Myotonia, Muscle Stiffness and Elasticity in Neuromuscular Disorders
Conditions: Neuromuscular Disorders
Sponsor: LMU Klinikum

Clinical Trial Protocol : MYOTONIA, MUSCLE STIFFNESS AND ELASTICITY IN NEUROMUSCULAR DISORDERS Page 1 of 15 
MYOTONIA, MUSCLE STIFFNESS AND ELASTICITY IN NEUROMUSCULAR DISORDERS 
Version: 1 [01-JUL-20191 
Study-Site: 
Principal lnvestigator 
Principal lnvestigator Back-up 
Fried ri eh-Bau r-1 nstitute 
Department of Neurology 
Klinikum München 
Ziemssenstr. 1 
80336 Munich 
Germany 
Dr. med. Stephan Wenninger 
Fried ri eh-Bau r-1 nstitute 
Dep. of Neurology 
Klinikum München 
Ziemssenstr. 1 
80336 Munich 
Germany 
Tel: +49 89 4400 57400 
Fax: +49 89 4400 57402 
Prof. Dr. med. 8. Schoser 
F ried ri eh-Bau r-1 nstitute 
Dep. of Neurology 
Ziemssenstr. 1 
80336 Munich 
Germany 
Tel: +49 89 4400 57400 
Fax: +49 89 4400 57402 
This protocol was designed and will be conducted, recorded, and reported in accordance with the 
principles of Good Clinical Practice (GCP) as stated in the International Conference on Harmonization 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use and any 
applicable national and regional laws. 
1 have read and agree to abide by the requirements of this protocol. 
lnvestigator Name (print) and Signature Klinikum der Universität München 
Friedrich-Baur-lnstitut 
Neurologische Klinik und Poliklinik 
. 
Dr. S. Wenninger 
Z1emssenstr. 1 • 80336 München 
Tel.: 089/4400-57470 • Fax -57402 
Date 
Clinical Trial Protocol "Myotonia and Stiffness in NMD" - Version 1 [01-JUL-2019I 

Clinical Trial Protocol: MYOTONIA, MUSCLE STIFFNESS AND ELASTICITY IN NEUROMUSCULAR DISORDERS Page 2 of 15 
1 SYNOPSIS/SUMMARY 
TITLE: 
disorders 
PROTOCOL NO.: 
Myotonia, 
muscle stiffness and 
elasticity 
in 
neuromuscular 
Myotonia and Stiffness in NMD V1 !01 . July 20191 
INVESTIGATOR STUDY SITE: Friedrich-Baur-lnstitute, Department of Neurology, Klinikum der 
Universität München. Ziemssenstr. 1, 80336 Munich, Germany 
OBJECTIVES: The primary objective ofthis study is to assess stiffness, muscle tone, relaxation periods 
and elasticity of various muscles in patients with dystrophic or non-dystrophic myotonia. The 
secondary objectives are (1) to provide reference values for stiffness, muscle tone, relaxation periods 
and elasticity of various muscles in patients with dystrophic or non-dystroph ic myotonia; to provide 
reference values for stiffness, muscle tone, relaxation periods and elasticity of various muscles in 
patients with non-myotonic neuromuscular disorders, (3) assess correlations between to compare 
result values for stiffness, muscle tone, relaxation periods and elasticity with cl inical muscle function 
tests, measured by clinical evaluation (MRC-scale) and the 6-minute walktest; (4) assess correlations 
between subcutaneous fat and muscle thickness and echogenicity, measured by muscle ultrasound 
and result values for stiffness, muscle tone, rela xation periods and elasticity. 
METHODOLOGY: This is a monocentric, blinded, cross-sectional explorative study in patients with 
neuromuscular diseases. 
NUMBER OF PATIENTS: Approximately 70 patients will be enrolled, about 5 each in the following 
disease groups: Limb-Girdle-Muscular Dystrophy (LGMD), Myotonie Dystrophies Type 1 and 2 
(DM1, DM2), Late-Onset-Pompe Disease (LOPD), Distal Myopathies, Congenital Myotonia, Spinal 
muscular atrophy Type 3 (SMA3), 
Amyotrophic lateral sclerosis 
(ALS) 
and 
peripheral 
Polyneuropathies (CIDP, HMSN). Approximately 20 healthy age- and gender-matched patients will 
be enrolled as a control group. 
