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| Name | Class |
|---|---|
| Massachusetts General Hospital | OTHER |
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The purpose of this research study is to find out whether the drug mexiletine will be effective in lowering motor neuron electrical activity in the brains and nerves in the arms of people with ALS. The investigators will also determine if there are any signs that the drug may slow down the progression of ALS and reduce muscle cramps and muscle twitching. This will be determined through transcranial magnetic stimulation (TMS) and threshold tracking nerve conduction studies (TTNCS). In this trial, the participants will be taking either 300mg/day of mexiletine, 600mg/day of mexiletine, or placebo (non-active study drug).
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily motor neurons, for which treatment designed to slow or arrest progression remains lacking. Mexiletine is a use-dependent sodium channel blocker that has been FDA-approved for decades for the treatment of cardiac arrhythmias and more recently to treat neuropathic pain in diabetic polyneuropathy. Mexiletine has been shown also to be protective of neurons following spinal cord, head injury, and cerebral ischemia, largely by blocking excitotoxicity. Based on previous studies, mexiletine appears to penetrate into the central nervous system at concentrations sufficient to confer significant protection. Recent unpublished studies in the laboratory of Dr. Robert Brown at the University of Massachusetts have also demonstrated that mexiletine ingestion in mice genetically engineered to express high levels of mutant cytosolic copper-zinc superoxide dismutase-1 (SOD1) transgene prolongs survival in these animals. As mexiletine already has FDA-approval as an anti-arrhythmic agent, much is known about the pharmacology and safety of this drug in non-ALS patients. We anticipate that by excluding subjects with a known history of cardiac disease and with the known neuroprotectant properties of this medication, mexiletine is a good choice for further study in an ALS clinical trial.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Mexiletine, 300 milligrams | Active Comparator | Mexiletine, 300 milligrams by mouth per day for 4 weeks. |
|
| Mexiletine, 600 milligrams | Active Comparator | Mexiletine, 600 milligrams by mouth per day for 4 weeks. |
|
| Placebo | Placebo Comparator | Placebo, by mouth per day for 4 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Mexiletine | Drug |
|
| |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Resting Motor Threshold | The resting motor threshold (RMT) assessed from single pulse transcranial magnetic stimulation (TMS) measurements made before treatment, after 4 weeks of treatment, and then again after a 4 week washout, was used as the primary pharmacodynamic marker of cortical hyperexcitability. RMT is the stimulus intensity required to produce and maintain a 0.2 mV peak-to-peak motor evoked potential of the abductor pollicis brevis muscle by TMS. A smaller RMT is thought to suggest greater neuronal excitability. | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 and from Week 4 to Week 8 reported |
| Measure | Description | Time Frame |
|---|---|---|
| Effect on Short-interval Intracortical Inhibition | Short-interval intracortical inhibition (SICI) is a measure of neuronal excitability measured by dual pulse TMS with a conditioned (80% of RMT) and test pulses (120% of RMT) to generate a stable MEP amplitude of 0.2 mV, averaged over interstimulus intervals of 1-7 ms. It is thought to reflect refractory cortical axons and subsequent resynchronization of cortico-cortical and corticomotoneuronal volleys or activation of non-GABAergic cortical inhibitory circuits (initial phase) and synaptic neurotransmission through GABAA receptors (second phase). The value for SICI thought to be maximally sensitive for detecting in changes in ALS subjects compared to controls is is derived by measuring the motor evoked potential amplitude (MEP) at an interstimulus interval of 3 ms (ISI 3 ms) and normalizing to the MEP amplitude at 120% of the resting motor threshold (MEP 120% RMT). A reduction in SICI reflecting greater excitability would generate a larger ratio of MEP ISI 3 ms/MEP 120% RMT. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised | The Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) is an instrument for evaluating the functional status of patients with ALS that includes functions related to speech, swallowing, salivation, fine motor control, gross motor function, and respiration. The score is the sum of 12 items (range 0 to 48) with higher scores reflecting better function. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Michael Weiss, MD | University of Washington | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Barrow Neurological Institute | Phoenix | Arizona | 85013 | United States | ||
| University of California, Irvine |
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| Label | URL |
|---|---|
| Northeast ALS Consortium Website | View source |
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Within 21 days prior to treatment assignment, patients were screened for eligibility based on inclusion/exclusion criteria. Failure to meet any of these criteria at the time of this screening would result in exclusion from the study, and these patients would not be assigned to a treatment group.
