Eosinophilic Duodenitis, Eosinophilic Gastroenteritis
Conditions
Keywords
Eosinophil, Eosinophilic, Eosinophilic gastrointestinal disorders, EGID, EoD
Brief summary
This is a Phase 3, multi-center, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of lirentelimab (AK002) given monthly for 6 doses in adult patients with active eosinophilic duodenitis. Subjects who complete the randomized, double-blind, placebo-controlled treatment may have the option to receive 6 doses of open-label lirentelimab (AK002) through the OLE Period of the study.
Interventions
DRUGAK002
Lirentelimab (AK002) is a humanized non-fucosylated immunoglobulin G1(IgG1) monoclonal antibody directed against Siglec-8.
OTHERPlacebo
Placebo
Sponsors
Allakos 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 80 Years
Healthy volunteers
No
Inclusion criteria
1. Provide written informed consent. 2. Male or female aged ≥18 and ≤80 years at the time of signing the informed consent for entry. 3. Baseline endoscopic biopsy with ≥30 eosinophils/hpf in 3 hpf in the duodenum, as determined by central histology assessment of biopsies collected during the screening EGD + colonoscopy, without any other significant cause for the eosinophilia. 4. Completion of at least 4 daily PRO questionnaires per week for a minimum of 3 weeks during screening. 5. A weekly average score of abdominal pain, nausea, or diarrhea ≥3 on the PRO questionnaire (score from 0-10) for at least 2 weeks of screening and a weekly average TSS of ≥10 for at least 2 weeks of screening. 6. Inadequate or loss of response to, or intolerant to standard therapies for EoD symptoms, which could include PPI, antihistamines, systemic or topical corticosteroids, and/or diet, among others. 7. If patient is on pre-existing dietary restrictions, willingness to maintain dietary restrictions throughout the study. 8. Willing and able to comply with all study procedures and visit schedule including follow-up visits. 9. Female patients must be either post-menopausal for at least 1 year with FSH level \>30 MIU/mL at screening or surgically sterile (tubal ligation, hysterectomy, or bilateral oophorectomy) for at least 3 months, or if of childbearing potential, have a negative pregnancy test and agree to use dual methods of contraception, or abstain from sexual activity from screening until the end of the study, or for 120 days following the last dose of study drug, whichever is longer. Male patients with female partners of childbearing potential must agree to use a highly effective method of contraception from screening until the end of the study or for 120 days following the last dose of study drug, whichever is longer. All fertile men with female partners of childbearing potential should be instructed to contact the Investigator immediately if they suspect their partner might be pregnant (e.g., missed or later menstrual period) at any time during study participation.
Exclusion criteria
1. Use of systemic or topical corticosteroids exceeding the equivalent of 10 mg/day prednisone within 4 weeks prior to the screening visit. 2. Baseline endoscopic biopsy with ≥30 eosinophils/hpf in 5 hpf in the gastric mucosa as determined by central histology assessment of biopsies collected during the screening EGD. 3. Change in the dose of corticosteroids (systemic or topical), PPI, leukotrienes, or diet therapy within 4 weeks prior to the screening visit. 4. Treatment with any immunosuppressive or immunomodulatory drugs that may interfere with the study within 12 weeks prior to the screening visit. 5. Prior exposure to AK002 or known hypersensitivity to any constituent of the study drug. 6. Active Helicobacter pylori infection, unless treated and confirmed to be negative by repeat EGD (for baseline eosinophil count) prior to randomization and symptoms remain consistent. 7. History of inflammatory bowel disease, other chronic inflammatory diseases in the colon (with the exception of eosinophilic colitis), celiac disease, achalasia, or esophageal surgery. 8. History of bleeding disorders and/or esophageal varices. 9. Other causes of duodenal eosinophilia or eosinophilic granulomatosis with polyangiitis. 10. Women who are pregnant, breastfeeding, or planning to become pregnant while participating in the study. 11. Presence of an abnormal laboratory value considered to be clinically significant by the Investigator. 