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| ID | Type | Description | Link |
|---|---|---|---|
| 2012-004847-61 | EudraCT Number |
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| Name | Class |
|---|---|
| Merck Sharp & Dohme LLC | INDUSTRY |
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The purpose of this study is to determine whether raltegravir is effective in preventing progression of relapsing remitting multiple sclerosis as determined by gadolinium- enhanced MRI.
There is accumulating research evidence that Human Endogenous Retrovirus (HERV) and herpes viruses (in particular Epstein-Barr Virus) are involved in the pathogenesis of multiple sclerosis. People with active MS have higher levels of HERVs than people either without MS or who have other neurological conditions. It has been shown that HERVs may produce neurotoxic proteins/antigens associated with MS activity and disease progression. This is the first clinical trial investigating the hypothesis that the antiretroviral drug raltegravir may suppress HERV activity and ameliorate progression of relapsing remitting MS. Raltegravir is an integrase inhibitor which blocks retroviral replication. A recent experimental study suggests that raltegravir may also be active against herpes viruses.
Eligible participants (see Inclusion/Exclusion Criteria) will be observed for 3 months having monthly brain Gadolinium enhanced MRIs and blood/urine/saliva sampling (baseline). Then they will be treated with raltegravir (one 400mg pill taken twice a day) for 3 months. During treatment period participants will continue to have monthly MRIs and blood/saliva/urine sampling. Participants will have monthly clinical and neurological examinations and they will complete questionnaires assessing response to treatment. Participants will have screening and study visits at The Royal London Hospital, Whitechapel. Monthly MRIs will be performed at the Institute of Neurology at Queens Square, London.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Raltegravir | Experimental | All eligible patients will complete a 3 months observation period (no medications) followed by 3 months on treatment period. During the treatment period patients will be treated with open label raltegravir 400mg twice daily. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Raltegravir | Drug | 400mg twice daily for 3 months |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| The Number of New or Recurrent Gd-enhancing Lesions That Appear on Brain T1-weighted MRI | Demonstrate in subjects with relapsing remitting multiple sclerosis a reduction in the number of new or recurrent Gd-enhancing lesions that appear on brain T1-weighted MRI over the period of treatment with raltegravir, compared to baseline. Within patient change in number of lesions was calculated by subtracting the after treatment period (3 months) minus before treatment period (3 months). | Baseline and at 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| The Cumulative Number of New or Enlarging T2 Weighted Lesions on Brain MRI. | Demonstrate a reduction in the cumulative number of new or enlarging T2 weighted lesions on brain MRI over the period of treatment with Raltegravir compared with baseline. Within-patient changes in lesion count calculated after-before. | Baseline and monthly for 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Mean Number of Adverse Events Per Patient | This outcome will be assessed by blood and urine sampling; collection of patient reported symptoms and neurological and physical exams. This measure is the total number of adverse events recorded for each type of event during the study period. The number of participants is 31 which is the number screened and enrolled in the study. Eleven participants did not meet the criterion for baseline i.e. having a gadolinium enhancing lesion on MRI at the baseline visit and therefore did not continue to the baseline observation period. The adverse events for the 11 participants who did not begin the study observation period were recorded during the screening period and added to the 20 participants who were studied during the 6 months of the study. Adverse events are recorded as total number during the study period. Each patient may have had more than one adverse event. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Julian Gold, Prof | Queen Mary University of London | Principal Investigator |
| Gavin Giovannoni | Queen Mary University of London | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Royal London Hospital | London | E1 2AT | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20422298 | Background | Christensen T. HERVs in neuropathogenesis. J Neuroimmune Pharmacol. 2010 Sep;5(3):326-35. doi: 10.1007/s11481-010-9214-y. Epub 2010 Apr 27. | |
| 22457345 | Background | Perron H, Germi R, Bernard C, Garcia-Montojo M, Deluen C, Farinelli L, Faucard R, Veas F, Stefas I, Fabriek BO, Van-Horssen J, Van-der-Valk P, Gerdil C, Mancuso R, Saresella M, Clerici M, Marcel S, Creange A, Cavaretta R, Caputo D, Arru G, Morand P, Lang AB, Sotgiu S, Ruprecht K, Rieckmann P, Villoslada P, Chofflon M, Boucraut J, Pelletier J, Hartung HP. Human endogenous retrovirus type W envelope expression in blood and brain cells provides new insights into multiple sclerosis disease. Mult Scler. 2012 Dec;18(12):1721-36. doi: 10.1177/1352458512441381. Epub 2012 Mar 28. |
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31 subjects screened. 8 had no evidence of Gd enhancing lesions in their baseline MRI and were screen failed. Of the 23 participants who were recruited into the study 3 were withdrawn prior to starting the treatment phase; one at the request of the participant and the remaining two due to MS relapse.