Subjects were enrolled at 9 Northeast ALS Consortium (NEALS) centers in the US. These NEALS centers were academic clinical research centers with established practices where sporadic ALS (sALS) patients are regularly seen and treated.
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| ID | Title | Description |
|---|---|---|
| FG000 | Mexiletine, 300 Milligrams | Mexiletine, 300 milligrams by mouth per day for 4 weeks. Mexiletine |
| FG001 | Mexiletine, 600 Milligrams | Mexiletine, 600 milligrams by mouth per day for 4 weeks. Mexiletine |
| FG002 | Placebo | Placebo, by mouth per day for 4 weeks. Placebo |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Mexiletine, 300 Milligrams | Mexiletine, 300 milligrams by mouth per day for 4 weeks. Mexiletine |
| BG001 | Mexiletine, 600 Milligrams | Mexiletine, 600 milligrams by mouth per day for 4 weeks. Mexiletine |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Resting Motor Threshold | The resting motor threshold (RMT) assessed from single pulse transcranial magnetic stimulation (TMS) measurements made before treatment, after 4 weeks of treatment, and then again after a 4 week washout, was used as the primary pharmacodynamic marker of cortical hyperexcitability. RMT is the stimulus intensity required to produce and maintain a 0.2 mV peak-to-peak motor evoked potential of the abductor pollicis brevis muscle by TMS. A smaller RMT is thought to suggest greater neuronal excitability. | Posted | Least Squares Mean | Standard Error | percentage of maximum stimulus output | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 and from Week 4 to Week 8 reported |
|
8 weeks
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Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Mexiletine, 300 Milligrams | Mexiletine, 300 milligrams by mouth per day for 4 weeks. Mexiletine |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Deep vein thrombosis | Vascular disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Inner ear signs and symptoms | Ear and labyrinth disorders | Non-systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Michael D. Weiss | University of Washington | 206-598-7688 | mdweiss@uw.edu |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jul 10, 2017 | Sep 17, 2019 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jan 10, 2019 | Sep 17, 2019 | SAP_001.pdf |
Not provided
| ID | Term |
|---|---|
| C531617 | Amyotrophic lateral sclerosis 1 |
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| D008801 | Mexiletine |
| ID | Term |
|---|---|
| D011437 | Propylamines |
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D010647 | Phenyl Ethers |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Placebo |
| Drug |
|
| Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported |
| Change in Motor Evoked Potential Amplitude | The motor evoked potential (MEP) amplitude is taken from single pulse transcranial magnetic stimulation (TMS) and reflects the density of corticomotoneuronal projections onto motor neurons and is affected by cortical hyperexcitability early in ALS where it is thought to be larger than age-matched controls and axonal degeneration later in the disease when it decreases in amplitude. The MEP is most reliable in assessing cortical motor neuronal preservation and excitability when normalized to the peak compound nerve action potential (CMAP) amplitude which reflects the integrity of peripheral motor nerve axons. It is also normalized here to 120% of the RMT to derive a ratio of MEP at 120% RMT/peak CMAP. | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported |
| Effect on Cortical Silent Period | The cortical silent period (CSP) is recorded with single pulse TMS as a duration from the onset of the MEP response to resumption of voluntary electromyography activity with the patient performing a voluntary contraction, set to 30% of maximal voluntary contraction. A shorter CSP compared to controls would reflect greater excitability. | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported |
| Effect on Strength Duration Time Constant | The strength duration time constant (SDTC) is used in threshold tracking nerve axonal excitability studies and is interpreted as a measure of axonal excitability that is dependent upon the biophysical properties of the axonal membrane at the node of Ranvier, especially persistent sodium current. It is derived from the relationship between stimulus duration and intensity. A higher SDTC would reflect greater excitability of motor nerve axons. | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported |
| Effect on Depolarizing Threshold Electrotonus (90-100 ms) | Depolarizing threshold electrotonus (90-100 ms) (TEd 90-100 ms) is used in threshold tracking nerve axonal excitability studies in which long-lasting subthreshold depolarizing currents are generated, measured at 90-100 ms following the stimulus. This measure is associated with a decrease in the membrane excitability threshold due to opening of potassium channels on the axonal membrane. Intrinsic changes in axonal excitability properties, such as thought to occur in ALS, could possibly alter this measure, presumably by decreasing TEd 90-100 ms more substantially than normal. | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported |
| Effect on Hyperpolarizing Threshold Electrotonus (90-100 ms) | Hyperpolarizing threshold electrotonus (90-100 ms) (TEh 90-100 ms) is used in threshold tracking nerve axonal excitability studies in which long-lasting subthreshold hyperpolarizing currents are generated, measured at 90-100 ms following the stimulus. This measure is associated with an increase in the membrane excitability threshold due to closure of potassium channels causing increased resistance of the internodal axonal membrane. Intrinsic changes in axonal excitability properties, such as thought to occur in ALS, could possibly alter this measure. | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported |
| Effect on Superexcitability | Superexcitability is a component of recovery cycle analysis assessing motor axonal excitability, employing threshold tracking nerve conduction study. It is a depolarizing afterpotential measured following a single supramaximal stimulus followed by a second smaller stimulus of variable intensity and reflects passive depolarization of the internodal axon. | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported |
| Effect on Subexcitability | Subexcitability is a component of recovery cycle analysis assessing motor axonal excitability, employing threshold tracking nerve conduction study. It is a late hyperpolarizing after potential measured following a single supramaximal stimulus followed by a second smaller stimulus of variable intensity and is related to the very slow turn-off of slow potassium channels. | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported |
| Effect on Frequency of Muscle Cramps | Will be assessed using a daily muscle cramps diary tabulated weekly beginning at Baseline. | Accessed at Screening, Baseline, Week 4, and Week 8; comparisons of treatments at Weeks 3-4 reported |
| Effect on Frequency of Fasciculations (Muscle Twitching) | Will be assessed using a daily fasciculations diary tabulated as a percentage of days from weeks 3-4. | Accessed at Screening, Baseline, Week 4, and Week 8; comparisons of treatments at Weeks 3-4 reported |
| Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported |
| Change in Slow Vital Capacity | Measure of decline in respiratory muscle strength | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported |
| Orange |
| California |
| 92868 |
| United States |
| Augusta University | Augusta | Georgia | 30912 | United States |
| Beth Israel Deaconess Medical Center | Boston | Massachusetts | 02215 | United States |
| University of Michigan | Ann Arbor | Michigan | 48109 | United States |
| Columbia Universtiy Medical Center | New York | New York | 10032 | United States |
| Pennsylvania State Hershey Medical Center | Hershey | Pennsylvania | 17033 | United States |
| University of Pittsburgh | Pittsburgh | Pennsylvania | 15213 | United States |
| Medical University of South Carolina | Charleston | South Carolina | 29425 | United States |
| University of Washington | Seattle | Washington | 98195 | United States |
| BG002 | Placebo | Placebo, by mouth per day for 4 weeks. Placebo |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| El Escorial Diagnosis | Participants were classified according to the El Escorial World Federation of Neurology Criteria for the Diagnosis of ALS (Brooks J Neurol Sci 1994) based on the extent of ALS disease signs and symptoms consistent with neurodegeneration of upper and lower motor neurons | Count of Participants | Participants |
|
| OG001 |
| Mexiletine, 600 Milligrams |
Mexiletine, 600 milligrams by mouth per day for 4 weeks. Mexiletine |
| OG002 | Placebo | Placebo, by mouth per day for 4 weeks. Placebo |
|
|
|
| Secondary | Effect on Short-interval Intracortical Inhibition | Short-interval intracortical inhibition (SICI) is a measure of neuronal excitability measured by dual pulse TMS with a conditioned (80% of RMT) and test pulses (120% of RMT) to generate a stable MEP amplitude of 0.2 mV, averaged over interstimulus intervals of 1-7 ms. It is thought to reflect refractory cortical axons and subsequent resynchronization of cortico-cortical and corticomotoneuronal volleys or activation of non-GABAergic cortical inhibitory circuits (initial phase) and synaptic neurotransmission through GABAA receptors (second phase). The value for SICI thought to be maximally sensitive for detecting in changes in ALS subjects compared to controls is is derived by measuring the motor evoked potential amplitude (MEP) at an interstimulus interval of 3 ms (ISI 3 ms) and normalizing to the MEP amplitude at 120% of the resting motor threshold (MEP 120% RMT). A reduction in SICI reflecting greater excitability would generate a larger ratio of MEP ISI 3 ms/MEP 120% RMT. | Posted | Geometric Least Squares Mean | 95% Confidence Interval | unitless ratio MEP ISI 3 ms/MEP 120% RMT | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported |
|
|
|
|
| Secondary | Change in Motor Evoked Potential Amplitude | The motor evoked potential (MEP) amplitude is taken from single pulse transcranial magnetic stimulation (TMS) and reflects the density of corticomotoneuronal projections onto motor neurons and is affected by cortical hyperexcitability early in ALS where it is thought to be larger than age-matched controls and axonal degeneration later in the disease when it decreases in amplitude. The MEP is most reliable in assessing cortical motor neuronal preservation and excitability when normalized to the peak compound nerve action potential (CMAP) amplitude which reflects the integrity of peripheral motor nerve axons. It is also normalized here to 120% of the RMT to derive a ratio of MEP at 120% RMT/peak CMAP. | MEP at 120% RMT/peak CMAP | Posted | Geometric Least Squares Mean | 95% Confidence Interval | unitless ratio of ms/ms | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported |
|
|
|
|
| Secondary | Effect on Cortical Silent Period | The cortical silent period (CSP) is recorded with single pulse TMS as a duration from the onset of the MEP response to resumption of voluntary electromyography activity with the patient performing a voluntary contraction, set to 30% of maximal voluntary contraction. A shorter CSP compared to controls would reflect greater excitability. | Posted | Least Squares Mean | 95% Confidence Interval | milliseconds | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported |
|
|
|
|
| Secondary | Effect on Strength Duration Time Constant | The strength duration time constant (SDTC) is used in threshold tracking nerve axonal excitability studies and is interpreted as a measure of axonal excitability that is dependent upon the biophysical properties of the axonal membrane at the node of Ranvier, especially persistent sodium current. It is derived from the relationship between stimulus duration and intensity. A higher SDTC would reflect greater excitability of motor nerve axons. | strength duration time constant | Posted | Geometric Least Squares Mean | 95% Confidence Interval | milliseconds | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported |
|
|
|
|
| Secondary | Effect on Depolarizing Threshold Electrotonus (90-100 ms) | Depolarizing threshold electrotonus (90-100 ms) (TEd 90-100 ms) is used in threshold tracking nerve axonal excitability studies in which long-lasting subthreshold depolarizing currents are generated, measured at 90-100 ms following the stimulus. This measure is associated with a decrease in the membrane excitability threshold due to opening of potassium channels on the axonal membrane. Intrinsic changes in axonal excitability properties, such as thought to occur in ALS, could possibly alter this measure, presumably by decreasing TEd 90-100 ms more substantially than normal. | Posted | Least Squares Mean | 95% Confidence Interval | percentage of threshold depolarization | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported |
|
|
|
|
| Secondary | Effect on Hyperpolarizing Threshold Electrotonus (90-100 ms) | Hyperpolarizing threshold electrotonus (90-100 ms) (TEh 90-100 ms) is used in threshold tracking nerve axonal excitability studies in which long-lasting subthreshold hyperpolarizing currents are generated, measured at 90-100 ms following the stimulus. This measure is associated with an increase in the membrane excitability threshold due to closure of potassium channels causing increased resistance of the internodal axonal membrane. Intrinsic changes in axonal excitability properties, such as thought to occur in ALS, could possibly alter this measure. | Posted | Least Squares Mean | 95% Confidence Interval | percentage threshold hyperpolarization | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported |
|
|
|
|
| Secondary | Effect on Superexcitability | Superexcitability is a component of recovery cycle analysis assessing motor axonal excitability, employing threshold tracking nerve conduction study. It is a depolarizing afterpotential measured following a single supramaximal stimulus followed by a second smaller stimulus of variable intensity and reflects passive depolarization of the internodal axon. | Posted | Least Squares Mean | 95% Confidence Interval | percentage of threshold change | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported |
|
|
|
|
