Netherton Syndrome
Conditions
Brief summary
This study is open to people with a skin disease called Netherton syndrome (NS). People can join the study if they are 12 years or older. The purpose of this study is to find out whether a medicine called spesolimab helps people with NS. Participants are divided into a spesolimab and a placebo group. Placebo injections look like spesolimab injections but do not contain any medicine. Every participant has a 2 in 3 chance of being in the spesolimab group. In the beginning, participants get the study medicine as an injection into a vein. Afterwards, they get it as an injection under the skin every month. After 4 months, participants in the placebo group switch to spesolimab treatment. Participants are in the study for up to 3 years. During this time, they visit the study site up to 42 times. The doctors regularly check participants' NS symptoms. The results are compared between the groups to see whether spesolimab works. The doctors also regularly check participants' general health and take note of any unwanted effects.
Interventions
Solution for infusion
DRUGPlacebo matching to spesolimab - solution for infusion
Solution for infusion
DRUGSpesolimab - solution for injection
Solution for injection
DRUGPlacebo matching to spesolimab - solution for injection
Solution for injection
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female patients, aged 12 years and older (weight minimum is 35kg). * Confirmed diagnosis of Netherton syndrome (NS) (causative SPINK5 mutations) at baseline (Visit 2). * At least moderate severity of erythema at baseline (visit 2) (Ichthyosis Area Severity Index (IASI) score ≥ 16 and IASI-Erythema (E) score ≥8) and ≥ 3 on Investigator Global Assessment (IGA) score. * Signed and dated written informed consent and assent in accordance with International Council on Harmonisation-Good Clinical Practice (ICH-GCP) and local legislation prior to admission in the trial * Women of childbearing potential (WOCBP) must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the clinical trial protocol (CTP) as well as in the patient, parent(s) (or patient's legal guardian) information.
Exclusion criteria
* Patients who have used topical corticosteroids (medium to high, US class I-V), topical retinoids, topical calcineurin inhibitors or keratolytics within 1 week prior to randomisation * Patients who have used emollient on the area to be biopsied in the previous 24 hours * Patients who have used systemic retinoids, other systemic immunosuppressants, systemic corticosteroids or phototherapy within 4 weeks prior to randomisation * Patients who have used systemic antibiotics within 2 weeks prior to randomisation * Patients who have received live vaccines within 4 weeks prior to randomisation * Patients who have received investigational products, biologics or immunoglobulins within 4 weeks or 5 half-lives (whichever is longer) prior to randomisation * Severe, progressive, or uncontrolled hepatic disease, defined as \>3-fold Upper Limit of Normal (ULN) elevation in Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) or alkaline phosphatase, or \>2-fold ULN elevation in total bilirubin * Patients who have any prior exposure to BI 655130 or another interleukin 36 receptor (IL-36R) inhibitor biologics * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| IASI Response, Defined as a Decrease of at Least 50% Absolute Change in IASI Score From Baseline at Week 16 (Yes/No) | At baseline and at Week 16. | Proportion of participants with an Ichthyosis Area Severity Index (IASI) response at Week 16 is reported. IASI response was defined as a decrease of at least 50% absolute change in IASI score from baseline at Week 16. Proportions were rounded to 3 decimal places. IASI is a composite score based on the global Congenital Ichthyosis Severity Instrument (CISI) score that captures differences in severity in different body regions as a function of their body surface area, and also standardizes the number of choices within the Likert scales for erythema and scaling. The score ranges from 0-48 (sum of a max score of 24 for erythema and 24 for scaling). A higher score means worse clinical severity. 95% confidence intervals (CI) are calculated using the method of Wilson. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Key Secondary Endpoint: IGA Response, Defined as a Decrease of at Least 1-grade Absolute Change in IGA Score From Baseline at Week 16 (Yes/No) | Baseline and at Week 16 after start of study treatment administration. | Proportion of participants with an Investigator Global Assessment (IGA) response at Week 16 is reported. Proportions were rounded to 3 decimal places. IGA response was defined as a decrease of at least 1-grade absolute change in IGA score from baseline at Week 16. IGA for Netherton Syndrome (NS) assessed the global severity of erythema and scaling in NS using a 5-point Likert scale ranging from 0=clear, to 4=severe. 95% confidence intervals (CI) are calculated using the method of Wilson. |
| IGA Score of 0 or 1 at Weeks 4, 8, 12 and 16 (Yes/No) | At Week 4, at Week 8, at Week 12, at Week 16 after start of study treatment administration. | Proportion of participants with an Investigator Global Assessment (IGA) score of 0 or 1 at Week 4, at Week 8, at Week 12 and at Week 16 after first study treatment administration is reported. Proportions were rounded to 3 decimal places. IGA for Netherton Syndrome (NS) assessed the global severity of erythema and scaling in NS using a 5-point Likert scale ranging from 0=clear, to 4=severe. 95% confidence intervals (CI) are calculated using the method of Wilson. |
| IASI Response, Defined as a Decrease of at Least 50% Absolute Change in IASI Score From Baseline at Weeks 4, 8, and 12 (Yes/No) | At baseline and at Week 4, at Week 8, at Week 12 after start of study treatment administration. | Proportion of participants with an Ichthyosis Area Severity Index (IASI) response at Weeks 4, 8, 12 is reported. Proportions were rounded to 3 decimal places. IASI response was defined as a decrease of at least 50% absolute change in IASI score from baseline at Week 4, Week 8 and Week 12. IASI is a composite score based on the global Congenital Ichthyosis Severity Instrument (CISI) score that captures differences in severity in different body regions as a function of their body surface area, and also standardizes the number of choices within the Likert scales for erythema and scaling. The score ranges from 0-48 (sum of a max score of 24 for erythema and 24 for scaling). A higher score means worse clinical severity. 95% confidence intervals (CI) are calculated using the method of Wilson. |
| IASI-E Subscore Response, Defined as a Decrease of at Least 50% Absolute Change in IASI-E Subscore at Weeks 4, 8, 12, and 16 (Yes/No) | At baseline and at Week 4, at Week 8, at Week 12, at Week 16 after start of study treatment administration. | Proportion of participants with an Ichthyosis Area Severity Index-Erythema (IASI-E) subscore response at Weeks 4, 8, 12 and 16 is reported. Proportions were rounded to 3 decimal places. IASI-E response was defined as a decrease of at least 50% absolute change in IASI-E subscore from baseline at Week 4, at Week 8, at Week 12 and at Week 16. IASI-E is a composite score based on the global Congenital Ichthyosis Severity Instrument (CISI) score that captures differences in severity in different body regions as a function of their body surface area, and also standardizes the number of choices within the Likert scales for erythema. The score ranges from 0-24. A higher score means worse clinical severity. 95% confidence intervals (CI) are calculated using the method of Wilson. |
| IASI-S Subscore Response, Defined as a Decrease of at Least 50% Absolute Change in IASI-S Subscore From Baseline at Weeks 4, 8, 12, and 16 (Yes/No) | At baseline and at Week 4, at Week 8, at Week 12, at Week 16 after start of study treatment administration. | Proportion of participants with an Ichthyosis Area Severity Index-Scaling (IASI-S) subscore response at Weeks 4, 8, 12 and 16 is reported. Proportions were rounded to 3 decimal places. IASI-S response was defined as a decrease of at least 50% absolute change in IASI-S subscore from baseline at Week 4, at Week 8, at Week 12 and at Week 16. IASI-S is a composite score based on the global Congenital Ichthyosis Severity Instrument (CISI) score that captures differences in severity in different body regions as a function of their body surface area, and also standardizes the number of choices within the Likert scales for scaling. The score ranges from 0-24. A higher score means worse clinical severity. 95% confidence intervals (CI) are calculated using the method of Wilson. |
| Percent Change From Baseline in IASI Score at Weeks 4, 8, 12 and 16 | MMRM model included measurements from baseline and Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 60, 68 after study treatment administration. MMRM values of percent change from baseline at Week 4, 8, 12, 16 are presented. | Percent change from baseline in IASI score at Weeks 4, 8, 12 and 16 is reported. IASI is a composite score based on the global Congenital Ichthyosis Severity Instrument (CISI) score that captures differences in severity in different body regions as a function of their body surface area, and also standardizes the number of choices within the Likert scales for erythema and scaling. The score ranges from 0-48 (sum of a max score of 24 for erythema and 24 for scaling). A higher score means worse clinical severity. Percent change of IASI score= (IASI score at Week X - IASI score at baseline)\*100/(IASI score at baseline). Week X=4, 8, 12, 16. Least Squares Mean (95% Confidence Interval) were calculated using mixed effect model with repeated measures (MMRM) which included the fixed, categorical effects of treatment at each visit, age group and the continuous effect of baseline at each visit as well as random effects of subject. |
| Absolute Change From Baseline in NRS Pain at Weeks 4, 8, 12 and 16 | MMRM model included measurements from baseline and Week 4, 8, 12, 16, 20, 24, 28, 32, 40, 52, 64 after study treatment administration. MMRM values of absolute change from baseline in NRS pain at Week 4, 8, 12, 16 are presented. | Absolute change from baseline in Numeric Pain Rating Scale (NRS) pain at Weeks 4, 8, 12 and 16 is presented. The NRS is a unidimensional measure of pain intensity, including chronic pain. The 11-point numeric scale ranges from '0' representing 'no pain' to '10' representing worst pain imaginable. Absolute change in NRS at Week X= (NRS pain at Week X) - (NRS pain at baseline). Week X= 4, 8, 12, 16. Least Squares Mean (95% Confidence Interval) were calculated using mixed effect model with repeated measures (MMRM) which included the fixed, categorical effects of treatment at each visit, age group and the continuous effect of baseline at each visit as well as random effects of subject. |
| Absolute Change From Baseline in NRS Itch at Weeks 4, 8, 12 and 16 | MMRM model included measurements from baseline and Week 4, 8, 12, 16, 20, 24, 28, 32, 40, 52, 64 after study treatment administration. MMRM values of absolute change from baseline in NRS itch at Week 4, 8, 12, 16 are presented. | The Numeric Pain Rating Scale (NRS) itch measures the intensity of itch. The scale ranges from '0' representing 'no itch' to 10 'worst imaginable itch'. Absolute change in NRS itch at Week X= (NRS itch at Week X) - (NRS itch at baseline). Week X= 4, 8, 12, 16. Least Squares Mean (95% Confidence Interval) were calculated using mixed effect model with repeated measures (MMRM) which included the fixed, categorical effects of treatment at each visit, age group and the continuous effect of baseline at each visit as well as random effects of subject. |
| Absolute Change From Baseline in DLQI Score at Weeks 8 and 16 | MMRM model included measurements from baseline and Week 8, 16, 24, 32, 52, after study treatment administration. MMRM values of absolute change from baseline in DLQI score at Week 8, 16 are presented. | Dermatology Life Quality Index (DLQI) assesses various dermatologic conditions and it measures the quality of life. It contains 10 questions which are score from 0 (not relevant) to 3 (very much). Question 7 is a "yes"/ "no" question where "yes" is scored as 3. Total score ranges from 0 to 30 in total. Scores of 0-1 indicate no effect, scores of 2-5 indicate a small effect, scores of 6-10 indicate moderate effect, score 11-20 indicate very large effect and scores 21-30 indicate an extremely large effect of the syndrome on the participant. Absolute change in DLQI score at Week X= (DLQI score at Week X) - (DLQI score at baseline). Week X= 8, 16. Least Squares Mean (95% Confidence Interval) were calculated using mixed effect model with repeated measures (MMRM) which included the fixed, categorical effects of treatment at each visit, age group and the continuous effect of baseline at each visit as well as random effects of subject. |
| Absolute Change From Baseline in CDLQI Score at Weeks 8 and 16 | At baseline and at Week 8 and at Week 16 after study treatment administration. | Children's Dermatology Life Quality Index (CDLQI) measures the impact of skin disease on the lives of children and young people. CDLQI total score is calculated by summing the scores of each question resulting in a range of 0 to 30. Scores of 0-1 indicate no effect, scores of 2-6 indicate a small effect, scores of 7-12 indicate moderate effect, score 13-18 indicate very large effect and scores 19-30 indicate an extremely large effect of the syndrome on the participant. Absolute change in CDLQI score at Week X= (CDLQI score at Week X) - (CDLQI score at baseline). Week X= 8, 16. |
| The Occurrence of Treatment Emergent Adverse Events Including Serious and/or Opportunistic Infections | From first study treatment administration until end of randomised period (Week 16) plus 16 weeks of residual effect period, up to 32 weeks. | Percentage of patients with treatment emergent adverse events including serious and/or opportunistic infections is presented. Percentages are rounded to one decimal place. |
Countries
Australia, Bulgaria, China, France, Germany, Israel, Italy, Japan, Malaysia, Netherlands, Portugal, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
This was a placebo-controlled trial to evaluate the efficacy and safety of spesolimab in the treatment of patients with Netherton syndrome.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 33.3 Years STANDARD_DEVIATION 18.2 |
| IASI score at baseline | 25.07 score on a scale STANDARD_DEVIATION 7.4 |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 24 Participants |
| Race/Ethnicity, Customized Not Stated | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 28 | 0 / 27 | 0 / 15 | 0 / 42 |
| other Total, other adverse events | 11 / 15 | 12 / 28 | 1 / 27 | 4 / 15 | 25 / 42 |
| serious Total, serious adverse events | 0 / 15 | 3 / 28 | 1 / 27 | 0 / 15 | 5 / 42 |
Outcome results
None listed