 
low dosage of mexiletine proposed for use in the present study is effective and has 
greater efficacy than other commonly used antimyotonia drugs, such as, dilantin, 
disopyramide, and tocainide. 19  In addition, there were no severe side effects, 
worsening of heart block, or worsening of bundle branch block in our previous 
mexiletine crossover study of DM1 patients evaluating two low to moderate dosages 
[150 mg three times daily and 200 mg three times daily]. 22 
 
We anticipate that treatment with mexiletine will reduce or eliminate myotonia in our 
patients, and that they will experience few if any side effects at the dosage we have 
proposed.   
 
There is a small risk of bruising from blood draws and muscle soreness from the 
quantitative myometry (QMT), manual muscle testing (MMT), maximum voluntary 
isometric contraction testing, and functional tests.  Dual energy x-ray absorptiometry 
(DEXA) uses 0.5-1.0 mREM which is only a fraction of that used in a routine chest x-ray 
(20-30mREM) and is considered to pose to significant risk. There is minimal risk of 
transient discomfort from direct irritation to the nerve associated with the electrical 
stimulation during the repetitive stimulation test (measuring duration of myotonia). 
 
Questionnaires, although we believe their content is benign, may produce mild 
emotional stress. 
 
Adequacy of Protection Against Risks 
 
1. Recruitment and Consent Procedures: 
Patients will be recruited from the University of Rochester Neuromuscular Disease 
Center and from the list of patients who have received permission from their regular 
physicians to participate in our ongoing research studies of DM1.  Both sexes will be 
recruited, as will members of all minorities.  Interested potential subjects will be 
contacted by phone by the study coordinator and questioned about their health status.  


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Interested potential subjects who report no history of medical or psychiatric disease and 
a previous diagnosis of DM1 will be asked to come to the Clinical Research Center 
(CRC) for a screening visit.  Women will be recruited only if they are using adequate 
birth control measures, or are postmenopausal, or have had a tubal ligation, or have 
had a hysterectomy.   
 
When possible, subjects will be provided with a copy of the consent form for their review 
prior to the screening visit.  Informed consent will be obtained by the principal 
investigator or study coordinator after details of the study and its requirements have 
been presented, and there has been an opportunity for the subject  to ask questions.  
Consent will be obtained only after complete information has been provided to the 
participant about the purpose of the study, the procedures, risks, benefits, contact 
persons, compensation, and care for injury, and voluntary participation.  The subject 
study personnel obtaining consent will sign the IRB approved consent form.  The 
subject will receive a copy of the consent form after it has been signed.  The original will 
be retained in the files of the investigator.     
 
2. Procedures for Protecting Against or Minimizing Risks: 
All subjects will be monitored closely by the CRC nursing staff and investigators during 
the procedures to prevent and minimize any potential risks or discomfort.  The nursing 
staff and study personnel will receive in-service training regarding these procedures. 
Each participant will be asked to report any continuing discomfort caused by any of the 
performed procedures.  
 
 
If a woman is pregnant, she will not continue in the study. 
 
Safety data receive appropriate review by our DSMB and independent medical monitor 
and will be given to the data manager who will keep the records in a locked file cabinet 
and maintain their confidentiality.  In all databases and reports, subjects will be 
identified by an ID number.  
 
In addition to the assessments during each evaluation on the CRC adverse events will 
be monitored during telephone calls at about 2 week intervals.  The laboratory studies 
will provide additional means to detect any evidence of major organ toxicity.   
 
Patients will be withdrawn from the study if intolerable side effects or severe adverse 
events, as determined by the PI, are identified.  Patients who cannot tolerate the 
medication or procedures, have surgery or other illnesses which affect the evaluations 
will have the drug discontinued.  Patients may withdraw at any time.  All withdrawals will 
be reported to the statistical center, DSMB, and safety monitor within 24 hours.  
Occurrence of a serious adverse event must be reported to the IRB and principal 
investigator, DSMB, and independent medical monitor within 24 hours.   
 
Costs and Reimbursement 
1. Costs to subjects 
 
 
There are no costs to the subjects for participating in this study. 


