Rendu Osler Weber (ROW)
Conditions
Interventions
Doses to be studied:
PART I:
• Group 1: 40 mg (higher dose) of VAD044
• Group 2: 30 mg (lower dose) of VAD044
• Group 3: Placebo
Dosage form and route: Oral gelatin capsules
PART II:
Dose to be studi
Sponsors
Vaderis Therapeutics AG
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: PART I 1. Patients aged >=18 years. 2. Able to understand and comply with the requirements for the study, including the epistaxis app completion using a smartphone. 3. Patients with definite diagnosis of HHT by the Curaçao criteria defined as having at least 3 of the following criteria: a. Spontaneous and recurrent epistaxis; b. Multiple telangiectases at characteristic sites: lips, oral cavity, fingers, nose; c. Visceral lesions: GI telangiectasia, pulmonary, hepatic, cerebral or spinal AVMs; d. A first degree relative with HHT according to these criteria. 4. Patients with typically several (>=5) epistaxis per week with some episodes of epistaxis reported to exceed 5 mins duration supported by clinical judgement, and an ESS >4 during the month prior to Screening. 5. Patients with anaemia (haemoglobin levels 40UI/L (as measured once during or before screening);, or (3) have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks before screening. In the case of bilateral oophorectomy alone, female patient is considered of non-childbearing potential only when the reproductive status of the patient has been confirmed by FSH hormone level assessment. 10. Male patients must agree to use two (2) reliable and acceptable methods of contraception with their female partner and refrain from donating sperm throughout the Treatment period until 30 days after last IMP administration (for details on contraception refer to Appendix 6). 11. The patient has given written informed consent, prior to any study-related procedures that are not part of normal medical care. PART II (as in part 1 except for the HHT severity criteria and COVID rules): 1. Completion of Part I of the study, through the End of Study Visit (Visit 12), within the previous 8 months. 2. All adverse events or serious adverse events occurring
Exclusion criteria
Exclusion criteria: PART I: 1. Patients with type 1 diabetes or uncontrolled type II diabetes (insulin or non-insulin dependent). 2. History or current diagnosis of ECG abnormalities indicating significant risk of safety for patients participating in the study such as: a. Concomitant clinically relevant cardiac findings, e.g., sustained ventricular tachycardia, and clinically significant second- or third-degree atrioventricular block without a pacemaker; b. History of familial long QT syndrome or known family history of Torsades de Pointes; c. Resting QTcF >=450 msec (male) or >=460 msec (female); d. Concomitant use of agents known to prolong the QT interval. 3. Grade 2 hypertension untreated (systolic blood pressure >=140 mmHg and/or diastolic blood pressure >=90 mmHg). Note that hypertension should be diagnosed according to standard clinical criteria and isolated blood pressure measurements above these values is not exclusionary. 4. Active COVID-19 infection confirmed by either polymerase chain reaction (PCR) or rapid antigen test. COVID-19 testing is not required for eligibility unless, in the opinion of the investigator, the patient is displaying symptoms concerning for acute COVID-19 infection. Note: The COVID test does not need to be repeated at Screening in case a test was performed in last 72 hours and lab results/data source shared with the site. In case of positive test, a negative test is needed within 2 weeks for the patient to be eligible. If active infection (confirmed by PCR or rapid antigen test) persists after 2 weeks, patients will not be eligible 5. Administration of live attenuated vaccine within 12 weeks of first IMP dose. 6. Administration of other vaccines, excluding COVID-19 and live-attenuated vaccines, within 14 days of first IMP dose. 7. Patients with active uncontrolled infection or known to be serologically positive for human immunodeficiency virus (HIV), hepatitis B (except after vaccination) or hepatitis C infection. 8. Patients with any other severe, progressive, or uncontrolled acute or chronic medical or psychiatric condition or clinical laboratory abnormalities that may increase the risk associated with study participation/treatment or may interfere with interpretation of study results, and, in the Investigator*s opinion, would make the patient inappropriate for entry in this study. 9. History of malignancy of any organ system, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases; with the exception of patients with removal of uncomplicated basal cell carcinoma, who may take part in the study. 10. Presence of ANY of the following laboratory abnormalities: a. Platelets <=100 × 109/L; b. Absolute neutrophil count <=1.5 × 109/L; c. Substantive renal disease (estimated Glomerular Filtration Rate [eGFR] <=60 mL/min/1.73m2 calculated using the MDRD Glomerular Filtration Rate [GFR] equation); d. Abnormal liver function tests such as aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, or serum bilirubin. The Investigator should be guided by the following criteria: ALT, AST, alkaline phosphatase, or serum bilirubin must NOT exceed 1.5 times upper limit of normal (ULN). 11. Any surgical or medical condition which might significantly alter the absorption of the study drug
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary Endpoint PART I: • AEs including SAEs and AEs of special interest (AESIs), physical exams, vital signs, electrocardiograms (ECGs), and safety laboratory parameters. PART II: Open-label part (part II) • AEs including SAEs and AEs of special interest (AESIs), physical exams, vital signs, electrocardiograms (ECGs), and safety laboratory parameters. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary Endpoints PART I: Key Secondary Endpoints: • Monthly* total number of epistaxis events (Week 12); • Monthly* total duration of epistaxis (Week 12); • Monthly* average of flow intensity (Week 12); • Monthly* average of the mod-ESS derived from the epistaxis digital app (Week 12); • Monthly* standard ESS measured at the study visits (Week 12); Other Secondary Endpoints: • Haemoglobin value at Week 12; • Ferritin and transferrin saturation levels at Week 12; • Total elemental iron received from iron infusion and estimated from blood transfusion (Treatment period compared to the 12 weeks preceding the Treatment period); • Total blood transfusion requirements (number of packed red blood cell [PRBC] units transfused during the Treatment period compared to the 12 weeks preceding the Treatment period); • Overall health-related quality of life (QoL) measured using SF-12 standard questionnaire at Week 12; • Monthly* NOSE HHT score (Week 12); • VAD044 PK parameters following repeat administration. • Phosphorylated protein kinase B (pAKT) inhibition levels in blood using PRP assay (subset of patients in selected sites) at Weeks 4, 8, 12 and 20. *Month refers to 28-day period for above endpoint assessments Open-label part (part II) • total number of epistaxis events at Months 1, 3, 6, 9 and 12; • total duration of epistaxis at Months 1, 3, 6, 9 and 12; • average of flow intensity at Months 1, 3, 6, 9 and 12; • mod-ESS derived from the epistaxis digital app at Months 3, 6, 9 and 12; • standard ESS measured at Months 3, 6, 9 and 12; • Haemoglobin value at Months 3, 6, 9 and 12; • Ferritin and transferrin saturation levels at Months 3, 6, 9 and 12; • Total elemental iron received from iron infusion and estimated from blood transfusion during the 12 months treatment duration period; • Total blood transfusion requirements during the 12 months treatment duration period; • Overall health-related quality of life (QoL) measured using SF-12 s | — |
Countries
Netherlands
Outcome results
None listed