A Randomized, Intra-patient, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Topically Administered PRN473 (SAR444727) in Patients With Mild to Moderate Atopic Dermatitis
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- Enrollment
- 39
- Locations
- 12
- Primary Endpoint
- Number of Participants With PCSA: Electrolyte Parameters
Study Overview
Brief Summary
This was a Ph2a study that consists of a double-blind, intra-patient placebo-controlled treatment period and an open-label uncontrolled treatment period with objective to evaluate the safety, tolerability, PK and preliminary efficacy of PRN473 in up to 40 patients with mild to moderate AD.
On Day 1 (Baseline) of the Blinded Period, 2 target lesions with a difference no greater than 1 point in Total Sign Score (TSS) were randomly assigned to treatment in an intra-patient 1:1 manner, one lesion to PRN473 and the other to matching placebo.
Participation took approximately 13 weeks, including up to a 5-week screening period, a 6-week treatment period, end of study assessments 1 day after last dose, and a safety follow-up phone call 2 weeks after last dose.
Detailed Description
Study duration per patient was approximately 56 days including a 42-days treatment period.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to 70 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Male and female adults 18 to 70 years of age (inclusive) at the time of informed consent.
- •Diagnosed with mild to moderate AD.
- •History of AD for at least 6 months as determined by the Investigator through patient interview.
- •Stable disease for the 4 weeks prior to the screening visit with no significant flares in AD as determined by the Investigator.
- •Validated Investigator Global Assessment-atopic dermatitis (vIGA-AD) score of Moderate or Mild at Screening. The vIGA-AD was evaluated for the entire body except scalp, palms, soles and genitals.
- •HadAD involvement (excluding scalp, palms, soles and genitals) of at least 1.0% BSA and no more than 14.0% BSA.
- •Had at least two target lesions 100 cm2 or greater with a difference no greater than 1 point in lesion TSS and at least 5 cm apart located on the trunk (excluding genitals) or upper extremities (excluding palms).
- •If female, patients with child-bearing potential must have a negative pregnancy test, and agree to practice true abstinence or agree to use highly effective contraception.
- •If male, agree to use a male condom and highly effective contraception with female partners of child-bearing potential.
- •In good health as judged by the Investigator.
Exclusion Criteria
- •Patients who had failed 2 or more prior systemic treatments for AD.
- •Patients who had received a live or attenuated vaccine in the last 12 weeks or intend to receive a live or attenuated vaccine during the study.
- •Patients who cannot discontinue prohibited medications and treatments prior to the Baseline visit and during the study.
- •Has unstable AD, based on the judgement of the Investigator, or any consistent requirement for high potency topical steroids to manage AD signs or symptoms.
- •Patients who had significant active systemic or localized bacterial, viral, fungal, and helminth infection in the last 30 days.
- •Patients unwilling to refrain from prolonged sun exposure or use of a tanning bed or other artificial light emitting devices for 4 weeks prior to Baseline and during the study.
- •Patients with other skin conditions that would interfere with evaluations of the effect of the study medication on AD, as determined by the Investigator.
- •Patients with known genetic dermatological conditions that overlap with AD, such as Netherton syndrome.
- •Previous used of a BTK inhibitor.
- •Women who were pregnant, wishing to become pregnant during the study, or were breastfeeding.
- •Patients were undergoing allergy (eg, food allergy testing or skin prick testing), patch testing, or food challenges, or plan to do so during the study.
- •Patients who had undergone major surgery within 4 weeks prior to Day 1 or patients who had a major surgery planned during the study.
- •Regular use of drugs of abuse or regular alcohol consumption within 6 months prior to the study.
Arms & Interventions
SAR444727 5% BID per lesion
During the double-blinded period, 2 target lesions per participant (with difference no greater than 1 point in total sign scores [TSS]) were randomized in 1:1 ratio to receive either SAR44727 Gel 5 percent (%) or matching placebo (i.e., each participant was treated with both SAR444727 5% BID and placebo in parallel). During open-label period, participants applied SAR444727 Gel, 5% twice daily (BID) to the all atopic dermatitis (AD)-affected areas, except the scalp, palms, soles and genitals through Days 15 to 42.
Intervention: PRN473 (SAR444727) (Drug)
Placebo then SAR444727 5% BID per lesion
Multiple topical doses of placebo for 14 days, and PRN473 (SAR444727) for 28 days
Intervention: PRN473 (SAR444727) (Drug)
Placebo then SAR444727 5% BID per lesion
Multiple topical doses of placebo for 14 days, and PRN473 (SAR444727) for 28 days
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Number of Participants With PCSA: Electrolyte Parameters
Time Frame: From the first IMP administration (Day 1) up to Day 45
Criteria for PCSA: Sodium: \<=129 millimoles (mmol)/L, \>=160 mmol/L; Potassium: \<3 mmol/L, \>=5.5 mmol/L and Chloride: \<80 mmol/L, \>115 mmol/L.
