Envenomation, Snake, Envenoming, Envenoming, Snake, Snakebites
Conditions
Keywords
envenoming, venom, snakebite, snakebite severity score, varespladib, snake, antidote, LY333013, sPLA2
Brief summary
This is a multicenter, randomized, double-blind, placebo-controlled, phase 2 study designed to evaluate the safety, tolerability and efficacy of varespladib-methyl, concurrently with standard of care (SOC), in subjects bitten by venomous snakes.
Detailed description
This is a multicenter, randomized, double-blind, placebo-controlled, phase 2 study designed to evaluate the safety, tolerability, and efficacy of varespladib-methyl, concurrently with SOC, in subjects bitten by venomous snakes. Approximately 110 male and female eligible subjects will be enrolled and randomized to receive active varespladib-methyl or placebo (in addition to SOC) in a 1:1 ratio (approximately 36 per group). There will be no stratification by type of snakebite, though randomization will be stratified by age group (5 to 11 years, 12 to 17 years, and ≥ 18 years) and by the presence or absence of severe neurologic symptoms defined by yes/no neurologic system subscore of the snakebite severity score of ≥ 2. Effective treatments for snakebite envenoming represents a deadly and unmet global medical need. While antivenoms comprise the SOC for treatment of snakebites, they suffer from several limitations including specificity of each antivenom for specific species of snake, limited access to antivenom in rural areas, practical storage requirements, and delays in administration. Treatment of snakebite envenoming with the small-molecule drug varespladib-methyl, which targets secreted phospholipase A₂ (sPLA₂) present in more than 95% of snake venoms, has the potential to overcome several limitations of serum-based antivenoms that underpin traditional SOC. This study in the United States and India will provide coverage of a broad spectrum of venomous snake genera, including elapids, pit vipers, and potentially exotics such as vipers and colubrids if encountered over the course of the study. The study is designed to cover differing geographies and differing sPLA₂ structures. Study sites have been and will be selected based on demonstrated historical incidence of snake bites from species deemed relevant to this study, to ensure a broad range of envenoming toxins are expected to be encountered in potential study subjects. The study design allows for both treatment arms (varespladib-methyl and placebo) to receive SOC (e.g., antivenom) concurrently. Thus, critically ill adult and pediatric subjects may receive emergency treatment in a timely manner while being evaluated for the potential clinical benefit associated with inhibition of venom sPLA₂ and inflammatory sPLA2s by varespladib-methyl. Because subjects with severe snakebites are admitted to emergency departments, this study was designed to screen, enroll, and administer treatment in a single visit at the hospital upon admission. Because varespladib-methyl is administered orally, subjects who demonstrate substantial improvement and are eligible for discharge from the hospital may continue investigational product treatment in an outpatient setting. Risks associated with the control (placebo) arm of this study include the same risks associated with SOC (antivenom).
Interventions
Varespladib-methyl (LY333013) is an IR, oval, white, film-coated tablet at a dosage strength of 250 mg for oral administration. Scaled pediatric doses of varespladib-methyl (LY333013) are supplied as 50 mg IR capsules for oral administration.
DRUGPlacebo
The oral placebo is supplied as a white film-coated oval tablet to match the appearance of the varespladib-methyl 250 mg tablet and contains a subset of the excipients present in the active tablet formulation: lactose monohydrate, microcrystalline cellulose, and magnesium stearate. Placebo for scaled pediatric dosing is supplied as an IR capsule to match the varespladib-methyl 50 mg capsule, and contains the excipients lactose monohydrate, microcrystalline cellulose, and magnesium stearate.
DRUGStandard of care (SOC)
SOC (including antivenom) will continue to be administered throughout the subject's participation in the study according to the protocol and the judgment of the Investigator.
Sponsors
Premier Research
Ophirex, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
All subjects, Investigators, and study personnel involved in the conduct of the study, including data management, will be blinded to treatment assignment except for a specified unblinded statistician and programmer from the study contract research organization who will have access to the randomization code. The unblinded study personnel will not participate in study procedures or data analysis prior to unblinding of the study data to all study-related personnel upon database lock. If an interim analysis is conducted, then unblinded personnel who are not otherwise involved in the study will prepare the data for review.
