PrecISE (Precision Interventions for Severe and/or Exacer... | NCT04129931

ID	Type	Description	Link
5U24HL138998-03	U.S. NIH Grant/Contract		View source

Name	Class
National Heart, Lung, and Blood Institute (NHLBI)	NIH

Label	Type	Description	Intervention Names
Medium Chain Triglycerides (MCT)	Experimental	Participants in this arm will receive Medium Chain Triglycerides (MCT) powder packets (12.5 g each) daily for the 16 week treatment period. Participants are assigned one packet per 500 kilocalories required to maintain bodyweight; the target dose for each participant is between 2 and 5 packets daily. Participants will mix the packets of MCT supplement powder into liquids or semi-solid food. Participants will be randomized to the treatment sequence and will receive either the active MCT or the matching placebo first or vice versa.	Drug: MCT Other: Placebo
Clazakizumab	Experimental	Participants randomized to this arm will receive a 12.5 mg dose of Clazakizumab via a subcutaneous injection at every study visit, every 4 weeks, during the 16-week treatment period at any point in the study. Participants will be randomized to the treatment sequence and will receive either the active Clazakizumab or the matching placebo first or vice versa.	Drug: Clazakizumab Other: Placebo
Broncho-Vaxom	Experimental	Participants randomized to this arm will receive 7 mg of Broncho-Vaxom once a day on an empty stomach for the 16-week treatment period duration at any point in the study. Participants will be randomized to the treatment sequence and will receive either the active Broncho-Vaxom or the matching placebo first or vice versa.	Drug: Broncho-Vaxom Other: Placebo
Imatinib	Experimental	Participants randomized to this arm will take two 100 mg Imatinib tablets orally once a day with a meal and an 8 oz glass of water for 2 weeks. Participants will then take four 100 mg tablets once a day with a meal and an 8 oz glass of water for 14 weeks. Participants will be randomized to the treatment sequence and will receive either the active Imatinib or the matching placebo first or vice versa.

Name	Type	Description	Arm Group Labels	Other Names
MCT	Drug	Mix 2-5 packets daily into liquid or food for 16 weeks.	Medium Chain Triglycerides (MCT)

Measure	Description	Time Frame
Forced Expiratory Volume in One Second (FEV1) Percent Predicted	Assessed prior to bronchodilator administration. Efficacy analyses will compare the end-of-period outcome values between test treatment and placebo.	Measured at 16 weeks after the start of treatment.
The Juniper Asthma Control Questionnaire (ACQ-6)	Asthma symptom control is assessed via ACQ-6, the average score of these six items (range 0-6). The seven-point response scale: 0 = 'totally controlled' and 6 = 'severely uncontrolled'. Negative change from baseline values indicate improved asthma control. Efficacy analyses will compare the end-of-period outcome values between test treatment and placebo.	Measured at 16 weeks after the start of treatment.

Measure	Description	Time Frame
CompEx Events Per Year	Composite outcome with exacerbations (CompEx) is an outcome specific to asthma and chronic obstructive pulmonary disease (COPD) that combines clinically-relevant deteriorations with exacerbations. Deterioration events defined based on daily recordings of peak expiratory flow (PEF) morning/evening (L/min), reliever use morning/evening (doses), symptoms morning/evening (score 0-3) from twice-daily recordings. Participants are asked to describe their morning and evening symptoms using the following scale: 0-No symptoms to report, 3-I could not sleep because of my asthma/I could not perform my normal activities because of my asthma.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Provision of signed and dated informed consent form
Started willingness to comply with all study procedures and availability for the duration of the study
Male or female, age ≥ 12 years
No change in asthma medications for the past 2 months and use of medium or high dose inhaled corticosteroids (ICS) (defined by Table 1A) + an additional asthma controller/biologic (defined in Tables 1B and 1C). Participants entered into the run-in on medium dose ICS will be switched to high dose ICS. They must meet all entry criteria at the time of randomization including the criteria for uncontrolled asthma as assessed by symptoms during the two weeks prior to the randomization.
Baseline poor or uncontrolled asthma, defined as meeting at least one of the following:
1. Forced Expiratory Volume in one second (FEV1) <80% predicted (for adults ≥18) or FEV1<90% (pediatric participants <18) AND with 12% bronchodilator reversibility
2. Poor symptom control - Asthma Control Questionnaire (ACQ-6) Score ≥1.5
3. ≥1 exacerbation defined as a documented burst of systemic corticosteroids (>3 days for adults and adolescents or >1 day for adolescents treated with dexamethasone) in prior year for those not receiving chronic oral corticosteriod (OCS) or an increase in >50% of baseline corticosteroid dose for ≥3 days in those receiving chronic OCS.
  - For patients on a biologic agent, at least one asthma exacerbation must have occurred at least 2 months after the initiation of the biologic agent. The definition of acceptable documentation for asthma exacerbations can be found in Section 6.5.3.
Evidence of asthma demonstrated by either bronchodilator reversibility or methacholine responsiveness either during the run-in or by historical evidence of either criterion if testing was performed under the same standards of the PrecISE Network at a PrecISE recruitment center. These criteria are defined as:
1. An increase in FEV1 ≥12% (and 200 ml) after up to 8 puffs of albuterol OR
2. Positive methacholine defined as provocative concentration causing a 20% decrease in FEV1 (PC20) ≤16 mg/ml, or provocative dose causing a 20% decline in FEV1 (PD20) ≤400 mcg/ml
Agreement to adhere to Lifestyle Considerations (see Section 5.4) throughout study duration
Owns a device compatible with the eDiary system used for CompEx, that is, an iOS 11+ device such as iPhone, iPad or iPod, or a smartphone or tablet running on Android 5.0+

Exclusion Criteria:

