Raynaud's Phenomenon Secondary to Systemic Sclerosis
Conditions
Keywords
systemic sclerosis, raynaud's phenomenon
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.
Interventions
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.
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.
Sponsors
Civi Biopharma, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
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.
Pre-assignment details
In this study 258 participants with Systemic Sclerosis (SSc) were screened.198 participants who had at least 10 symptomatic Raynaud's phenomenon (RP) attacks on the 5-day eligibility period were randomized: 98 to the placebo arm and 100 to the Iloprost arm. Two participants stopped the study prior to receiving any treatment. The number of participants who were randomized and started the treatment was 97 in the placebo arm and 99 in the Iloprost arm.
Participants by arm
| Arm | Count |
|---|---|
| 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.
Placebo 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. | 97 |
| 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.
Iloprost 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. | 99 |
| Total | 196 |
Baseline characteristics
| Characteristic | Iloprost Injection, for Intravenous Use | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 52.4 years STANDARD_DEVIATION 13.59 | 52.2 years STANDARD_DEVIATION 12.31 | 52.0 years STANDARD_DEVIATION 10.92 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants | 22 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 85 Participants | 171 Participants | 86 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 1 Participants |
| Phosphodiesterase-5 (PDE5) Inhibitors at Screening No | 59 Participants | 119 Participants | 60 Participants |
| Phosphodiesterase-5 (PDE5) Inhibitors at Screening Yes | 40 Participants | 77 Participants | 37 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 7 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 15 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) White | 87 Participants | 167 Participants | 80 Participants |
| Sex: Female, Male Female | 88 Participants | 174 Participants | 86 Participants |
| Sex: Female, Male Male | 11 Participants | 22 Participants | 11 Participants |
| Weekly frequency of symptomatic RP attacks at baseline | 32.49 Weekly frequency of RP attacks STANDARD_DEVIATION 26.393 | 30.58 Weekly frequency of RP attacks STANDARD_DEVIATION 22.701 | 28.63 Weekly frequency of RP attacks STANDARD_DEVIATION 18.113 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 97 | 0 / 99 |
| other Total, other adverse events | 78 / 97 | 99 / 99 |
| serious Total, serious adverse events | 0 / 97 | 1 / 99 |
Outcome results
Primary
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).
Population: The Intention-To-Treat (ITT) Population was defined as all randomized patients who initiated (received) study drug infusion.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change in Frequency of Symptomatic RP Attacks | -11.47 Number of RP attacks per week |
| Iloprost Injection, for Intravenous Use | Change in Frequency of Symptomatic RP Attacks | -12.73 Number of RP attacks per week |
p-value: 0.42195% CI: [-4.34, 1.82]ANCOVA
Secondary
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).
Population: The ITT-To-Treat (ITT) population, defined as all randomized patients who initiated (received) study drug infusion.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change in Severity of RP Attack Symptoms | -2.13 Score on a scale |
| Iloprost Injection, for Intravenous Use | Change in Severity of RP Attack Symptoms | -2.19 Score on a scale |
Secondary
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).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Percentage of Responders | 33 Participants |
| Iloprost Injection, for Intravenous Use | Percentage of Responders | 33 Participants |
Secondary
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).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Weekly Total Duration of Symptomatic RP Attacks. | -321.04 Minutes |
| Iloprost Injection, for Intravenous Use | Weekly Total Duration of Symptomatic RP Attacks. | -326.48 Minutes |