Moderate-to-severe Atopic Dermatitis
Conditions
Brief summary
This study will evaluate the efficacy, safety, pharmacokinetics and pharmacodynamics of CBP-201 in adult subjects with moderate to severe atopic dermatitis.
Detailed description
This is a randomized, double-blind, placebo-controlled, dose regimen finding study to assess the efficacy, safety, and steady-state PK profile of CBP-201 administered to eligible adult subjects with moderate to severe atopic dermatitis compared to placebo. CBP-201 is administered as a subcutaneous (SC) injection. The study is divided into a treatment period of 16 weeks and a follow-up period of 8 weeks.
Interventions
DRUGCBP-201
CBP-201 subcutaneous(SC) injection.
DRUGplacebo
subcutaneous(SC) injection
Sponsors
Connect Biopharm LLC
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 75 Years
Healthy volunteers
No
Inclusion criteria
1. Be an adult ≥18 and ≤ 75 years of age at the screening visit (Screening) with atopic dermatitis according to American Academy of Dermatology Consensus Criteria, (Eichenfield 2014) 2. Present for at least 1 year prior to the baseline visit (Baseline) with an inadequate response, in the judgement of the Investigator, to AD treatment with a topical regimen of corticosteroids, phosphodiesterase inhibitors or calcineurin inhibitors, or for whom topical treatments are otherwise medically inadvisable (eg, because of important side effect or safety risks) 3. Investigator Global Assessment (IGA) score ≥ 3 at Screening and Baseline. 4. Eczema Area and Severity Index (EASI) score ≥ 16 at Screening and Baseline 5. Body Surface Area (BSA) for total AD involvement ≥ 10% at Screening and Baseline 6. Able and willing to apply a stable dose of a bland emollient twice a day to affected areas for at least 7 days before Baseline and to continue for the duration of the study 7. Females of child-bearing potential (FCBP) and males who have not undergone a vasectomy must abstain from heterosexual activities or agree to use effective contraception throughout the entire study period.
Exclusion criteria
1. Have any of the following laboratory abnormalities at Screening: 1. Hemoglobin ≤ 90% of the lower limit of normal range (LLN) 2. White blood cell (WBC) below the LLN 3. Neutrophil count below the LLN 4. Platelet count below the LLN 2. Have undergone treatment with any of the following: 1. Topical agents such as corticosteroids, phosphodiesterase (PDE) inhibitors, Janus kinase (JAK) inhibitors, tacrolimus or pimecrolimus within 1 week prior to Baseline. Note that low to medium potency topical corticosteroids (TCS) are permitted after randomization to treat AD flares 2. Prior treatment with dupilumab or any antibody against IL-4Rα or IL-13 3. Systemic treatment for AD or other condition with steroids or other immunosuppressive/immunomodulating substances, e.g., cyclosporine, mycophenolate-mofetil, azathioprine, methotrexate or oral Janus kinase (JAK) inhibitors within 4 weeks prior to Baseline. Use of steroid inhalers and nasal corticosteroids is allowed. 4. Cell depleting agents, e.g. rituximab, within 6 months of Baseline or treatment with other biologics within 5 half-lives (if known) or 3 months prior to baseline visit, whichever is longer 5. Phototherapy (narrow band ultraviolet B \[NBUVB\], ultraviolet B \[UVB\], ultraviolet A1 \[UVA1\], psoralen + ultraviolet A \[PUVA\]), tanning beds, or any other light emitting device (LED), within 4 weeks of Baseline 6. ≥ 2 bleach baths within 2 weeks of Baseline 7. Prescription emollient to treat AD (e.g. Atopiclair®, MimyX®, Epicerum®, etc.) within 2 weeks of Baseline 8. Any investigational drug within 30 days or within 5 half-lives, whichever is longer, before Baseline. 9. Live (attenuated) vaccine within 8 weeks of Baseline. 10. Treatment with systemic traditional Chinese medicine (TCM) or herbal medications within 4 weeks before Baseline or treatment with topical TCM or herbal medications within 1 week before Baseline visit 3. Have any of the following: 1. Infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 4 weeks before Baseline, or superficial skin infection, such as impetigo, within 2 weeks before the Baseline (subjects may be rescreened after the infection has resolved) 2. A history of parasitic infection (e.g. helminth), within 6 months of Baseline 3. Per investigator judgement, known or suspected history of immunosuppression within 6 months of Baseline, including a history of invasive opportunistic infections, such as aspergillosis, coccidioidomycosis, histoplasmosis, human immunodeficiency virus (HIV), listeriosis, pneumocystosis, or tuberculosis, despite infection resolution; or unusually frequent, recurrent or prolonged infections. 4. Any history of vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC) 5. A history of malignancy with the following exceptions: completely treated carcinoma in situ of cervix or non-metastatic squamous or basal cell carcinoma of the skin 6. Positive results at Screening for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb) or hepatitis C antibody with positive HCV RNA polymerase chain reaction; positive HIV serology at screening 7. An allergy to L-histidine, trehalose or Tween (polysorbate) 80 4. Women must not be pregnant, planning to become pregnant or breast-feed during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Reduction in EASI Score From Baseline to Week 16 | Reduction from baseline to 16 weeks | EASI=Eczema Area Severity Index is a validated physician score for signs of atopic dermatitis. EASI can range from 0 to 72. An EASI score of 0 indicates clear/no eczema, 0.1 to 1.0 almost clear, 1.1 to 7 mild disease, 7.1 to 21 moderate disease, 21.1 to 50 severe disease, and 51-72 indicates very severe disease. EASI Sub-scale ranges are as follows: Head/neck can range from 0-7.2, Trunk 0-14.4, Upper Extremities 0-21.6, Lower Extremities can range from 0-28.8. To calculate EASI, % involvement is first assessed by body region with an Area involvement Score of 0-6 for each region: 0=0%, 1=1-9%, 2=10-29%, 3=30-39%, 4=50-69%, 5=70-89%, 6=90-100% involvement. Then 4 attributes (Erythema, Edema/Papulation, Excoriation, and Lichenification) are scored for severity (0= none, 1=mild, 2=moderate, 3=severe). A multiplier is applied head/neck=0.1, trunk=0.2, upper extremities= 0.3, lower extremities=0.4. The total EASI score is the sum of 4 regional sub-scores. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| vIGA of 0/1 at Week 16 | Response Rate at 16 weeks | Validated Investigator Global Assessment Score (vIGA) is assigned by the physician based on morphologic presentation of the disease in the clinic. The physician considers extent and severity of erythema, induration/papulation, lichenification, and oozing/crusting. A vIGA Score of 0=Clear, 1=Almost Clear, 2= Mild dermatitis, 3=Moderate dermatitis, and 4= Severe dermatitis. Patients are required to have a baseline IGA of 3 or 4. The response rate or percentage of patients achieving a vIGA of 0 or 1 (improved to clear or almost clear) at week 16 is the outcome. |
Countries
Australia, China, New Zealand, United States
Participant flow
Recruitment details
Patients were recruited based on physician referrral at academic and non-academic clinical centers between Jun 2020 and Sep 2021; 394 patients were screened. The first participant was randomized to treatment on 30 Jun 2020 and the last patient was randomized in April 2021. The last patient last visit was 22 Sept 2021.