Current participation in an interventional trial (e.g. drugs, diets, etc.)
Enrollment in a clinical trial where the study medication was administered within the past 60 days or within 5 half-lives (whichever is greater)
Physician diagnosis of other chronic pulmonary disorders associated with asthma-like symptoms, including, but not limited to, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, severe scoliosis or chest wall deformities that affect lung function, or congenital disorders of the lungs or airways
Receiving one or more immune-modulating therapies for diseases other than asthma
Receiving methotrexate, mycophenolate (CellCept®), or azathioprine (Imuran®)
Receiving aero allergen immunotherapy and not on at least 3 months of maintenance allergen immunotherapy
Underwent a bronchial thermoplasty within the last two years
Born before 35 weeks of gestation
Uncontrolled hypertension, defined as systolic blood pressure >160 mm/Hg, or diastolic blood pressure >100 mm/Hg
History of malignancy except non-melanoma skin cancer within the last five years
History of smoking
1. If <30 years old: Smoked for ≥5 pack-years*
  - Can still be enrolled if <30, smoked <5 5 pack years and none in past year, and normal (negative) urine cotinine
2. If 30-39 years old: Smoked for ≥10 pack years
  - Can still be enrolled if ≥30, smoked <10 pack years and none in past year, provided participant demonstrates a normal (negative) urine cotinine
3. If ≥40 years old: Smoked ≥15 pack years
  - Can still be enrolled if ≥40 years old, smoked <15 pack years and none in the last year, provided participant demonstrates normal (negative) urine cotinine. Patients with a smoking history of ≥10 to <15 pack years will also need to demonstrate a normal Diffusing Capacity for Carbon Monoxide (DLCO) (>70% predicted) * Smoking equivalent pack years. One pack of cigarettes a day for 1 year is equivalent to:
1. 1 cigar or pipe per day for 1 year
2. Smoked hookah or shisha =1 session per day for 1 year
3. Vaped e-cigarettes =0.5 mLs e-liquid per day for 1 year, or =1 cartridge/tank/pod per day for 1 year
4. 1 use of marijuana per day for 1 year
Active use of any inhalant >1 time per month in the past year
1. Active smoking of conventional tobacco, inhaling of marijuana or other drugs, or vaping of e-cigarettes or vape pods >1 time per month in the past year
2. Any form of tobacco qualifies, such as: 1 cigarette, 1 hookah or shisha sessions, 1 cigar, 1 pipe, etc.
3. Any electronic (e)-device included: e-cigarette e-cig, mod, vape pen, JUUL vaping device, e-cigar, e-hookah, e-pipe, vape pods, etc.
4. Any form of inhaled marijuana, including smoking marijuana leaves or inhaling tetrahydrocannabinol (THC) via e-cigarette or device
Substance abuse within the last year
Unwillingness to practice medically acceptable birth control or complete abstinence during the study, current pregnancy, or lactation. Medically acceptable birth control/abstinence is defined as:
1. Career, lifestyle, or sexual orientation precludes intercourse with a male partner
2. For those in a monogamous relationship that precludes sexual activity with other partners, one of the sexual partners has been sterilized by vasectomy (in males) or hysterectomy and/or bilateral salpingo-oophorectomy (in females)
3. Use of highly effective methods of birth control defined as those, alone or in combination, that result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. Contraception should be used for at least 1 month prior to screening, throughout study participation and for an additional 16 weeks after the end of the final test treatment.
  - Pregnancy tests will be given to each female participant prior to study enrollment and at each clinic visit
  - Each male participant will agree to inform his sexual partner(s) of the potential for harm to an unborn child. If a sexual partner becomes pregnant while he is participating in the study, he will notify study staff within 24 hours of receiving medical confirmation. His partner will be advised to promptly notify her doctor
  - Any pregnancy (of a participant or a partner) will be monitored for adverse events with respect to pregnancy outcome until one month after birth.
Requirement for daily systemic corticosteroids above 10 mg of prednisone (or equivalent) per day for the past 2 months
Respiratory infection within 1 month of screening
Intubation for asthma in the last 12 months
Use of warfarin, current or last 30 days
Any clinically significant abnormal findings in the history, physical examination, vital signs, electrocardiogram, hematology or clinical chemistry during run-in period, which in the opinion of the site investigator, may put the participant at risk because of his/her participation in the study, or may influence the results of the study, or the participant's ability to complete the entire duration of the study
Additional exclusions for specific interventions (and not for others) are listed in the Appendices I-VI, Section 5.2

Safety Exclusion Criteria:

Participants who meet the following criteria will be excluded from the study:

Hemoglobin <10 g/dL
Absolute Neutrophil Count (ANC) <1000/µl for black participants, <1500/µl for other participants
Lymphocytes <500/µl
Platelet count <100,000/µl
Alanine Transaminase (ALT)/Aspartate Aminotransferase (AST) >2x upper limits of normal (ULN)
Bilirubin ≥2x ULN
Estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 sq m
Positive Human Immunodeficiency Virus, Types 1 & 2 (HIV 1&2) Ab/Ag immunoassay followed by a confirmatory positive test (Geenius™ HIV-1/HIV-2 antibody differentiation immunoassay)
Positive Hepatitis B surface Ag (active infection) or Hepatitis B core total antibody (marker of past infection that could reactivate)
Positive Hepatitis C RNA test following positive Hepatitis C Antibody
EKG with significant clinical findings

A positive QuantiFERON-TB tuberculosis (TB) Gold test requires further screening. A participant may be included in PrecISE if at least one of the following criteria are met:

A chest radiograph (CXR) done within the last six months of the test that shows no evidence of active TB
A chest CT scan done within the last six months of the test that shows no evidence of active TB
Documentation of adequate treatment for latent TB In cases of an indeterminate QuantiFERON-TB test result, a second blood specimen must be drawn. A chest x-ray is not required if the participant has a negative QuantiFERON-TB Gold test.