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2. Honorarium  
Subjects will receive an honorarium of $150 after completing the baseline, 3 
month and 6 month follow-up visits (for a total of $450). A limited amount of travel 
money is also available.  
 
 
Data and Safety Monitoring Plan    
 
1. Reporting of adverse events 
 
The study will comply with Food and Drug Administration (FDA) regulations requiring 
expedited reporting of any adverse events (AE) that are serious, unexpected and 
associated with the use of a study drug.  All serious adverse events will be reported 
within 24 hours to the IRB, DSMB, Independent Medical Monitor, and FDA.   
 
Adverse events must be recorded starting from the time of informed consent until the 
final study visit.  Any medical condition present at the initial visit, which remains 
unchanged or improves, should not be recorded as an adverse event at subsequent 
visits.  However, if there is deterioration of a medical condition that was present at the 
initial visit, this should be considered a new adverse event and reported. All adverse 
events (AEs), whether or not they are considered related to the study, shall be recorded 
on the Case Report Forms (CRFs).  
 
Clinically significant changes (abnormalities), in the judgment of the investigator, 
in physical examination from the baseline exam will be recorded as an adverse 
event.   
 
The following information must be collected and recorded for each AE: 
 AE term (diagnosis) 
 Start date of AE 
 Stop date of AE 
 Severity of AE (mild, moderate, or severe) 
 Seriousness of AE (serious or non-serious) 
 Action taken regarding study medication (none, study medication dose 
reduced, study medication interrupted, or study medication stopped); 
 Action taken regarding AE (specific treatment instituted, subject 
hospitalized, etc.) 
 AE outcome (resolved, ongoing, death, or lost to follow-up) 
 AE causality (none, possible, probable) 
Relationship to study drug: 
The investigator, using the following explanations, will determine study drug 
relationship for each adverse event: 


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None  
The event is clearly related to other factors such as the subject's clinical state, 
therapeutic interventions, or concomitant drugs administered to the subject. 
 
Possible  
• The event follows a reasonable temporal sequence from the time of drug 
administration, 
• And/or follows a known response pattern to the trial drug, but could have 
been produced by other factors such as the subject's clinical state, 
therapeutic interventions, or concomitant drugs administered to the subject. 
Probable 
• The event follows a reasonable temporal sequence from the time of drug 
administration, 
• And follows a known response pattern to the study drug, 
• And cannot be reasonably explained by other factors such as the subject’s 
clinical state, therapeutic interventions, or concomitant drugs administered to 
the subject, 
• And either occurs immediately following trial drug administration, or improves 
on stopping the drug, or reappears on repeat exposure, or there is a positive 
reaction at the application site. 
 
Severity of an adverse event is defined as a qualitative assessment of the 
degree of intensity of an adverse event as is determined by the investigator or 
reported to him/her by the subject.  
The assessment of severity is made irrespective of drug relationship or 
seriousness of the experience and should be evaluated according to the 
following scale: 
1 = Mild– The adverse event is easily tolerated and does not interfere with daily 
activity. 
2 = Moderate– The adverse event is not easily tolerated and interferes with daily 
activity. 
3 = Severe– The adverse event is incapacitating and the subject is unable to 
function. 
 
Adverse side effects will be monitored during each CRC visit (baseline, month 3, month 
6) and during telephone calls at about 2 week intervals during the intervening weeks of 
the trial.  The adverse effects of mexiletine observed most commonly include: dizziness, 
lightheadedness, nervousness, nausea, vomiting, or upset stomach, diarrhea, 


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constipation, trembling, shaking of hands, blurred vision, tiredness, or weakness.  More 
serious side effects, which are less common include: irregular heart beat, chest pain, 
shortness of breath, trouble breathing, skin rash, severe itching, or hives.   
 
The laboratory studies will provide additional evidence of any major organ toxicity.  
Patients will also receive a diary to record adverse events as they occur as well as a 
schedule to remind them to take the study medication. 
 