Patients 18-55 years of age with RRMS, as per McDonald Criteria 2010, EDSS up to 6.0, relapse within the past 12 months or at least one active Gd enhanced lesion on brain MRI within the 3 months prior to consent. All participants were recruited at the Clinical Research Centre of the Royal London Hospital and drawn from greater London.
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| ID | Title | Description |
|---|---|---|
| FG000 | Raltegravir | All eligible patients will complete a 3 months observation period (no medications) followed by 3 months on treatment period. During the treatment period patients will be treated with open label raltegravir 400mg twice daily. Raltegravir: 400mg twice daily for 3 months |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Raltegravir | All eligible patients will complete a 3 months observation period (no medications) followed by 3 months on treatment period. During the treatment period patients will be treated with open label raltegravir 400mg twice daily. Raltegravir: 400mg twice daily for 3 months |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | The Number of New or Recurrent Gd-enhancing Lesions That Appear on Brain T1-weighted MRI | Demonstrate in subjects with relapsing remitting multiple sclerosis a reduction in the number of new or recurrent Gd-enhancing lesions that appear on brain T1-weighted MRI over the period of treatment with raltegravir, compared to baseline. Within patient change in number of lesions was calculated by subtracting the after treatment period (3 months) minus before treatment period (3 months). | ITT | Posted | Mean | Full Range | lesions | Baseline and at 6 months |
|
Adverse events were recorded from the time patients signed the informed consent to the end of the study period, which was up to 7 months for each patient, including screening period.
Adverse events were recorded from the time subjects signed the informed consent form. 31 patients signed the informed consent and 20 were eligible for enrollment in the observational and treatment phases of the study. 11 patients were deemed not eligible as they did not have active Gd-enhanced lesions during screening.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Raltegravir | All eligible patients will complete a 3 months observation period (no medications) followed by 3 months on treatment period. During the treatment period patients will be treated with open label raltegravir 400mg twice daily. Raltegravir: 400mg twice daily for 3 months |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| MS relapse | Nervous system disorders | Systematic Assessment | MS relapse requiring hospitalisation for administration of IV methylprednisolone. Normal practise would not be hospital admission but the patient had no care at home and due to MS relapse could care for self at home. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Adenopathies | Immune system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Professor Gavin Giovannoni | Queen Mary University of London | g.giovannoni@qmul.ac.uk |
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| ID | Term |
|---|---|
| D020529 | Multiple Sclerosis, Relapsing-Remitting |
| ID | Term |
|---|---|
| D009103 | Multiple Sclerosis |
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D000068898 | Raltegravir Potassium |
| ID | Term |
|---|---|
| D011760 | Pyrrolidinones |
| D011759 | Pyrrolidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| Change in Score on Multiple Sclerosis Functional Composite (MSFC). This a Composite Score Based on the Measurement of Time in Seconds for the Three Separate Measurements. | Explore preliminary clinical responses in relapsing-remitting multiple sclerosis subjects treated with Raltegravir, compared with baseline as measured by Patient Reported Outcomes (Questionnaires). The MSFC is a composite score consisting of the standardly derived composite score from 9-hole peg test (9HPT), timed walk and PASAT scores. 9HPT is measured as timed speed to complete the task; higher scores indicate less disability. The 25-foot walk is measured as timed speed; higher scores indicate less disability. The Paced Auditory Serial Addition Test (PASAT) The PASAT is a measure of cognitive function that assesses auditory information processing speed and flexibility, as well as calculation ability. It is a timed speed test measured in seconds. In the PASAT a lower score indicates less disability. | Baseline and monthly until month 6. |
| Changes in Kurtzke Extended Disability Status Scale (EDSS) Score | The Kurtzke Expanded Disability Status Scale (EDSS) is a method of quantifying disability in multiple sclerosis. The scale has been developed by John F. Kurtzke. The EDSS quantifies disability in eight Functional Systems (FS) and allows neurologists to assign a Functional System Score (FSS) in each of these. 0 = Normal 1-1.5 = No disability, but some abnormal neurological signs 2-2.5 = Minimal disability 3-4.5 = Moderate disability, affecting daily activities, but you can still walk. A lower score indicates less disability. 5-8 = More severe disability, impairing your daily activities and requiring assistance with walking 8.5-9.5 = Very severe disability, restricting you to bed 10 = Death EDSS scores were measured monthly over 6 months and the mean of the measurements for the first three months (baseline) was recorded to use calculate the change from baseline compared with the mean of measurements taken monthly during the second three months (treatment). | Baseline and monthly to month 6 |
| Cumulative Number of Gd-T1 Enhancing Lesions | This measure is the number of gadolinium-enhancing T1 lesions as determined by MRI taken on the monthly basis during the six months of the study. | At Baseline and monthly for 6 months |
| Percent of Subjects With Scans Free From Enhancing Lesions in Raltegravir Treated Subjects vs. Baseline | This measure is the cumulative percentage of subjects who had scans free from Gd enhancing lesions during the first three months (baseline) compared with the second three months (treatment). These percentages are expressed as a total percentage for the baseline and for the treatment periods. | Baseline to 6 months |
| Screening to six months |
| Effect of Raltegravir Therapy on Specific Inflammatory Marker of MS Activity. | Measured by Human C-Reactive Protein (HCRP) which is a measure of general inflammation. The higher the value the more inflammatory response is present. The HCRP was measured monthly for six months. The mean value for the baseline three months was compared with the mean value taken for the second (treatment) three months. | Baseline to 6 months |
| 19458321 | Background | Farrell RA, Antony D, Wall GR, Clark DA, Fisniku L, Swanton J, Khaleeli Z, Schmierer K, Miller DH, Giovannoni G. Humoral immune response to EBV in multiple sclerosis is associated with disease activity on MRI. Neurology. 2009 Jul 7;73(1):32-8. doi: 10.1212/WNL.0b013e3181aa29fe. Epub 2009 May 20. |
| 20805464 | Background | Nadal M, Mas PJ, Blanco AG, Arnan C, Sola M, Hart DJ, Coll M. Structure and inhibition of herpesvirus DNA packaging terminase nuclease domain. Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16078-83. doi: 10.1073/pnas.1007144107. Epub 2010 Aug 30. |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
|
| Secondary | The Cumulative Number of New or Enlarging T2 Weighted Lesions on Brain MRI. | Demonstrate a reduction in the cumulative number of new or enlarging T2 weighted lesions on brain MRI over the period of treatment with Raltegravir compared with baseline. Within-patient changes in lesion count calculated after-before. | ITT | Posted | Mean | Full Range | T2-weighted lesions | Baseline and monthly for 6 months |
|
|
|
| Secondary | Change in Score on Multiple Sclerosis Functional Composite (MSFC). This a Composite Score Based on the Measurement of Time in Seconds for the Three Separate Measurements. | Explore preliminary clinical responses in relapsing-remitting multiple sclerosis subjects treated with Raltegravir, compared with baseline as measured by Patient Reported Outcomes (Questionnaires). The MSFC is a composite score consisting of the standardly derived composite score from 9-hole peg test (9HPT), timed walk and PASAT scores. 9HPT is measured as timed speed to complete the task; higher scores indicate less disability. The 25-foot walk is measured as timed speed; higher scores indicate less disability. The Paced Auditory Serial Addition Test (PASAT) The PASAT is a measure of cognitive function that assesses auditory information processing speed and flexibility, as well as calculation ability. It is a timed speed test measured in seconds. In the PASAT a lower score indicates less disability. | ITT | Posted | Mean | Standard Deviation | seconds | Baseline and monthly until month 6. |
|
|
|
| Secondary | Changes in Kurtzke Extended Disability Status Scale (EDSS) Score | The Kurtzke Expanded Disability Status Scale (EDSS) is a method of quantifying disability in multiple sclerosis. The scale has been developed by John F. Kurtzke. The EDSS quantifies disability in eight Functional Systems (FS) and allows neurologists to assign a Functional System Score (FSS) in each of these. 0 = Normal 1-1.5 = No disability, but some abnormal neurological signs 2-2.5 = Minimal disability 3-4.5 = Moderate disability, affecting daily activities, but you can still walk. A lower score indicates less disability. 5-8 = More severe disability, impairing your daily activities and requiring assistance with walking 8.5-9.5 = Very severe disability, restricting you to bed 10 = Death EDSS scores were measured monthly over 6 months and the mean of the measurements for the first three months (baseline) was recorded to use calculate the change from baseline compared with the mean of measurements taken monthly during the second three months (treatment). | All patients enrolled in clinical trial | Posted | Mean | Standard Deviation | units on a scale | Baseline and monthly to month 6 |