Eligibility
Sex/Gender
ALL
Age
5 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Is a male or female subject ≥ 5 years of age with venomous snakebite and must present with an initial SSS of * 2 points in any SSS category other than gastrointestinal and 1 or more additional points in any other SSS category other than gastrointestinal or * ≥ 3 in any SSS category other than gastrointestinal. SSS scoring should be performed for inclusion assessment without waiting for receipt of Baseline hematological laboratory results. Gastrointestinal scores should not be used for inclusion. 2. Index event (snakebite) must be symptomatic and must have occurred within 10 hours of eligibility assessment. 3. Must meet one of two categories of inclusion criteria: Category 1: The patient has not yet completed first dose of antivenom: SSS inclusion score\* of ≥2 in one system and ≥1 in another system (2+1) OR ≥3 in at least one system. OR Category 2: The patient has completed an initial dose of antivenom: SSS inclusion score\* of ≥2 in one system and ≥1 in another system (2+1) OR ≥3 in at least one system AND CGI-I score of ≥5 (i.e., minimally worse, much worse, or very much worse). 4. Is willing (or legally authorized representative is willing) to provide informed consent prior to initiation of any study procedures.
Exclusion criteria
1. Has received antivenom treatment for envenoming prior to enrollment in this study. 2. Is considered by the investigator to have a clinically significant upper GI bleed evidenced by hematemesis, coffee-ground emesis or nasogastric aspirate, or hematochezia thought to originate from upper GI tract. 3. Has history of cerebrovascular accident or intracranial bleeding of any kind, acute coronary syndrome, myocardial infarction, or severe pulmonary hypertension. 4. Has known history of inherited bleeding or coagulation disorder. 5. Is, at Screening Visit, using the following anticoagulants: warfarin/coumadin, argatroban, bivalirudin, lepirudin, apixaban, dabigatran, clopidogrel, prasugrel, ticlopidine or another anticoagulant agent not specifically listed, or has used heparin, enoxaparin, fondaparinux, or other low molecular weight heparin or antiarrhythmic drugs within 14 days prior to treatment. 6. Has a history of chronic liver disease such as chronic active viral hepatitis, alcohol-related liver disease, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, hemochromatosis, primary biliary cirrhosis, primary sclerosing cholangitis, or autoimmune hepatitis. 7. Reports or has known pre-existing renal impairment or chronic kidney disease (defined as Stage 4 or receiving dialysis or hemofiltration). 8. Has a known allergy or significant adverse reaction to varespladib-methyl or related compounds. 9. Is considered by the Investigator to be unable to comply with protocol requirements due to geographic considerations, psychiatric disorders, or other compliance concerns. 10. Is pregnant, has a positive serum human chorionic gonadotropin (hCG) pregnancy test or not willing to use a highly effective method of contraception for 14 days after initial treatment, or is breast-feeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Combined Pulmonary, Cardiovascular, Hematologic, Nervous System, and Renal Subscores of the Snakebite Severity Score (SSS) | Baseline to 6 and 9 hours after first dose | Change from baseline (pre-dosing) to 6 and 9 hours after the first dose, in the combined pulmonary, cardiovascular, hematologic symptoms, nervous system, and renal subscores of the SSS. The values from each of these subscores will be totaled. The average of the 6- and 9-hour scores will be used as the post-treatment value. The Snakebite Severity Scale (SSS) is a tool used to measure the severity of envenoming based on up to 7 body categories: pulmonary, cardiovascular, gastrointestinal, nervous, and renal system (graded at levels from Grade 0 to Grade 3), local wound, and hematological, (graded at levels from Grade 0 to Grade 4). A higher score indicates worse symptoms. The minimum score for the five item SSS is 0 and the maximum score is 16, with the higher score indicating worse symptoms. For the primary outcome we are focusing only on 5 subscores, that does not include the local wound nor the gastrointestinal subscores. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC) of the Local Wound, Pulmonary, Cardiovascular, Hematologic Symptoms, Renal, and Nervous System Sections of the SSS | Baseline through Day 7 | Baseline (pre-dosing) through Day 7 in the AUC of the local wound, pulmonary, cardiovascular, hematologic symptoms, nervous, and renal system sections of the SSS. The Snakebite Severity Scale (SSS) is a tool used to measure the severity of envenoming based on 7 body categories: pulmonary, cardiovascular, gastrointestinal, nervous, and renal effects (graded at levels from Grade 0 to Grade 3), local wound and hematological, (graded at levels from Grade 0 to Grade 4). A higher score indicates worse symptoms. The maximum score for the SSS is 23. For this outcome, the maximum score is 20 and if this score was present for the entire first week (168 hours) the maximum AUC is 3,370. The minimum AUC is a score of 3 at baseline and a score of 0 at three hours, which gives an AUC of 5.25. |
| Area Under the Curve (AUC) of the Numeric Pain Rating Scale (NPRS) | From Baseline through Day 3 | Numeric Pain Rating Scale is a scale that goes from 0 to 10 with 10 being the worst possible pain. This measure is an AUC measure that is calculated from 0 to 48 hours using trapezoidal function in which the mean score for any given 2 periods of time is multiplied by the elapsed duration of time between those two periods. Each of these mean scores are summed to calculate the AUC. The minimum score is 0 and the maximum is 480. |
| Clinician Global Impression - Improvement | Day 2 | Clinician Global Impression - Improvement focus on improvement for Day 2. The scale is a 1 to 7 score with 1 indicating very much improved and 7 indicating very much worse. |
| Patient-Specific Functional Scale (PSFS) Score | Day 7 | PSFS total score on Day 7. The PSFS is a 3-item instrument which assesses functional abilities. The total score ranges from 0 to 10 with a lower score indicating greater functional difficulties. |
| Numeric Pain Rating Scale (NPRS) Score | Baseline through Day 28 | Change from baseline (pre-dosing) through Day 28 in NPRS score in patients able to respond pre-dosing through Day 28. The Numeric Pain Rating Scale is an 11-point scale for patient self-reporting of pain with scores ranging from 0 (no pain) to 10 (worst possible pain). |
| All-cause Mortality | Baseline through Day 28 | The number of patients experiencing the event (death). The all-cause mortality will be censored at Day 60. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), and AEs Leading to Discontinuation of Investigational Product (IP) | 28 Days after the initiation of study drug | Adverse events will be assessed from the time of signing informed consent to 28 days after initiating study drug. |
Countries
India, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Varespladib-methyl Varespladib-methyl is an immediate-release (IR), oval, white, film-coated tablet at a dosage strength of 250 mg for oral administration.
Scaled pediatric doses of varespladib-methyl are supplied as 50 mg IR capsules for oral administration.
Adult subjects will receive an initial loading dose of 500 mg (2 × 250 mg oral tablet) varespladib-methyl upon randomization, followed by dosing with 250 mg varespladib-methyl (1 × 250 mg oral tablet) approximately 12 hours later, and subsequent twice daily (BID) dosing with 1 × 250 mg varespladib-methyl oral tablets for the remainder of the 7-day treatment period. Tablets may be administered via naso- or orogastric tubes in patients requiring mechanical ventilation.
Pediatric subjects (5 to \< 18 years) will be administered doses of varespladib-methyl determined by allometric scaling, provided as 50 mg capsules. Age-appropriate capsules may be administered via naso- or orogastric tubes in patients requiring mechanical ventilation.
Varespladib Methyl: Varespladib-methyl (LY333013) is an IR, oval, white, film-coated tablet at a dosage strength of 250 mg for oral administration. Scaled pediatric doses of varespladib-methyl (LY333013) are supplied as 50 mg IR capsules for oral administration.
Standard of care (SOC): SOC (including antivenom) will continue to be administered throughout the subject's participation in the study according to the protocol and the judgment of the Investigator. | 45 |
| Placebo The oral placebo is supplied as a white film-coated oval tablet to match the appearance of the varespladib-methyl 250 mg tablet and contains a subset of the excipients present in the active tablet formulation: lactose monohydrate, microcrystalline cellulose, and magnesium stearate.
Placebo for scaled pediatric dosing is supplied as an immediate-release capsule to match the varespladib-methyl 50 mg capsule, and contains the excipients lactose monohydrate, microcrystalline cellulose, and magnesium stearate.