The following definitions will be utilized: 
 
An adverse event is any untoward medical occurrence in a subject that occurs 
during the conduct of a clinical study of a pharmaceutical product that does not 
necessarily have a causal relationship to the study drug.  This can, therefore, be 
any unfavorable and unintended physical sign, symptom, laboratory parameter, 
or disease entity that develops or worsens in severity during the course of the 
study, whether or not considered related to the study drug.  
 
A serious adverse event (SAE) is defined as any adverse drug experience 
occurring at any dose that results in any of the following outcomes: 
 
• Results in death, 
• Is life-threatening (NOTE: The term "life-threatening" in the definition of 
"serious" refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe.),  
• Results in inpatient hospitalization or prolongation of existing hospitalization, 
• Results in a permanent disability,  
• Results in a congenital anomaly/birth defect, 
• A new malignancy, 
• Overdose, suspected or confirmed. 
 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, the event may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition.   
 
2. Study Conduct 
 
The study will be conducted according to the protocol, Good Clinical Practice (as 
outlined in the ICH Guidelines and Code of Federal Regulations), and the Declaration of 
Helsinki.  Written informed consent for the study must be obtained from all subjects prior 
to protocol specific procedures being performed.  Subjects must be informed of their 
right to withdraw from the study at any time. 
 
3. Study Oversight 


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The principal investigator has primary oversight responsibility for this trial.  The PI will 
meet with the study coordinator, as well as any other necessary members of the 
research team as needed.  The meetings will include reviews of safety data, protocol 
deviations, adverse events, subject compliance, test article accountability and inventory, 
logs for screening, enrollment, and subject withdrawal, as well as any other pertinent 
issues identified by the PI, study coordinator, or other research team member. 
 
4. Data Safety Monitoring Board 
 
Working under the direct guidance of the FDA, a qualified data safety monitoring board 
(DSMB) has been established.  Written procedures for monitoring of the clinical trial to 
assure the quality of the study and to assure that each person involved in the monitoring 
process carries out their duties will be set to comply with FDA regulations.  These 
monitoring procedures will be included in a Manual of Operations for the study.  
5. Interim Analyses for Safety and Efficacy 
Interim analyses of safety data will be performed periodically throughout the project.  
While the safety of subjects will be the primary concern of the data safety monitoring 
board (DSMB), it is difficult to formulate precise stopping guidelines that would cover all 
of the possible situations that might arise.  Adverse events, particularly serious adverse 
events such as deaths and hospitalizations, will need to be carefully considered by the 
DSMB in terms of treatment group imbalances.  It is helpful to emphasize that our 
previous double-blind, randomized crossover trial of 20 DM1 patients treated with 150 
mg three times daily of mexiletine for 7 weeks was completed without any significant 
adverse events; and, that a subsequent second double-blind, randomized crossover 
trial of 20 DM1 patients treated with 200 mg three times daily of mexiletine for 7 weeks 
was also completed without any significant adverse events.  We do not anticipate 
encountering any expected side effect that based upon our advanced knowledge of 
mexiletine will constitute a reason to stop the study or specifically stop a given patient’s 
participation.  Severe confounding medical illness or severe trauma are reasons noted 
previously in this application for discontinuing patient participation.  We perform serial 
laboratory studies throughout the course of the treatment trial. If the DSMB observes 
trends in all patients that suggest that a given value(s) is rising or falling 2-3 fold outside 
the normal range and is not known to occur in the usual clinical course of DM1, this 
finding will prompt a discussion of the need to stop the study.  The same actions will 
occur if a serious medical illness develops in a significant portion of the DM1 patients 
receiving mexiletine which is not typically observed in the usual clinical course of a DM1 
patient. 
 
In addition, we will perform an interim analysis of the primary outcome variable after 
50% of the trial participants (20 participants) have completed 6 months of follow-up. We 
will use an O'Brien-Fleming stopping boundary whereby the interim analysis will be 
performed using a significance level of 0.003 and the final analysis will be performed 


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using a significance level of 0.049 (two-tailed). This will ensure that the overall 
probability of a Type I error is controlled at 0.05. 
 
