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| Name | Class |
|---|---|
| Radboud University Medical Center | OTHER |
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Coversin in Paroxysmal Nocturnal Haemoglobinuria (PNH) in patients with resistance to Eculizumab due to complement C5 polymorphisms.
Coversin, a small protein complement C5 inhibitor which prevents the cleavage of C5 by C5 convertase into C5a and C5b, will be used in an open label, non-comparative clinical trial in patients with PNH and proven resistance to eculizumab due to C5 polymorphisms. Patients will be treated with Coversin by daily subcutaneous injection for 6 months in order to determine the safety and efficacy of the drug in these circumstances. If satisfactory control of the PNH is achieved, and at the discretion of the Principal Investigator (PI), patients will have the option of remaining on Coversin and being entered into the long term follow-up study for 2 years.
Please note, 'Coversin' is used throughout, but Nomacopan is the official name/INN.
Please note, the end points were assessed for 6 months, but the adverse events were measured over the 2 year period.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Coversin (Nomacopan) | Other | This is an open label, non-comparator study. Patient will be given a single ablating dose of 0.57mg/kg per subject followed by daily repeat maintenance doses. The initial repeat dose will be 25% of the ablating dose. If this is insufficient to maintain complement inhibition at ≤10% of baseline (pre-treatment) level after 5 days of treatment the daily dose will be increased by doubling until that level of inhibition is achieved. In the event of 100% inhibition being achieved the dose may be titrated downwards at the PI's discretion until a satisfactory clinical result is obtained. If at any point in treatment complement inhibition falls to less than 50% of baseline a further ablating dose of 0.57mg/kg should be given. Coversin lyophilised powder in each vial was diluted with 0.6 mL water for injection prior to use. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Coversin | Drug | Patients enrolled in this protocol will initially be treated with an ablating dose of Coversin and daily repeat maintenance doses calculated according to body weight, the ablating dose to be 0.57mg/kg. Thereafter the daily repeat dose will be titrated according to clinical response and complement inhibition determined by CH50 ELISA. The initial repeat dose will be 25% of the ablating dose and this will be adjusted up or down if necessary once steady state is reached (5 days). |
| Measure | Description | Time Frame |
|---|---|---|
| Measurement of Ratio of LDH to the Upper Limit of Normal (ULN) | LDH is an indicator of disease progression in patients with PNH and is expected to fall to within 2x upper limit of normal (ULN) within 28 days in successfully treated patients. Units are measured in ratio of LDH:ULN, where the ULN is 250 U/L. The primary efficacy endpoint was the LDH AUC from Day 0 to 28 compared with 28 days pretreatment. Data for the 28 days pre-treatment was not collected, and as only one patient was recruited, the LDH values compared with baseline and the ratio of LDH to the Upper Limit of Normal (ULN) are presented. | Day 0 and Day 28 |
| Number and Type of Adverse Events (AE) | The number and type of reported AEs will be recorded as well as the opinion of the Principle Investigator (PI) as to their possible relationship to the study drug. | 2 years |
| Measure | Description | Time Frame |
|---|---|---|
| Measurement of Haemoglobin (Hb) at Days 28, 90, and 180, Absolute and Change From Baseline | Measuring change in mean Hb from Day 28, Day 90 and Day 180 (absolute and change from baseline) | Baseline, Day 28, Day 90 and Day 180 |
| Measurement of Haptoglobin (Hp) at Days 28, 90 and 180, Absolute and Change From Baseline |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Petra Dr Muus | Radboud University Medical Center | Principal Investigator |
| Saskia Dr Langemeijer | Radboud University Medical Center | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Dr Saskia Langemeijer | Nijmegen | 6525 GA | Netherlands |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31840801 | Result | Schols S, Nunn MA, Mackie I, Weston-Davies W, Nishimura JI, Kanakura Y, Blijlevens N, Muus P, Langemeijer S. Successful treatment of a PNH patient non-responsive to eculizumab with the novel complement C5 inhibitor coversin (nomacopan). Br J Haematol. 2020 Jan;188(2):334-337. doi: 10.1111/bjh.16305. Epub 2019 Dec 16. No abstract available. |
| Label | URL |
|---|---|
