Hidradenitis Suppurativa
Conditions
Brief summary
Izokibep is a small protein molecule that acts as a selective, potent inhibitor of interleukin 17A, to which it binds with high affinity. This study investigates izokibep in participants with active Hidradenitis Suppurativa (HS), including tumor necrosis factor-alpha inhibitor (TNFi) naïve participants, and those who had an inadequate response or intolerance to TNFi, or for whom TNFi is contraindicated.
Interventions
DRUGPlacebo
Solution for injection
DRUGIzokibep
Solution for injection
Sponsors
ACELYRIN Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
General * Participant has provided signed informed consent including consenting to comply with the requirements and restrictions listed in the informed consent form (ICF) and in protocol * 18 years of age or older * No known history of active tuberculosis unless adequately treated according to World Health Organization/Center for Disease Control and Prevention therapeutic guidance and determined to be fully recovered by a tuberculosis specialist Type of Participant and Disease Characteristics * Diagnosis of HS for ≥ 6 months prior to first dose of study drug * Hidradenitis suppurativa lesions present in ≥ 2 distinct anatomic areas, one of which is Hurley Stage II or Hurley Stage III * A total AN count of ≥ 5 at screening and Day 1 prior to enrollment/randomization * Participant must have had an inadequate response to oral antibiotics OR exhibited recurrence after discontinuation to, OR demonstrated intolerance to, OR have a contraindication to oral antibiotics for treatment of their HS * Must agree to use daily or a minimum of 3 days a week over-the-counter topical antiseptics * Participant must be willing to complete a daily skin pain diary
Exclusion criteria
Medical Conditions * Draining fistula count of \> 20 * Outpatient surgery ≤ 8 weeks prior or inpatient surgery ≤ 12 weeks prior to enrollment/randomization * Other active skin disease or condition that could interfere with study assessments * History of active inflammatory bowel disease (IBD) OR symptoms within the last year that may be suggestive of IBD * Chronic pain not associated with HS * Uncontrolled, clinically significant system disease * History of demyelinating disease or neurological symptoms suggestive of demyelinating disease * Malignancy within 5 years * The participant is at risk of self-harm or harm to others * Active infection or history of certain infections * Tuberculosis or fungal infection seen on available chest x-ray taken within 3 months prior to first dose of study drug or at screening (Exception: documented evidence of completed treatment and clinically resolved) * Known history of human immunodeficiency virus (HIV) Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Hidradenitis Suppurativa Clinical Response 75 (HiSCR75) at Week 12 | Week 12 | The percentage of participants achieving HiSCR75 was defined as meeting all 3 criteria below: * (\[abscess and inflammatory nodule (AN) count at baseline - AN count at current visit\] / AN count at baseline) × 100% ≥ 75% * Abscess count at baseline ≥ abscess count at the current visit * Draining fistula count at baseline ≥ draining fistula count at the current visit. HiSCR75 was evaluated using nonresponse imputation (NRI) and multiple imputation (MI) methods. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving HiSCR100 at Week 12 | Week 12 | The percentage of participants achieving HiSCR100 was defined as meeting all 3 criteria below: * (\[AN count at baseline - AN count at current visit\] / AN count at baseline) × 100% = 100% * Abscess count at baseline ≥ abscess count at the current visit * Draining fistula count at baseline ≥ draining fistula count at the current visit. HiSCR100 was evaluated using nonresponse imputation (NRI) and multiple imputation (MI) methods. |
| Percentage of Participants Achieving HiSCR50 at Week 12 | Week 12 | The percentage of participants achieving HiSCR50 was defined as meeting all 3 criteria below: * \[(AN count at baseline - AN count at current visit) / AN count at baseline\] × 100% ≥ 50% * Abscess count at baseline ≥ abscess count at the current visit * Draining fistula count at baseline ≥ draining fistula count at the current visit. HiSCR50 was evaluated using nonresponse imputation (NRI) and multiple imputation (MI) methods. |