Comorbid Conditions:

Comorbidities are commonly present in severe asthma. Specific questionnaires will be used to identify common comorbidities as follows:

Sleep apnea: STOP-BANG Questionnaire
GERD (GERD- Questionnaire)
VCD (Pittsburgh Vocal Cord Dysfunction (VCD) index)
Chronic Rhinitis Sinusitis (Sinonasal questionnaire-SNQ5)
Depression-Anxiety (Hospital anxiety and depression Scale: HADS) These questionnaires are best used as screening tools. As such they typically have high sensitivity but relatively low specificity. Many of their symptoms overlap with the symptoms reported by participants with asthma who do not suffer from these conditions. Therefore, participants who meet the established cut offs for these questionnaires will need to be evaluated by the investigator to consider the clinical significance of the positive questionnaire based on history and physical and available testing. The investigator will need to judge the presence, severity and control of a specific condition and determine if it is sufficiently controlled to keep the participant in the PrecISE protocol. If the comorbid condition(s) is/are not adequately controlled, the investigator may refer the participant for further evaluation/treatment, prior to enrollment in PrecISE. Rescreening is permitted (after at least four weeks) to determine if the participant is able to move forward in PrecISE once the comorbid condition(s) is/are under adequate control. It is expected that some of the participants may also have other conditions such as cardiovascular disease, diabetes and obesity. These should be evaluated clinically as part of the complete history and physical done at initial evaluation. Their inclusions should be based on the investigator clinical judgement in line with good clinical practice principles.

Name	Affiliation	Role
Anastasia Ivanova, PhD	University of North Carolina, Chapel Hill	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Mayo Clinic Scottsdale		Scottsdale	Arizona	85259	United States
University of Arizona Tucson

PubMed Identifier	Type	Citation	Retractions
28877019	Background	Israel E, Reddel HK. Severe and Difficult-to-Treat Asthma in Adults. N Engl J Med. 2017 Sep 7;377(10):965-976. doi: 10.1056/NEJMra1608969. No abstract available.
28679092	Background	Woodcock J, LaVange LM. Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both. N Engl J Med. 2017 Jul 6;377(1):62-70. doi: 10.1056/NEJMra1510062. No abstract available.

Label	URL
US Food and Drug Administration. Draft Guidance for Industry: Adaptive Designs for Clinical Trials of Drugs and Biologics.	View source

ID	Title	Description
FG000	All Participants	Participants could receive multiple interventions in different sequences under a multi-period crossover design wtih over 200 possible sequences. Clazakizumab: 12.5 mg subcutaneous injection given once every 4 weeks for 16 weeks. Lab driven dose reductions made based on safety lab data. Clazakizumab Placebo: 12.5 mg subcutaneous saline injection given once every 4 weeks for 16 weeks Medium ChainTriglycerides (MCT): Mix 2.5 packets daily into liquid or food for 16 weeks MCT Placebo: MCT-matching placebo packets. Mix 2-5 packets daily into liquid or food for 16 weeks Imatinib Mesylate: Two 100 mg tablets orally once a day with a meal and 8 oz water for 2 weeks. If well tolerated, participants titrated up to 4-100 mg tablets once daily with a meal and 8 oz water for 14 weeks Imatinib Placebo: Two 100 mg placebo tablets orally once a day with a meal and 8 oz water for 2 weeks. Then four 100 mg placebo tablets once a day with a meal and 8 oz water for 14 weeks Broncho-Vaxom: 7 mg taken orally once a day, on an empty stomach, for 16 weeks Broncho-Vaxom Placebo: 7 mg matching placebo taken orally once a day on an empty stomach for 16 weeks Cavosonstat: 50 mg capsule orally twice a day for 16 weeks Cavosonstat Placebo: 50 mg matching placebo capsule orally twice a day for 16 weeks

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Sep 27, 2024	Jan 20, 2026

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Forced Expiratory Volume in One Second (FEV1) Percent Predicted

Assessed prior to bronchodilator administration. Efficacy analyses will compare the end-of-period outcome values between test treatment and placebo.

Posted

Mean

95% Confidence Interval

percent predicted

Measured at 16 weeks after the start of treatment.

