{
    "info": {
        "nct_id": "NCT06470880",
        "official_title": "Circulating Tumour DNA Guided Adaptive BRAF and MEK Inhibitor Therapy",
        "inclusion_criteria": "Healthy volunteers allowed\nMust have minimum age of 18 Years",
        "exclusion_criteria": "",
        "miscellaneous_criteria": "Inclusion Criteria\n\nAt Screening\n\n1. Written and informed consent obtained from participant and agreement of participant to comply with the requirements of the study\n2. Histological confirmation of cutaneous melanoma\n3. ≥ 18 years of age\n4. Stage III un-resectable/ IV disease\n5. Measurable disease on CT (thorax, abdomen and pelvis, ± neck if indicated) and/or PET-CT, and CT or MRI (brain) scan (RECIST v1.1)\n6. BRAF p.V600E/K/R/D mutation confirmed (exact point mutation must be known)\n7. ECOG performance status 0/1/2\n8. Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to the first dose of study drugs\n9. Adequate organ function as defined below:\n\n   i. Haemoglobin ≥ 9 g/dL ii. White blood count ≥ 2 x109/L iii. ANCa ≥ 1.2 x109/L iv. Platelet count ≥ 75 x109/L v. Albumin ≥ 2.5 g/dL vi. Total bilirubinb ≤ 1.5 x ULNa vii. ASTa or ALTa ≤ 3 x ULNa viii. Calculated creatinine clearance ≥ 30ml/min\n10. Women of childbearing potential participating in the study (WOCBP see Appendix B for definition) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study drug.\n11. WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs plus at least 28 days following last dose of drug (either encorafenib or binimetinib), (see Appendix B).\n12. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment plus 90 days (duration of sperm turnover) from last dose of drug (either encorafenib or binimetinib), (see Appendix B).\n\n    At randomisation:\n13. Left Ventricular Ejection fraction (LVEF) ≥ 50% or ≥LLNa by ECHO\n14. BRAF ctDNA TAB level of ≥15 copies/ml of plasma\n\nExclusion Criteria\n\n1. Prior systemic targeted BRAF/MEKi therapy for stage IV (metastatic) melanoma (treatment for stage III allowed as long as RFS ≥26 weeks following discontinuation of drugs)\n2. BRAF wild-type malignant melanoma\n3. Metastasis to the brain or leptomeninges\n4. Any contraindication to treatment with encorafenib or binimetinib as per the local Summary of Product Characteristics\n5. Hypersensitivity to the active substance or to any of the excipients of encorafenib or binimetinib\n6. Current use of a prohibited medication as described in Section 8.9\n7. History of another malignancy. Exception: Patients who have been disease-free for 3 years, (i.e. patients with second malignancies that are indolent or definitively treated at least 3 years ago), curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS); stage 1, grade I endometrial carcinoma, or patients with a history of completely resected non-melanoma skin cancer. No additional therapy should be required whilst the patient is on study\n8. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the patient's safety, obtaining informed consent, or compliance with study procedures\n9. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection\n10. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption\n11. Child Pugh B or C liver disease\n12. Coronary syndromes (including myocardial infarction within 6 months or unstable angina)\n13. A history or evidence of current ≥ Class II congestive heart failure as defined by the NYHA guidelines with an ejection fraction of <50% (see appendix C)\n14. Treatment refractory hypertension defined as a blood pressure of systolic >150 mmHg and/or diastolic >95 mm Hg on >3 occasions which cannot be controlled by anti-hypertensive therapy\n15. Uncorrectable electrolyte abnormalities > CTCAE v5 Grade 1 (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia), long QT syndrome (baseline 1 QTC interval ≥ 480msec) or taking medicinal products known to prolong the QT interval\n16. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes)\n17. Females who are pregnant or breast-feeding and are not able to stop breast-feeding prior to first dose of study drugs (see section 7.5)\n18. Prisoners or patients who are involuntarily incarcerated\n19. Patients who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness"
    },
    "inclusion_lines": [
        {
            "line": "Healthy volunteers allowed",
            "criterions": [
                {
                    "exact_snippets": "Healthy volunteers allowed",
                    "criterion": "volunteer health status",
                    "requirements": [
                        {
                            "requirement_type": "status",
                            "expected_value": "healthy"
                        }
                    ]
                }
            ]
        },
        {
            "line": "Must have minimum age of 18 Years",
            "criterions": [
                {
                    "exact_snippets": "minimum age of 18 Years",
                    "criterion": "age",
                    "requirements": [
                        {
                            "requirement_type": "minimum",
                            "expected_value": {
                                "operator": ">=",
                                "value": 18,
                                "unit": "Years"
                            }
                        }
                    ]
                }
            ]
        }
    ],
    "exclusion_lines": [],
    "miscellaneous_lines": [
        {
            "line": "1. Written and informed consent obtained from participant and agreement of participant to comply with the requirements of the study",
            "criterions": [
                {
                    "exact_snippets": "Written and informed consent obtained from participant",