| Percentage of Participants Who Experienced One or More (≥ 1) Disease Flare at Week 12 | Up to Week 12 | HS flares were defined as ≥ 25% increase in AN count with a minimum increase of 2 AN relative to baseline, i.e. participants must meet all the following criteria: * (AN count at current visit- AN count at baseline) / AN count at baseline ×100% ≥ 25% * AN count at current visit- AN count at baseline ≥ 2. Participants who received antibiotic therapy that could affect HS were imputed as non-response (NRI). Other participants with missing data were imputed with multiple imputation. |
| Change From Baseline in Dermatology Life Quality Index (DLQI) | Baseline and Week 12 | DLQI included 10 items arranged in 6 categories: symptoms and feelings, daily activity, leisure, work or study, interpersonal relationships, and treatment. The total score could range from 0 (no impact to life quality) to 30 (maximum impact). |
| Percentage of Participants Achieving HiSCR90 at Week 12 | Week 12 | The percentage of participants achieving HiSCR90 was defined as meeting all 3 criteria below: * (\[AN count at baseline - AN count at current visit\] / AN count at baseline) × 100% ≥ 90% * Abscess count at baseline ≥ abscess count at the current visit * Draining fistula count at baseline ≥ draining fistula count at the current visit. HiSCR90 was evaluated using nonresponse imputation (NRI) and multiple imputation (MI) methods. |
| Percentage of Participants With Baseline NRS ≥ 4 Achieving at Least 3-point Reduction at Week 12 in Numeric Rating Scale (NRS) Patient Global Assessment of Skin Pain at Its Worst | Week 12 | NRS in Patient Global Assessment of Skin Pain ranged from 0 (no skin pain) to 10 (skin pain bad as you can imagine). The skin pain score at each visit was calculated using average of daily scores among the 7 days up to and including the day of visit, with a minimum of 4 days (consecutive or non-consecutive) with scores required. Reduction in NRS was evaluated using nonresponse imputation (NRI) and multiple imputation (MI) methods. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious AEs (SAEs) and Adverse Event of Special Interest (AESIs) in Period 1 | Up to Week 16 | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more of the criteria listed: results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event. The following events of special interest were monitored in this study: candida infection; inflammatory bowel disease (IBD); suicidal ideation; malignancies; major adverse cardiovascular and cerebrovascular events; tuberculosis; infections; cytopenias and systemic hypersensitivity reactions. Clinically significant changes in vital signs and laboratory tests recorded after treatment administration were documented as TEAEs. |
| Number of Participants With TEAEs, SAEs and AESIs in Period 2 | From Week 16 to follow-up, Week 59 | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more of the criteria listed: results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event. The following events of special interest were monitored in this study: candida infection; IBD; suicidal ideation; malignancies; major adverse cardiovascular and cerebrovascular events; tuberculosis; infections; cytopenias and systemic hypersensitivity reactions. Clinically significant changes in vital signs and laboratory tests recorded after treatment administration were documented as TEAEs. |
| Percentage of Participants With Baseline Hurley Stage II Who Achieved AN Count of 0, 1, or 2 at Week 12 | Week 12 | Calculated as observed values of 0, 1, or 2 for AN count (abscess count + inflammatory nodule count). AN count of 0, 1, or 2 was evaluated using nonresponse imputation (NRI) and multiple imputation (MI) methods. |
Countries
Canada, France, Germany, Hungary, Japan, Poland, Spain, United States
Participant flow
Recruitment details
A total of 258 participants were enrolled in Canada, France, Germany, Japan, Poland, Spain and the United States from June 2023 to January 2025. Participants were randomized to receive izokibep or placebo once weekly (QW) until Week 15 (Period 1). Then, all participants received izokibep QW from Week 16 until Week 51 (Period 2). The Sponsor decided to terminate the study early after all participants completed (or discontinued) treatment at Week 32.
Participants by arm
| Arm | Count |
|---|---|
| Placebo-Izokibep 160 mg QW Participants received placebo as a SC injection QW from Day 1 to Week 15, then izokibep as a SC injection QW from Week 16 to Week 51. | 129 |
| Izokibep 160 mg QW Participants received izokibep QW from Day 1 to Week 51. | 129 |
| Total | 258 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Decision by sponsor | 69 | 65 |
| Overall Study | Lost to Follow-up | 12 | 18 |
| Overall Study | Withdrawal by Subject | 29 | 37 |
Baseline characteristics
| Characteristic | Placebo-Izokibep 160 mg QW | Izokibep 160 mg QW | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 2 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 125 Participants | 127 Participants | 252 Participants |
| Age, Continuous | 37.4 years STANDARD_DEVIATION 12.85 | 37.1 years STANDARD_DEVIATION 11.89 | 37.3 years STANDARD_DEVIATION 12.35 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants | 12 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 108 Participants | 115 Participants | 223 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian | 10 Participants | 8 Participants | 18 Participants |
| Race/Ethnicity, Customized Black or African American | 28 Participants | 21 Participants | 49 Participants |
| Race/Ethnicity, Customized More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 5 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 90 Participants | 91 Participants | 181 Participants |
| Sex: Female, Male Female | 89 Participants | 89 Participants | 178 Participants |
| Sex: Female, Male Male | 40 Participants | 40 Participants | 80 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 / 129 | 0 / 129 | 0 / 109 | 0 / 100 |
| other Total, other adverse events | 35 / 129 | 93 / 129 | 69 / 109 | 40 / 100 |
| serious Total, serious adverse events | 5 / 129 | 1 / 129 | 3 / 109 | 4 / 100 |
Outcome results
Primary
Percentage of Participants Achieving Hidradenitis Suppurativa Clinical Response 75 (HiSCR75) at Week 12
The percentage of participants achieving HiSCR75 was defined as meeting all 3 criteria below: * (\[abscess and inflammatory nodule (AN) count at baseline - AN count at current visit\] / AN count at baseline) × 100% ≥ 75% * Abscess count at baseline ≥ abscess count at the current visit * Draining fistula count at baseline ≥ draining fistula count at the current visit. HiSCR75 was evaluated using nonresponse imputation (NRI) and multiple imputation (MI) methods.
Time frame: Week 12
Population: Full Analysis Set: all participants who were randomized.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo-Izokibep 160 mg QW | Percentage of Participants Achieving Hidradenitis Suppurativa Clinical Response 75 (HiSCR75) at Week 12 | 20.3 percentage of participants |
| Izokibep 160 mg QW | Percentage of Participants Achieving Hidradenitis Suppurativa Clinical Response 75 (HiSCR75) at Week 12 | 32.6 percentage of participants |
p-value: 0.018395% CI: [2.2, 23.7]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Dermatology Life Quality Index (DLQI)
DLQI included 10 items arranged in 6 categories: symptoms and feelings, daily activity, leisure, work or study, interpersonal relationships, and treatment. The total score could range from 0 (no impact to life quality) to 30 (maximum impact).
Time frame: Baseline and Week 12
Population: Full Analysis Set: all participants who were randomized. Only participants with a result at the timepoint are included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo-Izokibep 160 mg QW | Change From Baseline in Dermatology Life Quality Index (DLQI) | -2.71 Score on scale | Standard Error 0.519 |
| Izokibep 160 mg QW | Change From Baseline in Dermatology Life Quality Index (DLQI) | -4.87 Score on scale | Standard Error 0.536 |
p-value: 0.001195% CI: [-3.44, -0.88]Mixed model repeated measures (MMRM)
Secondary
Number of Participants With TEAEs, SAEs and AESIs in Period 2
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more of the criteria listed: results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event. The following events of special interest were monitored in this study: candida infection; IBD; suicidal ideation; malignancies; major adverse cardiovascular and cerebrovascular events; tuberculosis; infections; cytopenias and systemic hypersensitivity reactions. Clinically significant changes in vital signs and laboratory tests recorded after treatment administration were documented as TEAEs.