| Successful treatment of a PNH patient non-responsive to eculizumab with the novel complement C5 inhibitor coversin (nomacopan) | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Coversin | This is an open label, non-comparator study. Patient will be given a single ablating dose of 0.57mg/kg per subject followed by daily repeat maintenance doses. The initial repeat dose will be 25% of the ablating dose. If this is insufficient to maintain complement inhibition at ≤10% of baseline (pre-treatment) level after 5 days of treatment the daily dose will be increased by doubling until that level of inhibition is achieved. In the event of 100% inhibition being achieved the dose may be titrated downwards at the PI's discretion until a satisfactory clinical result is obtained. If at any point in treatment complement inhibition falls to less than 50% of baseline a further ablating dose of 0.57mg/kg should be given. Coversin: Patients enrolled in this protocol will initially be treated with an ablating dose of Coversin and daily repeat maintenance doses calculated according to body weight, the ablating dose to be 0.57mg/kg. Thereafter the daily repeat dose will be titrated according to clinical response and complement inhibition determined by CH50 ELISA. The initial repeat dose will be 25% of the ablating dose and this will be adjusted up or down if necessary once steady state is reached (5 days). |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Coversin | This is an open label, non-comparator study. Patient will be given a single ablating dose of 0.57mg/kg per subject followed by daily repeat maintenance doses. The initial repeat dose will be 25% of the ablating dose. If this is insufficient to maintain complement inhibition at ≤10% of baseline (pre-treatment) level after 5 days of treatment the daily dose will be increased by doubling until that level of inhibition is achieved. In the event of 100% inhibition being achieved the dose may be titrated downwards at the PI's discretion until a satisfactory clinical result is obtained. If at any point in treatment complement inhibition falls to less than 50% of baseline a further ablating dose of 0.57mg/kg should be given. Coversin: Patients enrolled in this protocol will initially be treated with an ablating dose of Coversin and daily repeat maintenance doses calculated according to body weight, the ablating dose to be 0.57mg/kg. Thereafter the daily repeat dose will be titrated according to clinical response and complement inhibition determined by CH50 ELISA. The initial repeat dose will be 25% of the ablating dose and this will be adjusted up or down if necessary once steady state is reached (5 days). |
| 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 | Measurement of Ratio of LDH to the Upper Limit of Normal (ULN) | LDH is an indicator of disease progression in patients with PNH and is expected to fall to within 2x upper limit of normal (ULN) within 28 days in successfully treated patients. Units are measured in ratio of LDH:ULN, where the ULN is 250 U/L. The primary efficacy endpoint was the LDH AUC from Day 0 to 28 compared with 28 days pretreatment. Data for the 28 days pre-treatment was not collected, and as only one patient was recruited, the LDH values compared with baseline and the ratio of LDH to the Upper Limit of Normal (ULN) are presented. | Single arm trial design, results from 1 enrolled participant. | Posted | Number | Ratio of LDH:ULN (250 U/L) | Day 0 and Day 28 |
|
Duration of the study (2 years)
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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 | Coversin | This is an open label, non-comparator study. Patient will be given a single ablating dose of 0.57mg/kg per subject followed by daily repeat maintenance doses. The initial repeat dose will be 25% of the ablating dose. If this is insufficient to maintain complement inhibition at ≤10% of baseline (pre-treatment) level after 5 days of treatment the daily dose will be increased by doubling until that level of inhibition is achieved. In the event of 100% inhibition being achieved the dose may be titrated downwards at the PI's discretion until a satisfactory clinical result is obtained. If at any point in treatment complement inhibition falls to less than 50% of baseline a further ablating dose of 0.57mg/kg should be given. Coversin: Patients enrolled in this protocol will initially be treated with an ablating dose of Coversin and daily repeat maintenance doses calculated according to body weight, the ablating dose to be 0.57mg/kg. Thereafter the daily repeat dose will be titrated according to clinical response and complement inhibition determined by CH50 ELISA. The initial repeat dose will be 25% of the ablating dose and this will be adjusted up or down if necessary once steady state is reached (5 days). |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Breakthrough Hemolysis | Blood and lymphatic system disorders | MedDRA (19.1) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Chief Scientific Officer | Akari Therapeutics plc | 02080040261 | miles.nunn@akaritx.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 11, 2015 | Aug 12, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D006457 | Hemoglobinuria, Paroxysmal |
| ID | Term |
|---|---|
| D000743 | Anemia, Hemolytic |
| D000740 | Anemia |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
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| ID | Term |
|---|---|
| C539676 | rEV576 protein, tick |
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|
|
Measuring change in mean Hp from Day 28, Day 90 and Day 180 (absolute and change from baseline) |
| Baseline, Day 28, Day 90 and Day 180 |
| Measurement of Lactate Dehydrogenase (LDH) at Baseline, Day 90 and Day 180 | Measuring the change in LDH at Baseline, Day 90 and Day 180. LDH is an indicator of disease progression in patients with PNH and is expected to fall to within 2x upper limit of normal (ULN) within 28 days in successfully treated patients. Units are measured in ratio of LDH:ULN, where the ULN is 250 U/L. | Baseline, Day 90 and Day 180 |