Pre-assignment details
After providing informed consent, patients were assessed for study eligibility within 45 days before the baseline visit. Of the 394 patients screeened, 226 patients met the eligibility criteria and were randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| CBP-201 150 Q2W CBP-201 1800 mg, 600 mg Loading dose followed by 150 mg Q2W for 16 weeks | 57 |
| CBP-201 300 Q2W CBP-201 3000 mg, 600 mg Loading dose followed by 300 mg Q2W for 16 weeks | 57 |
| CBP-201 300 Q4W CBP-201 1800 mg, 600 mg Loading dose followed by 300 mg Q4W for 16 weeks alternating with 2 mLs matched volume placebo Q4W for 16 weeks | 56 |
| Placebo Placebo, 4 mLs matched loading dose volume follwed by 2 mls matched volume Q2W for 16 weeks | 56 |
| Total | 226 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 2 |
| Overall Study | Death | 0 | 0 | 1 | 0 |
| Overall Study | Lack of Efficacy | 0 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 6 | 2 | 5 |
| Overall Study | Patient moving out of town | 1 | 0 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 2 |
| Overall Study | Pregnancy | 0 | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 6 | 5 | 3 | 4 |
Baseline characteristics
| Characteristic | CBP-201 150 Q2W | CBP-201 300 Q2W | CBP-201 300 Q4W | Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 3 Participants | 4 Participants | 2 Participants | 14 Participants |
| Age, Categorical Between 18 and 65 years | 52 Participants | 54 Participants | 52 Participants | 54 Participants | 212 Participants |
| Age, Continuous | 39.5 years STANDARD_DEVIATION 15.98 | 39.6 years STANDARD_DEVIATION 14.79 | 41.7 years STANDARD_DEVIATION 15.22 | 39.6 years STANDARD_DEVIATION 14.79 | 40.1 years STANDARD_DEVIATION 15.13 |
| BSA | 39.86 percentage STANDARD_DEVIATION 19.145 | 43.11 percentage STANDARD_DEVIATION 20.738 | 37.34 percentage STANDARD_DEVIATION 19.479 | 37.71 percentage STANDARD_DEVIATION 18.341 | 39.52 percentage STANDARD_DEVIATION 19.456 |
| EASI Score | 24.61 units on a scale STANDARD_DEVIATION 10.471 | 27.57 units on a scale STANDARD_DEVIATION 11.776 | 23.08 units on a scale STANDARD_DEVIATION 8.218 | 25.16 units on a scale STANDARD_DEVIATION 9.021 | 25.11 units on a scale STANDARD_DEVIATION 10.042 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 24 Participants | 27 Participants | 24 Participants | 92 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants | 33 Participants | 29 Participants | 32 Participants | 134 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| IGA Score IGA 3 = Moderate disease | 43 Participants | 34 Participants | 40 Participants | 39 Participants | 156 Participants |
| IGA Score IGA 4 = Severe disease | 14 Participants | 23 Participants | 16 Participants | 17 Participants | 70 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 17 Participants | 9 Participants | 12 Participants | 14 Participants | 52 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 7 Participants | 10 Participants | 6 Participants | 31 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) White | 30 Participants | 38 Participants | 32 Participants | 32 Participants | 132 Participants |
| Region of Enrollment Australia | 1 participants | 1 participants | 1 participants | 0 participants | 3 participants |
| Region of Enrollment China | 11 participants | 6 participants | 9 participants | 6 participants | 32 participants |
| Region of Enrollment New Zealand | 5 participants | 3 participants | 5 participants | 6 participants | 19 participants |
| Region of Enrollment United States | 40 participants | 47 participants | 41 participants | 44 participants | 172 participants |
| Sex: Female, Male Female | 30 Participants | 27 Participants | 28 Participants | 36 Participants | 121 Participants |
| Sex: Female, Male Male | 27 Participants | 30 Participants | 28 Participants | 20 Participants | 105 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 57 | 0 / 57 | 1 / 56 | 0 / 56 |
| other Total, other adverse events | 26 / 57 | 21 / 57 | 34 / 56 | 31 / 56 |
| serious Total, serious adverse events | 1 / 57 | 0 / 57 | 2 / 56 | 2 / 56 |
Outcome results
Primary
Percent Reduction in EASI Score From Baseline to Week 16
EASI=Eczema Area Severity Index is a validated physician score for signs of atopic dermatitis. EASI can range from 0 to 72. An EASI score of 0 indicates clear/no eczema, 0.1 to 1.0 almost clear, 1.1 to 7 mild disease, 7.1 to 21 moderate disease, 21.1 to 50 severe disease, and 51-72 indicates very severe disease. EASI Sub-scale ranges are as follows: Head/neck can range from 0-7.2, Trunk 0-14.4, Upper Extremities 0-21.6, Lower Extremities can range from 0-28.8. To calculate EASI, % involvement is first assessed by body region with an Area involvement Score of 0-6 for each region: 0=0%, 1=1-9%, 2=10-29%, 3=30-39%, 4=50-69%, 5=70-89%, 6=90-100% involvement. Then 4 attributes (Erythema, Edema/Papulation, Excoriation, and Lichenification) are scored for severity (0= none, 1=mild, 2=moderate, 3=severe). A multiplier is applied head/neck=0.1, trunk=0.2, upper extremities= 0.3, lower extremities=0.4. The total EASI score is the sum of 4 regional sub-scores.
Time frame: Reduction from baseline to 16 weeks
Population: All efficacy analyses were carried out using the FAS (all randomized subjects who received at least part of an SC dose of study drug based on planned treatment assignment (ie, as randomized).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| CBP-201 150 Q2W | Percent Reduction in EASI Score From Baseline to Week 16 | 57.56 percent reduction from Baseline | Standard Error 4.61 |
| CBP-201 300 Q2W | Percent Reduction in EASI Score From Baseline to Week 16 | 63.03 percent reduction from Baseline | Standard Error 4.961 |
| CBP-201 300 Q4W | Percent Reduction in EASI Score From Baseline to Week 16 | 63.50 percent reduction from Baseline | Standard Error 4.661 |
| Placebo | Percent Reduction in EASI Score From Baseline to Week 16 | 39.67 percent reduction from Baseline | Standard Error 4.638 |
Comparison: The primary efficacy analysis includes comparison of percentage reduction in EASI from baseline to Week 16 for CBP-201 300 mg Q2W regimen vs placebo.~The sample size of the study was determined based on power calculations for the primary endpoint in patients receiving CBP-201 300 mg Q2W.~Null hypothesis: CBP-201 300 Q2W is not superior to placebo in terms of percent reduction in EASI Score from Baseline to Week 16.p-value: 0.0007ANCOVA
Comparison: The sample size of the study was determined based on power calculations for the primary endpoint in patients receiving CBP-201 300 mg Q2W.~Null hypothesis: CBP-201 150 Q2W is not superior to placebo in terms of percent reduction in EASI Score from Baseline to Week 16.p-value: 0.0067ANCOVA
Comparison: The efficacy analysis includes comparing percentage reduction in EASI from baseline to Week 16 for CBP-201 300 mg Q4W regimen vs placebo.~The sample size of the study was determined based on power calculations for the primary endpoint in patients receiving CBP-201 300 mg Q2W.~Null hypothesis: CBP-201 300 Q4W is not superior to placebo in terms of percent reduction in EASI Score from Baseline to Week 16.p-value: 0.0004ANCOVA
Secondary
vIGA of 0/1 at Week 16
Validated Investigator Global Assessment Score (vIGA) is assigned by the physician based on morphologic presentation of the disease in the clinic. The physician considers extent and severity of erythema, induration/papulation, lichenification, and oozing/crusting. A vIGA Score of 0=Clear, 1=Almost Clear, 2= Mild dermatitis, 3=Moderate dermatitis, and 4= Severe dermatitis. Patients are required to have a baseline IGA of 3 or 4. The response rate or percentage of patients achieving a vIGA of 0 or 1 (improved to clear or almost clear) at week 16 is the outcome.
Time frame: Response Rate at 16 weeks
Population: All efficacy analyses were carried out using the FAS (all randomized subjects who received at least part of an SC dose of study drug), based on planned treatment assignment (ie, as randomized).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CBP-201 150 Q2W | vIGA of 0/1 at Week 16 | 9 Participants |
| CBP-201 300 Q2W | vIGA of 0/1 at Week 16 | 16 Participants |
| CBP-201 300 Q4W | vIGA of 0/1 at Week 16 | 11 Participants |
| Placebo | vIGA of 0/1 at Week 16 | 5 Participants |
Comparison: Null hypothesis: CBP-201 300 Q2W is not superior to placebo in terms of the number of patients achieving a vIGA score of 0/1 (clear/almost clear) at Week 16.p-value: 0.0089Chi-squared