Time frame: From Week 16 to follow-up, Week 59
Population: Safety Analysis Set Period 2: All participants who were randomized and received at least 1 administration of study treatment in Period 2 of the Study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo-Izokibep 160 mg QW | Number of Participants With TEAEs, SAEs and AESIs in Period 2 | TEAEs | 87 Participants |
| Placebo-Izokibep 160 mg QW | Number of Participants With TEAEs, SAEs and AESIs in Period 2 | SAEs | 3 Participants |
| Placebo-Izokibep 160 mg QW | Number of Participants With TEAEs, SAEs and AESIs in Period 2 | AESIs | 5 Participants |
| Izokibep 160 mg QW | Number of Participants With TEAEs, SAEs and AESIs in Period 2 | TEAEs | 66 Participants |
| Izokibep 160 mg QW | Number of Participants With TEAEs, SAEs and AESIs in Period 2 | SAEs | 4 Participants |
| Izokibep 160 mg QW | Number of Participants With TEAEs, SAEs and AESIs in Period 2 | AESIs | 1 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious AEs (SAEs) and Adverse Event of Special Interest (AESIs) in Period 1
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more of the criteria listed: results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event. The following events of special interest were monitored in this study: candida infection; inflammatory bowel disease (IBD); suicidal ideation; malignancies; major adverse cardiovascular and cerebrovascular events; tuberculosis; infections; cytopenias and systemic hypersensitivity reactions. Clinically significant changes in vital signs and laboratory tests recorded after treatment administration were documented as TEAEs.
Time frame: Up to Week 16
Population: Safety Analysis Set: All participants who were randomized and received at least 1 administration of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo-Izokibep 160 mg QW | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious AEs (SAEs) and Adverse Event of Special Interest (AESIs) in Period 1 | TEAEs | 76 Participants |
| Placebo-Izokibep 160 mg QW | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious AEs (SAEs) and Adverse Event of Special Interest (AESIs) in Period 1 | SAEs | 5 Participants |
| Placebo-Izokibep 160 mg QW | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious AEs (SAEs) and Adverse Event of Special Interest (AESIs) in Period 1 | AESIs | 3 Participants |
| Izokibep 160 mg QW | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious AEs (SAEs) and Adverse Event of Special Interest (AESIs) in Period 1 | TEAEs | 107 Participants |
| Izokibep 160 mg QW | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious AEs (SAEs) and Adverse Event of Special Interest (AESIs) in Period 1 | SAEs | 1 Participants |
| Izokibep 160 mg QW | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious AEs (SAEs) and Adverse Event of Special Interest (AESIs) in Period 1 | AESIs | 0 Participants |
Secondary
Percentage of Participants Achieving HiSCR100 at Week 12
The percentage of participants achieving HiSCR100 was defined as meeting all 3 criteria below: * (\[AN count at baseline - AN count at current visit\] / AN count at baseline) × 100% = 100% * Abscess count at baseline ≥ abscess count at the current visit * Draining fistula count at baseline ≥ draining fistula count at the current visit. HiSCR100 was evaluated using nonresponse imputation (NRI) and multiple imputation (MI) methods.
Time frame: Week 12
Population: Full Analysis Set: all participants who were randomized.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo-Izokibep 160 mg QW | Percentage of Participants Achieving HiSCR100 at Week 12 | 7.3 percentage of participants |
| Izokibep 160 mg QW | Percentage of Participants Achieving HiSCR100 at Week 12 | 21.4 percentage of participants |
p-value: 0.000895% CI: [6.1, 23.4]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Achieving HiSCR50 at Week 12
The percentage of participants achieving HiSCR50 was defined as meeting all 3 criteria below: * \[(AN count at baseline - AN count at current visit) / AN count at baseline\] × 100% ≥ 50% * Abscess count at baseline ≥ abscess count at the current visit * Draining fistula count at baseline ≥ draining fistula count at the current visit. HiSCR50 was evaluated using nonresponse imputation (NRI) and multiple imputation (MI) methods.
Time frame: Week 12
Population: Full Analysis Set: all participants who were randomized.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo-Izokibep 160 mg QW | Percentage of Participants Achieving HiSCR50 at Week 12 | 36.5 percentage of participants |
| Izokibep 160 mg QW | Percentage of Participants Achieving HiSCR50 at Week 12 | 47.9 percentage of participants |
p-value: 0.046295% CI: [0.2, 24.3]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Achieving HiSCR90 at Week 12
The percentage of participants achieving HiSCR90 was defined as meeting all 3 criteria below: * (\[AN count at baseline - AN count at current visit\] / AN count at baseline) × 100% ≥ 90% * Abscess count at baseline ≥ abscess count at the current visit * Draining fistula count at baseline ≥ draining fistula count at the current visit. HiSCR90 was evaluated using nonresponse imputation (NRI) and multiple imputation (MI) methods.
Time frame: Week 12
Population: Full Analysis Set: all participants who were randomized.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo-Izokibep 160 mg QW | Percentage of Participants Achieving HiSCR90 at Week 12 | 9.2 percentage of participants |
| Izokibep 160 mg QW | Percentage of Participants Achieving HiSCR90 at Week 12 | 24.3 percentage of participants |
p-value: 0.000795% CI: [6.7, 25]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Experienced One or More (≥ 1) Disease Flare at Week 12
HS flares were defined as ≥ 25% increase in AN count with a minimum increase of 2 AN relative to baseline, i.e. participants must meet all the following criteria: * (AN count at current visit- AN count at baseline) / AN count at baseline ×100% ≥ 25% * AN count at current visit- AN count at baseline ≥ 2. Participants who received antibiotic therapy that could affect HS were imputed as non-response (NRI). Other participants with missing data were imputed with multiple imputation.
Time frame: Up to Week 12
Population: Full Analysis Set: all participants who were randomized.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo-Izokibep 160 mg QW | Percentage of Participants Who Experienced One or More (≥ 1) Disease Flare at Week 12 | 31.1 percentage of participants |
| Izokibep 160 mg QW | Percentage of Participants Who Experienced One or More (≥ 1) Disease Flare at Week 12 | 28.3 percentage of participants |
p-value: 0.628595% CI: [-14.3, 8.6]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Baseline Hurley Stage II Who Achieved AN Count of 0, 1, or 2 at Week 12
Calculated as observed values of 0, 1, or 2 for AN count (abscess count + inflammatory nodule count). AN count of 0, 1, or 2 was evaluated using nonresponse imputation (NRI) and multiple imputation (MI) methods.
Time frame: Week 12
Population: Full Analysis Set: all participants who were randomized. Participants with Hurley Stage II at baseline were included.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo-Izokibep 160 mg QW | Percentage of Participants With Baseline Hurley Stage II Who Achieved AN Count of 0, 1, or 2 at Week 12 | 25.0 percentage of participants |
| Izokibep 160 mg QW | Percentage of Participants With Baseline Hurley Stage II Who Achieved AN Count of 0, 1, or 2 at Week 12 | 49.5 percentage of participants |
p-value: 0.001395% CI: [9.6, 39.7]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Baseline NRS ≥ 4 Achieving at Least 3-point Reduction at Week 12 in Numeric Rating Scale (NRS) Patient Global Assessment of Skin Pain at Its Worst
NRS in Patient Global Assessment of Skin Pain ranged from 0 (no skin pain) to 10 (skin pain bad as you can imagine). The skin pain score at each visit was calculated using average of daily scores among the 7 days up to and including the day of visit, with a minimum of 4 days (consecutive or non-consecutive) with scores required. Reduction in NRS was evaluated using nonresponse imputation (NRI) and multiple imputation (MI) methods.
Time frame: Week 12
Population: Full Analysis Set: all participants who were randomized. Participants with baseline NRS ≥ 4 were included.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo-Izokibep 160 mg QW | Percentage of Participants With Baseline NRS ≥ 4 Achieving at Least 3-point Reduction at Week 12 in Numeric Rating Scale (NRS) Patient Global Assessment of Skin Pain at Its Worst | 17.2 Percentage of participants |
| Izokibep 160 mg QW | Percentage of Participants With Baseline NRS ≥ 4 Achieving at Least 3-point Reduction at Week 12 in Numeric Rating Scale (NRS) Patient Global Assessment of Skin Pain at Its Worst | 33.5 Percentage of participants |
p-value: 0.024595% CI: [2.1, 30.6]Cochran-Mantel-Haenszel