| Change in Functional Assessment of Chronic Illness Therapy (FACIT) Score at Days 0, 28, 90 and 180 | Functional Assessment of Chronic Illness Therapy - fatigue (FACIT-F) is a 13 item instrument designed to assess fatigue/tiredness and it's impact on daily activities and functioning in a chronic disease setting. The scale for each question in relation to quality of life ranges from 0-4 where 0= not at all, 1= a little bit, 2= somewhat, 3 = quite a bit and 4= very much. An increase in the scale score indicates an improvement in quality of life (less fatigue). A maximum score of 52 is interpreted as no fatigue . Baseline is assumed as 0.0 to demonstrate the change in units. The subscale score (as presented) is determined as per FACIT-f guidance, by multiplying the sum of the item scores by the number of items in the subscale, then divide by the number of items answered. | Day 28, 90 and 180 |
| Change in Quality Of Life Questionnaire (QOQ) Score at Days 0, 28, 90 and 180 | The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 instrument measures the change in the quality of of life of patients in the trial. It comprises 30 questions on daily QOL and incorporates a global health status, five functional scales (physical, role, cognitive, emotional and social), three symptom scales (fatigue, nausea/vomiting, pain), and six single items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea, financial difficulties). All of the scales range in score from 0 to 100, A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems. Scale scores were calculated by averaging items within scales and transforming average scores linearly. | Day 28, 90 and 180 |
| Dependency on Blood Transfusion | Number of participants depending on blood transfusion prior to starting the study compared to during the study. | Day 0 through to study completion (2 years) |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Weight | Number | kg |
|
| Height | Number | cm |
|
| Serum Lactate Dehydrogenase | Number | U/L |
|
| Haemoglobin concentration (Hb) | Number | Millimole(s)/litre |
|
| Haptoglobin (Hp) concentration | Number | Gram(s)/litre |
|
| Dependency on blood transfusion | Number | participants |
|
|
|
| Primary | Number and Type of Adverse Events (AE) | The number and type of reported AEs will be recorded as well as the opinion of the Principle Investigator (PI) as to their possible relationship to the study drug. | Results from 1 enrolled participant. | Posted | Number | Events | 2 years |
|
|
|
| Secondary | Measurement of Haemoglobin (Hb) at Days 28, 90, and 180, Absolute and Change From Baseline | Measuring change in mean Hb from Day 28, Day 90 and Day 180 (absolute and change from baseline) | Results from 1 enrolled participant. | Posted | Number | millimole(s)/litre | Baseline, Day 28, Day 90 and Day 180 |
|
|
|
| Secondary | Measurement of Haptoglobin (Hp) at Days 28, 90 and 180, Absolute and Change From Baseline | Measuring change in mean Hp from Day 28, Day 90 and Day 180 (absolute and change from baseline) | Results from 1 enrolled participant. | Posted | Number | gram(s)/litre | Baseline, Day 28, Day 90 and Day 180 |
|
|
|
| Secondary | Measurement of Lactate Dehydrogenase (LDH) at Baseline, Day 90 and Day 180 | Measuring the change in LDH at Baseline, Day 90 and Day 180. LDH is an indicator of disease progression in patients with PNH and is expected to fall to within 2x upper limit of normal (ULN) within 28 days in successfully treated patients. Units are measured in ratio of LDH:ULN, where the ULN is 250 U/L. | Single arm trial design, results from 1 enrolled participant. | Posted | Number | Ratio of LDH:ULN (250 U/L) | Baseline, Day 90 and Day 180 |
|
|
|
| Secondary | Change in Functional Assessment of Chronic Illness Therapy (FACIT) Score at Days 0, 28, 90 and 180 | Functional Assessment of Chronic Illness Therapy - fatigue (FACIT-F) is a 13 item instrument designed to assess fatigue/tiredness and it's impact on daily activities and functioning in a chronic disease setting. The scale for each question in relation to quality of life ranges from 0-4 where 0= not at all, 1= a little bit, 2= somewhat, 3 = quite a bit and 4= very much. An increase in the scale score indicates an improvement in quality of life (less fatigue). A maximum score of 52 is interpreted as no fatigue . Baseline is assumed as 0.0 to demonstrate the change in units. The subscale score (as presented) is determined as per FACIT-f guidance, by multiplying the sum of the item scores by the number of items in the subscale, then divide by the number of items answered. | Posted | Number | FACIT-f scale (Change from Baseline) | Day 28, 90 and 180 |
|
|
|
| Secondary | Change in Quality Of Life Questionnaire (QOQ) Score at Days 0, 28, 90 and 180 | The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 instrument measures the change in the quality of of life of patients in the trial. It comprises 30 questions on daily QOL and incorporates a global health status, five functional scales (physical, role, cognitive, emotional and social), three symptom scales (fatigue, nausea/vomiting, pain), and six single items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea, financial difficulties). All of the scales range in score from 0 to 100, A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems. Scale scores were calculated by averaging items within scales and transforming average scores linearly. | Single arm trial design, results from 1 enrolled participant. | Posted | Number | Scores on a scale (Change from baseline) | Day 28, 90 and 180 |
