xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT05977920</url>
    </required_header>
    <id_info>
      <org_study_id>2022-02103</org_study_id>
      <nct_id>NCT05977920</nct_id>
    </id_info>
    <brief_title>Fasciculations in Healthy Adults After Consumption of Caffeine: an Ultrasound Study</brief_title>
    <official_title>Fasciculations in Healthy Adults After Consumption of Caffeine: an Ultrasound Study</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Zurich Regional Health Center</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Zurich Regional Health Center</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        Fasciculations are clinically defined as spontaneous intermittent contractions of a portion&#xD;
        of muscles. Depending on associated symptoms they may be a sign of lower motor neuron&#xD;
        disorder. The aim of this study is to investigate if fasciculations also occur in muscles&#xD;
        after caffeine consumption and if there is a difference between the muscles of the arms and&#xD;
        legs.&#xD;
  &#xD;
        The primary endpoint is detecting fasciculations in the muscles of the arms and legs after&#xD;
        the consumption of caffeine in healthy adults (20-35 years old and 35-50 years old) Secondary&#xD;
        endpoints of the study compares the proportions of fasciculations between two age groups&#xD;
        (20-35 years old and 35-50 years. A population of 26 subject per group and a total of 52&#xD;
        subject will be recruited for the study. A sample size of 26 in each group will have 90%&#xD;
        power to detect a difference between the two groups using a Fisher's exact test with a 0.05&#xD;
        two-sided significance level.&#xD;
  &#xD;
        Study Intervention Study participants will consume caffeine (6mg per kilogram bodyweight)&#xD;
        before the second ultrasound screening.&#xD;
  &#xD;
        Using ultrasound the sternocleidomastoideus, biceps brachii, interosseus dorsalis, quadriceps&#xD;
        femoris, gastrocnemius and abductor hallucis will be measure for 120 seconds 1o minutes&#xD;
        before and 45 minutes after caffeine consumption.&#xD;
  &#xD;
        Study Duration and Schedule Estimated duration for the study will be around 6 months.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Fasciculations are clinically defined as spontaneous intermittent contractions of a portion&#xD;
        of muscles [8]. They can also be assessed with electromyography and are classified as a&#xD;
        result of spontaneous depolarization of a lower motor neuron leading to the synchronous&#xD;
        contraction of all of the skeletal muscle fibers within a single motor unit [9]. On&#xD;
        ultrasound examination fasciculations are classified as involuntary twitching of small parts&#xD;
        of the muscle, lasting for 0.2 - 1.0 seconds [10]. They result from spontaneous discharges of&#xD;
        motor nerves, but the etiology and the site of origin of these discharges remains still&#xD;
        uncertain and is controversially discussed [11, 12]. Depending on the associated symptoms&#xD;
        they may be a sign of lower motor neuron disorder. They are a hallmark of amyotrophic lateral&#xD;
        sclerosis, a neurodegenerative disease affecting upper motor neurons in the brain and lower&#xD;
        motor neurons in the spinal cord, especially when they are widespread [13, 14].&#xD;
        Fasciculations can also be a normal phenomenon that almost everyone has experienced&#xD;
        occasionally in their lives or more frequently in healthy subjects after exercise [15]. It is&#xD;
        controversially discussed if fasciculations above the knee should raise the suspicion of a&#xD;
        disorder even if there are no other signs of lower motor neuron affection. In a recent Dutch&#xD;
        study the prevalence and distribution of fasciculations in healthy adults was assessed with&#xD;
        ultrasound and it could be shown, that strenuous physical exercise causes a temporary&#xD;
        increase in fasciculations but only in lower leg muscles in healthy adults [14]. However the&#xD;
        fasciculations were screened only for 10 seconds 30 minutes after exercise. It is well known&#xD;
        that the observation time for fasciculations should be 2 minutes to decide if a muscle is&#xD;
        &quot;fasciculation-free&quot; [15]. The aim of this study is to investigate if fasciculations also&#xD;
        occur in muscles after caffeine consumption and if there is a difference between the muscles&#xD;
        of the arms and legs.&#xD;
  &#xD;
        3 STUDY OBJECTIVES AND DESIGN 3.1 Hypothesis and primary objective The hypothesis about the&#xD;
        primary endpoint, the comparison of two proportions, can be examined by a Fisher exact test.&#xD;
  &#xD;
        The null hypothesis of the primary endpoint is, that there is no difference in the&#xD;
        proportions of fasciculations below and above the knee.&#xD;
  &#xD;
        The alternative hypothesis of the primary endpoint states a difference in the proportions of&#xD;
        fasciculations below and above the knee.&#xD;
  &#xD;
        Secondary objective / endpoint:&#xD;
  &#xD;
        Secondary endpoints of the study compares the proportions of fasciculations between two age&#xD;
        groupes (20-35 years old and 35-50 years old):&#xD;
  &#xD;
        The hypothesis of the secondary endpoints are examined again by a Fisher exact test.&#xD;
  &#xD;
        The null and alternative hypothesis of the secondary endpoints are analogous. 3.2 Primary and&#xD;
        secondary endpoints The primary endpoint is detecting fasciculations in the muscles of the&#xD;
        arms and legs after the consumption of caffeine in healthy adults (20-35 years old and 35-50&#xD;
