TerminatedPhase 3ACTRN12614000418673

Scleroderma-Pulmonary Arterial Hypertension Intervention with Apixaban: The SPHInX Study

A multi-centre, double-blind, randomised, placebo-controlled trial, of oral anticoagulation with apixaban in participants with Systemic Sclerosis-related Pulmonary Arterial Hypertension, measuring time to clinical worsening of Pulmonary Arterial Hypertension.

Sponsor

St Vincent's Hospital Melbourne Pty Ltd

Enrollment

170 participants

Start Date

Sep 8, 2014

Study Type

Interventional

Conditions

Pulmonary Arterial Hypertension Systemic Sclerosis

Summary

Among the rheumatological diseases, Systemic Sclerosis or Scleroderma (SSc), a multi-organ autoimmune disease characterized by increased scarring or fibrosis of tissues and narrowed blood vessels, carries the greatest burden of case-based mortality, reducing the average patient’s life expectancy by 34 years. One of the major causes of SSc related death is Pulmonary Arterial Hypertension (PAH) which develops in 10-15% of patients with SSc. PAH is a condition that narrows the blood vessels in the lungs making blood flow through the lungs more difficult and causing increased strain on the heart and as a result it can cause heart failure and death. Although new specific vasodilator therapies have become available in the last 10 years to treat PAH, some patients still experience poor health outcomes with the 3 year survival of patients with SSc-PAH being about 70%. Blood clot formation in the blood vessels that supply the lungs has been implicated as one of the events that occur in the complicated pathway leading to the development of PAH. For this reason, researchers have begun to consider whether the use of anticoagulant medications that can prevent blood clot formation, would be beneficial to patients with SSc-PAH. International clinical guidelines recommend the use of anticoagulant medication for some types of PAH, but due to a lack of convincing evidence, this therapy has not become part of standard care for SSc-PAH. The purpose of this study is to determine whether there are any health benefits to be gained from the addition of an oral anticoagulant medication, apixaban, in patients with SSc-PAH who are already prescribed advanced PAH therapy. This study is the first of its kind. Apixaban is approved in Australia for the prevention of blood clots in patients who have undergone elective total hip or total knee replacement surgery and to prevent stroke in some patients with Atrial Fibrillation/Flutter, however it is not approved to treat SSc-PAH. Therefore, it is an experimental treatment for SSc-PAH. The study will be a double blind placebo controlled study and will continue for 3 years. The primary outcome measure will be the time to clinical worsening of PAH. Secondary outcomes will include quality of life measures and health resource use.

Eligibility

Sex: Both males and femalesMin Age: 18 YearssMax Age: 75 Yearss

Inclusion Criteria24

Signed informed consent prior to initiation of any study-mandated procedure.
Male and female patients aged from 18 years to 75 years inclusive, with symptomatic permissible Group 1 pulmonary hypertension (PH) subcategories limited to
1 Idiopathic PAH
2 Heritable PAH, including genetic mutations in BMPR2, ALK-1, ENG, SMAD9, CAV1, KCNK3 or unknown
3 Associated with CTD such as:
3.1 Scleroderma as defined by the ACR/EULAR criteria for SSc
3.2 Systemic lupus erythematosus (SLE) patients that fulfill either the ACR or Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE
3.3 Mixed connective tissue disease
3.4 Rheumatoid or psoriatic arthritis
3.5 Dermatomyositis
3.6 Sjogren’s syndrome
PAH diagnosed by right heart catheterization (RHC). The RHC diagnosis may be at any time prior to baseline. The RHC must show:
1 Resting mean pulmonary arterial pressure (mPAP) greater than or equal to 25 mmHg,and
2 Resting pulmonary vascular resistance (PVR) greater than or equal to 3 woods units, and
3 Resting pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) less than or equal to 15 mmHg, or if PVR cannot or has not been measured, then mPAP greater than or equal to 30 mmHg with PCWP or LVEDP less than or equal to 15 mmHg.
6-minute walk distance (6MWD) greater than 50 meters at Screening/Baseline.
Other causes of PAH, in particular Chronic Thromboembolic Pulmonary Hypertension (CTEPH) must have been previously excluded by either a VQ scan or CT pulmonary angiography.
Currently taking at least one of the following medications in a stable dose for the 2 months prior to baseline visit: an endothelin antagonist (either bosentan, ambrisentan or macitentan) and/or a PDE-5 inhibitor (sildenafil or tadalafil).
Female subjects of childbearing potential must test negative for pregnancy.
Male and female subjects of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 28 days after the last dose of the study drug. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.
Female subjects who are not of childbearing potential must meet at least one of the following criteria
1 Have undergone documented hysterectomy and/or bilateral oophorectomy
2 Have medically confirmed ovarian failure or;
3 Achieved postmenopausal status, defined as: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause and have a serum follicle-stimulation hormone (FSH) level within the laboratory’s reference range for post-menopausal females.