|
|
|
| Secondary | Dependency on Blood Transfusion | Number of participants depending on blood transfusion prior to starting the study compared to during the study. | Results from 1 enrolled participant. | Posted | Number | participants | Day 0 through to study completion (2 years) |
|
|
|
| 0 |
| 1 |
| 1 |
| 1 |
| 1 |
| 1 |
| Lung infection | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
|
| Cough | General disorders | MedDRA (19.1) | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA (19.1) | Systematic Assessment |
|
| Flu like symptoms | General disorders | MedDRA (19.1) | Systematic Assessment |
|
| Injection site Reaction | General disorders | MedDRA (19.1) | Systematic Assessment |
|
| Malaise | General disorders | MedDRA (19.1) | Systematic Assessment |
|
| Non-cardiac chest pain | General disorders | MedDRA (19.1) | Systematic Assessment |
|
| Papulopustular rash | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Insomnia | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Haematuria | Renal and urinary disorders | MedDRA (19.1) | Systematic Assessment |
|
| Haemoglobinurea | Renal and urinary disorders | MedDRA (19.1) | Systematic Assessment |
|
| Coughing | Respiratory, thoracic and mediastinal disorders | MedDRA (19.1) | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA (19.1) | Systematic Assessment |
|
| Sore throat | Respiratory, thoracic and mediastinal disorders | MedDRA (19.1) | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA (19.1) | Systematic Assessment |
|
| Cold fingers and toes | Vascular disorders | MedDRA (19.1) | Systematic Assessment |
|
The PI of the clinical units has independent rights of publication but will agree to discuss any intended publications or presentations with the Sponsor and to allow the Sponsor reasonable time to make comments, file or add to patent applications or request changes to the manuscript
| D009190 |
| Myelodysplastic Syndromes |
| D001855 | Bone Marrow Diseases |
| Title | Measurements |
|---|---|
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| AE - moderate |
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| AE - severe |
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| AE- mild |
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| Title | Measurements |
|---|---|
|
| Day 90 (absolute) |
|
| Day 90 (change from baseline) |
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| Day 180 (absolute) |
|
| Day 180 (change from baseline) |
|
| Title | Measurements |
|---|---|
|
| Day 180 |
|
| Title | Measurements |
|---|
|
| Title | Measurements |
|---|
|
| Title | Measurements |
|---|---|
|
| Physical Functioning (day 28) |
|
| Physical Functioning (day 90) |
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| Physical Functioning (day 180) |
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| Role functioning (day 28) |
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| Role functioning (day 90) |
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| Role functioning (day 180) |
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| Emotional functioning (day 28) |
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| Emotional functioning (day 90) |
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| Emotional functioning (day 180) |
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| Cognitive functioning (day 28) |
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| Cognitive functioning (day 90) |
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| Cognitive functioning (day 180) |
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| Social functioning (day 28) |
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| Social functioning (day 90) |
|
| Social functioning (day 180) |
|
| Fatigue symptom scale (day 28) |
|
| Fatigue symptom scale (day 90) |
|
| Fatigue symptom scale (day 180) |
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| Nausea and vomiting symptom scale (day 28) |
|
| Nausea and vomiting symptom scale (day 90) |
|
| Nausea and vomiting symptom scale (day 180) |
|
| Pain symptom scale (day 28) |
|
| Pain symptom scale (day 90) |
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| Pain symptom scale (day 180) |
|
| Symptom: Dyspnoea (day 28) |
|
| Symptom: Dyspnoea (day 90) |
|
| Symptom: Dyspnoea (day 180) |
|
| Symptom: Insomnia (day 28) |
|
| Symptom: Insomnia (day 90) |
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| Symptom: Insomnia (day 180) |
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| Symptom: Appetite loss (day 28) |
|
| Symptom: Appetite loss (day 90) |
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| Symptom: Appetite loss (day 180) |
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| Symptom: constipation (day 28) |
|
| Symptom: constipation (day 90) |
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| Symptom: constipation (day 180) |
|
| Symptom: diarrhoea (day 28) |
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| Symptom: diarrhoea (day 90) |
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| Symptom: diarrhoea (day 180) |
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| Symptom: financial difficulties (day 28) |
|
| Symptom: financial difficulties (day 90) |
|
| Symptom: financial difficulties (day 190) |
|