                    "criterion": "informed consent",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "agreement of participant to comply with the requirements of the study",
                    "criterion": "agreement to comply with study requirements",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. Histological confirmation of cutaneous melanoma",
            "criterions": [
                {
                    "exact_snippets": "Histological confirmation of cutaneous melanoma",
                    "criterion": "cutaneous melanoma",
                    "requirements": [
                        {
                            "requirement_type": "confirmation method",
                            "expected_value": "histological"
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. ≥ 18 years of age",
            "criterions": [
                {
                    "exact_snippets": "≥ 18 years of age",
                    "criterion": "age",
                    "requirements": [
                        {
                            "requirement_type": "N/A",
                            "expected_value": {
                                "operator": ">=",
                                "value": 18,
                                "unit": "years"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. Stage III un-resectable/ IV disease",
            "criterions": [
                {
                    "exact_snippets": "Stage III un-resectable",
                    "criterion": "disease stage",
                    "requirements": [
                        {
                            "requirement_type": "stage",
                            "expected_value": "III"
                        },
                        {
                            "requirement_type": "resectability",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "IV disease",
                    "criterion": "disease stage",
                    "requirements": [
                        {
                            "requirement_type": "stage",
                            "expected_value": "IV"
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. Measurable disease on CT (thorax, abdomen and pelvis, ± neck if indicated) and/or PET-CT, and CT or MRI (brain) scan (RECIST v1.1)",
            "criterions": [
                {
                    "exact_snippets": "Measurable disease on CT (thorax, abdomen and pelvis, ± neck if indicated) and/or PET-CT, and CT or MRI (brain) scan (RECIST v1.1)",
                    "criterion": "measurable disease",
                    "requirements": [
                        {
                            "requirement_type": "imaging modality",
                            "expected_value": [
                                "CT",
                                "PET-CT",
                                "MRI"
                            ]
                        },
                        {
                            "requirement_type": "location",
                            "expected_value": [
                                "thorax",
                                "abdomen",
                                "pelvis",
                                "neck",
                                "brain"
                            ]
                        },
                        {
                            "requirement_type": "criteria",
                            "expected_value": "RECIST v1.1"
                        }
                    ]
                }
            ]
        },
        {
            "line": "6. BRAF p.V600E/K/R/D mutation confirmed (exact point mutation must be known)",
            "criterions": [
                {
                    "exact_snippets": "BRAF p.V600E/K/R/D mutation confirmed (exact point mutation must be known)",
                    "criterion": "BRAF mutation",
                    "requirements": [
                        {
                            "requirement_type": "mutation type",
                            "expected_value": [
                                "p.V600E",
                                "p.V600K",
                                "p.V600R",
                                "p.V600D"
                            ]
                        },
                        {
                            "requirement_type": "confirmation",
                            "expected_value": true
                        },
                        {
                            "requirement_type": "specificity",
                            "expected_value": "exact point mutation must be known"
                        }
                    ]
                }
            ]
        },
        {
            "line": "7. ECOG performance status 0/1/2",
            "criterions": [
                {
                    "exact_snippets": "ECOG performance status 0/1/2",
                    "criterion": "ECOG performance status",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": [
                                "0",
                                "1",
                                "2"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "8. Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to the first dose of study drugs",
            "criterions": [
                {
                    "exact_snippets": "Prior radiotherapy or radiosurgery must have been completed at least 2 weeks prior to the first dose of study drugs",
                    "criterion": "prior radiotherapy or radiosurgery",
                    "requirements": [
                        {
                            "requirement_type": "completion time",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2,
                                "unit": "weeks"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "9. Adequate organ function as defined below:",
            "criterions": [
                {