INCLUSION/EXCLUSION CRITERIA: 
lnclusion Criteria: A patient must meet all of the following criteria tobe elig ible for this study. For 
patients, (1) the participant is ~18 years of age and has a confirmed neuromuscular disease, (2) 
provides written consent and (3) is able and willing to perform study procedures. For healthy 
volunteers, age ~18 and written informed consent is obligatory and there is no clinical sign for any 
neuromuscular disorder. 
Exclusion Criteria: lf one of the following criteria is met, a patient will not be able to participate in 
this study: (1) The patient has severe comorbidities; (2) the patient is participating in another clinical 
study using investigational treatment; (3) the patient cannot perform required muscle function tests; 
(4) the patient, in the opinion of the lnvestigator, is unable to adhere to the requirements of the study. 
REGIMEN/STUDY PROCEDURES: 
After obtained informed consent, the following procedures will be performed: 
• 
at screening, patient's eligibility will be defined. 
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• 
at visit 1 (same day as Screening), the following procedures will be performed: (1) Collection 
of demographic and disease-related data (age, gender, diagnosis, age at onset of symptoms, 
age at diagnosis, severity and location of myotonia and severity and location of muscle 
stiffness, for both using numeric rating scale (NRS)). (2) Performing a 6-Minute-Walk-Test 
(meters). (3) Clinical evaluation of muscle strength of the following muscles, using the MRC-
Scale (0-5): on both sides thenar and hypothenar, m. biceps brachii, m. triceps brachii, m. 
deltoideus, m. quadriceps femoris, m. tibialis anterior and gastrocnemius muscles. (4) 
Semiquantitative measurement of cutis and subcutis, subcutaneous fat and muscle thickness 
by muscle ultrasound of the following muscles: on both sides thenar and hypothenar, m. biceps 
brachii, m. triceps brachii, m. deltoideus, m. quadriceps femoris, m. tibialis anterior and 
gastrocnemius muscles. Measurements will contain thickness of cutis in millimeters, the 
thickness of subcutaneous fat in millimeters, muscle thickness in millimeters at the point of 
measuremen~ of the MyotonPro® and semiquantitative measurement of muscle echogenicity, 
using Heckmatt scale 1-IV. (5) Measurement of rela xation time, stiffness and elasticity of the 
following muscles, using the MyotonPro® device: on both sides thenar and hypothenar, m. 
biceps brachii, m. triceps brachii, m. deltoideus, m. quadriceps femoris, m. tibialis anterior 
and gastrocnemius muscles. For the documentation of the results, please see section 
"MyotonPro® device". 
• 
at Visit 2 (+ 1-7 days after day 1 ), a measurement of relaxation time, stiffness and elasticity of 
the following muscles, using the MyotonPro® device: on both sides thenar and hypothenar, 
m. biceps brachii, m. triceps brachii, m. deltoideus, m. quadriceps femoris, m. tibialis anterior 
and gastrocnemius muscles will be performed for reliability purposes. For the documentation 
of the results, please see section "MyotonPro® device". 
STATISTICAL METHODS: 
All patients who participate in this study will be included in the analysis. Data collected in this study 
will be reported using summary tables, figures and patient data listings. Summary statistics (n, mean, 
median, standard deviation, minimum and maximum) will be calculated for the continuous variables 
and shift tables and/or frequencies, and percentages will be produced for the categorical variables. 
Due to the exploratory nature of this study, no formal inferential statistical tests will be performed . 