        years old) 3.3 Study design Monocentric Cross-sectional study. 3.4. Study intervention See&#xD;
        4.3 Study procedures 4 STUDY POPULATION AND STUDY PROCEDURES 4.1 Inclusion and exclusion&#xD;
        criteria, justification of study population A population of 26 subject per group and a total&#xD;
        of 52 subject will be recruited for the study.&#xD;
  &#xD;
        List the study inclusion criteria:&#xD;
  &#xD;
          -  Healthy subjects (male/female)&#xD;
  &#xD;
          -  Age 20-50 years old&#xD;
  &#xD;
        List the study exclusion criteria:&#xD;
  &#xD;
          -  neurological symptoms&#xD;
  &#xD;
          -  any neurological disease including neuropathies, myopathies or radiculopathies in&#xD;
             personal history&#xD;
  &#xD;
          -  systemic disease including vasculitis in personal history&#xD;
  &#xD;
          -  abnormal pulse in the arteria dorsalis pedis&#xD;
  &#xD;
          -  abnormal strength, sensation and tendon reflexes&#xD;
  &#xD;
          -  muscular atrophy in the studied muscles.&#xD;
  &#xD;
        4.2 Recruitment, screening and informed consent procedure Recruitment will be done within our&#xD;
        social circle and patient population. The investigators ask friends and acquaintances if they&#xD;
        would like to take part in the study. If the investigators don't find enough test subjects in&#xD;
        this way, the investigators will put up a notice at the University of Zurich or advertise&#xD;
        online. The subjects who agree to participate in the study will be informed about the exact&#xD;
        course of the study in a conversation and can then decide whether they agree to participate.&#xD;
        Only when they have decided to participate in the study, the inclusion and exclusion criteria&#xD;
        are queried on the basis of a precise anamnesis. This is followed by a neurological&#xD;
        examination (sensitivity test, examination for paresis, cranial nerve status, reflexes,&#xD;
        vibration sensation, standing and gait tests) as well as a measurement of blood pressure and&#xD;
        pulse.&#xD;
  &#xD;
        4.3 Study procedures&#xD;
  &#xD;
        The planned overall study duration, including recruitment period will be 6 months. The&#xD;
        recruitment and intervention will take place over 4 months. On the day of the examination,&#xD;
        the subjects should appear rested (not overtired) and feel good. First, the blood pressure&#xD;
        and pulse are measured. The neurological examination is carried out during the clarification&#xD;
        of the inclusion and exclusion criteria after the anamnesis interview (see 4.2). The subjects&#xD;
        should have taken at least 12 hours before the examination no caffeine and alcohol as well as&#xD;
        drugs or medications. They should eat and drink normally and should not be sober. 10 minutes&#xD;
        before taking caffeine, the ultrasound examination of the muscles is performed. The test&#xD;
        subject is lying down during this procedure while being calm and relaxed without tensing&#xD;
        their muscles. They should not be talking during both ultrasound examinations. Caffeine is&#xD;
        taken in the form of coffee. It does not matter in the study whether they are regular coffee&#xD;
        drinkers or not. Blood pressure and pulse are measured every 30 minutes after taking the&#xD;
        caffeine for 2 hours. In total, the test takes 3 hours.&#xD;
  &#xD;
        Using ultrasonography the sternocleidomastoideus, biceps brachii, interosseus dorsalis,&#xD;
        quadriceps femoris, gastrocnemius and abductor hallucis will be measured for 120 seconds&#xD;
        (with video recording) 10 minutes before and 45 minutes after caffeine consumption (6 mg per&#xD;
        kilogram body weight).&#xD;
  &#xD;
        4.4 Withdrawal and discontinuation In accordance with the Declaration of Helsinki a subject&#xD;
        has the right to withdraw from the study at any time without giving reason. Subjects who are&#xD;
        withdrawn by the Investigator because of an unacceptable adverse event will be termed a&#xD;
        withdrawal&quot; and will not be replaced. Under these circumstances the Investigator will&#xD;
        institute the appropriate follow-up investigations in accordance with accepted standards of&#xD;
        medical care including performance of tests at the time of withdrawal. Subjects who withdraw&#xD;
        from the study for any reasons will not be replaced.&#xD;
  &#xD;
        5 STATISTICS AND METHODOLOGY 5.1. Statistical analysis plan and sample size calculation&#xD;
  &#xD;
        Methods:&#xD;
  &#xD;
        For a comparison of the proportions of fasciculations above and below the knee a Fisher's&#xD;
        exact test for a comparison of proportions is applied, using the R function [16] fe.ssize&#xD;
        from the R package clinfun [17]. The investigators need to make assumptions about the&#xD;
        following quantities:&#xD;
  &#xD;
          -  Significance level α. The investigators set α = 0.05.&#xD;
  &#xD;
          -  Assumed proportions: In the first group (fasciculations above knee), one expects p1 ∈&#xD;
             {0.6, 0.55}.&#xD;
  &#xD;
        Note that for values of p1 close to 0 the number of patients needed varies substantially for&#xD;
        small changes in p1. The investigators compute sample sizes for assumed group 2 proportions&#xD;
        (fasciculations below knee) of p2 ∈ {0.1, 0.15}.&#xD;
  &#xD;
        • Power, the probability of rejecting the null hypothesis of equal proportions in the two&#xD;
        groups when the true difference is at least as assumed. The investigators compute sample&#xD;
        sizes for power 1 - β ∈ {0.8, 0.9}.&#xD;
  &#xD;
        Sample Size:&#xD;
  &#xD;
        In Table 1 the investigators provide sample sizes for the above assumptions.&#xD;
