Induction of Remission in RA Patients at Low Disease Activity by Additional Infliximab Therapy (Study P04644AM1) (TERMINATED)

Summary: This Phase 3, randomized, open-label, multicenter study in rheumatoid arthritis (RA) patients with low disease activity (Disease Activity Score 28 [DAS28] >2.8 and <3.5) is being conducted to evaluate induction of remission by adding infliximab to pre-existing treatment versus no additional treatment. All subjects eligible for this study, aged >35 to <=65 years, will have a diagnosis of RA according to American College of Rheumatology (ACR) criteria, and will be offered additional treatment with infliximab. Prior to the start of treatment, subjects must be on a stable regimen of disease modifying antirheumatic drugs (DMARDs) for at least 3 months. Subjects will be randomized (1:1) to basic therapy with or without infliximab for a total duration of 38 weeks followed by a follow-up period of up to 6 months. Subjects randomized to basic therapy + infliximab will receive infliximab 3 mg/kg at Weeks 0, 2, 6, 14, 22, 30, and 38. The primary objective of the study is to assess the rate of remission according to DAS 28 (<2.6) at the end of treatment (after 38 weeks). Safety assessments include the incidence of adverse events, serious adverse events, and clinically notable abnormal vital signs and laboratory values.
Inclusion criteria: inclusion criteria:

 Patients aged >35 and <=65 years with a diagnosis of rheumatoid arthritis (RA) according to American College of Rheumatology (ACR) criteria for at least 1 year and no more than 10 years prior to start of therapy; have active disease (Disease Activity Score [DAS] 28 >2.8 and <3.5), with changes in the DAS 28 score <0.6 within the 6 weeks before inclusion; have stable RA basic therapy according to standard criteria for at least 3 months; have a chest X-ray within 1 month prior to first infusion with no evidence of malignancy, infections, or fibrosis; and have screening laboratory test results that meet prespecified criteria. Patient must have at least one swollen joint. Patient must have evidence of erosive disease by x-ray at baseline.

Exclusion criteria: :

 Patients were excluded if they met any of the following criteria:

 Women who are pregnant, nursing, or planning pregnancy within 15 months after screening (i.e., approximately 6 months following last infusion);

 Use of any investigational drug within 1 month prior to screening or within 5 half-lives of the investigational agent, whichever is longer;

 History of any other therapeutic agent targeted at reducing tumor necrosis factor (TNF);

 History of previous administration of infliximab;

 History of receiving human/murine recombinant products or has a known allergy to murine products;

 Serious infection (such as hepatitis, pneumonia or pyelonephritis) in the previous 3 months. Less serious infections (such as acute upper respiratory tract infection [colds] or simple urinary tract infection) need not be considered exclusions at the discretion of the investigator.

 Active tuberculosis (TB) or evidence of latent TB (positive purified protein derivative [PPD] skin test, a history of old or latent TB or chest X-ray without adequate therapy for TB initiated prior to first infusion of study drug), or evidence of an old or latent TB infection without documented adequate therapy. Patients with a current close contact with an individual with active TB and patients who have completed treatment for active TB within the previous 2 years are explicitly excluded from the trial. Patients with a household member who has a history of active pulmonary TB should have had a thorough evaluation for TB prior to study enrollment as recommended by a local infectious disease specialist or published local guidelines of TB control agencies.

 Hepatitis B surface antigen or Hepatitis C (HCV) antibody positive; documented Human Immunodeficiency Virus (HIV) infection;

 Have an opportunistic infection, including but not limited to evidence of active cytomegalovirus, active pneumocystis carinii, aspergillosis, or atypical mycobacterium infection, etc, within the previous 6 months;

 Have current signs or symptoms of severe, progressive or uncontrolled renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, psychiatric, neurologic, or cerebral disease (including demyelinating diseases such as multiple sclerosis);

 Concomitant congestive heart failure >= New York Heart Association (NYHA) II;

 Have a transplanted organ (with the exception of a corneal transplant >3 months prior to screening);

 Fibromyalgia;

 Malignancy within the past 5 years (except for squamous or basal cell carcinoma of the skin that has been treated with no evidence of recurrence);

 History of lymphoproliferative disease including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy of unusual size or location (such as nodes in the posterior triangle of the neck, infraclavicular, epitrochlear, or peri-aortic areas), or splenomegaly; or

 Known recent substance abuse (drug or alcohol).

['infliximab', 'DMARDs (methotrexate; chloroquine; leflunomidum; cyclosporin A; sulfasalazine; OM 89.']


Significance of Peritoneal Washing Cytology Before and After Neoadjuvant Chemotherapy in Patients With Esophagogastric-junction Cancer

Summary: Background:~The prevalence of gastroesophageal-junction cancer (cancer between the distal part of the oesophagus, and proximal part of the stomach/GEJ-cancer) is increasing in Denmark with more than 400 patients per year. The 5-year overall survival is less than 10% for the 2/3 of the patients, which are not considered resectable. Even for the 1/3, which is treated with surgical intervention and neoadjuvant chemotherapy the overall-survival is approximately 30%.~The current Danish intended curative treatment consists of esophagectomy (surgical resection of the oesophagus with extended lymphadenectomy in abdomen and thorax (removal of lymphnodes)). Furthermore, perioperative chemotherapy consists of 6 series neoadjuvant chemotherapy (3 series before, and 3 series after operation).~Unresectable patients receive palliative chemotherapy and no resection. Peritoneal washing cytology (PWC) is a recommended prediagnostic modality in gastric cancer patients. The method is used to detect free peritoneal cancer cells in the abdominal cavity even when macroscopic carcinomatosis is not present (i.e. the cancer has spread to other parts of the abdomen).~Carcinomatosis can be found in up to 19% in gastric cancer patients often in the peritoneum. Positive peritoneal cytology (C1) can be identified in up to 7% of gastric cancer patients without metastases (C1M0), i.e. malignant cells can be identified in the peritoneal washing, but tumor spread has not been identified.~Lots of studies indicate that C1-disease is an independent prognostic predictor for decreased survival, and increased recurrence rate, comparable with M1 patients (i.e. patients with distant metastases).~The American Joint Committee on cancer recommends that C1 patients should be treated non-surgically - even when M1 disease has not been identified.~On the basis of the above, PWC can be used to identify patients at greater risk for recurrence, and thereby not candidates for intended curative treatment.~It is a fact, though, that C1M0 patients have a better survival than C1M1 patients. Currently, there is no level-1 evidence for specific treatment of C1M0 patients, why further research is required to approach this patient group in the most comprehensive way. The focus group of our study is therefore C1M0 patients, because of the difference in opinions. Furthermore most evidence is based on gastric carcinomas, why GEJ-cancer patients are the group, we will examine.~Purpose:~Peritoneal washing cytology (PWC) is performed as a standard prediagnostic modality at Rigshospitalet, for patients with gastric- and GEJ cancer, considered resectable at preceding multidisciplinary conference. Most studies in the past 20-years have focused on gastric cancer, and not specifically GEJ-cancer.~This study will determine the usefulness of peritoneal washing cytology, and thereby verifying our own standard regarding GEJ-cancer. Furthermore, we will determine the effect of neoadjuvant chemotherapy on free peritoneal tumor cells and its correlation with overall survival.~This study is intended as a validation of our own standard.
Inclusion criteria: inclusion criteria:

 patients with biopsy verified GEJ-cancer referred to the department of surgical gastroenterology, Rigshospitalet, which is considered resectable at MDT-conference.

 >18 years old

 informed consent

Exclusion criteria: :

 < 18 years old

 Not informed consent

:

 < 18 years old

 Not informed consent


Efficacy and Safety Study of Eltrombopag in Pediatric Patients With Thrombocytopenia From Chronic Idiopathic Thrombocytopenic Purpura (ITP)

Summary: Phase II, multi-center, 3 part, staggered cohort, open-label and double blind, randomized, placebo controlled study involving 3 age-determined cohorts (Cohort 1: between 12 and 17 years old; Cohort 2: between 6 and 11 years old; Cohort 3: between 1 and 5 years old). Daily dosing with eltrombopag will begin with 5 patients in the oldest age cohort in an open label fashion, and a review of safety, pharmacokinetic and platelet count data will be performed regularly. If no safety concerns are identified after 12 weeks, 18 additional patients will be randomised to placebo or eltrombopag (2:1 randomisation). After 7 weeks of randomized treatment, all patients will receive eltrombopag in an open label fashion. The total duration of treatment with eltrombopag will be 24 weeks. If at the time of the aforementioned 12 week review of the first 5 patients no safety issues are identified, dosing will begin in the next lower age cohort with an initial group of 5 patients. The same procedure will be followed in terms of safety review and subsequent enrolment and randomisation of the additional patients. Initiation of the younger age cohort will take place once data from the previous has been evaluated. Doses will be adjusted according to platelet counts and tolerability. The study will include a review of the safety data by a Data Safety Monitoring Board.
Inclusion criteria: inclusion criteria:

 Subjects between 1 year and <18 years of age at Day 1.

 Written informed consent from subject's guardian and accompanying informed assent from subject (for children over 6 years old).

 Confirmed diagnosis of chronic ITP, according to the American Society of Hematology / British Committee for Standards in Haematology (ASH/BCSH) guidelines [George, 1996; BCSH, 2003]. In addition, a peripheral blood smear or bone marrow examination should support the diagnosis of ITP with no evidence of other causes of thrombocytopenia.

 Subjects who are refractory or have relapsed after at least one prior ITP therapy or are not eligible, for a medical reason, for other treatments.

 Day 1 (or within 48 hours prior) platelet count <30 Gi/L.

 Previous therapy for ITP with immunoglobulins (IVIg and anti-D) must have been completed at least 2 weeks prior to Day 1 or have been clearly ineffective.

 Subjects treated with concomitant ITP medication (e.g. corticosteroids or azathioprine) must be receiving a dose that has been stable for at least 4 weeks prior to Day 1.

 Previous treatment for ITP with splenectomy, rituximab and cyclophosphamide must have been completed at least 4 weeks prior to Day 1 or have clearly been ineffective.

 Subjects must have prothrombin time (PT/INR) and activated partial thromboplastin time (aPTT) within 80 to 120% of the normal range.

 Subjects must have a complete blood count (CBC) not suggestive of another hematological disorder.

 The following clinical chemistries for the subjects MUST NOT exceed the upper limit of normal (ULN) reference range by more than 20%: creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, and alkaline phosphatase. In addition, total albumin must not be below the lower limit of normal (LLN) by more than 10%.

 For subjects of child-bearing potential (after menarche): subject must not be sexually active or is practicing an acceptable method of contraception (documented in chart). Female subjects (or female partners of male subjects) must use one of the following highly effective methods of contraception (i.e., Pearl Index <1.0%) from two weeks prior to administration of study medication, throughout the study, and 28 days after completion or premature discontinuation from the study:

 Complete abstinence from intercourse;

 Intrauterine device (IUD);

 Two forms of barrier contraception (diaphragm plus spermicide, and for males condom plus spermicide);

 Systemic contraceptives (combined or progesterone only).

Exclusion criteria: :

 Any clinically relevant abnormality, other than ITP, identified on the screening examination or any other medical condition or circumstance, which in the opinion of the investigator makes the subject unsuitable for participation in the study or suggests another primary diagnosis (e.g. thrombocytopenia is secondary to another disease).

 Concurrent or past malignant disease, including myeloproliferative disorder.

 Subjects who are not suitable for continuation of their current therapy for at least 7 additional additional weeks.

 Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding Day 1.

 History of platelet agglutination abnormality that prevents reliable measurement of platelet counts.

 Diagnosis of secondary immune thrombocytopenia, including those with laboratory or clinical evidence of HIV infection, anti-phospholipid antibody syndrome, chronic hepatitis B infection, hepatitis C virus infection, or any evidence of active hepatitis at the time of subject screening.

 Subject with Evans syndrome (autoimmune thrombocytopenia and autoimmune hemolysis).

 Subjects with known inherited thrombocytopenia (e.g. MYH-9 disorders)

 Subjects treated with drugs that affect platelet function (including but not limited to aspirin, clopidogrel and/or NSAIDs) or anti-coagulants for >3 consecutive days within 2 weeks of Day 1.

 Subjects who have previously received eltrombopag or any other thrombopoietin receptor agonist.

 For female subjects who have reached menarche status, an inability or unwillingness to provide a blood or urine specimen for pregnancy testing.

 Female subjects who are pregnant or lactating.


A Trial of Single Incision Versus Four Ports Laparoscopic Cholecystectomy

Summary: Background: Single-incision laparoscopic cholecystectomy (SILC) is increasingly being used as a minimally invasive surgery with potential benefits over 4-port laparoscopic cholecystectomy (LC) in terms of postoperative pain and faster recovery.~Methods: Seventy-three patients with symptomatic cholelithiasis were randomized to SILC (n=37) or LC (n=36). Data measures included operative details, adverse events, postoperative pain and analgesic requirements, success of the ambulatory process, return to normal activity and return to work, cosmetic results and quality of life score.
Inclusion criteria: inclusion criteria:

 age higher than 18 and lower than 80

 American Society of Anesthesiologists class (ASA) I-II,

 absence of any previous anesthetic complication,

 accompaniment by a responsible adult during 24 hours,

 symptomatic gallstones candidate to cholecystectomy

 and a signed informed consent.

Exclusion criteria: :

 a Body Mass Index (BMI) higher than 35,

 any laparoscopic contraindication,

 acute cholecystitis background, suspect of Mirizzi's Syndrome, common duct stones or malignancy,

 anti-inflammatory allergy

 psychiatric history that could hinder ambulatory procedure

['Single Incision Laparoscopic Cholecystectomy (SILC)', 'Four Ports Laparoscopic Cholecystectomy (4PLC)']


Magnetic Resonance (MR) Spectroscopy In Familial Mediterranean Fever (FMF) Patients

Summary: Familial Mediterranean fever (FMF) is an inherited disorder of unknown etiology, characterized by recurrent episodes of fever, peritonitis and/or pleuritis.~Fever is the cardinal manifestation of FMF and is present in most attacks accompanied by abdominal pain.~Another clinical manifestation in patients with FMF is exertional muscle pain, usually in the thigh, which appears even after minor exercise or physical activity in young patients with generally good health (other than FMF) and in good physical condition. Some patients also complain of ankle edema after relatively minor physical activity, which subsides after a night rest. Although these manifestations are quite common in FMF patients and form part of the minor criteria for the diagnosis, the etiopathogenesis has not been examined.~The purpose of the suggested study is to evaluate and characterize the anatomical and biochemical changes in the muscles of the thigh and in the ankle triggered by physical activity in FMF patients complaining of exertional lower leg myalgias and edema after minor physical exercise.
Inclusion criteria: inclusion criteria:

 Fulfilling the Tel Hashomer criteria for the diagnosis of FMF [5].

 Suffering from episodes of exertional leg pain and or exertional ankle edema

 18-45 years old

 On a stable (≥ 2 weeks) dose of oral colchicine therapy

 Non-smokers

Exclusion criteria: :

 with known peripheral vascular disease (PVD) and/or multiple risk factors for PVD (such as diabetes, hypertension, hyperlipidemia)

 Suffering from muscular or neurological diseases not related to FMF

 With elevated serum creatinine / liver enzymes/ creatine phosphokinase (CPK) levels.

 Suffering from claustrophobia, or with metal fragments in body tissue, or with other contraindications for MRI.