An uncontrolled, open label pilot-study assessing the efficacy in reducing bleeding severity, and the safety of oral tacrolimus in patients with hereditary hemorrhagic telangiectasia

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant inherited
disease, characterized by multisystemic abnormal vasculature [Govani and
Shovlin, 2009]. The prevalence of HHT is approximately 1 in 8000 individuals
with regional differences according to geographic location [Guttmacher et al.,
1995; Dakeishi et al., 2002; Westermann et al., 2003]. Clinical features of HHT
consist of the presence of recurrent spontaneous epistaxis (nosebleeds),
mucocutaneous telangiectasias and visceral arteriovenous malformations (AVMs)
usually located in the lungs, liver and brain. The quality of life of HHT
patients is frequently severely affected by the severe epistaxis [Geirdal et
al., 2014; Geisthoff et al., 2012; Zarabeitia et al., 2017]. The treatment of
epistaxis in HHT patients is challenging because standard epistaxis management
such as cautery rarely has a durable effect [Shah et al., 2002]. In cases of
severe epistaxis, invasive surgical measures such as laser photocoagulation,
septodermoplasty and complete nostril closure (Young*s procedure) and systemic
medical treatment are used in an attempt to reduce epistaxis severity [Garg et
al., 2014; Chin et al., 2016]. Endoscopic treatment with argon plasma
coagulation (APC) has demonstrated to reduce transfusion needs in HHT patients
with severe gastrointestinal bleeding, although the results may be less
satisfactory as in the non-HHT population [Sargeant et al., 1993]. Apart from
endoscopic treatment options, several medical treatments have been postulated
including hormonal therapy, antifibrinolytics, and thalidomide [Faughnan et
al., 2011]. Unfortunately, to date, none are recommended in the current HHT
guidelines due to lack of evidence [Faughnan et al., 2011]. Bleeding in HHT is
a chronic problem that requires continuous monitoring and treatment. Even with
treatment, severe epistaxis and/or gastrointestinal bleeding may result in
iron-deficient anemia which sometimes requires intravenous iron treatment or
blood transfusions.
HHT is caused by disruption of the transforming growth factor (TGF) * signaling
pathway due to mutations in the genes encoding for Endoglin (ENG, chromosome
9q34), activin A receptor type II-like 1 (ACVRL1/ALK1, chromosome 12q13) or
Mothers against decapentaplegic homolog 4 (SMAD4, chromosome 18q21) which cause
HHT type I (OMIM #187300), HHT type II (OMIM #600376), and the combined
Juvenile Polyposis/HHT syndrome (OMIM #175050), respectively [McAllister et
al., 1994; Johnson et al., 1996; Gallione et al., 2004]. These genes in the TGF
* pathway are highly expressed in vascular endothelial cells and play an
important role in angiogenesis and vascular function. Haploinsufficiency in ENG
and ACVRL1 is recognized at the underlying cause of HHT [Ardelean and Letarte,
2015]. In addition, evidence exists that elevated levels of vascular
endothelial growth factor (VEGF) also interplay in the pathological mechanism
of the HHT phenotype. This is supported by the fact that increased plasma
levels of VEGF have been found in HHT patients [Cirulli et al., 2003; Sadick et
al., 2005].
Tacrolimus, an immunosuppressive drug, used for prevention of organ transplant
rejection, has recently been investigated as therapeutic option for HHT. In
Vitro, tacrolimus has shown to increase ALK1 and ENG signaling [Albinana et
al., 2011; Ruiz et al., 2017]. Moreover, tacrolimus has shown to inhibit
angiogenesis by anti-VEGF effects [Ardelean and Letarte, 2015; Ruiz et al.,
2017]. In a case-report with a patient suffering from HHT and pulmonary
arterial hypertension, tacrolimus treatment reduced the epistaxis significantly
and decreased fatigue symptoms [Sommer et al., 2019]. In the Netherlands, 3 HHT
patients are currently being treated with tacrolimus as last resort option (of
which 2 in our HHT center). An adult female, received tacrolimus for her
high-output heart failure caused by her liver AVMs, another adult female for
severe epistaxis and a child suffering from melena due to severe
gastrointestional telangiectasia requiring blood transfusions have been
treated. The complaints in all three cases have significantly reduced in
severity. The target value of tacrolimus for HHT (between 2-3 ng/L) is lower
compared to use in organ transplant recipients (for example lung transplant
recipients: 5-15 ng/L). In current HHT research, tacrolimus has gained a lot of
interest and the first trial with nasal tacrolimus ointment for severe
epistaxis has recently been completed (NCT03152019) with fairly good results as
presented on the international HHT conference 2019. The lack of good
alternatives for severe bleeding treatment, and current data concerning HHT and
tacrolimus treatment are reason enough to investigate this treatment further.
In addition, the expected side-effects of tacrolimus are much less because much
lower serum levels of tacrolimus have shown significantly positive effects on
epistaxis than are needed for organ transplant recipients. Therefore, we
designed a non-randomized, open label, pilot-study to investigate the effects
of oral tacrolimus on bleeding severity in HHT patients.