  &#xD;
        Significance level α Power 1 - β p1 p2 n per group for Fisher's exact test 0.05 0.05 0.05&#xD;
        0.05 0.8 0.8 0.8 0.8 0.6 0.6 0.55 0.55 0.1 0.15 0.1 0.15 17 22 19 25 0.05 0.05 0.05 0.05 0.9&#xD;
        0.9 0.9 0.9 0.6 0.6 0.55 0.55 0.1 0.15 0.1 0.15 20 26 24 32 Total number in study for&#xD;
        Fisher's exact test 34 44 38 50 40 52 48 64&#xD;
  &#xD;
        Table 1: Sample sizes.&#xD;
  &#xD;
        A sample size of 26 in each group will have 90% power to detect a difference between&#xD;
        proportions of p1 = 0.6 (fasciculations above knee) and p2 = 0.15 (fasciculations below knee)&#xD;
        using a Fisher's exact test with a 0.05 two-sided significance level. This results in a total&#xD;
        sample size of 52.&#xD;
  &#xD;
        5.2. Handling of missing data and drop-outs The number of fasciculations can be viewed again,&#xD;
        because the ultrasound examinations are recorded as a film and can be viewed again at any&#xD;
        time. If data should nevertheless be lost, the relevant subject will be asked whether he can&#xD;
        take part again on another day or whether new participants will be recruited.&#xD;
  &#xD;
        Drop-outs are replaced by recruitment of new subjects. 6 REGULATORY ASPECTS AND SAFETY 6.1&#xD;
        Local regulations / Declaration of Helsinki This study is conducted in compliance with the&#xD;
        protocol, the current version of the Declaration of Helsinki, the ICH-GCP, the HRA as well as&#xD;
        other locally relevant legal and regulatory requirements.&#xD;
  &#xD;
        6.2 (Serious) Adverse Events and notification of safety and protective measures An Adverse&#xD;
        Event (AE) is any untoward medical occurrence in a patient or a clinical investigation&#xD;
        subject which does not necessarily have a causal relationship with the trial procedure. An AE&#xD;
        can therefore be any unfavourable or unintended finding, symptom, or disease temporally&#xD;
        associated with a trial procedure, whether or not related to it.&#xD;
  &#xD;
        A Serious Adverse Event (SAE) (ClinO, Art. 63) is any untoward medical occurrence that&#xD;
  &#xD;
          -  Results in death or is life-threatening,&#xD;
  &#xD;
          -  Requires in-patient hospitalisation or prolongation of existing hospitalisation,&#xD;
  &#xD;
          -  Results in persistent or significant disability or incapacity, or&#xD;
  &#xD;
          -  Causes a congenital anomaly or birth defect&#xD;
  &#xD;
        Both Investigator and Sponsor-Investigator make a causality assessment of the event to the&#xD;
        trial intervention, (see table below based on the terms given in ICH E2A guidelines). Any&#xD;
        event assessed as possibly, probably or definitely related is classified as related to the&#xD;
        trial intervention.&#xD;
  &#xD;
        Relationship Description Definitely Temporal relationship Improvement after dechallenge*&#xD;
        Recurrence after rechallenge (or other proof of drug cause) Probably Temporal relationship&#xD;
        Improvement after dechallenge No other cause evident Possibly Temporal relationship Other&#xD;
        cause possible Unlikely Any assessable reaction that does not fulfil the above conditions Not&#xD;
        related Causal relationship can be ruled out&#xD;
  &#xD;
        *Improvement after dechallenge only taken into consideration, if applicable to reaction&#xD;
  &#xD;
        Both Investigator and Sponsor-Investigator make a severity assessment of the event as mild,&#xD;
        moderate or severe. Mild means the complication is tolerable, moderate means it interferes&#xD;
        with daily activities and severe means it renders daily activities impossible.&#xD;
  &#xD;
        Reporting of SAEs (see ClinO, Art. 63) All SAEs are documented and reported immediately&#xD;
        (within a maximum of 24 hours) to the Sponsor-Investigator of the study.&#xD;
  &#xD;
        If it cannot be excluded that the SAE occurring in Switzerland is attributable to the&#xD;
        intervention under investigation, the Investigator reports it to the Ethics Committee via&#xD;
        BASEC within 15 days.&#xD;
  &#xD;
        Follow up of (Serious) Adverse Events Describe the follow up procedures of participants&#xD;
        terminating the study with reported ongoing (S)AEs until resolution or stabilisation.&#xD;
  &#xD;
        Notification of safety and protective measures (see ClinO, Art 62, b) If immediate safety and&#xD;
        protective measures have to be taken during the conduct of the study, the investigator&#xD;
        notifies the Ethics committee of these measures, and of the circumstances necessitating them,&#xD;
        within 7 days.&#xD;
  &#xD;
        6.3 (Periodic) safety reporting An annual safety report (ASR) is submitted once a year to the&#xD;
        local Ethics Committee by the Investigator (ClinO, Art. 43 Abs 1).&#xD;
  &#xD;
        6.4 Amendments Substantial changes to the study setup and study organization, the protocol&#xD;
        and relevant study documents are submitted to the Ethics Committee for approval before&#xD;
        implementation. Under emergency circumstances, deviations from the protocol to protect the&#xD;
        rights, safety and well-being of human subjects may proceed without prior approval of the&#xD;
        Ethics Committee. Such deviations shall be documented and reported to the Ethics Committee as&#xD;
        soon as possible.&#xD;
  &#xD;
        Substantial amendments are changes that affect the safety, health, rights and obligations of&#xD;
        participants, changes in the protocol that affect study objective(s) or central research&#xD;
        topic, changes of study site(s) or of study leader and sponsor (ClinO, Art. 29).&#xD;
  &#xD;