12. Any disease, condition (medical or surgical), or cardiac abnormality, which, in the opinion of the Investigator, would place the patient at increased risk. 13. History of malignancy, except carcinoma in situ, early stage prostate cancer, or non-melanoma skin cancers. However, patients with cancers that have been in remission for more than 5 years and are considered cured can be enrolled. 14. Treatment for a clinically significant helminthic parasitic infection within 6 months of screening. 15. Positive helminthic infection on Ova and Parasite (O&P) test. 16. Seropositive for Strongyloides stercoralis at screening. 17. Seropositive for HIV or hepatitis at screening, except for vaccinated patients or patients with past but resolved hepatitis, at screening. 18. Vaccination with live attenuated vaccines within 30 days prior to initiation of treatment in the study, during the treatment period, or vaccination expected within 5 half-lives (4 months) of study drug administration. This exclusion criterion does not apply to all types and formulations of vaccines (including live attenuated vaccines) authorized by FDA or other regulatory authority for the prevention of COVID-19, which may be administered before, during, or after the study. 19. Participation in a concurrent interventional study with the last intervention occurring within 30 days prior to study drug administration (or 90 days or 5 half-lives, whichever is longer, for biologic products). 20. Known history of alcohol, drug, or other substance abuse or dependence that is considered by the Investigator to be ongoing and clinically significant. 21. Any other reason that in the opinion of the Investigator or the Medical Monitor makes the patient unsuitable for enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Tissue Eosinophil Responders at Week 24 | At Week 24 | A tissue eosinophil responder is defined as mean eosinophil count \<=15 cells/HPF in 3 duodenal HPFs |
| Change in PRO Total Symptom Score (TSS) From Baseline to Weeks 23-24 | Baseline to Weeks 23 - 24 | The PRO Total Symptom Score (TSS) is a patient reported outcome (PRO) questionnaire comprises the following 6 symptoms: Abdominal pain intensity, Nausea intensity, Fullness before meal intensity, Loss of appetite intensity, Bloating intensity, and Abdominal cramping intensity. TSS scores can range from 0 to 60, with a lower score indicating less- severe symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment Responders | At Weeks 23-24 and Week 24, Respectively | Treatment responders defined by \>30% improvement in TSS and eosinophil count ≤15 cells per hpf in 3 duodenal hpf |
| Subjects Who Achive ≥50% Reduction in TSS From Baseline to Weeks 23-24 | At Weeks 23-24 | The PRO Total Symptom Score (TSS) is a patient reported outcome (PRO) questionnaire comprises the following 6 symptoms: Abdominal pain intensity, Nausea intensity, Fullness before meal intensity, Loss of appetite intensity, Bloating intensity, and Abdominal cramping intensity. TSS scores can range from 0 to 60, with a lower score indicating less- severe symptoms. |
| Percent Change in Tissue Eosinophils From Baseline to Week 24 | Baseline to Week 24 | Tissue eosinophil count obtained in biopsy specimens from the duodenum using esophago-gastro-duodenoscopy (EGD) |
| Percent Change in Weekly TSS Over Time Using MMRM | Baseline to Week 24 | The PRO Total Symptom Score (TSS) is a patient reported outcome (PRO) questionnaire comprises the following 6 symptoms: Abdominal pain intensity, Nausea intensity, Fullness before meal intensity, Loss of appetite intensity, Bloating intensity, and Abdominal cramping intensity. TSS scores can range from 0 to 60, with a lower score indicating less- severe symptoms. |
| Subjects Who Achieve ≥70% Reduction in TSS From Baseline to Weeks 23-24 | At Weeks 23-24 | The PRO Total Symptom Score (TSS) is a patient reported outcome (PRO) questionnaire comprises the following 6 symptoms: Abdominal pain intensity, Nausea intensity, Fullness before meal intensity, Loss of appetite intensity, Bloating intensity, and Abdominal cramping intensity. TSS scores can range from 0 to 60, with a lower score indicating less- severe symptoms. |
| Subjects Achieving Eosinophils Count ≤1 Cell/Hpf in 3 Highest Duodenal Hpf at Week 24 | At Week 24 | Tissue eosinophil count obtained in biopsy specimens from the duodenum using esophago-gastro-duodenoscopy (EGD) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 3.0 mg/kg of Lirentelimab (AK002) Subjects in this arm will receive 6 monthly doses of lirentelimab (AK002) at 3 mg/kg.