                    "exact_snippets": "Adequate organ function",
                    "criterion": "organ function",
                    "requirements": [
                        {
                            "requirement_type": "adequacy",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "i. Haemoglobin ≥ 9 g/dL ii. White blood count ≥ 2 x109/L iii. ANCa ≥ 1.2 x109/L iv. Platelet count ≥ 75 x109/L v. Albumin ≥ 2.5 g/dL vi. Total bilirubinb ≤ 1.5 x ULNa vii. ASTa or ALTa ≤ 3 x ULNa viii. Calculated creatinine clearance ≥ 30ml/min",
            "criterions": [
                {
                    "exact_snippets": "Haemoglobin ≥ 9 g/dL",
                    "criterion": "haemoglobin",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": ">=",
                                "value": 9,
                                "unit": "g/dL"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "White blood count ≥ 2 x109/L",
                    "criterion": "white blood count",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2,
                                "unit": "x109/L"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "ANCa ≥ 1.2 x109/L",
                    "criterion": "ANCa",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": ">=",
                                "value": 1.2,
                                "unit": "x109/L"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Platelet count ≥ 75 x109/L",
                    "criterion": "platelet count",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": ">=",
                                "value": 75,
                                "unit": "x109/L"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Albumin ≥ 2.5 g/dL",
                    "criterion": "albumin",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": ">=",
                                "value": 2.5,
                                "unit": "g/dL"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Total bilirubinb ≤ 1.5 x ULNa",
                    "criterion": "total bilirubin",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 1.5,
                                "unit": "x ULNa"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "ASTa or ALTa ≤ 3 x ULNa",
                    "criterion": "ASTa or ALTa",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": "<=",
                                "value": 3,
                                "unit": "x ULNa"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Calculated creatinine clearance ≥ 30ml/min",
                    "criterion": "calculated creatinine clearance",
                    "requirements": [
                        {
                            "requirement_type": "level",
                            "expected_value": {
                                "operator": ">=",
                                "value": 30,
                                "unit": "ml/min"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "10. Women of childbearing potential participating in the study (WOCBP see Appendix B for definition) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study drug.",
            "criterions": [
                {
                    "exact_snippets": "Women of childbearing potential ... must have a negative serum or urine pregnancy test",
                    "criterion": "pregnancy test",
                    "requirements": [
                        {
                            "requirement_type": "result",
                            "expected_value": "negative"
                        }
                    ]
                },
                {
                    "exact_snippets": "minimum sensitivity 25 IU/L or equivalent units of HCG",
                    "criterion": "pregnancy test sensitivity",
                    "requirements": [
                        {
                            "requirement_type": "sensitivity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 25,
                                "unit": "IU/L"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "within 72 hours prior to the start of study drug",
                    "criterion": "timing of pregnancy test",
                    "requirements": [
                        {
                            "requirement_type": "timing",
                            "expected_value": "within 72 hours prior to the start of study drug"
                        }
                    ]
                }
            ]
        },
        {
            "line": "11. WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drugs plus at least 28 days following last dose of drug (either encorafenib or binimetinib), (see Appendix B).",
            "criterions": [
                {
                    "exact_snippets": "WOCBP must agree to follow instructions for method(s) of contraception",
                    "criterion": "contraception agreement",
                    "requirements": [
                        {
                            "requirement_type": "agreement",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "duration of treatment with study drugs plus at least 28 days following last dose of drug",
                    "criterion": "contraception duration",
                    "requirements": [
                        {
                            "requirement_type": "duration",
                            "expected_value": "duration of treatment with study drugs plus at least 28 days following last dose of drug"
                        }
                    ]
                }
            ]
        },
        {
            "line": "12. Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment plus 90 days (duration of sperm turnover) from last dose of drug (either encorafenib or binimetinib), (see Appendix B).",
            "criterions": [
                {
                    "exact_snippets": "Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception",
                    "criterion": "contraception agreement",
                    "requirements": [
                        {
                            "requirement_type": "agreement",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "duration of treatment plus 90 days (duration of sperm turnover) from last dose of drug",
                    "criterion": "contraception duration",
                    "requirements": [
                        {
                            "requirement_type": "duration",
                            "expected_value": "duration of treatment plus 90 days"
                        }
                    ]
                }
            ]
        },
        {
            "line": "13. Left Ventricular Ejection fraction (LVEF) ≥ 50% or ≥LLNa by ECHO",
            "criterions": [
                {
                    "exact_snippets": "Left Ventricular Ejection fraction (LVEF) ≥ 50%",
                    "criterion": "Left Ventricular Ejection fraction (LVEF)",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": {
                                "operator": ">=",
                                "value": 50,
                                "unit": "%"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "Left Ventricular Ejection fraction (LVEF) ... ≥LLNa by ECHO",
                    "criterion": "Left Ventricular Ejection fraction (LVEF)",
                    "requirements": [
                        {
                            "requirement_type": "value",
                            "expected_value": ">=LLNa by ECHO"
                        }
                    ]
                }
            ]
        },
        {
            "line": "14. BRAF ctDNA TAB level of ≥15 copies/ml of plasma",
            "criterions": [
                {
                    "exact_snippets": "BRAF ctDNA TAB level of ≥15 copies/ml of plasma",
                    "criterion": "BRAF ctDNA TAB level",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">=",
                                "value": 15,
                                "unit": "copies/ml of plasma"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "1. Prior systemic targeted BRAF/MEKi therapy for stage IV (metastatic) melanoma (treatment for stage III allowed as long as RFS ≥26 weeks following discontinuation of drugs)",
            "criterions": [
                {
                    "exact_snippets": "Prior systemic targeted BRAF/MEKi therapy for stage IV (metastatic) melanoma",
                    "criterion": "prior systemic targeted BRAF/MEKi therapy",
                    "requirements": [
                        {
                            "requirement_type": "stage",
                            "expected_value": "IV (metastatic) melanoma"
                        }
                    ]
                },
                {
                    "exact_snippets": "treatment for stage III allowed as long as RFS ≥26 weeks following discontinuation of drugs",
                    "criterion": "treatment for stage III",
                    "requirements": [
                        {
                            "requirement_type": "RFS following discontinuation of drugs",
                            "expected_value": {
                                "operator": ">=",
                                "value": 26,
                                "unit": "weeks"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "2. BRAF wild-type malignant melanoma",
            "criterions": [
                {
                    "exact_snippets": "BRAF wild-type malignant melanoma",
                    "criterion": "BRAF mutation status",
                    "requirements": [
                        {
                            "requirement_type": "mutation type",
                            "expected_value": "wild-type"
                        }
                    ]
                },
                {
                    "exact_snippets": "BRAF wild-type malignant melanoma",
                    "criterion": "malignant melanoma",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "3. Metastasis to the brain or leptomeninges",
            "criterions": [
                {
                    "exact_snippets": "Metastasis to the brain",
                    "criterion": "brain metastasis",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Metastasis to the ... leptomeninges",
                    "criterion": "leptomeningeal metastasis",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "4. Any contraindication to treatment with encorafenib or binimetinib as per the local Summary of Product Characteristics",
            "criterions": [
                {
                    "exact_snippets": "Any contraindication to treatment with encorafenib",
                    "criterion": "contraindication to encorafenib",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Any contraindication to treatment with ... binimetinib",
                    "criterion": "contraindication to binimetinib",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "5. Hypersensitivity to the active substance or to any of the excipients of encorafenib or binimetinib",
            "criterions": [
                {
                    "exact_snippets": "Hypersensitivity to the active substance or to any of the excipients of encorafenib",
                    "criterion": "hypersensitivity to encorafenib",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "Hypersensitivity to the active substance or to any of the excipients of ... binimetinib",
                    "criterion": "hypersensitivity to binimetinib",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "6. Current use of a prohibited medication as described in Section 8.9",
            "criterions": [