        A list of substantial changes is also available on www.swissethics.ch. A list of all&#xD;
        non-substantial amendments will be submitted once a year to the competent EC together with&#xD;
        the ASR.&#xD;
  &#xD;
        6.5 Notification and reporting upon completion, discontinuation or interruption of the study&#xD;
        Upon regular study completion, the Ethics Committee is notified via BASEC within 90 days&#xD;
        (ClinO, Art. 38).&#xD;
  &#xD;
        Provide a statement that the Sponsor-Investigator and any other competent authority may&#xD;
        terminate the study prematurely according to certain circumstances, e.g:&#xD;
  &#xD;
        The Sponsor-Investigator may terminate the study prematurely according to certain&#xD;
        circumstances, e.g.&#xD;
  &#xD;
          -  Ethical concerns,&#xD;
  &#xD;
          -  Insufficient participant recruitment,&#xD;
  &#xD;
          -  When the safety of the participants is doubtful or at risk (e.g. when the benefit-risk&#xD;
             assessment is no longer positive),&#xD;
  &#xD;
          -  Alterations in accepted clinical practice that make the continuation of the study&#xD;
             unwise, or&#xD;
  &#xD;
          -  Early evidence of harm or benefit of the experimental intervention&#xD;
  &#xD;
        Upon premature study termination or study interruption, the Ethics Committee is notified via&#xD;
        BASEC within 15 days (ClinO, Art. 38).&#xD;
  &#xD;
        6.6 Insurance In the event of study-related damage or injuries, the liability of the&#xD;
        institution (Spital Wetzikon) provides compensation, except for claims that arise from&#xD;
        misconduct or gross negligence.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">June 30, 2023</start_date>
    <completion_date type="Anticipated">September 30, 2024</completion_date>
    <primary_completion_date type="Actual">June 30, 2023</primary_completion_date>
    <phase>N/A</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>N/A</allocation>
      <intervention_model>Single Group Assignment</intervention_model>
      <intervention_model_description>There is only one group.</intervention_model_description>
      <primary_purpose>Diagnostic</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>The primary endpoint is detecting fasciculations in the muscles of the arms and legs after the consumption of coffein in healthy adults (20-35 years old and 35-50 years old)</measure>
      <time_frame>1 year</time_frame>
      <description>We use ultrasound to detect the number of fasciculations before and after the consumption of caffeine in 6 muscles (arms and legs) to ascertain whether or not caffeine has an effect on the number fasciculations and if the muscles of either the upper or lower extremities are more involved. More details are provided in the detailed study description.</description>
    </primary_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">50</enrollment>
    <condition>Neurologic Symptoms</condition>
    <arm_group>
      <arm_group_label>Only one Arm</arm_group_label>
      <arm_group_type>Other</arm_group_type>
      <description>s. description</description>
    </arm_group>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Caffeine</intervention_name>
      <description>s. description</description>
      <arm_group_label>Only one Arm</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion criteria:&#xD;
  &#xD;
            -  Healthy subjects (male/female)&#xD;
  &#xD;
            -  age 20-50 years old&#xD;
  &#xD;
          Exclusion criteria:&#xD;
  &#xD;
            -  Clinical neurological symptoms&#xD;
  &#xD;
            -  Clinical signs for Neuropathy&#xD;
  &#xD;
            -  Clinical signs for Myopathy&#xD;
  &#xD;
            -  Clinical signs for Vasculitis&#xD;
  &#xD;
            -  Clinical signs for heart disease&#xD;
  &#xD;
            -  Clinical signs for gastric or duodenal ulcera&#xD;
  &#xD;
            -  Any medicine&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>50 Years</maximum_age>
      <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
    </eligibility>
    <overall_contact>
      <last_name>David Czell, MD</last_name>
      <phone>+41764217222</phone>
      <email>david.czell@hin.ch</email>
    </overall_contact>
    <location>
      <facility>
        <name>GZO</name>
        <address>
          <city>Wetzikon</city>
          <state>Zurich</state>
          <zip>8620</zip>
          <country>Switzerland</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>David Czell</last_name>
        <phone>+41764217222</phone>
        <email>david.czell@hin.ch</email>
      </contact>
    </location>
    <location_countries>
      <country>Switzerland</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>May 21, 2023</study_first_submitted>
    <study_first_submitted_qc>August 2, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 7, 2023</study_first_posted>
    <last_update_submitted>August 2, 2023</last_update_submitted>
    <last_update_submitted_qc>August 2, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 7, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Fasciculation</mesh_term>
      <mesh_term>Neurologic Manifestations</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Caffeine</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT05977920
  org study id: 2022-02103
  nct id: NCT05977920
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  Fasciculations are clinically defined as spontaneous intermittent contractions of a portion
        of muscles. Depending on associated symptoms they may be a sign of lower motor neuron
        disorder. The aim of this study is to investigate if fasciculations also occur in muscles
        after caffeine consumption and if there is a difference between the muscles of the arms and
        legs.
  
        The primary endpoint is detecting fasciculations in the muscles of the arms and legs after
        the consumption of caffeine in healthy adults (20-35 years old and 35-50 years old) Secondary
        endpoints of the study compares the proportions of fasciculations between two age groups
        (20-35 years old and 35-50 years. A population of 26 subject per group and a total of 52
        subject will be recruited for the study. A sample size of 26 in each group will have 90%
        power to detect a difference between the two groups using a Fisher's exact test with a 0.05
        two-sided significance level.
  
        Study Intervention Study participants will consume caffeine (6mg per kilogram bodyweight)
        before the second ultrasound screening.
  
        Using ultrasound the sternocleidomastoideus, biceps brachii, interosseus dorsalis, quadriceps
        femoris, gastrocnemius and abductor hallucis will be measure for 120 seconds 1o minutes
        before and 45 minutes after caffeine consumption.
  
        Study Duration and Schedule Estimated duration for the study will be around 6 months.
  Fasciculations are clinically defined as spontaneous intermittent contractions of a portion
        of muscles [8]. They can also be assessed with electromyography and are classified as a
        result of spontaneous depolarization of a lower motor neuron leading to the synchronous
        contraction of all of the skeletal muscle fibers within a single motor unit [9]. On
        ultrasound examination fasciculations are classified as involuntary twitching of small parts
        of the muscle, lasting for 0.2 - 1.0 seconds [10]. They result from spontaneous discharges of
        motor nerves, but the etiology and the site of origin of these discharges remains still
        uncertain and is controversially discussed [11, 12]. Depending on the associated symptoms
        they may be a sign of lower motor neuron disorder. They are a hallmark of amyotrophic lateral
        sclerosis, a neurodegenerative disease affecting upper motor neurons in the brain and lower
        motor neurons in the spinal cord, especially when they are widespread [13, 14].
        Fasciculations can also be a normal phenomenon that almost everyone has experienced
        occasionally in their lives or more frequently in healthy subjects after exercise [15]. It is
        controversially discussed if fasciculations above the knee should raise the suspicion of a
        disorder even if there are no other signs of lower motor neuron affection. In a recent Dutch
        study the prevalence and distribution of fasciculations in healthy adults was assessed with
        ultrasound and it could be shown, that strenuous physical exercise causes a temporary
        increase in fasciculations but only in lower leg muscles in healthy adults [14]. However the
        fasciculations were screened only for 10 seconds 30 minutes after exercise. It is well known
        that the observation time for fasciculations should be 2 minutes to decide if a muscle is
        "fasciculation-free" [15]. The aim of this study is to investigate if fasciculations also
        occur in muscles after caffeine consumption and if there is a difference between the muscles
        of the arms and legs.
  
