E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Gastrointestinal bleeding and epistaxis caused by hereditary hemorrhagic telangiectasia. Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant inherited disease characterized by mucocutaneous telangiectasis. Telangiectasis predominantly observed in the nasal mucosa and gut, and are abnormal, thin walled blood vessel that can easily rupture leading to hemorrhage. |
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E.1.1.1 | Medical condition in easily understood language |
A genetic disorder called Hereditary Hemorrhagic Telangiectasia, also known as Rendu-Osler-Weber syndrome |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10038554 |
E.1.2 | Term | Rendu-Osler-Weber syndrome |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the efficacy and safety of oral tacrolimus in reducing bleeding severity in HHT patients with severe epistaxis and/or gastrointestinal bleeding. The primary objective is to measure the hemoglobin level at the beginning and during the trial. |
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E.2.2 | Secondary objectives of the trial |
As secondary outcomes, reduction in the epistaxis severity score (ESS), quality of life, the safety (side-effects, (s)AEs) of the therapy, and difference in monthly epistaxis duration, epistaxis frequency, the use of iron infusions, blood transfusions, mean ferritin will be evaluated after 20 weeks of therapy compared to the parameters at baseline. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. Oral tacrolimus for epistaxis in hereditary hemorrhagic telangiectasia 2. Oral tacrolimus for gastrointestinal bleeding in hereditary hemorrhagic telangiectasia |
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E.3 | Principal inclusion criteria |
• Patients with HHT: o Definite HHT according to the Curacao criteria (3 positive criteria or more) AND/OR o Genetically confirmed HHT • Suffering from epistaxis at least on average of 4 days per week or documented gastrointestinal teleangiectasis by endoscopy with suspicion of bleeding; • In the last six months suffering from anemia, iron deficiency or use iron treatment or blood transfusions; • Failure or partial failure of local treatment with systemic treatment indicated by ENT specialist or gastroenterologist; • Adult (18 years or older at time of inclusion).
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E.4 | Principal exclusion criteria |
• Hypersensitivity or allergy for tacrolimus • Patients with a severe disease with a life-expectancy <1 year; • Women that are pregnant, nursing, have a pregnancy wish in the study period or who use anticonception inadequately; • Patients currently receiving chemotherapy; • Patients receiving drugs that are contraindicated when using tacrolimus (see chapter 14.1, section G). • Patients who do not understand English or Dutch language sufficiently enough; • Patients who refuse informed consent.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome of this study is the difference in hemoglobin levels at the baseline compared to that at the end of the trial |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary end point will be evaluated at the baseline and at the end of the trial. The difference will be calculated |
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E.5.2 | Secondary end point(s) |
• Difference in monthly epistaxis severity measured with: o Epistaxis severity score (ESS); o Monthly number of episodes; o Monthly duration; o Monthly intensity; o VAS score of epistaxis. • Difference in biochemical blood values: Hb and ferritin. • Differences in required number of blood transfusions and iron infusions. • Difference in quality of life with SF-36 and fatigue complaints (MFI-20) between baseline and end of the study.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
All the secondary end points will be evaluated at the baseline and at the end of the trial. The only exception is the difference in required number of blood transfusions and iron infusions. We will compare the number of required number of blood transfusions and iron infusions during the trial (20 weeks) and to the same period prior to the trial |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |