Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Prospective, Randomized Clinical Trial Comparing Rivaroxaban vs Warfarin in High Risk Patients With Antiphospholipid Syndrome
Brief Summary: Primary Study Objective(s) The primary objective is to demonstrate the non-inferiority of Rivaroxaban 20 mg (or 15mgqd in case of moderate renal insufficiency) versus warfarin (INR 2.0-3.0) with respect to the occurrence of the cumulative end point of incident acute thrombosis (arterial or venous) confirmed by appropriate imaging studies, major bleedings, and death in triple aPL-positive APS patients.

Study Design A multicentre, interventional, prospective, parallel, randomised, controlled, open-label, Rivaroxaban 20 mg qd (or 15mg qd in patients with moderate renal insufficiency) vs warfarin (INR target 2.5), non-inferiority study, in 535 triple aPL-positive APS patients in approximately 40 Internal Medicine and Thrombosis centres. Each local Institutional Review Board will approve the study.

Study Population Patients of both sexes, of age 18-75, affected by anti-phospholipid syndrome, with a high probability of recurrences as defined by triple aPL-positivity, are eligible for this study.

Primary Outcome variables The primary cumulative outcome measure will be incident acute thrombosis (arterial or venous) confirmed by appropriate imaging studies, major bleeding, or death.

Secondary Outcome variables Separate evaluation of arterial and venous thrombosis and all-cause death.

04.27.2015: An amendment has been made. Enrollment permitted till 75 years of age.


Options:
A: Inclusion Criteria:

History of 3 or more consecutive miscarriages and positive antiphospholipid antibodies on at least two occasions more than 6 weeks apart before becoming pregnant and an unsuccessful pregnancy with aspirin + heparin with a karyotype of miscarriage either unavailable or normal (46XX/ 46XY).

Exclusion Criteria:

Abnormal karyotype of women or partner, previous thromboembolism, SLE, diabetes mellitus, hypertension, sensitivity to aspirin, heparin and prednisolone, multiple pregnancy.
B: Inclusion Criteria:

1. Signed and dated informed consent form
2. Male or female of age 18-75 years
3. Triple aPL-positivity in the last blood sampling defined as:

   * aCL IgG/M (≥40 GPL or MPL, medium-to-high titer, and/or greater than the 99th percentile) and
   * aB2GPI IgG/M (≥40 U, medium-to-high titer, and/or greater than the 99th percentile) and
   * LA test positive based on the International Society of Thrombosis \& Hemostasis Recommendations.
   * Positivity of aCL and abeta2GPI must be of the same isotype.
   * To confirm triple positivity for aPL and to validate the laboratory diagnosis, plasma (at least 2ml prepared by double centrifugation at 2000g) from patients of each Center will be stored at -80°C and later on sent in dry ice and retested in a reference laboratory (Padua Thrombosis Centre). Expenses for shipment will be in charge to the coordinator Center.
4. History of thrombosis (objectively proven arterial, venous, and/or biopsy proven microthrombosis) and/or pregnancy morbidity according to Miyaki

Exclusion Criteria:

Subjects meeting any of the following criteria will not be enrolled in the study:

1. Severe hypersensitivity reaction to rivaroxaban
2. Calculated CLCR \<30 mL/min at the screening visit
3. Current pregnancy or breast feeding. Pregnancy is highly discouraged in these patients and if programmed patients are excluded from the study. If sexually active, be practicing an effective method of birth control (e.g., intrauterine device, double-barrier method, contraceptive patch, male partner sterilization) before entry and throughout the study
4. Concomitant treatment with other anticoagulants, such as unfractionated heparin, low molecular weight heparins (enoxaparin, dalteparin, etc.) heparin derivatives (fondaparinux), other oral anticoagulants (dabigatran etexilate, apixaban) in the case they can not be substituted with the study drugs.
5. Patients taking interfering medications: pharmacologic interactions may occur with strong inhibitors of p-glycoprotein and of CYP3A4, e.g., azole-antimycotics, such as ketoconazole, itraconazole, voriconazole, posaconazole, and HIV protease inhibitors; coadministration of rivaroxaban is therefore contraindicated in these cases. Several drugs used in neurological patients, such as phenobarbital, phenytoin, carbamazepine, and st john's wort (hypericum), are p-glycoprotein inducers and should be avoided. Whenever possible, it would be better to use levetiracetam and topiramate as antiepileptic therapy.
6. Hemorrhage Risk-Related Criteria

   * History of or condition associated with increased bleeding risk including, but not limited to:
   * Major surgical procedure or trauma within 30 days before the randomization visit
   * Clinically significant gastrointestinal bleeding within 6 months before the randomization visit
   * History of intracranial, intraocular, spinal, or atraumatic intra-articular bleeding
   * Chronic hemorrhagic disorder
   * Known intracranial neoplasm, arteriovenous malformation, or aneurysm
   * Planned invasive procedure with potential for uncontrolled bleeding.
   * Sustained uncontrolled hypertension: systolic blood pressure ≥180 mmHg
7. Known liver cirrhosis or ALT above three times the upper normal value.
C: Inclusion Criteria:

* Women experiencing one or two pregnancy losses at any point in gestation in the past that were not elective termination(s). At least one of these losses must be well documented by one of the following:

  * Sonogram demonstrating anembryonic loss, embryonic loss or fetal death.
  * Histologic confirmation of products of conception that were spontaneously passed per vagina or surgically obtained.
  * Hospital records of fetus delivery.
  * Late menses and positive serum hCG or positive urine hCG documented by hospital or clinic records followed by either a negative hospital/clinic pregnancy test or a decline in urinary hCG level over 3 days.
  * Home pregnancy tests without hCG confirmation from a healthcare provider (either serum or urine) will not be accepted.
* No more than 5 pregnancies in total including the pregnancy loss(es).\*
* Up to two prior pregnancies that did not end in a loss.\*

  \*Women may have up to two pregnancies beyond 20 weeks that were not losses, two spontaneous pregnancy losses at any time in the past, and up to one therapeutic or elective termination (two therapeutic or elective terminations if no other pregnancies). Ectopic and molar pregnancies would, for the purpose of enrollment, be considered in the same category as therapeutic termination pregnancies. Women with more than two live births or those with more than two losses, regardless of the week of gestation of the loss, are excluded.
* Presence of intact tubes (both), ovaries (both), and uterus.
* Between 18 and 40 years of age at time of baseline visit.
* Regular menstrual periods between 21 - 42 days in length (within the last 12 months). Regular menstrual periods are defined as no more than an 8-day difference between the woman's shortest and longest cycle.
* No more than one missed menses in the past 12 months (other than those missed due to pregnancy or breastfeeding).
* Actively trying to conceive with a male partner and not using contraception by the baseline visit.
* Not currently pregnant at the baseline or randomization visits.
* Ability and willingness to give informed consent.
* Willingness to be randomized and to take daily study pills for 6 months to a possible 15 months

Exclusions Criteria:

* Known allergies to aspirin or non-steroidal anti-inflammatory agents.
* Clinical indication for anticoagulant therapy. These include prior or current thrombosis, antiphospholipid syndrome (APS) or known major thrombophilia.
* Clinical indication for chronic use of NSAIDs such as rheumatoid arthritis.
* Indication for additional folic acid supplementation, such as prior infant with neural tube defect (NTD), seizure disorder.
* Medical contraindication to aspirin therapy. These include uncontrolled asthma, nasal polyps, bleeding disorders, or history of gastrointestinal ulcer.
* Presence of major medical disorders (regardless of severity). These include diabetes, hypertension, systemic lupus erythematosus (SLE), untreated or active cancer (any cancer in remission or non-melanoma skin cancer is not included in the exclusion criteria), liver disease, renal disease, rheumatoid arthritis, cardiac disease, pulmonary disease other than mild asthma, neurologic disease requiring medical treatment, uncontrolled hypothyroidism, uncontrolled seizure disorder. Untreated vitamin B12 deficiency, severe anemia (Hct \< 30%), hemophilia, gout, nasal polyps, among others.
* Currently undergoing/planned use of assisted reproductive techniques during trial (IVF; IUI; Clomid).
* History of infertility or sub-fertility. This includes any of the following:

  * No conception after ≥ 1 year of unprotected intercourse and actively trying to conceive.
  * Any prior medical treatment for infertility.
  * Prior treatment for known pelvic inflammatory disease.
  * Known male infertility or sperm abnormality (current partner).
  * Known tubal occlusion, anovulation, uterine abnormality, or endometriosis stage III or IV.
  * History of polycystic ovarian syndrome.
* Presence of unstable mental disorder. These include bipolar illness, schizophrenia, uncontrolled depression, uncontrolled anxiety disorder.
* Known current or recent alcohol abuse or illicit drug use.
* Current diagnosis of sexually transmitted infection (STI) (temporary exclusion)
D: Inclusion Criteria:

* Patients with a minimum of three consecutive pregnancy losses before 10 weeks gestation
* Positive lupus anticoagulant and/or anticardiolipin antibodies (IgG and IgM) on at least two occasions twelve weeks apart .
* Age between 19 - 37 years,
* Body mass index between 19-30

Exclusion Criteria:

* Parental chromosomal abnormalities
* Uterine abnormalities
* Luteal phase defect
* Systemic lupus erythematosus
* Previous thromboembolism
* Sensitivity to aspirin.

Answer: B