Clinical Trial Protocol "Myotonia and Stiffness in NMD" - Version 1 [01-JUL-20191 

2 TABLE OF CONTENTS 
Study ........................................................................... 10 
Myotonia, 
muscle stiffness and 
elasticity in 
7.2.2 Premature Patient Discontinuation from the Study 
neuromuscular disorders 
1 
.................................................................................... 10 
7.3 DISCUSSION OF STUDY DESIGN, INCLUDING CHOICE OF CONTROL 
1 SYNOPSIS/SUMMARY ................................................... 2 
GROUP .... ........................... ................................................ 10 
2 TABLE OF CONTENTS ..................................................... 4 
8 RISKS AND BENEFITS .................................................... 10 
3 RESPONSIBILITIES ......................................................... 5 
8.1 SUMMARY OF POTENTIAL RISKS ......................................... 10 
4 BACKGROUND .............................................................. 5 
8.2 SUMMARY OF POTENTIAL BENEFITS .................................... 10 
5 STUDY OBJECTIVES ....................................................... 6 
9 ADVERSE EVENTS REPORTING ...................................... 11 
5.1 PRIMARY ÜBJECTIVE .......................................................... 6 
10 STATISTICAL METHODS AND PLAN NEO ANALYSES ....... 11 
5.2 SECONDARY ÜBJECTIVES .................................................... 6 
10.1 GENERAL CONSIDERATIONS ............................................ 11 
6. STUDY POPULATION .................................................... 6 
10.2 DETERMINATION OF SAMPLE SIZE .................................... 11 
10.3 DEMOGRAPHICS AND BASELINE (HARACTERISTICS ............... 11 
6.1 INCLUSION CRITERIA ......................................................... 6 
10.4 PATIENT ÄCCOUNTABILITY .............................................. 11 
6.2 EXCLUSION CRITERIA ......................................................... 7 
10.5 MYOTONPRO® MEASUREMENT RELIABILITY ........................ 12 
6.3 NUMBER OF PATIENTS ....................................................... 7 
10.6 MISSING OR INVALID DATA ............................................. 12 
6.4 RECRUITMENT ................................................................. 7 
11 DATA MANAGEMENT AND DATA PROTECTION ........... 12 
7 INVESTIGATIONAL PLAN ............................................... 7 
12 SPECIAL REQUIREMENTS AND PROCEDURES ............... 12 
7.1 STUDY DESIGN ................................ ................................. 7 
7.1.1 Screening .............................................................. 8 
12.1 INSTITUTIONAL AND ETHICS REVIEW ................................. 12 
7.1.2 Visit 1 (same day as Screening) ............................ 8 
12.2 (HANGES TO THE CONDUCT OF THE STUDY OR PROTOCOL .... 13 
7.1.3 Visit 2 (+1-7 days after day 1) .............................. 8 
12.3 PATIENT INFORMED CONSENT .... ............................ ........ . 13 
7.1.4 MyotonPro ® Device .............................................. 8 
12.4 (ASE REPORT FORMS .................................................... 13 
7.1.5. Six-Minute walktest ........................................... 9 
12.5 RECORD RETENTION ............................... ....................... 13 
7.1.6. Semiquantitative muscle ultrasound .................. 9 
12.6 (UNICAL STUDY REPORT ................................................ 13 
7.1.7. Hand-held Dynamometry of muscle strength ... 10 
13 ABBREVIATIONS ........................................................ 13 
7.2 (OMPLETION OF A PATIENT
1S PARTICIPATION IN THE STUDY .... 10 
14 LITERATURE ............................................................... 14 
7.2.1 Completion of a Patient's Participation in the 

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3 RESPONSIBILITIES 
The scientific experts responsible for this study are Dr. S. Wenninger (PI) and Prof. B. Schoser (Backup PI). 
This is a non-funded study. All costs are covered by internal funds of the Friedrich-Baur-lnstitute. 
4 BACKGROUND 
In neuromuscular diseases, muscular involvement is extremely heterogeneous. The high variability is not 
only present in various neuromuscular diseases, but also within one type of disease itself. Since phenotypes 
vary among affected patients, a lang delay between the onset of symptoms and diagnosis is common in 
neuromuscular disorders (11. In myotonic dystrophies, specific muscles are affected by myotonia and 
stiffness, whereas other muscles or muscle groups may not or only be slightly affected or may show signs of 
weakness and atrophy (21. In non-dystrophic myotonia like congenital myotonia Becker and Thomson, a 
generalized muscles stiffness is present in almost all patients at younger ages. For dystrophic and non-
dystrophic myotonia, hallmarks are a delayed relaxation and stiffness of affected muscles after voluntary 
contraction [3, 41, but phenotypes show high variability. Non-invasively, myotonia and muscle stiffness is 
typically only described clinically, but not objectively measured. Semi-invasively, the severity of myotonia 
can be assessed by electromyography, requiring a high logistic and technical effort including sophisticated 
computerized measurements, which makes implementation in clinical practice almost impossible. In several 
Limb-girdle-muscular dystrophies (LGMD), muscles are selectively affected by fatty infiltration and atrophy. 
This becomes most evident in autosomal recessive LGMD2L, where the medial gastrocnemius muscles are 
selectively affected by fatty infiltration and atrophy at early stages of the disease, while proximal muscles are 
more likely to cause myalgia and reduced muscular endurance, but da not show signs of fatty infiltration [51. 
In Late-Onset Pampe disease (LOPD), abdominal and paraspinal muscles are early and primarily affected [6-
81. In contrast, affection of the second motoneuron (Amyotrophic lateral sclerosis (ALS); spinal muscular 
atrophy (SMA)) as weil as diseases with affection of the peripheral nervous system (chronic inflammatory 
demyelinating polyneuropathy (CIDP) or different forms of hereditary sensory and motor neuropathies 
(HMSN)) cause muscular atrophy without signs fatty infiltration, but are associated with muscular cramps in 
the majority of cases [9-121. For assessing fatty infiltration of muscles or muscular atrophy, magnetic 
resonance imaging (MRI) is increasingly used as a complement to clinical and electrophysiological 
examination in neuromuscular disease, but costs and time are limitations [131. Muscle ultrasound has proven 
to have a high sensitivity and specificity for characterizing and detecting neuromuscular disorders but is 
always compl'ementary to clinical and electrophysiological flndings (141. lt may be useful to detect and 
describe muscular movements like fasciculations and myokymia, but a correlation of myotonia or muscle 
stiffness with clinical disease severity is paar [15, 161. 
Ta assess myotonia and muscle stiffness in neuromuscular disorders, we use a handheld device that allows 
non-invasive measurement of relaxation time, stiffness and elasticity. For .this, the MyotonPro®, a 
commercially available device, is used to evaluate the stiffness, myotonia and elasticity of muscle fibers by 
applying short pulses to the underlying tissue (171. lts validity and reliability were proven in a !arge cohort 
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Page 6 of 15 
of healthy volunteers as weil as patients with different types of muscle diseases (17-221. A brief pulse of a 
few seconds causes the underlying tissue to oscillate and send back a signal that is picked up and processed 
by the device. This allows to evaluate relaxation time, stiffness and elasticity of the tissue and may help to 
assess the severity of myotonia and stiffness in neuromuscular patients. The following measurements will be 
performed automatically, analyzing the oscillation curves and calculating the tissue tone (frequency (Hz)), 
the tissue stiffness (N/m), the decrement as parameter for the elastic stiffness of the tissue and viscoelastic 
parameters like relaxation time (in milliseconds) and creep as non-elastic tissue strain. The device has 
recently been used in patients with altered muscle elasticity and stiffness like Parkinson's disease, stroke 
and Duchenne muscular dystrophy [19-21, 23-251 as weil as assessing muscular atrophy and viscoelasticity 
due to immobility in healthy subjects (221. 
So far, the knowledge of muscle elasticity, myotonia and stiffness in various neuromuscular diseases is 
scarce. The study aims to test elasticity, myotonia and stiffness in various neuromuscular diseases and to 
provide reference values for different neuromuscular disease groups. 
5 STUDY ÜBJECTIVES 
5.1 Primary Objective 
The primary objective of this study is to assess stiffness, muscle tone, relaxation periods and elasticity of 
various muscles in patients with dystrophic or non-dystrophic myotonia. 
5.2 Secondary Objectives 
The secondary objectives of this study are 
• 
to provide reference values for stiffness, muscle tone, relaxation periods and elasticity of various 
muscles in patients with dystrophic or non-dystrophic myotonia, 
• 
to provide reference values for stiffness, muscle tone, relaxation periods and elasticity of various 
muscles in patients with non-myotonic neuromuscular disorders, 
• 
assess correlations between to compare result values for stiffness, muscle tone, relaxation periods 
and elasticity with clinical muscle function tests, measured by clinical evaluation (MRC-scale) and the 
6-minute walktest, 
• 
assess correlations between subcutaneous fat and muscle thickness and echogenicity, measured by 
muscle ultrasound and result values for stiffness, muscle tone, relaxation periods and elasticity 
6. STUDY POPULATION 
6.1 lnclusion Criteria 
A patient must meet all the following criteria to be eligible for this study. For patients, (1) the participant is ~18 
years of age and has a confirmed neuromuscular disease, (2) provides written consent and (3) is able and willing 
to perform study procedures. For healthy volunteers, age ~18 and written informed consent is obligatory and 
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there is no clinical sign for any neuromuscular disorder. 
6.2 Exclusion Criteria 
lf one of the following criteria is met, a patient will not be able to participate in this study: (1) The patient 
has severe comorbidities; (2) the patient is participating in another clinical study using investigational 
treatment; (3) the patient cannot perform required muscle function tests; (4) the patient, in the opinion of 
the investigator, is unable to adhere to the requirements of the study. 
