Intravenous Iloprost in Subjects With Symptomatic Raynaud's Phenomenon Secondary to Systemic Sclerosis (Phase 3)

Phase 3

Completed

Conditions: Raynaud's Phenomenon Secondary to Systemic Sclerosis

Interventions: Drug: Iloprost Injection, for intravenous use
Drug: Placebo IV infusion

Registration Number: NCT04040322

Lead Sponsor: Civi Biopharma, Inc.

Brief Summary: This is a Phase 3, multicenter, double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of iloprost on the frequency of and relief from symptomatic digital ischemic episodes in subjects with systemic sclerosis.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 198

Inclusion Criteria

Male or female subjects must be greater than or equal to 18 years of age.
Subjects must have a diagnosis of Systemic Sclerosis as defined by the 2013 American College of Rheumatology criteria/EULAR criteria
Subjects must have a diagnosis or history of Raynaud's Phenomenon, self-reported or reported by a physician, with at least a 2-phase color change in finger(s) of pallor, cyanosis, and/or reactive hyperemia in response to cold exposure or emotion
Subjects must have a minimum of 10 symptomatic Raynaud's Phenomenon attacks, documented in the electronic patient-reported outcomes (ePRO) diary, occurring over at least 3 separate days of the 3- to 5-day eligibility period
Subjects must complete a minimum of 80% of the daily ePRO diary entry during the baseline period
Female subjects of childbearing potential and male subjects must agree to use contraception for the duration of the study.
Subjects must be willing and able to comply with the study requirements and give informed consent for participation in the study

Exclusion Criteria

Female subjects who are pregnant or breastfeeding
Subjects with systolic blood pressure <85 mmHg
Subjects with an estimated glomerular filtration rate <15 mL/min/1.73 m2
Subjects with an alanine aminotransferase and/or aspartate aminotransferase value >3 × the upper limit of normal at screening
Subjects who have a digital ulcer infection within 30 days of screening
Subjects with a history of cervical or digital sympathectomy, or botulism toxin injections in their hands [for RP or digital ulcers] within 90 days of screening. Subjects should not have a planned botulism toxin or sympathectomy during their participation in the study.
Subjects with gangrene or digital amputation within 6 months of screening
Subjects with current intractable diarrhea or vomiting
Subjects with a risk of clinically significant bleeding events, including those with coagulation or platelet disorders at screening
Subjects with a history of major trauma or hemorrhage within 30 days of screening.
Subjects with clinically significant chronic intermittent bleeding, such as active gastric antral vascular ectasia or active peptic ulcer disease, within 60 days of screening
Subjects who have had any cerebrovascular events (eg, transient ischemic attack or stroke) within 6 months of screening
Subjects with a history of myocardial infarction or unstable angina within 6 months of screening. Subjects should not have a planned coronary procedure during their participation in the study
Subjects with acute or chronic congestive heart failure (New York Heart Association Class III [moderate] or Class IV [severe]) at screening
Subjects with a history of more than mild restrictive or congestive cardiomyopathy uncontrolled by medication or implanted device
Subjects with a history of life-threatening cardiac arrhythmias
Subjects with a history of hemodynamically significant aortic or mitral valve disease
Subjects with a history of known pulmonary hypertension, pulmonary arterial hypertension, or pulmonary veno-occlusive disease
Subjects with a history of significant restrictive lung disease, defined as forced vital capacity <45% predicted and diffusing capacity of the lungs for carbon monoxide <40% predicted (uncorrected for hemoglobin)
Subjects with scleroderma renal crisis within 6 months of screening
Subjects with a concomitant life-threatening disease with a life expectancy <12 months
Subjects who have a clinically significant disorder that, in the opinion of the Investigator, could contraindicate the administration of study drug, affect compliance, interfere with study evaluations, or confound the interpretation of study results
Subjects who have taken or are currently taking any parenteral, inhaled, or oral prostacyclin or prostacyclin receptor agonists (eg, epoprostenol, treprostinil, iloprost, and selexipag) within 8 weeks of screening
Subjects who have initiated or had a dose change of any of the following within 2 weeks of screening: oral, topical, or intravenous (IV) vasodilators (eg, calcium channel blockers, phosphodiesterase-5 (PDE5) inhibitors [eg, sildenafil, tadalafil, or vardenafil], nitrates, and fluoxetine)
Subjects with any history of acetaminophen intolerability (eg, allergic reaction to acetaminophen)
Subjects with any malignancy that requires treatment during the study period, that has required treatment within 1 year of screening (including excision of skin cancer) or that is currently not in remission
Subjects who have used any investigational medication or device for any indication within 30 days or 5 half-lives (whichever is longer)
Subjects who have participated in ES-201 or ES-301 studies and were randomized and treated with study drug

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Iloprost Injection, for intravenous use	Iloprost Injection, for intravenous use	Subjects will receive study drug for 5 consecutive days as an IV infusion over 6 hours each day via a peripheral line. Study drug will be initiated at a starting dose 0.5 ng/kg/min up to 2.0 ng/kg/min.
Placebo	Placebo IV infusion	Subjects will receive study drug for 5 consecutive days as an IV infusion over 6 hours each day via a peripheral line. Study drug will be initiated at a starting dose 0.5 ng/kg/min up to 2.0 ng/kg/min.

Primary Outcome Measures

Name	Time	Method
Change in Frequency of Symptomatic RP Attacks	From baseline (Day 10 to Day 25 of screening period) to the end ofthe efficacy follow-up (Day 8 to Day 21).	The primary efficacy parameter is the change in the weekly frequency of symptomatic RP attacks from baseline. The baseline weekly frequency of symptomatic RP attacks was defined as the average number of weekly symptomatic RP attacks that occurred during the 10- to 25-day baseline ePRO diary completion period. The double-blind endpoint weekly frequency of symptomatic RP attacks was defined as the average number of weekly symptomatic RP attacks that occurred during Days 8 to 21, inclusive

Secondary Outcome Measures

Name	Time	Method
Change in Severity of RP Attack Symptoms	From baseline (Day 10 to Day 25 of screening period) to the end of the efficacy follow-up (Day 8 to Day 21).	Change in overall severity of RP attack symptoms as registered in electronic diary. It was measured using an 11-point numeric rating scale (NRS) as follows: 0 = no pain/numbness/tingling/discomfort, 1 to 3 = mild pain/numbness/tingling/discomfort, 4 to 6 = moderate pain/numbness/tingling/discomfort, and 7 to 10 = severe pain/numbness/tingling/discomfort. The severity of the symptoms (pain, numbness, discomfort or tingling) was rated by the patient in the electronic diary (ePRO). The symptom with the worst average baseline value for each patient was compared to the average severity rate of that symptom which occurred during Days 8 to 21 of the treatment period. If more than 1 symptom had the same value, the symptom used for analysis was based on the following order of rank: pain\>numbness\>tingling\>discomfort.
Weekly Total Duration of Symptomatic RP Attacks.	From baseline (Day 10 to Day 25 of screening period) to the end of the efficacy follow-up (Day 8 to Day 21).	The weekly duration is calculated as the average duration of a systematic RP attack times weekly frequency, as registered in electronic diary. The baseline weekly duration was calculated as the average duration of a systematic RP attack times weekly frequency during the 10- to 25-day baseline electronic diary completion period. The end of the efficacy follow-up weekly duration of symptomatic RP attacks is calculated as the average duration of a systematic RP attack times weekly frequency during Days 8 to 21, inclusive.
Percentage of Responders	From baseline (Day 10 to Day 25 of screening period) to the end of the efficacy follow-up (Day 8 to Day 21).	The responders are defined as participants that have at least 50% reduction in weekly total duration of symptomatic RP attacks and at least 50% reduction in overall severity from baseline. Duration of symptomatic RP attacks and severity of attacks are obtained from electronic diary.

Trial Locations

Locations (30): Arizona Arthritis & Rheumatology Research, PLLC
🇺🇸
Phoenix, Arizona, United States
Mayo Clinic - Scottsdale
🇺🇸
Scottsdale, Arizona, United States
University of Arizona - Arthritis Research Center
🇺🇸
Tucson, Arizona, United States
Cedars-Sinai Medical Center
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Los Angeles, California, United States
University of California, Los Angeles Medical Center
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Los Angeles, California, United States
Stanford University Medical Center
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Palo Alto, California, United States
University of California San Francisco
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San Francisco, California, United States
Georgetown University Medical Center - Department of Rheumatology
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Washington, District of Columbia, United States
Northwestern Medical Faculty Foundation
🇺🇸
Chicago, Illinois, United States
University Medical Center New Orleans
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New Orleans, Louisiana, United States
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Arizona Arthritis & Rheumatology Research, PLLC
🇺🇸Phoenix, Arizona, United States