AK002: Lirentelimab (AK002) is a humanized non-fucosylated immunoglobulin G1(IgG1) monoclonal antibody directed against Siglec-8. | 46 |
| Placebo Subjects in this arm will receive 6 monthly doses of placebo at 3 mg/kg.
Placebo: Placebo | 47 |
| Total | 93 |
Baseline characteristics
| Characteristic | 3.0 mg/kg of Lirentelimab (AK002) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 49 years | 50 years | 50 years |
| Age, Customized <65 years | 38 Participants | 42 Participants | 80 Participants |
| Age, Customized >=65 years | 8 Participants | 5 Participants | 13 Participants |
| Baseline Duodenal Eosinophil Count | 43.9 Eosinophils/HPF STANDARD_DEVIATION 13.2 | 39.0 Eosinophils/HPF STANDARD_DEVIATION 10.2 | 41.4 Eosinophils/HPF STANDARD_DEVIATION 12 |
| Baseline Patient Reported Outcome Total and Symptom Scores | 30.1 Score on a scale STANDARD_DEVIATION 10.3 | 26.1 Score on a scale STANDARD_DEVIATION 9.1 | 28.1 Score on a scale STANDARD_DEVIATION 9.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 5 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants | 42 Participants | 81 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 4 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 11 Participants | 18 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 38 Participants | 32 Participants | 70 Participants |
| Region of Enrollment United States | 46 Participants | 47 Participants | 93 Participants |
| Sex: Female, Male Female | 38 Participants | 39 Participants | 77 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 0 / 47 |
| other Total, other adverse events | 18 / 46 | 19 / 47 |
| serious Total, serious adverse events | 2 / 46 | 1 / 47 |
Outcome results
Primary
Change in PRO Total Symptom Score (TSS) From Baseline to Weeks 23-24
The PRO Total Symptom Score (TSS) is a patient reported outcome (PRO) questionnaire comprises the following 6 symptoms: Abdominal pain intensity, Nausea intensity, Fullness before meal intensity, Loss of appetite intensity, Bloating intensity, and Abdominal cramping intensity. TSS scores can range from 0 to 60, with a lower score indicating less- severe symptoms.
Time frame: Baseline to Weeks 23 - 24
Population: Modified Intention-to-treat
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 3.0 mg/kg of Lirentelimab (AK002) | Change in PRO Total Symptom Score (TSS) From Baseline to Weeks 23-24 | -12.7 Score on a scale | Standard Error 1.7 |
| Placebo | Change in PRO Total Symptom Score (TSS) From Baseline to Weeks 23-24 | -13.0 Score on a scale | Standard Error 1.7 |
p-value: 0.882295% CI: [-4, 4.7]Mixed Models Analysis
Primary
Proportion of Tissue Eosinophil Responders at Week 24
A tissue eosinophil responder is defined as mean eosinophil count \<=15 cells/HPF in 3 duodenal HPFs
Time frame: At Week 24
Population: Modified Intention-to-treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 3.0 mg/kg of Lirentelimab (AK002) | Proportion of Tissue Eosinophil Responders at Week 24 | 38 Participants |
| Placebo | Proportion of Tissue Eosinophil Responders at Week 24 | 2 Participants |
p-value: <0.000195% CI: [62.2, 89.1]Fisher Exact
Secondary
Number of Treatment Responders
Treatment responders defined by \>30% improvement in TSS and eosinophil count ≤15 cells per hpf in 3 duodenal hpf
Time frame: At Weeks 23-24 and Week 24, Respectively
Population: Modified Intention-to-treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 3.0 mg/kg of Lirentelimab (AK002) | Number of Treatment Responders | 21 Participants |
| Placebo | Number of Treatment Responders | 1 Participants |
p-value: <0.000195% CI: [23.5, 59.9]Fisher Exact
Secondary
Percent Change in Tissue Eosinophils From Baseline to Week 24
Tissue eosinophil count obtained in biopsy specimens from the duodenum using esophago-gastro-duodenoscopy (EGD)
Time frame: Baseline to Week 24
Population: Modified Intention-to-treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 3.0 mg/kg of Lirentelimab (AK002) | Percent Change in Tissue Eosinophils From Baseline to Week 24 | -99.9 Percentage of Change | Standard Deviation 0.4 |
| Placebo | Percent Change in Tissue Eosinophils From Baseline to Week 24 | -24.1 Percentage of Change | Standard Deviation 30.5 |
p-value: <0.000195% CI: [-85.2, -64.7]ANCOVA
Secondary
Percent Change in Weekly TSS Over Time Using MMRM
The PRO Total Symptom Score (TSS) is a patient reported outcome (PRO) questionnaire comprises the following 6 symptoms: Abdominal pain intensity, Nausea intensity, Fullness before meal intensity, Loss of appetite intensity, Bloating intensity, and Abdominal cramping intensity. TSS scores can range from 0 to 60, with a lower score indicating less- severe symptoms.