6.3 Number of patients 
Approximately 70 patients will be enrolled, about 3-5 each in the following disease groups: Limb-Girdle-
Muscular Dystrophy (LGMD), Myotonie Dystrophies Type 1 and 2 (DM1, DM2), Late-Onset-Pompe Disease 
(LOPD), Distal Myopathies, Congenital Myotonia, Spinal muscular atrophy Type 3 (SMA3), Amyotrophic 
lateral sclerosis (ALS) and peripheral Polyneuropathies (CIDP, HMSN). 20 healthy age- and gender-
matched patients will be enrolled as a control group. 
6.4 Recruitment 
Patients will be asked to participate during their routine treatment at the in-patient clinic of the Friedrich-
Baur-lnstitute or will be asked during appointments at the out-patient-clinic ofthe Friedrich-Baur-lnstitute. 
Healthy volunteers (e.g. relatives from patients) will be asked to participate during routine appointments 
of their relatives. 
7 INVESTIGATIONAL PLAN 
7.1 Study Design 
This is a cross-sectional, blinded, monocentric, explorative study to evaluate the stiffness, muscle tone, 
relaxation periods and elasticity of various muscles in patients with neuromuscular diseases. Local ethic 's 
approval is obligatory before the recruitment of the first patient. The patient must provide informed consent 
prior to performing any protocol-related procedure at the screening visit. The estimated duration of this study 
is 12 months or as soon as a total of 50 patients with neuromuscular diseases and 20 healthy volunteers are 
evaluated. The person assessing the muscle stiffness and myotonia, using the MyotonPro® device, will be 
blinded to the diagnosis, to medical history as weil as results from the clinical tests (clinical muscle strength, 
6-minute-walk-test) and results of muscle ultrasound assessments. The study duration for one patient or one 
healthy volunteer is two to a maximum of seven days. All relevant data will be assessed within visit 1. At the 
second visit (visit 2), only measurements of the MyotonPro® will be repeated to evaluate the reliability of the 
measurements. 
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Both patients and healthy volunteers will perform the following assessments: 
7.1.1 Screening 
At screening, the patient's eligibility will be defined. 
7.1.2 Visit 1 (same day as Screening) 
• 
Collection of demographic and disease-related data (age, gender, diagnosis, age at onset of symptoms, 
age at diagnosis, severity and location of myotonia and severity and location of muscle stiffness, for 
both using numeric rating scale (NRS)). 
• 
Performing a 6-Minute-Walk-Test (meters). 
• 
Clinical evaluation of muscle strength of the following muscles, using the MRC-Scale (0-5): on both 
sides thenar and hypothenar, m. biceps brachii, m. triceps brachii, m. deltoideus, m. quadriceps 
femoris, m. tibialis anterior and gastrocnemius muscles. 
• 
Semiquantitative measurement of cutis and subcutis, subcutaneous fat and muscle thickness by muscle 
ultrasound ofthe following muscles: on both sides thenar and hypothenar, m. biceps brachii, m. triceps 
brachii, m. deltoideus, m. quadriceps femoris, m. tibialis anterior and gastrocnemius muscles. 
Measurements will contain the thickness of cutis in millimeters, the thickness of subcutaneous fat in 
millimeters, the muscle thickness in millimeters at the point of measurement of the MyotonPro® and a 
semiquantitative measurement of muscle echogenicity, using the Heckmatt scale 1-IV. 
• 
Measurement of relaxation time, stiffness and elasticity of the following muscles, using the 
MyotonPro® device: on both sides thenar and hypothenar, m. biceps brachii, m. triceps brachii, m. 
deltoideus, m. quadriceps femoris, m. tibialis anterior and gastrocnemius muscles. For the 
documentation of the results, please see section "Myoton Pro® device". 
7.1.3 Visit 2 (+1-7 days after day 1) 
• 
Measurement of relaxation time, stiffness and elasticity of the following muscles, using the 
MyotonPro® device: on both sides thenar and hypothenar, m. biceps brachii, m. triceps brachii, m. 
deltoideus, m. quadriceps femoris, m. tibialis anterior and gastrocnemius muscles. For the 
documentation of the results, please see section "Myoton Pro® device". 
The total duration of assessments performed on screening and visit 1 will be approximately 2 hours. The total 
duration of visit 2 will be about 30 minutes. 