The dosing of placebo will match that of varespladib-methyl.
Placebo: The oral placebo is supplied as a white film-coated oval tablet to match the appearance of the varespladib-methyl 250 mg tablet and contains a subset of the excipients present in the active tablet formulation: lactose monohydrate, microcrystalline cellulose, and magnesium stearate.
Placebo for scaled pediatric dosing is supplied as an IR capsule to match the varespladib-methyl 50 mg capsule, and contains the excipients lactose monohydrate, microcrystalline cellulose, and magnesium stearate.
Standard of care (SOC): SOC (including antivenom) will continue to be administered throughout the subject's participation in the study according to the protocol and the judgment of the Investigator. | 50 |
| Total | 95 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | 1 left AMA | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Subject changed hospitals | 0 | 1 |
| Overall Study | unable to complete due to work | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 3 |
Baseline characteristics
| Characteristic | Varespladib-methyl | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 6 Participants | 4 Participants | 10 Participants |
| Age, Categorical >=65 years | 6 Participants | 3 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 33 Participants | 43 Participants | 76 Participants |
| Age, Continuous | 37.6 years STANDARD_DEVIATION 18.6 | 41.9 years STANDARD_DEVIATION 15.9 | 39.9 years STANDARD_DEVIATION 17.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 41 Participants | 47 Participants | 88 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 30 Participants | 30 Participants | 60 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 4 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 | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 10 Participants | 17 Participants | 27 Participants |
| Region of Enrollment India | 31 participants | 31 participants | 62 participants |
| Region of Enrollment United States | 14 participants | 19 participants | 33 participants |
| Sex: Female, Male Female | 10 Participants | 11 Participants | 21 Participants |
| Sex: Female, Male Male | 35 Participants | 39 Participants | 74 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 45 | 0 / 50 |
| other Total, other adverse events | 19 / 45 | 28 / 50 |
| serious Total, serious adverse events | 1 / 45 | 0 / 50 |
Outcome results
Primary
Change in the Combined Pulmonary, Cardiovascular, Hematologic, Nervous System, and Renal Subscores of the Snakebite Severity Score (SSS)
Change from baseline (pre-dosing) to 6 and 9 hours after the first dose, in the combined pulmonary, cardiovascular, hematologic symptoms, nervous system, and renal subscores of the SSS. The values from each of these subscores will be totaled. The average of the 6- and 9-hour scores will be used as the post-treatment value. The Snakebite Severity Scale (SSS) is a tool used to measure the severity of envenoming based on up to 7 body categories: pulmonary, cardiovascular, gastrointestinal, nervous, and renal system (graded at levels from Grade 0 to Grade 3), local wound, and hematological, (graded at levels from Grade 0 to Grade 4). A higher score indicates worse symptoms. The minimum score for the five item SSS is 0 and the maximum score is 16, with the higher score indicating worse symptoms. For the primary outcome we are focusing only on 5 subscores, that does not include the local wound nor the gastrointestinal subscores.
Time frame: Baseline to 6 and 9 hours after first dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Varespladib-methyl | Change in the Combined Pulmonary, Cardiovascular, Hematologic, Nervous System, and Renal Subscores of the Snakebite Severity Score (SSS) | 1.1 Snakebite Severity Score | Standard Error 0.3 |
| Placebo | Change in the Combined Pulmonary, Cardiovascular, Hematologic, Nervous System, and Renal Subscores of the Snakebite Severity Score (SSS) | 1.5 Snakebite Severity Score | Standard Error 0.2 |
Secondary
All-cause Mortality
The number of patients experiencing the event (death). The all-cause mortality will be censored at Day 60.
Time frame: Baseline through Day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Varespladib-methyl | All-cause Mortality | 0 Participants |
| Placebo | All-cause Mortality | 0 Participants |
Secondary
Area Under the Curve (AUC) of the Local Wound, Pulmonary, Cardiovascular, Hematologic Symptoms, Renal, and Nervous System Sections of the SSS
Baseline (pre-dosing) through Day 7 in the AUC of the local wound, pulmonary, cardiovascular, hematologic symptoms, nervous, and renal system sections of the SSS. The Snakebite Severity Scale (SSS) is a tool used to measure the severity of envenoming based on 7 body categories: pulmonary, cardiovascular, gastrointestinal, nervous, and renal effects (graded at levels from Grade 0 to Grade 3), local wound and hematological, (graded at levels from Grade 0 to Grade 4). A higher score indicates worse symptoms. The maximum score for the SSS is 23. For this outcome, the maximum score is 20 and if this score was present for the entire first week (168 hours) the maximum AUC is 3,370. The minimum AUC is a score of 3 at baseline and a score of 0 at three hours, which gives an AUC of 5.25.
Time frame: Baseline through Day 7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Varespladib-methyl | Area Under the Curve (AUC) of the Local Wound, Pulmonary, Cardiovascular, Hematologic Symptoms, Renal, and Nervous System Sections of the SSS | 421 Snakebite severity score X hours | Standard Error 45 |
| Placebo | Area Under the Curve (AUC) of the Local Wound, Pulmonary, Cardiovascular, Hematologic Symptoms, Renal, and Nervous System Sections of the SSS | 430 Snakebite severity score X hours | Standard Error 44 |
Secondary
Area Under the Curve (AUC) of the Numeric Pain Rating Scale (NPRS)
Numeric Pain Rating Scale is a scale that goes from 0 to 10 with 10 being the worst possible pain. This measure is an AUC measure that is calculated from 0 to 48 hours using trapezoidal function in which the mean score for any given 2 periods of time is multiplied by the elapsed duration of time between those two periods. Each of these mean scores are summed to calculate the AUC. The minimum score is 0 and the maximum is 480.
Time frame: From Baseline through Day 3
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Varespladib-methyl | Area Under the Curve (AUC) of the Numeric Pain Rating Scale (NPRS) | 170 scores on a scale * hours | Standard Error 17 |
| Placebo | Area Under the Curve (AUC) of the Numeric Pain Rating Scale (NPRS) | 173 scores on a scale * hours | Standard Error 18 |
Secondary
Clinician Global Impression - Improvement
Clinician Global Impression - Improvement focus on improvement for Day 2. The scale is a 1 to 7 score with 1 indicating very much improved and 7 indicating very much worse.
Time frame: Day 2
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Varespladib-methyl | Clinician Global Impression - Improvement | 2.3 score on a scale | Standard Error 0.2 |
| Placebo | Clinician Global Impression - Improvement | 2.4 score on a scale | Standard Error 0.2 |
Secondary
Numeric Pain Rating Scale (NPRS) Score
Change from baseline (pre-dosing) through Day 28 in NPRS score in patients able to respond pre-dosing through Day 28. The Numeric Pain Rating Scale is an 11-point scale for patient self-reporting of pain with scores ranging from 0 (no pain) to 10 (worst possible pain).
Time frame: Baseline through Day 28
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Varespladib-methyl | Numeric Pain Rating Scale (NPRS) Score | 6.4 score on a scale | Standard Error 0.2 |
| Placebo | Numeric Pain Rating Scale (NPRS) Score | 6.1 score on a scale | Standard Error 0.2 |
Secondary
Patient-Specific Functional Scale (PSFS) Score
PSFS total score on Day 7. The PSFS is a 3-item instrument which assesses functional abilities. The total score ranges from 0 to 10 with a lower score indicating greater functional difficulties.
Time frame: Day 7
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Varespladib-methyl | Patient-Specific Functional Scale (PSFS) Score | 5.89 score on a scale | Standard Error 0.29 |
| Placebo | Patient-Specific Functional Scale (PSFS) Score | 5.86 score on a scale | Standard Error 0.29 |
Other Pre-specified
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), and AEs Leading to Discontinuation of Investigational Product (IP)
Adverse events will be assessed from the time of signing informed consent to 28 days after initiating study drug.
Time frame: 28 Days after the initiation of study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Varespladib-methyl | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), and AEs Leading to Discontinuation of Investigational Product (IP) | 19 Participants |
| Placebo | Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), and AEs Leading to Discontinuation of Investigational Product (IP) | 28 Participants |