Time frame: Baseline to Week 24
Population: Modified Intention-to-treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 3.0 mg/kg of Lirentelimab (AK002) | Percent Change in Weekly TSS Over Time Using MMRM | Week 2 | -16.5 Percentage of Change | Standard Deviation 41.8 |
| 3.0 mg/kg of Lirentelimab (AK002) | Percent Change in Weekly TSS Over Time Using MMRM | Week 4 | -22.6 Percentage of Change | Standard Deviation 34.6 |
| 3.0 mg/kg of Lirentelimab (AK002) | Percent Change in Weekly TSS Over Time Using MMRM | Week 6 | -30.4 Percentage of Change | Standard Deviation 35.4 |
| 3.0 mg/kg of Lirentelimab (AK002) | Percent Change in Weekly TSS Over Time Using MMRM | Week 8 | -31.4 Percentage of Change | Standard Deviation 37.5 |
| 3.0 mg/kg of Lirentelimab (AK002) | Percent Change in Weekly TSS Over Time Using MMRM | Week 10 | -38.0 Percentage of Change | Standard Deviation 33.1 |
| 3.0 mg/kg of Lirentelimab (AK002) | Percent Change in Weekly TSS Over Time Using MMRM | Week 12 | -40.4 Percentage of Change | Standard Deviation 33 |
| 3.0 mg/kg of Lirentelimab (AK002) | Percent Change in Weekly TSS Over Time Using MMRM | Week 14 | -45.0 Percentage of Change | Standard Deviation 35.6 |
| 3.0 mg/kg of Lirentelimab (AK002) | Percent Change in Weekly TSS Over Time Using MMRM | Week 16 | -47.0 Percentage of Change | Standard Deviation 35.7 |
| 3.0 mg/kg of Lirentelimab (AK002) | Percent Change in Weekly TSS Over Time Using MMRM | Week 18 | -46.4 Percentage of Change | Standard Deviation 33.7 |
| 3.0 mg/kg of Lirentelimab (AK002) | Percent Change in Weekly TSS Over Time Using MMRM | Week 20 | -46.7 Percentage of Change | Standard Deviation 36.3 |
| 3.0 mg/kg of Lirentelimab (AK002) | Percent Change in Weekly TSS Over Time Using MMRM | Week 22 | -50.7 Percentage of Change | Standard Deviation 37.2 |
| 3.0 mg/kg of Lirentelimab (AK002) | Percent Change in Weekly TSS Over Time Using MMRM | Week 24 | -46.3 Percentage of Change | Standard Deviation 37.5 |
| Placebo | Percent Change in Weekly TSS Over Time Using MMRM | Week 22 | -46.5 Percentage of Change | Standard Deviation 34.8 |
| Placebo | Percent Change in Weekly TSS Over Time Using MMRM | Week 2 | -13.3 Percentage of Change | Standard Deviation 37.6 |
| Placebo | Percent Change in Weekly TSS Over Time Using MMRM | Week 14 | -43.7 Percentage of Change | Standard Deviation 30.9 |
| Placebo | Percent Change in Weekly TSS Over Time Using MMRM | Week 4 | -19.7 Percentage of Change | Standard Deviation 29.1 |
| Placebo | Percent Change in Weekly TSS Over Time Using MMRM | Week 20 | -48.3 Percentage of Change | Standard Deviation 31.4 |
| Placebo | Percent Change in Weekly TSS Over Time Using MMRM | Week 6 | -31.2 Percentage of Change | Standard Deviation 31.2 |
| Placebo | Percent Change in Weekly TSS Over Time Using MMRM | Week 16 | -49.6 Percentage of Change | Standard Deviation 31.8 |
| Placebo | Percent Change in Weekly TSS Over Time Using MMRM | Week 8 | -32.6 Percentage of Change | Standard Deviation 33 |
| Placebo | Percent Change in Weekly TSS Over Time Using MMRM | Week 24 | -42.5 Percentage of Change | Standard Deviation 30.9 |
| Placebo | Percent Change in Weekly TSS Over Time Using MMRM | Week 10 | -35.4 Percentage of Change | Standard Deviation 31.8 |
| Placebo | Percent Change in Weekly TSS Over Time Using MMRM | Week 18 | -50.3 Percentage of Change | Standard Deviation 30.3 |
| Placebo | Percent Change in Weekly TSS Over Time Using MMRM | Week 12 | -38.1 Percentage of Change | Standard Deviation 37 |
Comparison: Weeks 24 Percent Change from Baselinep-value: 0.680595% CI: [-18.1, 11.8]Mixed Models Analysis
Secondary
Subjects Achieving Eosinophils Count ≤1 Cell/Hpf in 3 Highest Duodenal Hpf at Week 24
Tissue eosinophil count obtained in biopsy specimens from the duodenum using esophago-gastro-duodenoscopy (EGD)
Time frame: At Week 24
Population: Modified Intention-to-treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 3.0 mg/kg of Lirentelimab (AK002) | Subjects Achieving Eosinophils Count ≤1 Cell/Hpf in 3 Highest Duodenal Hpf at Week 24 | 37 Participants |
| Placebo | Subjects Achieving Eosinophils Count ≤1 Cell/Hpf in 3 Highest Duodenal Hpf at Week 24 | 0 Participants |
p-value: <0.000195% CI: [64.8, 90.6]Fisher Exact
Secondary
Subjects Who Achieve ≥70% Reduction in TSS From Baseline to Weeks 23-24
The PRO Total Symptom Score (TSS) is a patient reported outcome (PRO) questionnaire comprises the following 6 symptoms: Abdominal pain intensity, Nausea intensity, Fullness before meal intensity, Loss of appetite intensity, Bloating intensity, and Abdominal cramping intensity. TSS scores can range from 0 to 60, with a lower score indicating less- severe symptoms.
Time frame: At Weeks 23-24
Population: Modified Intention-to-treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 3.0 mg/kg of Lirentelimab (AK002) | Subjects Who Achieve ≥70% Reduction in TSS From Baseline to Weeks 23-24 | 11 Participants |
| Placebo | Subjects Who Achieve ≥70% Reduction in TSS From Baseline to Weeks 23-24 | 8 Participants |
p-value: 0.450295% CI: [-13.8, 26.3]Fisher Exact
Secondary
Subjects Who Achive ≥50% Reduction in TSS From Baseline to Weeks 23-24
The PRO Total Symptom Score (TSS) is a patient reported outcome (PRO) questionnaire comprises the following 6 symptoms: Abdominal pain intensity, Nausea intensity, Fullness before meal intensity, Loss of appetite intensity, Bloating intensity, and Abdominal cramping intensity. TSS scores can range from 0 to 60, with a lower score indicating less- severe symptoms.
Time frame: At Weeks 23-24
Population: Modified Intention-to-treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 3.0 mg/kg of Lirentelimab (AK002) | Subjects Who Achive ≥50% Reduction in TSS From Baseline to Weeks 23-24 | 13 Participants |
| Placebo | Subjects Who Achive ≥50% Reduction in TSS From Baseline to Weeks 23-24 | 14 Participants |
p-value: 195% CI: [-22.2, 18]Fisher Exact