The data collected will be stored in a local database, that is password protected and only read- and editable for 
persons directly involved in the study. 
7.1.4 MyotonPro® Device 
The MyotonPro® Device is a r;:ommercially available electronic device for non-invasive .measurement of muscle 
stiffness, muscle tone, relaxation periods and viscoelasticity. The method of measurement consists of recording 
. . 
' , .. 
' 
\ 
' 
; 
. damp_e,d natural oscillation of soft biological tissue in the form of an acceleration signal and the subsequent 
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simultaneous computation of the parameters of State of Tension, Biomechanical and Viscoelastic properties. A 
damped natural oscillation is induced by an exterior, low force quick-release mechanical impulse under 
constant pre-load. The tip of the myometer will be placed on the tissue perpendicular to the underlying muscle. 
The device gets activated by a slight pressure on the tip which exerts a local impact on the tissue utilizing a 
briet mechanical impulse. This causes a minor deformation of the underlying muscle tissue. After the impact, 
the tip is quickly released, and the damped oscillatory behaviour of the tissue will be recorded by an 
accelerometer in the device. The viscoelastic stiffness of the underlying tissue.will automatically be calculated 
using the following equations (S=stiffness; D=elasticity; R=relaxation): 
S = amax ' mprobe 
!).[ 
S stands for stiffness, measured in N/m, and is the biomechanical property of a muscle that characterizes the 
resistance to a contraction or to an external force that deforms its initial shape. Elasticity Dis the logarithmic 
decrement of a tissue·s natural oscillation. Elasticity is the biomechanical property of a muscle that 
characterizes the ability to recover its initial shape after a contraction or removal of an external force of 
deformation. The Relaxation R is the time for a muscle to recover its shape from deformation. The functionality 
of the MyotonPro®, its way of measurement and the calculations have been tested and validated in a high 
number of clinical studies. Therefore, this study is not intended to validate the measurements of the 
MyotonPro® device itself nor its safety and accuracy of measurements, but to evaluate measurement results in 
patients with neuromuscular diseases and elaborate reference values. 
7.1.5. Six-Minute walktest 
The six-minute walktest (6MWT) measures the distance an individual is able to walk over a total of six 
minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. The 
individual is allowed to self-pace and rest as needed as they traverse back and forth along a marked 
walkway. The 6MWT has been used with a variety of other conditions than the chronic obstructive 
pulmonary disease (COPD) such as heart failure and strake and f,' widely used in neuromuscular diseases 
[261. The six-minute-walk-test will be conducted as recommende by the American Thoracic Society [271. 
In this study, the six-minute-walk test will be performed once n visit 1 to detect the impact of muscle 
weakness, muscle stiffness and myotonia on muscular endurancr . 
7.1.6. Semiquantitative muscle ultrasound 
. 
· 
Muscle ultrasound is an ideal imaging modality that allows fo 
I 
atraumatic, noninvasive, radiation-free 
point-of-care neuromuscular imaging [281. Muscular dystrophies are typically associated with an increase 
in the echogenicity from the muscle substance, distal attenuation of muscle echo and a corresponding loss 
of bone echo. Spinal muscular atrophies and neuropathies also sr owed an increase in muscle echo along 
with atrophy of the muscle and increase in depth of subcutaneo
1
us tissue, _ but a persisting bo_ne e~ho: In 
several other myopathies, similar changes are seen (291. In sem i-quantitative muscle ultrasound, muscle 
. 
''. 
intensity will be documented using the 4-point Heckmatt score (281. 
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7.1.7. Hand-held Dynamometry of muscle strength 
Muscle strength will be assessed by handheld dynamometry using the MicroFET2 myometer, produced 
by- Hoggan Health lndustries. This test is widely used in patients with neuromuscular diseases [30, 311. 
To perform a test, the examiner holds the dynamometer stationary while the patient exerts a maximal 
force against the dynamometer. The patient makes a gradual increase in force and then completes an 
isometric hold for 4-5 seconds. The following muscle groups will be tested: Arm abduction, elbow flexion, 
elbow extension, knee extension, knee flexion, foot extension, foot flexion. 
7.2 Completion of a Patient's Participation in the Study 
7.2.1 Completion of a Patient's Participation in the Study 
The length of a patient's participation will be from the time the informed consent form is signed until the last 
planned assessment/visit. A patient will be considered "completed" if all study procedures of the second visit 
have been carried out. 
7.2.2 Premature Patient Discontinuation from the Study 
Patients are free to withdraw consent and/or discontinue participation in the study at any time, without prejudice 
to further treatment. For patients who prematurely discontinue from the study, the lnvestigator or designee will 
contact the patient 4 to 7 days after withdrawal to assess any AEs. Post-study serious adverse events (SAEs) will 
be reported accordingly. A patient's participation in the study may also be discontinued at any time at the 
discretion of the lnvestigator. Patients who are prematurely withdrawn from the study will be asked to complete 
all discontinuation assessments prior to withdrawal, if possible. A patient will be considered early terminated if 
the patient does not complete the study after enrollment. Patients who are withdrawn from the study will not be 
replaced (i.e., a patient's study number will not be reused); however, additional patients may be enrolled to offset 
patient dropouts. 
7.3 Discussion of Study Design, lncluding Choice of Control Group 
This is a monocentric, blinded, cross-sectional explorative study designed to evaluate myotonia, muscle 
stiffness and elasticity in 70 patients with neuromuscular disorders. For statistical comparison, we plan to 
recruit 20 healthy subjects as a control group. 
8 RISKS AND BENEFITS 
8.1 Summary of Potential Risks 
Study-specific procedures and associated risks are bulleted below: 
• 
Functional testing (six-minute-walk-test): falls, shortness of breath, muscle soreness, myalgia and fatigue 
8.2 Summary of Potential Benefits 
Analyzing muscle stiffness and myotonia in an easy and non-invasive way could help to detect dystrophic 
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and non-dystrophic myotonia earlier on the course of the disease and support early diagnosis. Besides, 
treatment effects could be objectively measured and observed. 
9 ÄDVERSE EVENTS REPORTING 
Detailed listings of patients who experience AEs or SAEs will be presented. The incidence of treatment-
emergent AEs and SAEs will be tabulated (frequencies and percentages) by severity, and by relationship to 
treatment. Adverse event severity will be categorized as mild, moderate, or severe. In tabulating severity of AEs 
on a per-patient basis, the greatest severity will be assigned to a patient should there be more than one 
occurrence of the same AE with different reported severities. Relationships of the AE to treatment will be 
categorized as not related, unlikely related, possibly related, or related . The highest level of the association will 
be reported in patients with differing relationships for the same AE. Listings of AEs and SAEs for all patients 
will be provided, which will include severity and relationship to the study procedures, the actions taken 
regarding the study procedures as weil as the patient's outcome. A separate listing for patients who withdraw 
from the study due to AEs will be provided. The incidence of AEs leading to study discontinuations will also be 
summarized. 
10 STATISTICAL METHODS ÄND PLANNED ÄNALYSES 
10.1 General Considerations 
All patients who participate in this study will be included in the analysis. Data collected in this study will be 
reported using summary tables, figures and patient data listings. Summary statistics (n, mean, median, standard 
deviation, minimum and maximum) will be calculated for the continuous variables and shift tables and/or 
frequencies, and percentages will be produced for the categorical variables. Due to the exploratory nature of 
this study, no formal inferential statistical tests will be performed. 
10.2 Determination of Sample Size 
50 patients and 20 healthy subjects will be enrolled in this study. No formal sample size calculations have been 
performed. This is an exploratory pilot-study and is not powered to make any statistical inferences. 
10.3 Demographics and Baseline Characteristics 
Demographie and baseline data on medical history and neuromuscular disease history as weil as patient-related 
data will be summarized using exploratory and descriptive statistics for continuous variables and frequency 
distribution for categorical variables. To compare the mean values of two groups, the t-test will be used, to 
compare frequencies between two groups, the ch i-square test. Correlations are calculated by using the 
Spearman and Pearson coefficient. 
10.4 Patient Accountability 
Data from all patients who are enrolled in the study will be included in the summary of patient accpuntability. 
The frequency and percentage of patients who are enrolled in the study, discontinued from the study, and 
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completed the study, along with reasons for discontinuation, will be summarized. 
10.5 MyotonPro® measurement reliability 
To·ensure high reliability in measurements performed with the MyotonPro® device, a second measurement 
will be performed within 1-7 days after visit 1 (Test-Retestl. The degree of similarity between the two 
measurements is determined by computing a correlation coefficient. In addition, 95% confidence intervals will 
be used to estimate the change from baseline to the second study visit. All data will be presented by study visit 
in by-patient listings. 