ID	Title	Description
OG000	Cavosonstat	Participants randomized to this arm will take one 50 mg cavosonstat tablet orally twice a day for the 16-week treatment period duration at any point in the study. Only the biomarker positive subgroup participants with ADH5 genotypes rs7669660 TT and rs11547772 AA are included.
OG001	Cavosonstat Arm Placebo	For this arm, study treatment may include cavosonstat matched placebo or non cavosonstat matched placebo. Minimally, all cavosonstat matched placebo is included. If a cavosonstat matched placebo was unavailable for a participant who was randomized to active cavosonstat, any placebo (up to a maximum of two placebos) administered to the participant was included. Only the biomarker positive subgroup participants with ADH5 genotypes rs7669660 TT and rs11547772 AA are included. The following placebos are available: Cavosonstat Matching Placebo: 50 mg matching placebo tablet orally twice a day for 16 weeks MCT Matching Placebo: MCT matching placebo packets. Mix 2-5 packets into liquid or food daily for 16 weeks Clazakizumab Matching Placebo: 12.5 mg subcutaneous saline injection given once every 4 weeks, total of 4 injections Broncho-Vaxom Matching Placebo: 7 mg matching placebo taken orally once a day on an empty stomach for 16 weeks Imatinib Matching Placebo: encapsulated placebo orally once a day with a meal and an 8 oz glass of water for 16 weeks
OG002	Broncho-Vaxom	Participants randomized to this arm will receive 7 mg of Broncho-Vaxom once a day on an empty stomach for the 16-week treatment period duration at any point in the study.
OG003	Broncho-Vaxom Arm Placebo	For this arm, study treatment may include Broncho-Vaxom matched placebo or non-Broncho-Vaxom matched placebo. Minimally, all Broncho-Vaxom matched placebo is included. If a Broncho-Vaxom matched placebo was unavailable for a participant who was randomized to active Broncho-Vaxom, any placebo (up to a maximum of two placebos) administered to the participant was included. The following placebos are available: Cavosonstat Matching Placebo: 50 mg matching placebo tablet orally twice a day for 16 weeks MCT Matching Placebo: MCT matching placebo packets. Mix 2-5 packets into liquid or food daily for 16 weeks Clazakizumab Matching Placebo: 12.5 mg subcutaneous saline injection given once every 4 weeks, total of 4 injections Broncho-Vaxom Matching Placebo: 7 mg matching placebo taken orally once a day on an empty stomach for 16 weeks Imatinib Matching Placebo: encapsulated placebo orally once a day with a meal and an 8 oz glass of water for 16 weeks
OG004	Imatinib	At any point in the study, participants randomized to this arm will take two encapsulated 100 mg imatinib tablets orally once a day with a meal and an 8 oz glass of water for 2 weeks. Participants will then take four encapsulated 100 mg tablets once a day with a meal and an 8 oz glass of water for 14 weeks.
OG005	Imatinib Arm Placebo	For this arm, study treatment may include imatinib matched placebo or non-imatinib matched placebo. Minimally, all imatinib matched placebo is included. If an imatinib matched placebo was unavailable for a participant who was randomized to active imatinib, any placebo (up to a maximum of two placebos) administered to the participant was included. The following placebos are available: Cavosonstat Matching Placebo: 50 mg matching placebo tablet orally twice a day for 16 weeks MCT Matching Placebo: MCT matching placebo packets. Mix 2-5 packets into liquid or food daily for 16 weeks Clazakizumab Matching Placebo: 12.5 mg subcutaneous saline injection given once every 4 weeks, total of 4 injections Broncho-Vaxom Matching Placebo: 7 mg matching placebo taken orally once a day on an empty stomach for 16 weeks Imatinib Matching Placebo: encapsulated placebo orally once a day with a meal and an 8 oz glass of water for 16 weeks
OG006	Medium Chain Triglycerides (MCT)	Participants in this arm will receive Medium Chain Triglycerides (MCT) powder packets (12.5 g each) daily during the 16-week treatment period. Participants will mix 2-5 packets of MCT supplement powder into liquids or semi-solid food daily.
OG007	MCT Arm Placebo	For this arm, study treatment may include MCT matched placebo or non- MCT matched placebo. Minimally, all MCT matched placebo is included. If an MCT matched placebo was unavailable for a participant who was randomized to active MCT, any placebo (up to a maximum of two placebos) administered to the participant was included. The following placebos are available: Cavosonstat Matching Placebo: 50 mg matching placebo tablet orally twice a day for 16 weeks MCT Matching Placebo: MCT matching placebo packets. Mix 2-5 packets into liquid or food daily for 16 weeks Clazakizumab Matching Placebo: 12.5 mg subcutaneous saline injection given once every 4 weeks, total of 4 injections Broncho-Vaxom Matching Placebo: 7 mg matching placebo taken orally once a day on an empty stomach for 16 weeks Imatinib Matching Placebo: encapsulated placebo orally once a day with a meal and an 8 oz glass of water for 16 weeks
OG008	Clazakizumab	Participants randomized to this arm will receive a 12.5 mg dose of clazakizumab via a subcutaneous injection at every study visit, every 4 weeks, 4 injections total, during the 16-week treatment period
OG009	Clazakizumab Arm Placebo	For this arm, study treatment may include clazakizumab matched placebo or non-clazakizumab matched placebo. Minimally, all clazakizumab matched placebo is included. If a clazakizumab matched placebo was unavailable for a participant who was randomized to active clazakizumab, any placebo (up to a maximum of two placebos) administered to the participant was included. The following placebos are available: Cavosonstat Matching Placebo: 50 mg matching placebo tablet orally twice a day for 16 weeks MCT Matching Placebo: MCT matching placebo packets. Mix 2-5 packets into liquid or food daily for 16 weeks Clazakizumab Matching Placebo: 12.5 mg subcutaneous saline injection given once every 4 weeks, total of 4 injections Broncho-Vaxom Matching Placebo: 7 mg matching placebo taken orally once a day on an empty stomach for 16 weeks Imatinib Matching Placebo: encapsulated placebo orally once a day with a meal and an 8 oz glass of water for 16 weeks

Units	Counts
Participants	OG00072 OG00185 OG002125 OG003

Title

Denominators

Categories

Title	Measurements
	OG00065.6(61.2 to 70.0) OG00166.0(61.4 to 70.6) OG00270(66.2 to 73.8) OG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	As indicated in the arm description, the primary analysis of cavosonstat was only in participants with ADH5 genotypes rs7669660 TT and rs11547772 AA	Mixed Models Analysis		0.447	compared with 0.05	Mean Difference (Final Values)	-1.10			2-Sided	95	-3.93	1.74					Superiority
OG002

Primary

The Juniper Asthma Control Questionnaire (ACQ-6)

Asthma symptom control is assessed via ACQ-6, the average score of these six items (range 0-6). The seven-point response scale: 0 = 'totally controlled' and 6 = 'severely uncontrolled'. Negative change from baseline values indicate improved asthma control. Efficacy analyses will compare the end-of-period outcome values between test treatment and placebo.

Posted

Mean

95% Confidence Interval

score on a scale

Measured at 16 weeks after the start of treatment.

ID	Title	Description
OG000	Cavosonstat	Participants randomized to this arm will take one 50 mg cavosonstat tablet orally twice a day for the 16-week treatment period duration at any point in the study. Only the biomarker positive subgroup participants with ADH5 genotypes rs7669660 TT and rs11547772 AA are included.
OG001	Cavosonstat Arm Placebo	For this arm, study treatment may include cavosonstat matched placebo or non cavosonstat matched placebo. Minimally, all cavosonstat matched placebo is included. If a cavosonstat matched placebo was unavailable for a participant who was randomized to active cavosonstat, any placebo (up to a maximum of two placebos) administered to the participant was included. Only the biomarker positive subgroup participants with ADH5 genotypes rs7669660 TT and rs11547772 AA are included. The following placebos are available: Cavosonstat Matching Placebo: 50 mg matching placebo tablet orally twice a day for 16 weeks MCT Matching Placebo: MCT matching placebo packets. Mix 1-2 packets, as instructed by a physician, into liquid or food three times daily for 16 weeks Clazakizumab Matching Placebo: 12.5 mg subcutaneous saline injection given once every 4 weeks, total of 4 injections Broncho-Vaxom Matching Placebo: 7 mg matching placebo taken orally once a day on an empty stomach for 16 weeks Imatinib Matching Placebo: encapsulated placebo orally once a day with a meal and an 8 oz glass of water for 16 weeks

Secondary

CompEx Events Per Year

Composite outcome with exacerbations (CompEx) is an outcome specific to asthma and chronic obstructive pulmonary disease (COPD) that combines clinically-relevant deteriorations with exacerbations. Deterioration events defined based on daily recordings of peak expiratory flow (PEF) morning/evening (L/min), reliever use morning/evening (doses), symptoms morning/evening (score 0-3) from twice-daily recordings. Participants are asked to describe their morning and evening symptoms using the following scale: 0-No symptoms to report, 3-I could not sleep because of my asthma/I could not perform my normal activities because of my asthma.

Posted

Mean

95% Confidence Interval

CompEx events per year

Assessed over 16 weeks of treatment

ID	Title	Description
OG000	Cavosonstat	Participants randomized to this arm will take one 50 mg cavosonstat tablet orally twice a day for the 16-week treatment period duration at any point in the study. Only the biomarker positive subgroup participants with ADH5 genotypes rs7669660 TT and rs11547772 AA are included.
OG001	Cavosonstat Arm Placebo	For this arm, study treatment may include cavosonstat matched placebo or non cavosonstat matched placebo. Minimally, all cavosonstat matched placebo is included. If a cavosonstat matched placebo was unavailable for a participant who was randomized to active cavosonstat, any placebo (up to a maximum of two placebos) administered to the participant was included. Only the biomarker positive subgroup participants with ADH5 genotypes rs7669660 TT and rs11547772 AA are included. The following placebos are available: Cavosonstat Matching Placebo: 50 mg matching placebo tablet orally twice a day for 16 weeks MCT Matching Placebo: MCT matching placebo packets. Mix 1-2 packets, as instructed by a physician, into liquid or food three times daily for 16 weeks Clazakizumab Matching Placebo: 12.5 mg subcutaneous saline injection given once every 4 weeks, total of 4 injections Broncho-Vaxom Matching Placebo: 7 mg matching placebo taken orally once a day on an empty stomach for 16 weeks Imatinib Matching Placebo: encapsulated placebo orally once a day with a meal and an 8 oz glass of water for 16 weeks

Secondary

Forced Vital Capacity (FVC) Pre-bronchodilation

Assessed prior to bronchodilator administration

Posted

Mean

95% Confidence Interval

% predicted

Measured at 16 weeks after the start of treatment.

ID	Title	Description
OG000	Cavosonstat	Participants randomized to this arm will take one 50 mg cavosonstat tablet orally twice a day for the 16-week treatment period duration at any point in the study. Only the biomarker positive subgroup participants with ADH5 genotypes rs7669660 TT and rs11547772 AA are included.
OG001	Cavosonstat Arm Placebo	For this arm, study treatment may include cavosonstat matched placebo or non cavosonstat matched placebo. Minimally, all cavosonstat matched placebo is included. If a cavosonstat matched placebo was unavailable for a participant who was randomized to active cavosonstat, any placebo (up to a maximum of two placebos) administered to the participant was included. Only the biomarker positive subgroup participants with ADH5 genotypes rs7669660 TT and rs11547772 AA are included. The following placebos are available: Cavosonstat Matching Placebo: 50 mg matching placebo tablet orally twice a day for 16 weeks MCT Matching Placebo: MCT matching placebo packets. Mix 1-2 packets, as instructed by a physician, into liquid or food three times daily for 16 weeks Clazakizumab Matching Placebo: 12.5 mg subcutaneous saline injection given once every 4 weeks, total of 4 injections Broncho-Vaxom Matching Placebo: 7 mg matching placebo taken orally once a day on an empty stomach for 16 weeks Imatinib Matching Placebo: encapsulated placebo orally once a day with a meal and an 8 oz glass of water for 16 weeks

Secondary

FEV1 % Predicted Post-bronchodilation

Assessed after 4 puffs of bronchodilator administration

Posted

Mean

95% Confidence Interval

percent predicted

Measured at 16 weeks after the start of treatment.

ID	Title	Description
OG000	Cavosonstat	Participants randomized to this arm will take one 50 mg cavosonstat tablet orally twice a day for the 16-week treatment period duration at any point in the study. Only the biomarker positive subgroup participants with ADH5 genotypes rs7669660 TT and rs11547772 AA are included.
OG001	Cavosonstat Arm Placebo	For this arm, study treatment may include cavosonstat matched placebo or non cavosonstat matched placebo. Minimally, all cavosonstat matched placebo is included. If a cavosonstat matched placebo was unavailable for a participant who was randomized to active cavosonstat, any placebo (up to a maximum of two placebos) administered to the participant was included. Only the biomarker positive subgroup participants with ADH5 genotypes rs7669660 TT and rs11547772 AA are included. The following placebos are available: Cavosonstat Matching Placebo: 50 mg matching placebo tablet orally twice a day for 16 weeks MCT Matching Placebo: MCT matching placebo packets. Mix 1-2 packets, as instructed by a physician, into liquid or food three times daily for 16 weeks Clazakizumab Matching Placebo: 12.5 mg subcutaneous saline injection given once every 4 weeks, total of 4 injections Broncho-Vaxom Matching Placebo: 7 mg matching placebo taken orally once a day on an empty stomach for 16 weeks Imatinib Matching Placebo: encapsulated placebo orally once a day with a meal and an 8 oz glass of water for 16 weeks

Secondary

Exacerbations

Annualized rate of severe exacerbations during the 16-week treatment periods, modified intent-to-treat (mITT) population. An asthma exacerbation in PrecISE is defined as a worsening of asthma requiring the use of a systemic corticosteroid (at least 3 days of treatment) to prevent a serious outcome.

