1. Introduction

           1.1 Background

           Due to the genetic background of the disease, every single neuroendocrine cell of the
           pancreas is a potential progenitor of neuroendocrine tumors (NETs). More than 90% of
           patients with multiple endocrine neoplasia type 1 (MEN1) develop multiple pancreatic
           neuroendocrine tumors (pNETs) "viewable" by transgastric endosonography and/or cross
           sectional and/or functional imaging. These tumors are the most common cause for
           premature death in MEN1 (1, 2).

           While functioning pNETs are to be treated to reduce or cure hormonal excess, the
           strategies of addressing non-functioning (NF) pNETs are under discussion. Treatment
           ranges from "watchful waiting" to subtotal or total pancreatectomy (3-6). The latter may
           prove to be an "overtreatment" resulting in diabetic metabolic status and subsequently
           in general long-term complications.

           Somatostatin analogs (SAs) have shown promising results with regard to progression-free
           survival in patients with metastatic NETs of the midgut (9-11).

           As shown recently in a retrospective study of 40 patients with early-stage MEN1
           duodeno-pancreatic NETs, treatment with SAs was safe and effective, resulting in
           long-time suppression of tumor and hormonal activity and 10% objective response. The
           authors suggest to start therapy with SAs early on in patients with MEN1-related NETs
           (12). Apart from this clinical study, there is one case report on SAs for MEN-1-related
           insulinoma (13).

           MEN1 is an orphan disease (ORPHA652).

        2. Rationale and objectives

           In this prospective, randomized observation study, the benefits of subcutaneous
           application of somatostatin analogs (SAs) every 28 days (group 1) will be compared to no
           treatment (group 2). It has not been proven if the beneficial effects of SAs shown in
           advanced disease are also applicable to patients with early stage (≤20mm) pancreatic
           neuroendocrine tumors in MEN1. "Watch and wait" without medical treatment is the
           standard approach for MEN1 patients in this early stage of pancreatic disease. We
           hypothesize that SAs can decelerate tumor progression (according to our outcome
           parameters).

        3. Study design

      3.1 Design

      Prospective, randomized, controlled, observation trial

      3.2 Study population

      Patients with proven MEN 1 (see eligibility criteria) will be recruited after discussing
      her/his individual clinical situation in the interdisciplinary tumor board.

      The listed examinations and tests will be carried out in each patient before the first day of
      study participation:

        -  Medical history and physical examination

        -  Height and weight

        -  Biochemical parameters (chromogranin A [CgA] level)

      3.3 Description of study days

      The patients will be evaluated in six-monthly intervals biochemically and radiologically
      (according to the protocol below).

      3.4 Withdrawal and replacement of subjects

      Patients will be withdrawn under the following circumstances:

        -  At their own request

        -  If the investigators feel it would not be in the best interests of the patient to
           continue.

      In all cases, the reasons why study subjects were withdrawn will be recorded in detail in the
      case report forms (CRFs) and in the subjects' medical records. Should the study be
      discontinued prematurely, all study materials (completed, partially completed and empty CRFs)
      will be retained.

      4 Methods of evaluation

      Functional imaging (DOTA-conjugated peptide PET-CT or MRI) will be performed and venous blood
      samples will be drawn as baseline evaluation for general laboratory tests and Chromogranin A
      (CgA).

      4.1 Imaging modalities

      DOTA-conjugated peptide PET-CT or MRI will be acquired on baseline and after 12, 24, 36, 48
      and 60 months

      Radiological interim assessments will be performed by MRI at 6, 18, 30, 42 and 54 months.

      4.2 Laboratory parameters

      A venous blood sample will be drawn at each assessment (baseline, 6, 12, 18, 24, 30, 36, 42,
      48, 54, 60 months). CgA will be determined in each sample, general laboratory tests will be
      made yearly (starting from baseline).

      4.3 Adverse events (AE)

      An AE is any event during a clinical study, including intercurrent illness or accident, which
      impairs the well-being of the patient; it may also take the form of an abnormal laboratory
      value. The term AE does not imply a causal relationship with the study therapy.

      All subjects experiencing AEs - whether considered associated with the study therapy or not -
      will be monitored until symptoms subside and any abnormal laboratory values have returned to
      baseline, or until there is a satisfactory explanation for the changes observed, or until
      death, in which case a full pathologist's report will be supplied, if possible. All findings
      must be reported on an "AE" page in the "case report form (CRF)".

      All AEs are divided into the categories "serious" and "non-serious". This determines the
      procedure that must be used to report/document the AE (see below).

      4.3.1 Definition of serious and non-serious adverse events

      A serious AE is:

        -  Any event that is fatal or life-threatening

        -  Any event that is permanently disabling

        -  Any event that requires hospitalization AEs that do not fall into these categories are
           defined as non-serious.

      4.3.2 Reporting /documentation of adverse events AEs will be collected by spontaneous
      reporting.

      4.3.3 Assessment of severity

      Regardless of the classification of an AE as serious or non-serious (see above), its severity
      must be assessed as mild, moderate or severe, according to medical criteria alone:

      Mild = does not interfere with routine activities, considered as acceptable

      Moderate = interferes with routine activities

      Severe = impossible to perform routine activities, considered as unacceptable

      Further categories: Requires treatment, requires discontinuation of study, or has residual
      effect.

      It should be noted that a severe AE need not be serious in nature and that a serious AE need
      not, by definition, be severe.

      Regardless of severity, all serious AEs must be reported as above.

      4.4 Data handling procedures A CRF will be completed for each patient. Trained personnel will
      check the entries and any errors or inconsistencies will be clarified immediately. The
      results of the pre-study screening examination will be documented in the study master file.

      4.5 Biometric methods

      4.5.1 Biometric methods

        1. Descriptive analysis

        2. After analysis for data distribution, parametric or non-parametric statistical tests
           will be applied

      4.5.2 Biometric methods - adverse events/safety investigations

      All AEs will be properly listed and an appropriate method will be used to summarize the data.

      5 Ethical and legal aspects The study will be performed in accordance with the guidelines of
      the Declaration of Helsinki (1964), including current revisions.

      5.1 Informed consent of the patient Before being admitted to the clinical investigation,
      patients must have consented to participate after the nature, scope and possible consequences
      of the clinical study have been made understandable to them in writing.

      Patients must give a written consent. Their consent will be confirmed by the signature of one
      investigator.

      5.2 Acknowledgment/approval of the study Before the start of the study, the study protocol
      will be submitted to the Ethics Committee of the Medical University of Vienna and, if
      necessary, to the responsible Ethics Committees of the participating centers.

      5.3 Confidentiality

      All subjects' names will be kept secret in the investigators' files. Subjects will be
      identified throughout documentation and evaluation by the number allotted to them at the
      beginning of the study. The subjects will be informed that all study findings will be stored
      and handled in strictest confidence.

      6 Documentation and use of study findings

      6.1 Documentation of study findings All findings collected during the study will be entered
      on the CRFs. CRFs will be completed immediately after the final examination.

      6.2 Use of study findings The findings of this study will be published by the investigators
      in a scientific journal and presented at scientific meetings. The manuscript will be
      circulated to all co-investigators before submission.

      7 Protocol amendments If any modifications become necessary or desirable, these will be
      documented in writing; major changes will require the approval of all investigators and the
      Ethics Committee.