|
|
|
| Secondary | Cumulative Number of Gd-T1 Enhancing Lesions | This measure is the number of gadolinium-enhancing T1 lesions as determined by MRI taken on the monthly basis during the six months of the study. | ITT | Posted | Mean | Full Range | Gadolinium enhancing T1 lesions | At Baseline and monthly for 6 months |
|
|
|
| Secondary | Percent of Subjects With Scans Free From Enhancing Lesions in Raltegravir Treated Subjects vs. Baseline | This measure is the cumulative percentage of subjects who had scans free from Gd enhancing lesions during the first three months (baseline) compared with the second three months (treatment). These percentages are expressed as a total percentage for the baseline and for the treatment periods. | ITT | Posted | Number | percentage of subjects | Baseline to 6 months |
|
|
|
| Other Pre-specified | Mean Number of Adverse Events Per Patient | This outcome will be assessed by blood and urine sampling; collection of patient reported symptoms and neurological and physical exams. This measure is the total number of adverse events recorded for each type of event during the study period. The number of participants is 31 which is the number screened and enrolled in the study. Eleven participants did not meet the criterion for baseline i.e. having a gadolinium enhancing lesion on MRI at the baseline visit and therefore did not continue to the baseline observation period. The adverse events for the 11 participants who did not begin the study observation period were recorded during the screening period and added to the 20 participants who were studied during the 6 months of the study. Adverse events are recorded as total number during the study period. Each patient may have had more than one adverse event. | ITT | Posted | Mean | Full Range | Adverse events | Screening to six months |
|
|
|
| Other Pre-specified | Effect of Raltegravir Therapy on Specific Inflammatory Marker of MS Activity. | Measured by Human C-Reactive Protein (HCRP) which is a measure of general inflammation. The higher the value the more inflammatory response is present. The HCRP was measured monthly for six months. The mean value for the baseline three months was compared with the mean value taken for the second (treatment) three months. | ITT | Posted | Mean | Full Range | ng/mL | Baseline to 6 months |
|
|
|
| 1 |
| 31 |
| 31 |
| 31 |
|
| Itchy eyes | Immune system disorders | Systematic Assessment |
|
| Allergic skin rash worsening | Immune system disorders | Systematic Assessment |
|
| Hayfever congestion | Immune system disorders | Systematic Assessment |
|
| Hayfever worsening | Immune system disorders | Systematic Assessment |
|
| Headache | General disorders | Systematic Assessment |
|
| Liver function test abnormal | General disorders | Systematic Assessment |
|
| Liver function test increased | General disorders | Systematic Assessment |
|
| Dizziness | General disorders | Systematic Assessment |
|
| Fall | General disorders | Systematic Assessment |
|
| Insomnia | General disorders | Systematic Assessment |
|
| Poor sleep | General disorders | Systematic Assessment |
|
| Nausea | General disorders | Systematic Assessment |
|
| Swelling in left arm | General disorders | Systematic Assessment |
|
| Stomach pain | General disorders | Systematic Assessment |
|
| Loss of libido | General disorders | Systematic Assessment |
|
| Pyrexia | General disorders | Systematic Assessment |
|
| Dysphonia | General disorders | Systematic Assessment |
|
| Problems concentrating | General disorders | Systematic Assessment |
|
| Stiff neck | General disorders | Systematic Assessment |
|
| Fainting | General disorders | Systematic Assessment |
|
| Vivid dreams | General disorders | Systematic Assessment |
|
| Tiredness | General disorders | Systematic Assessment |
|
| Night sweats | General disorders | Systematic Assessment |
|
| Dry mouth | General disorders | Systematic Assessment |
|
| Weight loss diet | General disorders | Systematic Assessment |
|
| Lack of motivation | General disorders | Systematic Assessment |
|
| Asymptomatic low blood pressure | General disorders | Systematic Assessment |
|
| Chest pain | General disorders | Systematic Assessment |
|
| Choking on liquids | General disorders | Systematic Assessment |
|
| Flushing to face | General disorders | Systematic Assessment |
|
| Strange sensation when swallowing | General disorders | Systematic Assessment |
|
| Swelling feelings in fingers | General disorders | Systematic Assessment |
|
| Depression | Psychiatric disorders | Systematic Assessment |
|
| Depression worsening | Psychiatric disorders | Systematic Assessment |
|
| Low mood | Psychiatric disorders | Systematic Assessment |
|
| Anxiety | Psychiatric disorders | Systematic Assessment |
