Institutional Review Board, Hospital for Special Surgery
July 29, 2013
The safety of study participants is our top priority. The trial is approved and periodically reviewed by an Institutional Review Board (IRB), which includes doctors, administrators, ethicists, and members of the general public. The safety of clinical trials is reviewed by the U.S. Food and Drug Administration.
Before enrolling in a clinical trial, the investigator will explain the purpose of the trial, its expected benefits, any possible risks or side effects, and what your role will be. This is the time to ask questions! If you want to join the trial, you must sign the informed consent documents. You can leave a clinical trial at any time without penalty.
For further information, see Understanding Clinical Trials.
Jessica K. Gordon, MD
Uzunma Udeh, BA
Nina Paddu, BA
Jason Zheng, Pharm.D
Eric Greenberg, Pharm.D
Matt Tobin, Pharm.D
The purpose of this clinical research study is to evaluate the effectiveness and safety of macitentan, to reduce the number of new digital ulcers associated with scleroderma. This study will evaluate the effect of macitentan therapy on the development of new digital ulcers and improvement on hand function.
Eligible patients must meet all of the following inclusion criteria during the initial screening visit of the study and prior to first dose of study medication:
o Signed informed consent prior to any study-mandated procedure.
o Patients = 18 years of age.
o Women of childbearing potential must use two reliable methods of contraception.
? Women of childbearing potential* with a negative serum pre-treatment pregnancy test are allowed in the study if they consistently and correctly use (from screening and up to 30 days after study treatment discontinuation) two reliable methods of contraception at the same time. Reliable methods of contraception include intrauterine devices or intrauterine systems, tubal sterilization, hormonal methods (combined or progesterone only oral contraceptives, transdermal patches, vaginal rings, injections, implants) and barrier methods (male condom, diaphragm, or cervical cap). A partners vasectomy still requires one additional method of contraception. Abstinence, the rhythm method, or contraception by the other partner alone, will not be considered reliable methods of contraception. *A woman is considered to have childbearing potential unless she meets at least one of the following criteria:
Previous bilateral salpingo-oophorectomy or hysterectomy
Premature ovarian failure confirmed by a specialist gynaecologist pre-pubescence, XY genotype, Turner syndrome, uterine agenesis
Age ? 50 years and not treated with any kind of hormone replacement therapy (HRT) for at least 2 years prior to screening, with amenorrhea for at least 24 consecutive months prior to screening. An assessment of serum follicle stimulating hormone (FSH) showing a level of ? 40 IU/L at screening may be used to exclude childbearing potential, based on the discretion of the investigator.
o Diagnosis of SSc according to the classification criteria of the American College of Rheumatology (ACR) [Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee 1980], or having ever met criteria for CREST syndrome (with sclerodactyly and 2 out of the 4 remaining criteria: calcinosis, Raynaud's phenomenon, esophageal dysmotility, and telangiectasia). The ACR criteria for the classification of SSc require 1 major criterion, or 2 of the 3 minor criteria as per the table above.
? Systemic sclerosis is sub-classified as:
Diffuse SSc involving scleroderma skin change in locations proximal to the elbows or knees inclusive of the chest and abdomen (face involvement does not qualify).
Individuals with skin thickening proximal to the wrist who are within 6 months of their first non-Raynaud manifestation AND who have palpable tendon friction rubs in at least two locations are also classified as diffuse SSc.
Limited SSc characterized by scleroderma skin change restricted to sites distal to the elbows and knees (face involvement does not disqualify).
? Patients who are not classifiable by the above descriptions cannot be included in the study.
o At least one visible, active ischemic digital ulcer (DU) at baseline, located at or distal to the PIP joints or at the digital tip, and that developed or worsened within 8 weeks prior to screening. Must meet protocol defined qualifications for active DU:
? An active DU is defined as a lesion on the finger with visually discernable depth and a loss of continuity of epithelial coverage that is associated with pain not felt definition does not include fissures, paronychia, digital pitting scars, extrusion of calcium, and indeterminate lesions (lesions of which denudation is not clearly visible and cannot be judged, because of the presence of a scab or necrotic tissue).
? Only DUs from the PIP joints distally, including the digital tip will be assessed.
? Digital ulcers proximal to PIP joints, such as those over the metacarpophalangeal (MCP) joints will not be assessed.
? History of at least one additional active ischemic DU within 6 months, or at least two within 12 months prior to Screening (Visit 1).
Eligible patients must meet none of the following exclusion criteria:
o DUs due to condition other than SSc.
o Symptomatic pulmonary arterial hypertension (PAH).
o Body mass index (BMI: kg/m2) < 18.
o Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5times the upper limit of normal (ULN).
Hemoglobin < 75% of the lower limit of the normal range.
Systolic blood pressure < 95 mmHg or diastolic blood pressure < 50 mmHg at
Screening (Visit 1) and Randomization (Visit 2).
Severe malabsorption, defined as greater than 15% unintentional loss of body weight in the last 6 months prior to randomization; any severe organ failure (e.g., lung, kidney), or any life-threatening condition.
Comorbidities, other than SSc, that could seriously affect the assessment of hand function.
Females who are pregnant or breastfeeding or plan to do so during the course of this study.
Substance or alcohol abuse or dependence, within 12 months prior to Screening (Visit 1) or tobacco use at any level within the past 6 months prior to Screening (Visit 1).
Treatment with PDE5 inhibitors (e.g., sildenafil, tadalafil).
Patients on statins (e.g., atorvastatin, simvastatin), who have received treatment for less than 3 months prior to Screening (Visit 1) or whose treatment has not been stable during this period.
Patients on vasodilators, such as calcium channel blockers, ACE-inhibitors, nitroglycerin, alpha adrenergic blockers, or angiotensin II receptor antagonists, N-acetylcysteine, antiplatelet aggregation therapy and low molecular weight heparin who have received treatment for less than 2 weeks prior to Screening (Visit 1) or whose treatment has not been stable during this period.
Treatment with prostanoids regardless of the route of administration within 3 months prior to Screening (Visit 1).
Treatment with disease modifying agents such as methotrexate and cyclophosphamide if present for less than 3 months prior to Screening (Visit 1) or whose treatment has not been stable for at least 1 month prior to Screening (Visit 1).
Treatment with oral corticosteroids (? 10 mg/day of prednisone or equivalent).
Treatment with endothelin receptor antagonists (ERAs) within 3 months prior to Screening (Visit 1).
Systemic antibiotics (oral and IV) to treat infected DU(s) within 4 weeks prior to Screening (Visit 1).
Use of topical growth factors, hyperbaric oxygen.
Local injection of botulinum toxin in an affected finger within 4 weeks prior to Screening (Visit 1).
Surgical sympathectomy of the upper limbs or surgical wound debridement within 1 month prior to Screening (Visit 1).
Treatment with cytochrome P450 3A (CYP3A) inducers, such as rifabutin, rifampin, rifapentin, carbamazepine, phenobarbital, phenytoin, St. Johns wort, within 4 weeks prior to Screening (Visit 1).
Known hypersensitivity to drugs of the same class as the study drug, or any of their excipients.
Planned treatment, or treatment with another investigational drug within 4 weeks prior to Screening (Visit 1).
Any condition that prevents compliance with the protocol or adherence to therapy, including inability to speak, read, or understand the local language well enough to complete all study assessments.
Nina Paddu, BA