| Secondary | Effect on Subexcitability | Subexcitability is a component of recovery cycle analysis assessing motor axonal excitability, employing threshold tracking nerve conduction study. It is a late hyperpolarizing after potential measured following a single supramaximal stimulus followed by a second smaller stimulus of variable intensity and is related to the very slow turn-off of slow potassium channels. | Posted | Least Squares Mean | 95% Confidence Interval | percentage of threshold change | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported |
|
|
|
|
| Secondary | Effect on Frequency of Muscle Cramps | Will be assessed using a daily muscle cramps diary tabulated weekly beginning at Baseline. | Posted | Geometric Least Squares Mean | 95% Confidence Interval | muscle cramps/week | Accessed at Screening, Baseline, Week 4, and Week 8; comparisons of treatments at Weeks 3-4 reported |
|
|
|
|
| Secondary | Effect on Frequency of Fasciculations (Muscle Twitching) | Will be assessed using a daily fasciculations diary tabulated as a percentage of days from weeks 3-4. | Posted | Median | Inter-Quartile Range | percentage of days with fasciculations | Accessed at Screening, Baseline, Week 4, and Week 8; comparisons of treatments at Weeks 3-4 reported |
|
|
|
| Other Pre-specified | Change in the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised | The Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) is an instrument for evaluating the functional status of patients with ALS that includes functions related to speech, swallowing, salivation, fine motor control, gross motor function, and respiration. The score is the sum of 12 items (range 0 to 48) with higher scores reflecting better function. | Posted | Least Squares Mean | 95% Confidence Interval | score on a scale | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported |
|
|
|
|
| Other Pre-specified | Change in Slow Vital Capacity | Measure of decline in respiratory muscle strength | Posted | Least Squares Mean | 95% Confidence Interval | maximum percent predicted | Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported |
|
|
|
|
| 0 |
| 8 |
| 0 |
| 8 |
| 5 |
| 8 |
| EG001 | Mexiletine, 600 Milligrams | Mexiletine, 600 milligrams by mouth per day for 4 weeks. Mexiletine | 0 | 6 | 0 | 6 | 5 | 6 |
| EG002 | Placebo | Placebo, by mouth per day for 4 weeks. Placebo | 0 | 6 | 1 | 6 | 5 | 6 |
| Dental pain and sensation disorders | Gastrointestinal disorders | Non-systematic Assessment |
|
| Diarrhoea (excl infective) | Gastrointestinal disorders | Non-systematic Assessment |
|
| Dyspeptic signs and symptoms | Gastrointestinal disorders | Non-systematic Assessment |
|
| Gastrointestinal atonic and hypomotility disorders NEC | Gastrointestinal disorders | Non-systematic Assessment |
|
| Nausea and vomiting symptoms | Gastrointestinal disorders | Non-systematic Assessment |
|
| Oral dryness and saliva altered | Gastrointestinal disorders | Non-systematic Assessment |
|
| Oral soft tissue pain and paraesthesia | Gastrointestinal disorders | Non-systematic Assessment |
|
| General signs and symptoms NEC | General disorders | Non-systematic Assessment |
|
| Implant and catheter site reactions | General disorders | Non-systematic Assessment |
|
| Oedema NEC | General disorders | Non-systematic Assessment |
|
| Lower respiratory tract and lung infections | Infections and infestations | Non-systematic Assessment |
|
| Non-site specific injuries NEC | Injury, poisoning and procedural complications | Non-systematic Assessment |
|
| Muscle pains | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Muscle related signs and symptoms NEC | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Musculoskeletal and connective tissue signs and symptoms NEC | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Headaches NEC | Nervous system disorders | Non-systematic Assessment |
|
| Neurological signs and symptoms NEC | Nervous system disorders | Non-systematic Assessment |
|
| Speech and language abnormalities | Nervous system disorders | Non-systematic Assessment |
|
| Tremor (excl congenital) | Nervous system disorders | Non-systematic Assessment |
|
| Disturbances in initiating and maintaining sleep | Psychiatric disorders | Non-systematic Assessment |
|
| Bladder and urethral symptoms | Renal and urinary disorders | Non-systematic Assessment |
|
| Breathing abnormalities | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Upper respiratory tract signs and symptoms | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Erythemas | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| Rashes, eruptions and exanthems NEC | Skin and subcutaneous tissue disorders | Non-systematic Assessment |
|
| Peripheral embolism and thrombosis | Vascular disorders | Non-systematic Assessment |
|
| Asthenic | General disorders | Non-systematic Assessment |
|
Not provided
Not provided
| D010636 |
| Phenols |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |