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CompletedNCT04040322Updated May 25, 2025Results posted

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

A Phase 3 interventional study of Placebo IV infusion and Iloprost Injection, for intravenous use in Raynaud's Phenomenon Secondary to Systemic Sclerosis, sponsored by Civi Biopharma, Inc.. Completed at 30 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-05-25.

Sponsored by Civi Biopharma, Inc. · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
198
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study 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.

02

Conditions studied

  • Raynaud's Phenomenon Secondary to Systemic Sclerosis

Keywords

  • systemic sclerosis
  • raynaud's phenomenon
03

In context

Neoplasm Metastasis

3,517 studies on the registry are indexed under Neoplasm Metastasis; 885 are open to participants now.

This study's enrollment of 198 is above the median of 54 across 2,767 interventional studies indexed under Neoplasm Metastasis.

Browse Neoplasm Metastasis studies →

Lead sponsor

Civi Biopharma, Inc. is the lead sponsor of 3 studies on the registry; none are open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

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

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
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
198 participants (actual)

Study arms

  • Placebo comparator
    Placebo

    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.

    Drug: Placebo IV infusion

  • Active comparator
    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.

    Drug: Iloprost Injection, for intravenous use

Interventions

  • DrugPlacebo IV infusion

    Study drug will be initiated at a starting dose of 0.5 ng/kg/min up to 2.0 ng/kg/min. Subjects will receive study drug for 5 consecutive days as an IV infusion over 6 hours each day via a peripheral line.

  • DrugIloprost Injection, for intravenous use

    Study drug will be initiated at a starting dose of 0.5 ng/kg/min up to 2.0 ng/kg/min. Subjects will receive study drug for 5 consecutive days as an IV infusion over 6 hours each day via a peripheral line.

06

What researchers measure

Primary outcomes

  1. Change in Frequency of Symptomatic RP Attacks

    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

    Time frame: From baseline (Day 10 to Day 25 of screening period) to the end ofthe efficacy follow-up (Day 8 to Day 21).

Secondary outcomes

  1. Change in Severity of RP Attack Symptoms

    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.

    Time frame: From baseline (Day 10 to Day 25 of screening period) to the end of the efficacy follow-up (Day 8 to Day 21).

  2. Weekly Total Duration of Symptomatic RP Attacks.

    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.

    Time frame: From baseline (Day 10 to Day 25 of screening period) to the end of the efficacy follow-up (Day 8 to Day 21).

  3. Percentage of Responders

    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.

    Time frame: From baseline (Day 10 to Day 25 of screening period) to the end of the efficacy follow-up (Day 8 to Day 21).

07

Results

Posted May 25, 2025

Participant flow

The study was initiated on 14 October 2019 and completed on 07 May 2021. It was conducted in 31 sites located in the United States.

Participant flow — Overall Study
MilestonePlaceboIloprost Injection, for Intravenous Use
Started9799
Completed9799
Not completed00

Outcome measures

PrimaryChange in Frequency of Symptomatic RP Attacks

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

Time frame:
From baseline (Day 10 to Day 25 of screening period) to the end ofthe efficacy follow-up (Day 8 to Day 21).
Reported as:
Least squares mean · Number of RP attacks per week
Change in Frequency of Symptomatic RP Attacks
Number of RP attacks per weekPlaceboIloprost Injection, for Intravenous Use
Change in Frequency of Symptomatic RP Attacks-11.47 (-13.69 to -9.25)-12.73 (-14.92 to -10.55)
Statistical analysis
  • Placebo vs Iloprost Injection, for Intravenous Use · ANCOVA · p = 0.4210 (Threshold for statistical significance was p \< 0.05) · Least squares mean difference in change: -1.26 · 95% CI -4.34 to 1.82
SecondaryChange in Severity of RP Attack Symptoms

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.

Time frame:
From baseline (Day 10 to Day 25 of screening period) to the end of the efficacy follow-up (Day 8 to Day 21).
Reported as:
Least squares mean · Score on a scale
Change in Severity of RP Attack Symptoms
Score on a scalePlaceboIloprost Injection, for Intravenous Use
Change in Severity of RP Attack Symptoms-2.13 (-2.51 to -1.75)-2.19 (-2.57 to -1.82)
SecondaryWeekly Total Duration of Symptomatic RP Attacks.

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.

Time frame:
From baseline (Day 10 to Day 25 of screening period) to the end of the efficacy follow-up (Day 8 to Day 21).
Reported as:
Least squares mean · Minutes
Weekly Total Duration of Symptomatic RP Attacks.
MinutesPlaceboIloprost Injection, for Intravenous Use
Weekly Total Duration of Symptomatic RP Attacks.-321.04 (-385.03 to -257.05)-326.48 (-389.53 to -263.44)
SecondaryPercentage of Responders

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.

Time frame:
From baseline (Day 10 to Day 25 of screening period) to the end of the efficacy follow-up (Day 8 to Day 21).
Reported as:
Count of participants · Participants
Percentage of Responders
ParticipantsPlaceboIloprost Injection, for Intravenous Use
Percentage of Responders3333

Adverse events

Collected over All AEs and SAEs were collected during the full study period from the signing of the ICF until the last study visit, Visit 9, at day 35 (+7 days).. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Placebo0/97 (0%)0/97 (0%)78/97 (80.4%)
Iloprost Injection, for Intravenous Use0/99 (0%)1/99 (1%)99/99 (100%)
Most frequent serious events
Most frequent serious events
EventPlaceboIloprost Injection, for Intravenous Use
Hand fractureInjury, poisoning and procedural complications0/971/99
Limb traumatic amputationInjury, poisoning and procedural complications0/971/99
Most frequent other events
Showing 10 of 19
Most frequent other events
EventPlaceboIloprost Injection, for Intravenous Use
HeadacheNervous system disorders38/9785/99
NauseaGastrointestinal disorders15/9757/99
FlushingVascular disorders7/9728/99
Pain in jawMusculoskeletal and connective tissue disorders4/9727/99
VomitingGastrointestinal disorders5/9724/99
FatigueGeneral disorders9/9715/99
Infusion site painGeneral disorders6/9715/99
DiarrhoeaGastrointestinal disorders9/9713/99
Skin ulcerSkin and subcutaneous tissue disorders12/9711/99
DizzinessNervous system disorders10/9710/99

Baseline characteristics

Age, Continuous
Age, Continuous(years)PlaceboIloprost Injection, for Intravenous UseTotal
Mean52.0 ± 10.9252.4 ± 13.5952.2 ± 12.31
Sex: Female, Male
Sex: Female, Male(Participants)PlaceboIloprost Injection, for Intravenous UseTotal
Female8688174
Male111122
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)PlaceboIloprost Injection, for Intravenous UseTotal
Hispanic or Latino101222
Not Hispanic or Latino8685171
Unknown or Not Reported123
Race (NIH/OMB)
Race (NIH/OMB)(Participants)PlaceboIloprost Injection, for Intravenous UseTotal
American Indian or Alaska Native022
Asian527
Native Hawaiian or Other Pacific Islander101
Black or African American9615
White8087167
More than one race000
Unknown or Not Reported224
Phosphodiesterase-5 (PDE5) Inhibitors at Screening
Phosphodiesterase-5 (PDE5) Inhibitors at Screening(Participants)PlaceboIloprost Injection, for Intravenous UseTotal
Yes374077
No6059119
Weekly frequency of symptomatic RP attacks at baseline
Weekly frequency of symptomatic RP attacks at baseline(Weekly frequency of RP attacks)PlaceboIloprost Injection, for Intravenous UseTotal
Mean28.63 ± 18.11332.49 ± 26.39330.58 ± 22.701
08

Study locations

30 sites
  • Arizona Arthritis & Rheumatology Research, PLLC
    Phoenix, Arizona 85032, United States
  • Mayo Clinic - Scottsdale
    Scottsdale, Arizona 85259, United States
  • University of Arizona - Arthritis Research Center
    Tucson, Arizona 85724, United States
  • Cedars-Sinai Medical Center
    Los Angeles, California 90048, United States
  • University of California, Los Angeles Medical Center
    Los Angeles, California 90059, United States
  • Stanford University Medical Center
    Palo Alto, California 94305, United States
  • University of California San Francisco
    San Francisco, California 94143, United States
  • Georgetown University Medical Center - Department of Rheumatology
    Washington, District of Columbia 20007, United States
  • Northwestern Medical Faculty Foundation
    Chicago, Illinois 60611, United States
  • University Medical Center New Orleans
    New Orleans, Louisiana 70112, United States
  • Johns Hopkins University School of Medicine
    Baltimore, Maryland 21224, United States
  • Tufts Medical Center
    Boston, Massachusetts 02111, United States
  • University of Michigan
    Ann Arbor, Michigan 48109-5422, United States
  • West Michigan Rheumatology PLLC
    Grand Rapids, Michigan 49546, United States
  • University of Minnesota Maple Grove
    Minneapolis, Minnesota 55369, United States
  • University of Nebraska Medical Center
    Omaha, Nebraska 68198, United States
  • Robert Wood Johnson Medical School
    New Brunswick, New Jersey 08903, United States
  • Hospital for Special Surgery
    New York, New York 10021, United States
  • Columbia University Medical Center
    New York, New York 10032, United States
  • University of Cincinnati - Scleroderma Center
    Cincinnati, Ohio 45267, United States
  • Cleveland Clinic
    Cleveland, Ohio 44195, United States
  • Ohio State University
    Columbus, Ohio 43210, United States
  • The University of Toledo Medical Center (UTMC) - Ruppert Health Center
    Toledo, Ohio 43614, United States
  • University of Pennsylvania
    Philadelphia, Pennsylvania 19104, United States
  • University of Pittsburgh Medical Center
    Pittsburgh, Pennsylvania 15261, United States
  • Medical University of South Carolina (MUSC)
    Charleston, South Carolina 29425, United States
  • University of Texas Houston - Division of Rheumatology and Clinical Immunogenetics
    Houston, Texas 77030, United States
  • University of Utah
    Salt Lake City, Utah 84132, United States
  • Virginia Mason Medical Center
    Seattle, Washington 98101, United States
  • Froedtert Hospital and the Medical College of Wisconsin
    Milwaukee, Wisconsin 53226, United States
09

References and documents

Study documents

  • Study protocol · May 18, 2020
  • Statistical analysis plan · Jun 7, 2021

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on May 25, 2025, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT04040322
Lead sponsor
Civi Biopharma, Inc.
Responsible party
Sponsor
First posted
Jul 31, 2019
Start date
Oct 14, 2019
Primary completion
Jun 9, 2021
Completion
Jun 9, 2021
Results posted
May 25, 2025
Last update
May 25, 2025

Study contacts

Wade Benton, Pharm D
study director · Eicos Sciences, Inc.

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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