Exclusion Criteria27

Patients will not be entered into the study if they meet any of the following criteria:
Patients with pulmonary hypertension (PH) due to any other cause other than idiopathic, heritable or CTD-PAH.
Patients with moderate or severe obstructive lung disease:
FEV1/FVC < 70% and FEV1 < 65% of predicted value after bronchodilator administration.
Patients with moderate or severe restrictive lung disease:
FVC < 70% of predicted value, provided that HRCT demonstrates moderate to severe changes of ILD; or FVC < 60% of predicted value, regardless of ILD on HRCT.
Patients with moderate or severe hepatic impairment (Child-Pugh B and C).
Patients with documented left ventricular dysfunction (i.e. ejection fraction < 45%)
Patients with severe renal insufficiency (estimated creatinine clearance < 25 mL/min, or serum creatinine > 200 µmol/L).
Patients who are receiving or have been receiving any investigational drugs within 1 month before the Baseline Visit.
Patients receiving continuous intravenous epoprostenol or iloprost at the Screening or Baseline Visits or be planned to initiate this therapy within the next 3 months.
Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements.
Life expectancy due to another condition of less than 12 months.
Females who are lactating or pregnant (positive pre-randomization serum pregnancy test) or plan to become pregnant during the study.
Known hypersensitivity to drugs of the same class as the study drug, or any of the excipients of the drug formulations.
Patient with GIT bleeding in the last 12 months due to gastric antral vascular ectasia (GAVE) or unexplained iron deficiency anemia (in the last 12 months).
Patients with Hb <10.0 g/dL at Screening.
Patients with significant falls risk in whom anticoagulation would be inappropriate.
Patients who have received any oral or subcutaneous anticoagulants (e.g. warfarin, apixaban, rivaroxaban, dabigatran, enoxaparin, dalteparin or heparin) for more than 3 months since the diagnosis of PAH.
Patients with a prosthetic valve who require long term oral anticoagulation.
Patients who are currently in atrial fibrillation.
Patients with PAH not on either an ETRA or PDE-5 inhibitor.
Patients with known bleeding disorders and/or Platelet count < 100 at screening visit and/or INR >1.2 at screening visit.
Brain, spinal or eye surgery within the last one month.
Uncontrolled Systemic Hypertension defined as either systolic BP at screening >179mmHg or diastolic BP >109 mmHg.
Documented episode of either Pulmonary embolus or Deep venous thrombosis since diagnosis of PAH on RHC.
Patients with a current, or active in the last one month, major bleed that is life threatening, causes chronic sequelae or consumes major health care resources, ie. symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, intramuscular with compartment syndrome, or bleeding causing a fall in Hb greater than or equal to 20g/L leading to transfusion of two or more units of whole blood or red cells.

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Interventions

The study drug, apixaban 2.5mg, will be administered orally in the form of a reddish brown, plain, oval shaped, shallow bi-convex film coated tablet, twice daily for 3 years. Participants will kee

The study drug, apixaban 2.5mg, will be administered orally in the form of a reddish brown, plain, oval shaped, shallow bi-convex film coated tablet, twice daily for 3 years. Participants will keep a diary to record any missed dose and adherence to the intervention will be monitored by counting unused tablets at study follow-up visits.