Severe bleeding in HHT is a chronic problem that requires continuous monitoring
and treatment. For severe cases, with daily epistaxis or iron infusion and red
blood cell transfusion dependent patients, systemic treatment with thalidomide
or bevacizumab are the last resort options to treat the severe anemia
[Dupuis-Girod et al., 2012; Invernizzi et al., 2015]. However, these options
are not ideal. The severe side-effects of thalidomide such as severe drowsiness
and peripheral polyneuropathy are reason enough to stop therapy. A study
performed in the St. Antonius Hospital showed that only a minority of the HHT
patients continued taking thalidomide due to severe side-effects despite strong
reduction in epistaxis severity [Hosman et al., 2015]. Bevacizumab has been
demonstrated to be effective, however the intravenous administration and high
costs make the drug as first choice less attractive [Bose et al., 2009;
Dupuis-Girod et al., 2012]. So, the warrant for new, affordable and safe drugs
is still present for the treatment of severe bleeding in HHT. Tacrolimus has
shown promising results in vitro and in vivo. Tacrolimus could therefore
potentially be a good alternative for thalidomide and bevacizumab in the
treatment of epistaxis and/or gastrointestinal bleeding in HHT patients.

Study hypothesis
The primary study hypothesis states that oral treatment with tacrolimus will
reduce the bleeding severity in HHT.

Research question and primary outcome
What is the effect of oral tacrolimus treatment on hemoglobin levels in HHT
patients with severe bleeding from epistaxis and/or gastrointestinal bleeding
with the need for iron treatment and/or blood transfusions despite extensive
local treatment?

Secondary outcome(s)
* The epistaxis severity score (ESS)
* Frequency and severity of epistaxis measured with epistaxis diary in HHT
* Difference in monthly epistaxis duration and frequency after treatment
compared to baseline.
* Difference in the mean hemoglobin (Hb) and ferritin levels in HHT patients
with epistaxis.
* Difference in quality of life in HHT patients with epistaxis following
treatment.
* Effects of tacrolimus on other HHT associated symptoms such as
gastrointestinal blood loss and presence of telangiectases.
* Safety, side-effects and (serious) adverse events of oral tacrolimus in HHT
patients with epistaxis.
* Long term efficacy at 1 and 3 months after tacrolimus treatment on severity
of epistaxis.

General description
An open label, single-center, uncontrolled pilot-study with 20 HHT patients
with severe bleeding will be performed. Patients will receive standard care for
epistaxis and/or gastrointestinal bleeding and once daily tacrolimus (Advagraf®
met gereguleerde afgifte (MGA)) for 20 weeks.

Duration of the trial
The duration of the trial will be 24 weeks. The first four weeks patients will
record their epistaxis severity in a diary, followed by 20 weeks treatment.
Following the trial, tacrolimus will be stopped and patients will be followed
up by the researcher to investigate the long-term efficacy at 1 and 3 months.
If bleeding will reoccur, patients are allowed to restart tacrolimus treatment
and the patients will be monitored by the treating pulmonologists as well of
the St. Antonius Hospital.

Participating center(s)
St. Antonius Hospital, Nieuwegein, department of pulmonology, cardiology,
gastroenterology and department of Ear, Nose, and Throat (ENT).

Study timeline
* Study start: November 2019.
* Recruitment end: March 2020.
* Study end: June 2020.
* Completion of Clinical Study Report (CSR): July 2020.
* Publication date: November 2020.

Patients will receive once daily oral tacrolimus (Advagraf® MGA) for 20 weeks
with a target value of 2-3 *g/L tacrolimus. The initial dose will be 1 mg daily
of tacrolimus. The dose of tacrolimus will be increased or decreased based on
the target value (with steps of 0.5 * 1 mg per week). The estimated required
dose needed to acquire the tacrolimus target value of 2-3 *g/L is 3-5 mg per
day. The target value is based on a case-report with tacrolimus and HHT, and 3
patients currently being treated with tacrolimus for HHT related symptoms
[Sommer et al., 2019].

The burden consist of 4 extra visits, several blood samples, recording an
epistaxis diary and filling in questionnaires (SF*36 and MFI-20). There is a
risk for the known side*effects of the tacrolimus, although much lower than
reported in the literature due to lower target value required for beneficial
effects on HHT symptoms. The potential benefit for participating patients is
that tacrolimus may reduce the severity of bleeding.