        3 STUDY OBJECTIVES AND DESIGN 3.1 Hypothesis and primary objective The hypothesis about the
        primary endpoint, the comparison of two proportions, can be examined by a Fisher exact test.
  
        The null hypothesis of the primary endpoint is, that there is no difference in the
        proportions of fasciculations below and above the knee.
  
        The alternative hypothesis of the primary endpoint states a difference in the proportions of
        fasciculations below and above the knee.
  
        Secondary objective / endpoint:
  
        Secondary endpoints of the study compares the proportions of fasciculations between two age
        groupes (20-35 years old and 35-50 years old):
  
        The hypothesis of the secondary endpoints are examined again by a Fisher exact test.
  
        The null and alternative hypothesis of the secondary endpoints are analogous. 3.2 Primary and
        secondary endpoints The primary endpoint is detecting fasciculations in the muscles of the
        arms and legs after the consumption of caffeine in healthy adults (20-35 years old and 35-50
        years old) 3.3 Study design Monocentric Cross-sectional study. 3.4. Study intervention See
        4.3 Study procedures 4 STUDY POPULATION AND STUDY PROCEDURES 4.1 Inclusion and exclusion
        criteria, justification of study population A population of 26 subject per group and a total
        of 52 subject will be recruited for the study.
  
        List the study inclusion criteria:
  
          -  Healthy subjects (male/female)
  
          -  Age 20-50 years old
  
        List the study exclusion criteria:
  
          -  neurological symptoms
  
          -  any neurological disease including neuropathies, myopathies or radiculopathies in
             personal history
  
          -  systemic disease including vasculitis in personal history
  
          -  abnormal pulse in the arteria dorsalis pedis
  
          -  abnormal strength, sensation and tendon reflexes
  
          -  muscular atrophy in the studied muscles.
  
        4.2 Recruitment, screening and informed consent procedure Recruitment will be done within our
        social circle and patient population. The investigators ask friends and acquaintances if they
        would like to take part in the study. If the investigators don't find enough test subjects in
        this way, the investigators will put up a notice at the University of Zurich or advertise
        online. The subjects who agree to participate in the study will be informed about the exact
        course of the study in a conversation and can then decide whether they agree to participate.
        Only when they have decided to participate in the study, the inclusion and exclusion criteria
        are queried on the basis of a precise anamnesis. This is followed by a neurological
        examination (sensitivity test, examination for paresis, cranial nerve status, reflexes,
        vibration sensation, standing and gait tests) as well as a measurement of blood pressure and
        pulse.
  
        4.3 Study procedures
  
        The planned overall study duration, including recruitment period will be 6 months. The
        recruitment and intervention will take place over 4 months. On the day of the examination,
        the subjects should appear rested (not overtired) and feel good. First, the blood pressure
        and pulse are measured. The neurological examination is carried out during the clarification
        of the inclusion and exclusion criteria after the anamnesis interview (see 4.2). The subjects
        should have taken at least 12 hours before the examination no caffeine and alcohol as well as
        drugs or medications. They should eat and drink normally and should not be sober. 10 minutes
        before taking caffeine, the ultrasound examination of the muscles is performed. The test
        subject is lying down during this procedure while being calm and relaxed without tensing
        their muscles. They should not be talking during both ultrasound examinations. Caffeine is
        taken in the form of coffee. It does not matter in the study whether they are regular coffee
        drinkers or not. Blood pressure and pulse are measured every 30 minutes after taking the
        caffeine for 2 hours. In total, the test takes 3 hours.
  
        Using ultrasonography the sternocleidomastoideus, biceps brachii, interosseus dorsalis,
        quadriceps femoris, gastrocnemius and abductor hallucis will be measured for 120 seconds
        (with video recording) 10 minutes before and 45 minutes after caffeine consumption (6 mg per
        kilogram body weight).
  
        4.4 Withdrawal and discontinuation In accordance with the Declaration of Helsinki a subject
        has the right to withdraw from the study at any time without giving reason. Subjects who are
        withdrawn by the Investigator because of an unacceptable adverse event will be termed a
        withdrawal" and will not be replaced. Under these circumstances the Investigator will
        institute the appropriate follow-up investigations in accordance with accepted standards of
        medical care including performance of tests at the time of withdrawal. Subjects who withdraw
        from the study for any reasons will not be replaced.
  
        5 STATISTICS AND METHODOLOGY 5.1. Statistical analysis plan and sample size calculation
  
        Methods:
  
        For a comparison of the proportions of fasciculations above and below the knee a Fisher's
        exact test for a comparison of proportions is applied, using the R function [16] fe.ssize
        from the R package clinfun [17]. The investigators need to make assumptions about the
        following quantities:
  
          -  Significance level α. The investigators set α = 0.05.
  
          -  Assumed proportions: In the first group (fasciculations above knee), one expects p1 ∈
             {0.6, 0.55}.
  
        Note that for values of p1 close to 0 the number of patients needed varies substantially for
        small changes in p1. The investigators compute sample sizes for assumed group 2 proportions
        (fasciculations below knee) of p2 ∈ {0.1, 0.15}.
  
        • Power, the probability of rejecting the null hypothesis of equal proportions in the two
        groups when the true difference is at least as assumed. The investigators compute sample
        sizes for power 1 - β ∈ {0.8, 0.9}.
  
        Sample Size:
  
        In Table 1 the investigators provide sample sizes for the above assumptions.
  
        Significance level α Power 1 - β p1 p2 n per group for Fisher's exact test 0.05 0.05 0.05
        0.05 0.8 0.8 0.8 0.8 0.6 0.6 0.55 0.55 0.1 0.15 0.1 0.15 17 22 19 25 0.05 0.05 0.05 0.05 0.9
        0.9 0.9 0.9 0.6 0.6 0.55 0.55 0.1 0.15 0.1 0.15 20 26 24 32 Total number in study for
        Fisher's exact test 34 44 38 50 40 52 48 64
  
        Table 1: Sample sizes.
  
        A sample size of 26 in each group will have 90% power to detect a difference between
        proportions of p1 = 0.6 (fasciculations above knee) and p2 = 0.15 (fasciculations below knee)
        using a Fisher's exact test with a 0.05 two-sided significance level. This results in a total
        sample size of 52.
  
        5.2. Handling of missing data and drop-outs The number of fasciculations can be viewed again,
        because the ultrasound examinations are recorded as a film and can be viewed again at any
        time. If data should nevertheless be lost, the relevant subject will be asked whether he can
        take part again on another day or whether new participants will be recruited.
  
        Drop-outs are replaced by recruitment of new subjects. 6 REGULATORY ASPECTS AND SAFETY 6.1
        Local regulations / Declaration of Helsinki This study is conducted in compliance with the
        protocol, the current version of the Declaration of Helsinki, the ICH-GCP, the HRA as well as
        other locally relevant legal and regulatory requirements.
  
        6.2 (Serious) Adverse Events and notification of safety and protective measures An Adverse
        Event (AE) is any untoward medical occurrence in a patient or a clinical investigation
        subject which does not necessarily have a causal relationship with the trial procedure. An AE
        can therefore be any unfavourable or unintended finding, symptom, or disease temporally
        associated with a trial procedure, whether or not related to it.
  
        A Serious Adverse Event (SAE) (ClinO, Art. 63) is any untoward medical occurrence that
  
          -  Results in death or is life-threatening,
  
          -  Requires in-patient hospitalisation or prolongation of existing hospitalisation,
  
          -  Results in persistent or significant disability or incapacity, or
  
          -  Causes a congenital anomaly or birth defect
  
        Both Investigator and Sponsor-Investigator make a causality assessment of the event to the
        trial intervention, (see table below based on the terms given in ICH E2A guidelines). Any
        event assessed as possibly, probably or definitely related is classified as related to the
        trial intervention.
  
        Relationship Description Definitely Temporal relationship Improvement after dechallenge*
        Recurrence after rechallenge (or other proof of drug cause) Probably Temporal relationship
        Improvement after dechallenge No other cause evident Possibly Temporal relationship Other
        cause possible Unlikely Any assessable reaction that does not fulfil the above conditions Not
        related Causal relationship can be ruled out
  
        *Improvement after dechallenge only taken into consideration, if applicable to reaction
  
        Both Investigator and Sponsor-Investigator make a severity assessment of the event as mild,
        moderate or severe. Mild means the complication is tolerable, moderate means it interferes
        with daily activities and severe means it renders daily activities impossible.
  
        Reporting of SAEs (see ClinO, Art. 63) All SAEs are documented and reported immediately
        (within a maximum of 24 hours) to the Sponsor-Investigator of the study.
  
        If it cannot be excluded that the SAE occurring in Switzerland is attributable to the
        intervention under investigation, the Investigator reports it to the Ethics Committee via
        BASEC within 15 days.
  
        Follow up of (Serious) Adverse Events Describe the follow up procedures of participants
        terminating the study with reported ongoing (S)AEs until resolution or stabilisation.
  
        Notification of safety and protective measures (see ClinO, Art 62, b) If immediate safety and
        protective measures have to be taken during the conduct of the study, the investigator
        notifies the Ethics committee of these measures, and of the circumstances necessitating them,
        within 7 days.
  
        6.3 (Periodic) safety reporting An annual safety report (ASR) is submitted once a year to the
        local Ethics Committee by the Investigator (ClinO, Art. 43 Abs 1).
  
        6.4 Amendments Substantial changes to the study setup and study organization, the protocol
        and relevant study documents are submitted to the Ethics Committee for approval before
        implementation. Under emergency circumstances, deviations from the protocol to protect the
        rights, safety and well-being of human subjects may proceed without prior approval of the
        Ethics Committee. Such deviations shall be documented and reported to the Ethics Committee as
        soon as possible.
  
        Substantial amendments are changes that affect the safety, health, rights and obligations of
        participants, changes in the protocol that affect study objective(s) or central research
        topic, changes of study site(s) or of study leader and sponsor (ClinO, Art. 29).
  
        A list of substantial changes is also available on www.swissethics.ch. A list of all
        non-substantial amendments will be submitted once a year to the competent EC together with
        the ASR.
  
        6.5 Notification and reporting upon completion, discontinuation or interruption of the study
        Upon regular study completion, the Ethics Committee is notified via BASEC within 90 days
        (ClinO, Art. 38).
  
        Provide a statement that the Sponsor-Investigator and any other competent authority may
        terminate the study prematurely according to certain circumstances, e.g:
  
        The Sponsor-Investigator may terminate the study prematurely according to certain
        circumstances, e.g.
  
          -  Ethical concerns,
  
          -  Insufficient participant recruitment,
  
          -  When the safety of the participants is doubtful or at risk (e.g. when the benefit-risk
             assessment is no longer positive),
  
          -  Alterations in accepted clinical practice that make the continuation of the study
             unwise, or
  
          -  Early evidence of harm or benefit of the experimental intervention
  
        Upon premature study termination or study interruption, the Ethics Committee is notified via
        BASEC within 15 days (ClinO, Art. 38).
  
        6.6 Insurance In the event of study-related damage or injuries, the liability of the
        institution (Spital Wetzikon) provides compensation, except for claims that arise from
        misconduct or gross negligence.
  allocation: N/A
  intervention model: Single Group Assignment
  intervention model description: There is only one group.
  primary purpose: Diagnostic
  masking: None (Open Label)
  measure: The primary endpoint is detecting fasciculations in the muscles of the arms and legs after the consumption of coffein in healthy adults (20-35 years old and 35-50 years old)
  time frame: 1 year
  description: We use ultrasound to detect the number of fasciculations before and after the consumption of caffeine in 6 muscles (arms and legs) to ascertain whether or not caffeine has an effect on the number fasciculations and if the muscles of either the upper or lower extremities are more involved. More details are provided in the detailed study description.
  arm group label: Only one Arm
  arm group type: Other
  description: s. description
  intervention type: Other
  intervention name: Caffeine
  description: s. description
  arm group label: Only one Arm
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 50 Years
  healthy volunteers: Accepts Healthy Volunteers
  last name: David Czell, MD
  phone: +41764217222
  email: david.czell@hin.ch
  facility: 
  status: Recruiting
  contact: 
  country: Switzerland
  responsible party type: Sponsor
  mesh term: Fasciculation
  mesh term: Neurologic Manifestations
  mesh term: Caffeine
  sharing ipd: No