Magnetic Resonance Imaging to diagnose endometriosis using Ablavar ®
as contrast agent - a feasibility study

Endometriosis is characterised by the presence of functional endometrial tissue
outside the uterine cavity. It affects 10-15% of women during pre-menopause and
has a big social and professional impact because of its association with
dyspareunia, dysmenorrhea, pelvic pain and subfertility. In addition, the
health costs for endometriosis are as high as $22 billion per year in the US.
Clinically, endometriosis can be peritoneal, ovarian (endometrioma) or
adenomyotic nodules, also called deep invasive lesions, which can infiltrate
different organs in the peritoneal cavity (rectum, bladder, uterus). The
majority of affected patients have stage one disease, i.e. peritoneal.
The diagnosis of endometriosis is currently based on symptoms. However, because
of the large overlap with other gynaecologic, gastro-intestinal and urogenital
disturbances, the correct diagnosis is often made 8-11 years after the patient
has reported the first complaints.
Although endometriomas can be diagnosed by ultrasound and deep invasive lesions
by careful physical examination and MRI, superficial peritoneal endometriosis
cannot be easily diagnosed either at physical examination, or by using
ultrasound or MRI. The gold standard for the detection of peritoneal disease
remains laparoscopy.
Therefore, the development of a non-invasive diagnostic test is a recognised
priority in endometriosis research and is needed to: (i) allow an early
diagnosis, without an invasive procedure like laparoscopy, especially in young
women; (ii) avoid costs and risks of laparoscopic examination; (iii) select
which patients need further invasive evaluation; (iv) allow adequate
pre-operative planning, which is essential for treatment success; (v)
distinguish recurrent disease from post-operative fibrosis, which presents
similar symptoms as endometriosis.
Endometriosis is characterised by vigorous angiogenesis, and we have recently
demonstrated in a pre-clinical study that endometriosis-associated angiogenesis
can be visualised by CE-MRI. Contrarily to the most commonly used gadolinium,
which has shown already little accuracy and a sensitivity lower than 40% in
diagnosing peritoneal endometriosis, we have devised a small-animal-study in
which endometriotic lesions were surgically induced in mice and could be
visualised by CE-MRI using gadovosveset-trsodium (currently marketed under the
name Ablavar ® by Lantheus Medical Imaging). Specifically, distinct dynamics of
contrast inwash and outwash in endometriosis compared to the surrounding
tissues (abdominal wall) was observed and could be used to establish a
diagnostic protocol. Gadovosveset-trsodium is used for angiography in animal
models and in human and it has a high tolerability and a safe profile in humans.

The feasibility of Ablavar ® to detect peritoneal endometriosis in human should
be tested

Primary Objective: test the feasibility of Dynamic-CE-MRI using Ablavar ® as
contrast agent to detect peritoneal endometriosis in women.

Secondary Objective(s): # To assess the image quality of Ablavar ®-enhanced
MRI in comparison to unenhanced MRI;
# To assess the confidence level of diagnosis of Ablavar ®-enhanced MRI in
comparison to laparoscopy (reference standard).

The study is conducted as an open-label, single group feasibility clinical
trial. No control group will be included. The diagnostic results of CE-MRI will
be compared to the diagnosis performed with laparoscopy and histology (standard
reference).
Duration of the study: from January to March 2013.
Setting: 1. Physical examination. Women presenting at the Maastricht University
Medical Centre for symptoms of recurrent endometriosis will be examined by the
gynaecologist. For the present feasibility study, five women with a palpable
superficial nodule at physical examination and prescribed with a laparoscopic
diagnosis/treatment will be asked to participate to the study and eventually
enrolled.
2. Hospitalisation for laparoscopy. Prior to laparoscopy, a conventional T1 and
T2 weighted MRI (routine procedure at our centre) and Ablavar ®-enhanced MRI
will be performed on patients. Digitalised images of the peritoneal cavity will
be made during laparoscopy.
3. Digitalised images of the peritoneal cavity will be scored for the presence
of endometriosis, to be able to relate the laparoscopic presence of
endometriosis to the MRI findings by two radiologists.

Subjects will get an extra MRI sing a contrast agent (Ablavar).

The present study includes MRI and the application of the intravascular
contrast agent Ablavar ®. There are very few risks associated with MRI scans.
The changing radiofrequencies and magnetic fields can theoretically produce
heat, but this is not known to be associated with relevant side effects. The
risk of the injection of MR contrast agents is considered to be low. According
to the Summary of Product Characteristics of Ablavar ®, the most common adverse
drug reactions were pruritus, paresthesia, headache, nausea, vasodilation,
burning sensations and dysgeusia. Most of the undesirable effects were mild to
moderate in intensity. Rare serious adverse events were observed in clinical
trials (coronary artery disease, hyperglycemia, gangrene, chest pain, and
anaphylactoid reaction; see paragraph 5.4).
This study aims at the elaboration of a potentially useful non-invasive MRI
tool to diagnose endometriosis, and it is the promise of this study that the
results will help to establish a non-invasive diagnostic test.
In light of the relatively low rate of side effects and the promise of
developing a safe and non-invasive imaging method for patients with
endometriosis, the benefit-risk ratio for this study is regarded as
favourable. Patients in whom a theoretical risk of Ablavar ®-enhanced MRI
cannot be a priori excluded are not allowed to enter this study (pregnant
women, patients with metal implants, etc.).