|
| Panick attacks increased | Psychiatric disorders | Systematic Assessment |
|
| Emotional instability | Psychiatric disorders | Systematic Assessment |
|
| Menopause onset | Reproductive system and breast disorders | Systematic Assessment |
|
| Erectile dysfunction | Reproductive system and breast disorders | Systematic Assessment |
|
| Pelvic mass | Reproductive system and breast disorders | Systematic Assessment |
|
| Haematoma | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Bruised knee (due to fall) | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Broken toenail | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Cut knee | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Twisted knee | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Hurt wrist | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Hypertension | Cardiac disorders | Systematic Assessment |
|
| Tachycardia | Cardiac disorders | Systematic Assessment |
|
| Hypertension worsening | Cardiac disorders | Systematic Assessment |
|
| Arrhythmia | Cardiac disorders | Systematic Assessment |
|
| Wheeze | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Dyslipidemia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Mycrocytic anemia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Hypoglycemia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Normocytic anaemia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Multiple sclerosis relapse | Nervous system disorders | Systematic Assessment |
|
| Multiple sclerosis sensory relapse | Nervous system disorders | Systematic Assessment |
|
| Sensory disturbance | Nervous system disorders | Systematic Assessment |
|
| Fatigue | Nervous system disorders | Systematic Assessment |
|
| Fatigue increased | Nervous system disorders | Systematic Assessment |
|
| Migraine | Nervous system disorders | Systematic Assessment |
|
| Dysaesthesia worsening | Nervous system disorders | Systematic Assessment |
|
| Nystagmus | Nervous system disorders | Systematic Assessment |
|
| Neuropathic pain | Nervous system disorders | Systematic Assessment |
|
| Tremor in hands | Nervous system disorders | Systematic Assessment |
|
| Numbness (loss of sensation) | Nervous system disorders | Systematic Assessment |
|
| tremor in arms worsened | Nervous system disorders | Systematic Assessment |
|
| Subjective worsening in leg weakness | Nervous system disorders | Systematic Assessment |
|
| Neurologial signs worsening | Nervous system disorders | Systematic Assessment |
|
| Back pain (burning sensation) | Nervous system disorders | Systematic Assessment |
|
| Visaul fatigue | Eye disorders | Systematic Assessment |
|
| Decreased vision | Eye disorders | Systematic Assessment |
|
| Stye | Eye disorders | Systematic Assessment |
|
| Gastroenteritis | Gastrointestinal disorders | Systematic Assessment |
|
| Defective gastro-ileal valve | Gastrointestinal disorders | Systematic Assessment |
|
| Bloated abdomen (during antibiotics) | Gastrointestinal disorders | Systematic Assessment |
|
| Bladder dysfunction | Renal and urinary disorders | Systematic Assessment |
|
| Dysuria | Renal and urinary disorders | Systematic Assessment |
|
| Bladder problems worsening | Renal and urinary disorders | Systematic Assessment |
|
| Itching | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Eczema | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Fungal infection | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Fungal infection worsening | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Dry skin | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Petechial purpura | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Naevus | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Scar from mole removal | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Rash on face | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Mole on toe | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Allergic rash worsening | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Pain worsening | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Carpal tunnel syndrome | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Cramps in legs | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Common cold | Infections and infestations | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | Systematic Assessment |
|
| Sore throat | Infections and infestations | Systematic Assessment |
|
| Cough | Infections and infestations | Systematic Assessment |
|
| Sinusitis | Infections and infestations | Systematic Assessment |
|
| Tooth infection | Infections and infestations | Systematic Assessment |
|
| Chest infection | Infections and infestations | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | Systematic Assessment |
|
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| D003711 | Demyelinating Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
|