                {
                    "exact_snippets": "Current use of a prohibited medication",
                    "criterion": "prohibited medication use",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "7. History of another malignancy. Exception: Patients who have been disease-free for 3 years, (i.e. patients with second malignancies that are indolent or definitively treated at least 3 years ago), curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS); stage 1, grade I endometrial carcinoma, or patients with a history of completely resected non-melanoma skin cancer. No additional therapy should be required whilst the patient is on study",
            "criterions": [
                {
                    "exact_snippets": "History of another malignancy",
                    "criterion": "history of another malignancy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "disease-free for 3 years",
                    "criterion": "disease-free status",
                    "requirements": [
                        {
                            "requirement_type": "duration",
                            "expected_value": {
                                "operator": ">=",
                                "value": 3,
                                "unit": "years"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "curatively treated in situ cancer of the cervix",
                    "criterion": "in situ cancer of the cervix",
                    "requirements": [
                        {
                            "requirement_type": "treatment status",
                            "expected_value": "curatively treated"
                        }
                    ]
                },
                {
                    "exact_snippets": "ductal carcinoma in situ (DCIS)",
                    "criterion": "ductal carcinoma in situ (DCIS)",
                    "requirements": [
                        {
                            "requirement_type": "treatment status",
                            "expected_value": "curatively treated"
                        }
                    ]
                },
                {
                    "exact_snippets": "stage 1, grade I endometrial carcinoma",
                    "criterion": "endometrial carcinoma",
                    "requirements": [
                        {
                            "requirement_type": "stage",
                            "expected_value": "1"
                        },
                        {
                            "requirement_type": "grade",
                            "expected_value": "I"
                        }
                    ]
                },
                {
                    "exact_snippets": "history of completely resected non-melanoma skin cancer",
                    "criterion": "non-melanoma skin cancer",
                    "requirements": [
                        {
                            "requirement_type": "resection status",
                            "expected_value": "completely resected"
                        }
                    ]
                },
                {
                    "exact_snippets": "No additional therapy should be required whilst the patient is on study",
                    "criterion": "additional therapy requirement",
                    "requirements": [
                        {
                            "requirement_type": "requirement",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "8. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the patient's safety, obtaining informed consent, or compliance with study procedures",
            "criterions": [
                {
                    "exact_snippets": "serious or unstable pre-existing medical conditions",
                    "criterion": "pre-existing medical conditions",
                    "requirements": [
                        {
                            "requirement_type": "severity/stability",
                            "expected_value": "serious or unstable"
                        }
                    ]
                },
                {
                    "exact_snippets": "psychiatric disorders",
                    "criterion": "psychiatric disorders",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "other conditions that could interfere with the patient's safety, obtaining informed consent, or compliance with study procedures",
                    "criterion": "conditions interfering with study participation",
                    "requirements": [
                        {
                            "requirement_type": "interference",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "9. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection",
            "criterions": [
                {
                    "exact_snippets": "Known Human Immunodeficiency Virus (HIV) ... infection",
                    "criterion": "Human Immunodeficiency Virus (HIV) infection",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Hepatitis B Virus (HBV) ... infection",
                    "criterion": "Hepatitis B Virus (HBV) infection",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "Hepatitis C Virus (HCV) infection",
                    "criterion": "Hepatitis C Virus (HCV) infection",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "10. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption",
            "criterions": [
                {
                    "exact_snippets": "rare hereditary problems of galactose intolerance",
                    "criterion": "galactose intolerance",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "rare hereditary problems of ... total lactase deficiency",
                    "criterion": "total lactase deficiency",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "rare hereditary problems of ... glucose-galactose malabsorption",