Posted

Mean

95% Confidence Interval

exacerbations per year

Assessed over 16 weeks of treatment

ID	Title	Description
OG000	Cavosonstat	Participants randomized to this arm will take one 50 mg cavosonstat tablet orally twice a day for the 16-week treatment period duration at any point in the study. Only the biomarker positive subgroup participants with ADH5 genotypes rs7669660 TT and rs11547772 AA are included.
OG001	Cavosonstat Arm Placebo	For this arm, study treatment may include cavosonstat matched placebo or non cavosonstat matched placebo. Minimally, all cavosonstat matched placebo is included. If a cavosonstat matched placebo was unavailable for a participant who was randomized to active cavosonstat, any placebo (up to a maximum of two placebos) administered to the participant was included. Only the biomarker positive subgroup participants with ADH5 genotypes rs7669660 TT and rs11547772 AA are included. The following placebos are available: Cavosonstat Matching Placebo: 50 mg matching placebo tablet orally twice a day for 16 weeks MCT Matching Placebo: MCT matching placebo packets. Mix 1-2 packets, as instructed by a physician, into liquid or food three times daily for 16 weeks Clazakizumab Matching Placebo: 12.5 mg subcutaneous saline injection given once every 4 weeks, total of 4 injections Broncho-Vaxom Matching Placebo: 7 mg matching placebo taken orally once a day on an empty stomach for 16 weeks Imatinib Matching Placebo: encapsulated placebo orally once a day with a meal and an 8 oz glass of water for 16 weeks

Secondary

Number of Participants With At Least One Asthma-Free Day

An asthma free day is a day where 1) there is no use of albuterol rescue (excluding the use of albuterol as pre-exercise treatment), 2) no daytime or nighttime asthma symptoms, 3) no peak expiratory flow of less than 80% of the predetermined reference value.

Posted

Count of Participants

Participants

Assessed over 16 weeks of treatment

ID	Title	Description
OG000	Cavosonstat	Participants randomized to this arm will take one 50 mg cavosonstat tablet orally twice a day for the 16-week treatment period duration at any point in the study. Only the biomarker positive subgroup participants with ADH5 genotypes rs7669660 TT and rs11547772 AA are included.
OG001	Cavosonstat Arm Placebo	For this arm, study treatment may include cavosonstat matched placebo or non cavosonstat matched placebo. Minimally, all cavosonstat matched placebo is included. If a cavosonstat matched placebo was unavailable for a participant who was randomized to active cavosonstat, any placebo (up to a maximum of two placebos) administered to the participant was included. Only the biomarker positive subgroup participants with ADH5 genotypes rs7669660 TT and rs11547772 AA are included. The following placebos are available: Cavosonstat Matching Placebo: 50 mg matching placebo tablet orally twice a day for 16 weeks MCT Matching Placebo: MCT matching placebo packets. Mix 1-2 packets, as instructed by a physician, into liquid or food three times daily for 16 weeks Clazakizumab Matching Placebo: 12.5 mg subcutaneous saline injection given once every 4 weeks, total of 4 injections Broncho-Vaxom Matching Placebo: 7 mg matching placebo taken orally once a day on an empty stomach for 16 weeks Imatinib Matching Placebo: encapsulated placebo orally once a day with a meal and an 8 oz glass of water for 16 weeks

Secondary

Number of Participants With At Least One Symptom-free Day

A symptom free day is a day with no asthma symptoms (symptom score = 0) for both morning and evening daily diary entries.

Posted

Count of Participants

Participants

Assessed over 16 weeks of treatment

ID	Title	Description
OG000	Cavosonstat	Participants randomized to this arm will take one 50 mg cavosonstat tablet orally twice a day for the 16-week treatment period duration at any point in the study. Only the biomarker positive subgroup participants with ADH5 genotypes rs7669660 TT and rs11547772 AA are included.
OG001	Cavosonstat Arm Placebo	For this arm, study treatment may include cavosonstat matched placebo or non cavosonstat matched placebo. Minimally, all cavosonstat matched placebo is included. If a cavosonstat matched placebo was unavailable for a participant who was randomized to active cavosonstat, any placebo (up to a maximum of two placebos) administered to the participant was included. Only the biomarker positive subgroup participants with ADH5 genotypes rs7669660 TT and rs11547772 AA are included. The following placebos are available: Cavosonstat Matching Placebo: 50 mg matching placebo tablet orally twice a day for 16 weeks MCT Matching Placebo: MCT matching placebo packets. Mix 1-2 packets, as instructed by a physician, into liquid or food three times daily for 16 weeks Clazakizumab Matching Placebo: 12.5 mg subcutaneous saline injection given once every 4 weeks, total of 4 injections Broncho-Vaxom Matching Placebo: 7 mg matching placebo taken orally once a day on an empty stomach for 16 weeks Imatinib Matching Placebo: encapsulated placebo orally once a day with a meal and an 8 oz glass of water for 16 weeks

Secondary

Healthcare Utilization

The combined total number of: asthma-specific Emergency Department visits, asthma-specific hospital admissions, and asthma-specific ICU admissions. The investigators report the number of participants with at least one asthma-specific Emergency Department visit, asthma-specific hospital admission, or asthma-specific ICU admission

Posted

Count of Participants

Participants

Assessed over 16 weeks of treatment

ID	Title	Description
OG000	Cavosonstat	Participants randomized to this arm will take one 50 mg cavosonstat tablet orally twice a day for the 16-week treatment period duration at any point in the study. Only the biomarker positive subgroup participants with ADH5 genotypes rs7669660 TT and rs11547772 AA are included.
OG001	Cavosonstat Arm Placebo	For this arm, study treatment may include cavosonstat matched placebo or non cavosonstat matched placebo. Minimally, all cavosonstat matched placebo is included. If a cavosonstat matched placebo was unavailable for a participant who was randomized to active cavosonstat, any placebo (up to a maximum of two placebos) administered to the participant was included. Only the biomarker positive subgroup participants with ADH5 genotypes rs7669660 TT and rs11547772 AA are included. The following placebos are available: Cavosonstat Matching Placebo: 50 mg matching placebo tablet orally twice a day for 16 weeks MCT Matching Placebo: MCT matching placebo packets. Mix 1-2 packets, as instructed by a physician, into liquid or food three times daily for 16 weeks Clazakizumab Matching Placebo: 12.5 mg subcutaneous saline injection given once every 4 weeks, total of 4 injections Broncho-Vaxom Matching Placebo: 7 mg matching placebo taken orally once a day on an empty stomach for 16 weeks Imatinib Matching Placebo: encapsulated placebo orally once a day with a meal and an 8 oz glass of water for 16 weeks

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Run-in Period	Participants using their asthma control medication were assessed for lung function and symptoms	0	950	19	950	74	950
EG001	Cavosonstat	Participants randomized to this arm will take one 50 mg cavosonstat tablet orally twice a day for the 16-week treatment period duration at any point in the study	2	99	10	99	65	99
EG002	Cavosonstat-Matching Placebo	Participants who receive cavosonstat matched placebo Cavosonstat Matching Placebo: 50 mg matching placebo tablet orally twice a day for 16 weeks	0	57	4	57	40	57
EG003	Broncho-Vaxom	Participants randomized to this arm will receive 7 mg of Broncho-Vaxom once a day on an empty stomach for the 16-week treatment period duration at any point in the study	0	126	4	126	82	126
EG004	Broncho-Vaxom-Matching Placebo	Participants who receive Broncho-Vaxom matched placebo Broncho-Vaxom Matching Placebo: 7 mg matching placebo taken orally once a day on an empty stomach for 16 weeks	0	66	4	66	40	66
EG005	Imatinib	At any point in the study, participants randomized to this arm will take two encapsulated 100 mg imatinib tablets orally once a day with a meal and an 8 oz glass of water for 2 weeks. Participants will then take four encapsulated 100 mg tablets once a day with a meal and an 8 oz glass of water for 14 weeks	0	133	12	133	105	133
EG006	Imatinib-Matching Placebo	Participants who receive imatinib matched placebo Imatinib Matching Placebo: encapsulated placebo orally once a day with a meal and an 8 oz glass of water for 16 weeks	0	92	9	92	65	92
EG007	Medium Chain Triglycerides (MCT)	Participants in this arm will receive Medium Chain Triglycerides (MCT) powder packets (10 g each) at each treatment visit at any point in the study. Participants will mix 1-2 packets of MCT supplement powder into liquids or semi-solid food and ingest 3 times a day during the 16-week treatment period	0	120	3	120	80	120
EG008	MCT-Matching Placebo	Participants who receive MCT matched placebo MCT Matching Placebo: MCT matching placebo packets. Mix 2-5 packets daily into liquid or food for 16 weeks	0	76	5	76	49	76
EG009	Clazakizumab	Participants randomized to this arm will receive a 12.5 mg dose of clazakizumab via a subcutaneous injection at every study visit, every 4 weeks, 4 injections total, during the 16-week treatment period	0	118	9	118	92	118
EG010	Clazakizumab-Matching Placebo	Participants who receive clazakizumab matched placebo Clazakizumab Matching Placebo: 12.5 mg subcutaneous saline injection given once every 4 weeks, total of 4 injections	0	77	6	77	52	77

Serious Adverse Events

Term	Organ System	Assessment Type	Statistical Information
Angina unstable	Cardiac disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0021 events1 affected57 at risk EG0030 events0 affected126 at risk EG0040 events0 affected66 at risk EG0050 events0 affected133 at risk EG0060 events0 affected92 at risk EG0070 events0 affected120 at risk EG0081 events1 affected76 at risk EG0090 events0 affected118 at risk EG0100 events0 affected77 at risk
Myocardial infarction	Cardiac disorders	Systematic Assessment	EG0001 events1 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Asthma	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0003 events3 affected950 at risk EG0011 events1 affected99 at risk EG0020 events0 affected57 at risk EG003
Oesophagitis	Gastrointestinal disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Pneumonia bacterial	Infections and infestations	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Hip Fracture	Injury, poisoning and procedural complications	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Appendicectomy	Surgical and medical procedures	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Impaired gastric emptying	Gastrointestinal disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0012 events2 affected99 at risk EG0020 events0 affected57 at risk EG003
Colitis ischaemic	Gastrointestinal disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0021 events1 affected57 at risk EG003
Migraine	Nervous system disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0021 events1 affected57 at risk EG003
Subarachnoid haemorrhage	Nervous system disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0011 events1 affected99 at risk EG0020 events0 affected57 at risk EG003
Syncope	Nervous system disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0021 events1 affected57 at risk EG003
Cardiac arrest	Cardiac disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0011 events1 affected99 at risk EG0020 events0 affected57 at risk EG003
Abscess limb	Infections and infestations	Systematic Assessment	EG0000 events0 affected950 at risk EG0011 events1 affected99 at risk EG0020 events0 affected57 at risk EG003
COVID-19	Infections and infestations	Systematic Assessment	EG0001 events1 affected950 at risk EG0011 events1 affected99 at risk EG0020 events0 affected57 at risk EG003
Fall	Injury, poisoning and procedural complications	Systematic Assessment	EG0000 events0 affected950 at risk EG0011 events1 affected99 at risk EG0020 events0 affected57 at risk EG003
Acute kidney injury	Surgical and medical procedures	Systematic Assessment	EG0000 events0 affected950 at risk EG0011 events1 affected99 at risk EG0020 events0 affected57 at risk EG003
Knee arthroplasty	Surgical and medical procedures	Systematic Assessment	EG0000 events0 affected950 at risk EG0011 events1 affected99 at risk EG0020 events0 affected57 at risk EG003
Atrial fibrillation	Cardiac disorders	Systematic Assessment	EG0001 events1 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Atrial flutter	Cardiac disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Cellulitis	Infections and infestations	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Tooth abscess	Infections and infestations	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Gastroenteritis	Gastrointestinal disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Wrist fracture	Injury, poisoning and procedural complications	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Cerebrovascular accident	Nervous system disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Cystitis haemorrhagic	Renal and urinary disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Asthmatic crisis	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0002 events2 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Transient ischaemic attack	Vascular disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Hypersensitivity	Immune system disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Gastrointestinal haemorrhage	Gastrointestinal disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Pneumonia	Infections and infestations	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Sepsis	Infections and infestations	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Breast cancer	Reproductive system and breast disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Invasive ductal breast carcinoma	Reproductive system and breast disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Flank pain	General disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Accidental overdose	Injury, poisoning and procedural complications	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Serotonin syndrome	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Squamous cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Pancreaticoduodenectomy	Surgical and medical procedures	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Pulmonary embolism	Vascular disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Prostate cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Rectal cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Neutropenia	Blood and lymphatic system disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Thrombocytosis	Blood and lymphatic system disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0001 events1 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Nasal polyps	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Umbilical hernia repair	Surgical and medical procedures	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Troponin I increased	Investigations	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Hypoglycaemia	Metabolism and nutrition disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Meningitis	Infections and infestations	Systematic Assessment	EG0000 events0 affected950 at risk EG0011 events1 affected99 at risk EG0020 events0 affected57 at risk EG003
intestinal preferation	Gastrointestinal disorders	Systematic Assessment	EG0001 events1 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
colitis ulcerative	Gastrointestinal disorders	Systematic Assessment	EG0001 events1 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
suicidal ideation	Psychiatric disorders	Systematic Assessment	EG0001 events1 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
depression	Psychiatric disorders	Systematic Assessment	EG0001 events1 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
oedema peripheral	Cardiac disorders	Systematic Assessment	EG0001 events1 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
craniocerebral injury	Nervous system disorders	Systematic Assessment	EG0001 events1 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
urosepsis	Infections and infestations	Systematic Assessment	EG0001 events1 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
diverticulatis	Gastrointestinal disorders	Systematic Assessment	EG0001 events1 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
somnolence	Nervous system disorders	Systematic Assessment	EG0001 events1 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
hypotension	Cardiac disorders	Systematic Assessment	EG0001 events1 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003