 
6. Independent Medical Monitor 
 
The independent Medical Monitor (Dr. [REDACTED]) will be responsible for monitoring 
the conduct and progress of the study as well as evaluating clinical situations and 
communicating new safety information to the PI and the FDA.  The independent Medical 
Monitor will review aggregate data (adverse events and safety labs) and ascertain 
whether adverse events are thought to be occurring more frequently than expected.  If 
they are, they will be reported by memo to the PI and the DSMB.  The independent 
Medical Monitor will review the SAE notification form to determine if the event is 
unexpected and associated with the use of study medication.  The site may be called to 
provide further information, if necessary.  The progress of each SAE will be followed by 
the independent Medical Monitor until resolution or until an appropriate endpoint is 
reached (resolution or determination of the event to be chronic and/or stabilized).   
 
7. Adverse Event Monitoring 
 
The PI will review data regarding adverse events and laboratory abnormalities in a 
blinded fashion.  An independent medical monitor will receive and review reports of all 
adverse events.  The independent DSMB can review unblinded data as necessary.  In 
the rare event that an investigator needs immediate knowledge of the subject’s 
treatment assignment for emergent care of the subject, individual treatment assignment 
envelopes generated by the Biostatistics Center will be available.    
 
8. Data Management 
 
The original Case Report Forms (CRFs) for each visit will be sent to the Neuromuscular 
Disease Data Center (NMD-CC), with a duplicate copy stored in the subject’s research 
chart. All original and duplicate CRFs will be kept under double lock by the Data 
Manager at the NMD-CC. Completed CRFs will be entered into a SAS database on the 
Neurology file server. Access to study subject CRFs and Statistical Analysis Software 
(SAS) database will be limited to study personnel. For each CRF, custom data entry 
screens will be developed with error checking built in using SAS/FSP software by the 
Study Data Manager. SAS/FSP software provides convenient interactive capabilities for 
data entry, editing, and retrieval.  
 
To minimize data entry errors Screen Control Language (SCL) will be developed to edit 
individual fields and perform cross-field validation.  When SCL detects an invalid data 
value, entry is suspended. An appropriate error message is displayed, prompting the 
data entry clerk to resolve the discrepancy before entry can be completed.  Batch SAS 
programs will also check for inconsistencies and incompleteness of data after initial 
entry.  The Data Manager will develop edit check programs, and these programs will 
generate output that describes data discrepancies found in the database.  All CRFs are 


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reviewed for clarity and completeness.  In addition, all output generated by the edit 
check program will be reviewed by a Data Manager. Data discrepancies identified 
through edit check programs, manual review of CRFs, or clinical reviews will generate 
queries which will be e-mailed to the investigator/coordinator on a Data Clarification 
Form (DCF). The DCF will identify the subject, visit number, CRF number, and the data 
element flagged for review. The study coordinator will investigate the discrepancy.  
The DCF must be completed showing what corrections need to be made (or indicating 
why no changes are necessary) and signed by the site investigator or coordinator, then 
faxed back to the NMD-CC. Data entry staff at the NMD-CC will enter the response to 
the DCF into the database and the data manager will verify that they have been entered 
correctly.  The original DCF will be filed by the study coordinator with the corresponding 
CRF source documents.  
 
All DCFs should be returned to the NMD-C within two weeks after the DCF was sent to 
the investigator/coordinator. All completed CRFs should be sent to the NMD-CC with 
two weeks after each study visit. Any CRF or DCF that is not received within the two 
weeks will generate request to the coordinator with a copy to the investigator. 
NMD-CC Data Manager will perform a final quality audit of a random sample of 5 
patients at the end of the study. All CRFs from the random sample of patients will be 
100% verified against the database. If the error rate is less than or equal to 0.1% (an 
accuracy rate of at least 99.9%) and the errors encountered are not significant, NMD-
CC will correct the errors and finalize the database. If the error rate is greater than 0.1% 
or if the errors encountered are significant (i.e. an adverse event was not entered), a 
rework of these sections of the database will be performed, and these sections will be 
re-audited on another 5 patient random sample.  
Upon completion of the study, the cleaned databases are locked and send to the study 
biostatistician for final analysis. 
 