Number of Participants With PCSA: Renal Function Parameters
Time Frame: From the first IMP administration (Day 1) up to Day 45
Criteria for PCSA: Creatinine: \>=150 micromoles per liter (mcmol/L), \>=30% change from baseline, \>=100% change from baseline.
Number of Participants With PCSA: Liver Function Parameters
Time Frame: From the first IMP administration (Day 1) up to Day 45
Liver function parameters assessments included alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, lactate dehydrogenase, total bilirubin, direct bilirubin, and gamma glutamyl transferase (GGT).
Number of Participants With PCSA: Urinalysis
Time Frame: From the first IMP administration (Day 1) up to Day 45
Urinalysis parameters assessments included potential of Hydrogen (pH), urobilinogen, and specific gravity.
Number of Participants With PCSA in 12-Lead Electrocardiogram (ECG)
Time Frame: From the first IMP administration (Day 1) up to Day 45
Criteria for PCSA: HR: less than (\<) 50 beats per minute (bpm), \> 90 bpm, \> 90 bpm and increase from baseline \> = 20 bpm, \> 100 bpm; PR interval: \> 200 milliseconds (msec), \> 200 msec and increase from baseline \>= 25 %, \> 220 msec; QRS interval: greater than (\>) 110 msec, \> 110 msec and increase from baseline greater than or equal to (\>=) 25%, \> 120 msec; QT interval: \> 500 msec; QTc interval \> 450 msec; \> 480 msec, increase from baseline (30-60) msec, increase from baseline \> 60 msec.
Number of Participants With PCSA: Hematology
Time Frame: From the first IMP administration (Day 1) up to Day 45
Criteria for PCSA: Hemoglobin (Hb) \<=115 grams per liter (g/L) (Male\[M\]) or \<=95 g/L (Female\[F\]), \>= 185 g/L (M) or \>=165 g/L (F), decrease from baseline \>= 20 g/L; Hematocrit: \<=0.37 volume/volume (v/v) (M) or \<=0.32 v/v (F), \>=0.55 v/v (M) or \>=0.5 v/v (F); Red blood cells (RBC): \>=6 Tera/L; Platelets: \< 100 Giga/L, \>=700 Giga/L; Neutrophils: \<1.5 Giga/L (Non-Black \[NB\]) or \<1.0 Giga/L (Black \[B\]); Lymphocytes: \> 4.0 Giga/L; Monocytes: \>0.7 Giga/L; Basophils: \>0.1 Giga/L; Eosinophils: \>0.5 Giga/L or \>upper limit of normal (ULN) (if ULN \>=0.5 Giga/L).
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
Time Frame: From the first IMP administration (Day 1) up to Day 58
An AE was defined as any untoward medical occurrence in a participant temporally associated with the use of investigational medicinal product (IMP), whether or not considered related to the IMP. SAEs were any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were AEs that occurred from the time of the first IMP in the safety analysis period.
Number of Participants With Potentially Clinically Significant Abnormalities (PCSA): Vital Signs
Time Frame: From the first IMP administration (Day 1) up to Day 45
Vital signs assessments included supine systolic blood pressure, supine diastolic blood pressure, supine heart rate (HR), and body temperature. Criteria for PCSA: Supine SBP: ≤ 95 mmHg and decrease from baseline ≥ 20 mmHg, ≥ 160 mmHg and increase from baseline ≥ 20 mmHg; Supine DBP : ≤ 45 mmHg and decrease from baseline ≥ 10 mmHg, ≥ 110 mmHg and increase from baseline ≥ 10 mmHg; Orthostatic SBP: ≤ -20 mmHg; Orthostatic DBP: ≤ -10 mmHg; Supine PR: ≤ 50 beats/min and decrease from baseline ≥ 20 beats/min, ≥ 120 beats/min and increase from baseline ≥ 20 beats/min; Weight :≥ 5% decrease from baseline, ≥ 5% increase from baseline
Number of Participants With PCSA: Metabolic Parameters
Time Frame: From the first IMP administration (Day 1) up to Day 45
Criteria for PCSA: Glucose: \<=3.9 mmol/L and \< lower limit of normal range (LLN); \>=11.1 mmol/L (unfasted \[unfas\]) or \>=7 mmol/L (fasted \[fas\]); Albumin: \<=25 g/L; Creatine kinase (CK): \> 3 ULN, \> 10 ULN; C-Reactive protein: \> 2 ULN or 10 mg(milligram)/L (if ULN not provided).
Percentage of Participants With Application-Site Event During Double-Blind Period
Time Frame: From the first IMP administration (Day 1) up to Week 2
Grading of application-site local tolerability symptoms (burning, pruritus, and erythema) were recorded using the grading scale following each dosing during the double-blind period. Grading of application site tolerability symptoms graded from 0 (none) to 3 (severe).
Secondary Outcomes
- Maximum Plasma Concentration (Cmax) of SAR444727(Day 1, 4 hours post-dose; Day 15, 1 hour post-dose and Day 43, 12 hours post-dose)