Other Adverse Events

Term	Organ System	Assessment Type	Statistical Information
Abdominal distension	Gastrointestinal disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0012 events2 affected99 at risk EG0020 events0 affected57 at risk EG0030 events0 affected126 at risk EG0041 events1 affected66 at risk EG0053 events3 affected133 at risk EG0061 events1 affected92 at risk EG00710 events10 affected120 at risk EG0084 events4 affected76 at risk EG0092 events2 affected118 at risk EG0100 events0 affected77 at risk
Abdominal pain	Gastrointestinal disorders	Systematic Assessment	EG0002 events2 affected950 at risk EG0012 events2 affected99 at risk EG0022 events2 affected57 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG0007 events7 affected950 at risk EG0014 events4 affected99 at risk EG0024 events4 affected57 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG0003 events3 affected950 at risk EG0010 events0 affected99 at risk EG0023 events3 affected57 at risk EG003
Bronchitis	Infections and infestations	Systematic Assessment	EG0003 events3 affected950 at risk EG0013 events3 affected99 at risk EG0022 events2 affected57 at risk EG003
COVID-19	Infections and infestations	Systematic Assessment	EG0002 events2 affected950 at risk EG00110 events10 affected99 at risk EG0029 events9 affected57 at risk EG003
Constipation	Gastrointestinal disorders	Systematic Assessment	EG0001 events1 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Contusion	Injury, poisoning and procedural complications	Systematic Assessment	EG0000 events0 affected950 at risk EG0011 events1 affected99 at risk EG0022 events2 affected57 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0008 events8 affected950 at risk EG0012 events2 affected99 at risk EG0023 events3 affected57 at risk EG003
Diarrhoea	Gastrointestinal disorders	Systematic Assessment	EG0004 events4 affected950 at risk EG0012 events2 affected99 at risk EG0022 events2 affected57 at risk EG003
Dizziness	Nervous system disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0013 events3 affected99 at risk EG0023 events3 affected57 at risk EG003
Fatigue	General disorders	Systematic Assessment	EG0003 events3 affected950 at risk EG0011 events1 affected99 at risk EG0023 events3 affected57 at risk EG003
Gastroenteritis	Gastrointestinal disorders	Systematic Assessment	EG0004 events4 affected950 at risk EG0013 events3 affected99 at risk EG0023 events3 affected57 at risk EG003
Headache	Nervous system disorders	Systematic Assessment	EG0006 events6 affected950 at risk EG0015 events5 affected99 at risk EG0020 events0 affected57 at risk EG003
Injection site reaction	General disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0020 events0 affected57 at risk EG003
Muscle spasms	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0013 events3 affected99 at risk EG0021 events1 affected57 at risk EG003
Myalgia	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG0004 events4 affected950 at risk EG0012 events2 affected99 at risk EG0023 events3 affected57 at risk EG003
Nasopharyngitis	Infections and infestations	Systematic Assessment	EG0000 events0 affected950 at risk EG0017 events7 affected99 at risk EG0026 events6 affected57 at risk EG003
Nausea	Gastrointestinal disorders	Systematic Assessment	EG0002 events2 affected950 at risk EG0012 events2 affected99 at risk EG0022 events2 affected57 at risk EG003
Oedema	General disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0012 events2 affected99 at risk EG0023 events3 affected57 at risk EG003
Oral candidiasis	Infections and infestations	Systematic Assessment	EG0008 events8 affected950 at risk EG0013 events3 affected99 at risk EG0024 events4 affected57 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG0010 events0 affected99 at risk EG0023 events3 affected57 at risk EG003
Rash	Skin and subcutaneous tissue disorders	Systematic Assessment	EG0003 events3 affected950 at risk EG0012 events2 affected99 at risk EG0021 events1 affected57 at risk EG003
Sinusitis	Infections and infestations	Systematic Assessment	EG00013 events13 affected950 at risk EG0014 events4 affected99 at risk EG0022 events2 affected57 at risk EG003
Upper respiratory tract infection	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0000 events0 affected950 at risk EG00110 events10 affected99 at risk EG0026 events6 affected57 at risk EG003
Vomiting	Gastrointestinal disorders	Systematic Assessment	EG0001 events1 affected950 at risk EG0011 events1 affected99 at risk EG0021 events1 affected57 at risk EG003

ID	Term
D001982	Bronchial Diseases
D012140	Respiratory Tract Diseases
D008173	Lung Diseases, Obstructive
D008171	Lung Diseases
D012130	Respiratory Hypersensitivity
D006969	Hypersensitivity, Immediate
D006967	Hypersensitivity
D007154	Immune System Diseases

ID	Term
D001549	Benzamides
D000577	Amides
D009930	Organic Chemicals
D001565	Benzoates
D000146	Acids, Carbocyclic
D002264	Carboxylic Acids
D001555	Benzene Derivatives
D006841	Hydrocarbons, Aromatic
D006844	Hydrocarbons, Cyclic
D006838	Hydrocarbons
D010879	Piperazines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D011743	Pyrimidines

ID	Term
C000604955	clazakizumab
C030259	Broncho-Vaxom
D000068877	Imatinib Mesylate
C000626473	cavosonstat