10.6 Missing or Invalid Data 
All data will be analyzed as they were collected in the database. lt is not planned to impute missing data using 
statistical methods. 
11 DATA MANAGEMENT AND DATA PROTECTION 
The medical and study-related data (questionnaires, examination data) and the declaration of consent remain 
with the investigator or at the Friedrich-Ba ur-Institute of the LMU Muni eh and are kept strictly confidential. All 
data collected is stored and evaluated electronically in a database in a double pseudonymized form. 
Pseudonymized means that the patient's name will be deleted, and a number assigned to the data. Double 
pseudonymization means that the secret number is internally re-encoded to increase security. Only the age of 
patients is recorded from the personal data. No personal identifying numbers (e.g. identity card number) or 
addresses are used. To be on the safe side, the data is stored separately in different databases. The assignment 
between the name and the number is stored by the investigational doctor in a secure place, a corresponding 
decryption list remains in the Friedrich-Baur-lnstitute and is only accessible to authorized persons from the 
Friedrich-Baur-lnstitute. The decryption list remains at the Friedrich-Baur-lnstitute of the LMU Munich. The 
database is stored on a server of the University Hospital of Munich, to which only study staff of the Friedrich 
Baur Institute have access. Confidential and private aspects ofthe database are protected by special regulations. 
This includes double pseudonymization and the use of bug-proof connections. 
All confidential documents are kept for up to 10 years after the end of the study and then destroyed. The 
obligation of confidentiality, data storage and storage are in accordance with the Data Protection Act Directive 
95/46/EC. 
12 SPECIAL REOUIREMENTS ÄND PROCEDURES 
This protocol was designed and will be conducted, recorded, and reported in compliance with the International 
Conference on Harmonization (ICH)/Good Clinical Practice (GCP) guideline. These requirements are stated in 
the ICH Guideline Topic E6 entitled "Guideline for Good Clinical Practice". 
1.2.1 lnstitutional and Ethics Review 
. _ljhjs P,rotocol and a patient informed consent form (ICF) must be reviewed and approved ·by an IRB/LE(: before 
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enrollment of patients. Documentation of IRB/IEC and the approved consent form must be received by the 
lnvestigator or its designee prior to obtaining the patient's informed consent. 
12.2 Changes to the Conduct of the Study or Protocol 
Any changes in the study protocol, such as changes in the study design, objectives or endpoints, inclusion and 
exclusion criteria, and/or procedures (except to eliminate an immediate hazard) will be implemented only after 
the mutual agreement of the I nvestigator or designee. All protocol changes must be documented in the protocol 
amendment(s). Protocol amendment(s) must be signed by the lnvestigator and approved by the IRB/IEC prior 
to implementation. Any changes in study conduct that result from a pending amendment will be considered 
protocol deviations until IRB/IEC approval is granted. Documentation of IRB/IEC approval must be returned to 
the lnvestigator or designee. 
12.3 Patient lnformed Consent 
lnvestigators must adhere to Good Clinical Practice, which includes ethical principles that have their origin in 
the Declaration of Helsinki, when developing the patient informed consent form and when obtaining consent 
from the patient. Written informed consent is required prior to enrollment in the study. lt is the responsibility 
of the lnvestigator to document the consent process within the source documents and obtain consent using an 
IRB/1 EC approved consent form. 
12.4 Case Report Forms 
Data will be entered by the site onto the paper CRFs (pCRF) and locally stored databases (Excel). Any erroneous 
entries made on the pCRFs should be corrected. Changes made to the data after initial entry into the pCRF will 
be unambiguously corrected and signed. 
12.5 Record Retention 
The lnvestigator is responsible for oversight and maintenance of the study records and patient source 
documents. The I nvestigator must retain study records for at least 10 years after the last marketing approval has 
been granted, or at least 10 years have elapsed since the formal discontinuation of the clinical program. 
However, these documents should be retained for a langer period, if required by other applicable requirements 
(e.g., applicable local regulatory requirement) . Patient records or other source data must be kept for the 
maximum time mandated by the hospital, but not less than 10 years. 
12.6 Clinical Study Report 
A final clinical study report will be produced after study completion. 
13 ÄBBREVIATIONS 
Abbreviation 
6MWT 
AE 
Term 
6-minute walktest 
adverse event 
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CRF 
GCP 
14 LITERATURE 
Case report form 
Good Clinical Practice 
Page 14 of 15 
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