                    "criterion": "glucose-galactose malabsorption",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "11. Child Pugh B or C liver disease",
            "criterions": [
                {
                    "exact_snippets": "Child Pugh B or C liver disease",
                    "criterion": "Child Pugh liver disease",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": [
                                "B",
                                "C"
                            ]
                        }
                    ]
                }
            ]
        },
        {
            "line": "12. Coronary syndromes (including myocardial infarction within 6 months or unstable angina)",
            "criterions": [
                {
                    "exact_snippets": "Coronary syndromes (including myocardial infarction within 6 months or unstable angina)",
                    "criterion": "coronary syndromes",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "myocardial infarction within 6 months",
                    "criterion": "myocardial infarction",
                    "requirements": [
                        {
                            "requirement_type": "time since event",
                            "expected_value": {
                                "operator": "<=",
                                "value": 6,
                                "unit": "months"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "unstable angina",
                    "criterion": "unstable angina",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "13. A history or evidence of current ≥ Class II congestive heart failure as defined by the NYHA guidelines with an ejection fraction of <50% (see appendix C)",
            "criterions": [
                {
                    "exact_snippets": "A history or evidence of current ≥ Class II congestive heart failure as defined by the NYHA guidelines",
                    "criterion": "congestive heart failure",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": ">= Class II"
                        }
                    ]
                },
                {
                    "exact_snippets": "ejection fraction of <50%",
                    "criterion": "ejection fraction",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": "<",
                                "value": 50,
                                "unit": "%"
                            }
                        }
                    ]
                }
            ]
        },
        {
            "line": "14. Treatment refractory hypertension defined as a blood pressure of systolic >150 mmHg and/or diastolic >95 mm Hg on >3 occasions which cannot be controlled by anti-hypertensive therapy",
            "criterions": [
                {
                    "exact_snippets": "Treatment refractory hypertension defined as a blood pressure of systolic >150 mmHg",
                    "criterion": "systolic blood pressure",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">",
                                "value": 150,
                                "unit": "mmHg"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "diastolic >95 mm Hg",
                    "criterion": "diastolic blood pressure",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">",
                                "value": 95,
                                "unit": "mm Hg"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "on >3 occasions",
                    "criterion": "blood pressure measurement occasions",
                    "requirements": [
                        {
                            "requirement_type": "quantity",
                            "expected_value": {
                                "operator": ">",
                                "value": 3,
                                "unit": "occasions"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "cannot be controlled by anti-hypertensive therapy",
                    "criterion": "control by anti-hypertensive therapy",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "15. Uncorrectable electrolyte abnormalities > CTCAE v5 Grade 1 (e.g. hypokalaemia, hypomagnesaemia, hypocalcaemia), long QT syndrome (baseline 1 QTC interval ≥ 480msec) or taking medicinal products known to prolong the QT interval",
            "criterions": [
                {
                    "exact_snippets": "Uncorrectable electrolyte abnormalities > CTCAE v5 Grade 1",
                    "criterion": "electrolyte abnormalities",
                    "requirements": [
                        {
                            "requirement_type": "severity",
                            "expected_value": {
                                "operator": ">",
                                "value": 1,
                                "unit": "CTCAE v5 Grade"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "long QT syndrome",
                    "criterion": "long QT syndrome",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "baseline 1 QTC interval ≥ 480msec",
                    "criterion": "QTC interval",
                    "requirements": [
                        {
                            "requirement_type": "length",
                            "expected_value": {
                                "operator": ">=",
                                "value": 480,
                                "unit": "msec"
                            }
                        }
                    ]
                },
                {
                    "exact_snippets": "taking medicinal products known to prolong the QT interval",
                    "criterion": "medicinal products known to prolong the QT interval",
                    "requirements": [