9. Risk/Benefit Assessment  
 
We believe that the relatively mild side effects and risks of treatment associated with 
mexiletine in patients with DM1 will be heavily outweighed by the likely improvement in 
their muscle function resulting from this treatment.  If our results lead to a new approved 
indication for the use of mexiletine as an antimyotonia therapy, this finding will have a 
wide beneficial effect for all patients with DM1. 
 
Inclusion of Women and Minorities 
 
Myotonic dystrophy (DM-1) has a prevalence rate of approximately 1 per 7,500.  We 
anticipate that our study population will have no gender differences, but there may be a 
relative predominance of certain ethnic backgrounds.  The prevalence rates of DM1 in 
major ethnic populations have not been established within the United States, but DM1 
prevalence rates in Africa are much lower than those in Europe and the United States. 
23,24  The demographics of myotonic dystrophy in Monroe County are not known.  
However, the latest demographics of Monroe County (White 80.8%, Black 14.7%, 
Hispanic 5.7%, Asian 2.8%, Native American 0.3%) indicate that our area contains 


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minority populations similar to the national distribution 
(http://quickfacts.census.gov/qfd/index.html; accessed on 2/2/2009).  We have based 
our recruitment projections to reflect the demographics of Monroe County which closely 
parallel those of the general U.S. population.  We will send information describing this 
study to the local and national offices of the Muscular Dystrophy Association as well as 
the NIH.  It is our hope that this will increase the diversity of the patients enrolled in our 
clinical trial.  Based on the above information, we expect the ethnic distribution of 
enrollment to be as indicated in the Table 3.  
 
 
Targeted/Planned Enrollment 
 
TABLE 3: 
  
Targeted/Planned Enrollment Table 
 
Study 
Title: 
A Randomized, Placebo Controlled, Clinical Efficacy Trial of Mexiletine for Myotonic 
Dystrophy Type-1 (DM1). 
Total Planned 
Enrollment: 
60 myotonic dystrophy patients 
 
TARGETED/PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
2 
2 
4 
Not Hispanic or Latino 
28 
28 
56 
Ethnic Category: Total of All Subjects * 
30 
30 
60 
Racial Categories 
 
American Indian/Alaska Native 
0 
0 
0 
Asian 
2 
1 
3 
Native Hawaiian or Other Pacific Islander  
0 
0 
0 
Black or African American  
4 
4 
8 
White 
24 
25 
49 
Racial Categories: Total of All Subjects * 
30 
30 
60 
          


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Goldman, A., Ramsay, M., and Jenkins, T.  "New founder haplotypes at the myotonic 
dystrophy locus in Southern Africa".  Am.J.Hum.Genet. 56:1373-1378, 1995. 
 
 
 
 
 
Inclusion of Children 
 
Children have not been included for several reasons.  Patients with a history of 
congenital DM1 have been excluded because they have a different natural history from 
the adult onset form of this disease. 
 
These patients if they survive the neonatal period often have significant intellectual 
impairment as well as difficulty with hypotonia and muscle weakness, respiratory and 
gastrointestinal dysfunction.  These symptoms gradually lessen in severity throughout 
childhood and the patients may slowly regain close to normal muscle function during 
their early teens.  After a few years these patients gradually develop manifestations 
typical for classical myotonic dystrophy of Steinert.  The extent to which residual 
manifestations of congenital-childhood onset DM1contributes to differences in the 
clinical course in adult life is unknown and poses difficulty in interpreting the response to 
treatments compared to individuals who clearly have an onset in adult life.  The majority 
of children with DM have had onset very early in childhood or in infancy and have 
clinical features associated with congenital DM.  Myotonia is often not apparent or 
prominent in childhood myotonic dystrophy. 23,24  The typical onset for DM1 occurs in the 
late teens, early twenties, or later in life.  Because of the very small number of DM1 
children with myotonia, because of differences in the natural history of DM1 with early 
childhood onset, and because the safety and effectiveness of mexiletine in the 
paediatric population have not been established, we have excluded children from 
present investigation.   


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