                        {
                            "requirement_type": "usage",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "16. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes)",
            "criterions": [
                {
                    "exact_snippets": "history or current evidence/risk of retinal vein occlusion (RVO)",
                    "criterion": "retinal vein occlusion (RVO)",
                    "requirements": [
                        {
                            "requirement_type": "history or current evidence/risk",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "history or current evidence/risk of ... central serous retinopathy (CSR)",
                    "criterion": "central serous retinopathy (CSR)",
                    "requirements": [
                        {
                            "requirement_type": "history or current evidence/risk",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "presence of predisposing factors to RVO or CSR",
                    "criterion": "predisposing factors to RVO or CSR",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": true
                        }
                    ]
                },
                {
                    "exact_snippets": "uncontrolled glaucoma",
                    "criterion": "glaucoma",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": "uncontrolled"
                        }
                    ]
                },
                {
                    "exact_snippets": "ocular hypertension",
                    "criterion": "ocular hypertension",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": "uncontrolled"
                        }
                    ]
                },
                {
                    "exact_snippets": "uncontrolled hypertension",
                    "criterion": "hypertension",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": "uncontrolled"
                        }
                    ]
                },
                {
                    "exact_snippets": "uncontrolled diabetes mellitus",
                    "criterion": "diabetes mellitus",
                    "requirements": [
                        {
                            "requirement_type": "control",
                            "expected_value": "uncontrolled"
                        }
                    ]
                },
                {
                    "exact_snippets": "history of hyperviscosity or hypercoagulability syndromes",
                    "criterion": "hyperviscosity or hypercoagulability syndromes",
                    "requirements": [
                        {
                            "requirement_type": "history",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "17. Females who are pregnant or breast-feeding and are not able to stop breast-feeding prior to first dose of study drugs (see section 7.5)",
            "criterions": [
                {
                    "exact_snippets": "Females who are pregnant",
                    "criterion": "pregnancy",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "breast-feeding and are not able to stop breast-feeding prior to first dose of study drugs",
                    "criterion": "breast-feeding",
                    "requirements": [
                        {
                            "requirement_type": "ability to stop",
                            "expected_value": true
                        }
                    ]
                }
            ]
        },
        {
            "line": "18. Prisoners or patients who are involuntarily incarcerated",
            "criterions": [
                {
                    "exact_snippets": "Prisoners",
                    "criterion": "prisoner status",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                },
                {
                    "exact_snippets": "patients who are involuntarily incarcerated",
                    "criterion": "involuntary incarceration",
                    "requirements": [
                        {
                            "requirement_type": "presence",
                            "expected_value": false
                        }
                    ]
                }
            ]
        },
        {
            "line": "19. Patients who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness",
            "criterions": [
                {
                    "exact_snippets": "compulsorily detained for treatment of ... psychiatric ... illness",
                    "criterion": "psychiatric illness",
                    "requirements": [
                        {
                            "requirement_type": "detention status",
                            "expected_value": "compulsorily detained for treatment"
                        }
                    ]
                },
                {
                    "exact_snippets": "compulsorily detained for treatment of ... physical (e.g., infectious disease) illness",
                    "criterion": "physical illness",
                    "requirements": [
                        {
                            "requirement_type": "detention status",
                            "expected_value": "compulsorily detained for treatment"
                        }
                    ]
                }
            ]
        }
    ],
    "failed_inclusion": [],
    "failed_exclusion": [],
    "failed_miscellaneous": [
        {
            "line": "Inclusion Criteria",
            "criterions": []
        },
        {
            "line": "At Screening",
            "criterions": []
        },
        {
            "line": "At randomisation:",
            "criterions": []
        },
        {
            "line": "Exclusion Criteria",
            "criterions": []
        }
    ]
}