Blood Coagulation Disorders, Snake Bite
Conditions
Keywords
Snake Bite, Venom and antivenom kinetics
Brief summary
This phase II study was a prospective, randomized, open-label, multi-center study in the United States, involving patients from 18 to 70 years of age, comparing Anavip (Antivenin Crotalinae \[pit viper\] equine immune F(ab)2; Instituto Bioclon, Mexico City, Mexico) against CroFab (Protherics Inc., Nashville, Tennessee), the only currently approved product for treatment of Crotalinae (pit viper) envenomation in the US. The study was designed to evaluate the hypothesis that lasting correction of snakebite induced thrombocytopenia and hypofibrinogenemia are possible following correction with F(ab)2 antivenom, by analyzing in detail the relationships among platelet count, fibrinogen, venom levels, and antivenom levels in subjects presenting with thrombocytopenia following crotaline viper envenomation. In the study we expected to see a fall in platelet count following Fab treatment, commensurate with that reported in the past. We hypothesized that following F(ab)2 treatment there would be a slower drop in post-treatment platelet counts, with a relatively higher platelet count at any given point in the follow-up period. We further hypothesized that an initial rise and later fall in platelet count would correspond with rise and fall in antivenom levels, and would be mirrored by concurrent drop and rise in levels of unbound circulating venom.
Detailed description
The overall objective of this Phase 2 open-label comparative study was to demonstrate that the F(ab)2 antivenom Anavip has significantly longer plasma persistence than does Fab, and that this is associated with a slower rise in venom levels and slower decline in platelet count and fibrinogen following hospital discharge of envenomated subjects. The effectiveness of F(ab)2 in preventing the recurrence of coagulopathies after the subject's discharge from hospital will indicate that, inherently, F(ab)2 antivenom has an improved safety profile relative to the Fab antivenom CroFab in treating envenomation by crotaline vipers. Each subject was assessed for quantitative serum venom levels. Relatively few historical data exist to support the use of venom levels as a surrogate endpoint in envenomation. However, changes in venom levels have been correlated with coagulopathic effects, during both the acute phase of venom toxicity and the post treatment period of recurrent venom effect. Validation of this surrogate endpoint via correlation of venom effect with platelet count and fibrinogen level in this phase II study is intended to support future studies. The secondary endpoints were the determination of coagulation abnormalities during the follow up period.
Interventions
BIOLOGICALAnavip
Anavip, 10 vials Intravenous (IV) every 2 hours until initial control has been achieved; then 3 maintenance doses of 4 vials every 6 hrs
BIOLOGICALCroFab
CroFab, 5 vials Intravenous (IV) every 2 hours until initial control has been achieved; then 3 maintenance doses of 2 vials every 6 hrs
Sponsors
University of Arizona
Instituto Bioclon S.A. de C.V.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* men and women 18 to 70 years of age * presenting for emergency treatment of pit viper bite * informed consent document read and signed by subject
Exclusion criteria
* allergy to horse serum, sheep serum, or papaya * current use of any antivenom, or use within the last month * current participation in a clinical drug study, or participation within the last month * pregnancy or breast-feeding * underlying medical conditions that significantly alter blood coagulation: thrombocytopenia, hemophilia, familial dysfibrinogenemia, leukemia, recent ingestion of superwarfarin compounds (rat poison) * use of any medication expected to affect platelet count, coagulation factors, or fibrinogen: chemotherapeutic agents, warfarin, heparin, aspirin * No clinical indications of snake bite envenomation
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Detection of Plasma Venom Levels During the Post Acute Treatment Period. | Follow up after Maintenance doses were completed. Two Weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| >50,000 Platelets/mm3 | Follow up after maintenance dose | Thrombocytopenia during follow up period. Two weeks |
Countries
United States
Participant flow
Recruitment details
Subjects arriving at participating centers with a pit viper bite were evaluated with respect to the inclusion/exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Anavip Crotalinae (Pit Viper) Equine Immune F(ab)2 Antivenom Anavip, 10 vials IV every 2 hours until initial control has been achieved; then 3 maintenance doses of 4 vials every 6 hrs | 6 |
| CroFab Crotalidae Polyvalent Immune Fab, Ovine Antivenom CroFab, 5 vials IV every 2 hours until initial control has been achieved; then 3 maintenance doses of 2 vials every 6 hrs | 6 |
| Total | 12 |
Baseline characteristics
| Characteristic | Anavip Crotalinae (Pit Viper) Equine Immune F(ab)2 Antivenom | CroFab Crotalidae Polyvalent Immune Fab, Ovine Antivenom | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 6 Participants | 12 Participants |
| Age, Continuous | 50.2 years STANDARD_DEVIATION 4.8 | 40.7 years STANDARD_DEVIATION 16.5 | 45.3 years STANDARD_DEVIATION 12.6 |
| Sex: Female, Male Female | 5 Participants | 1 Participants | 6 Participants |
| Sex: Female, Male Male | 1 Participants | 5 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 6 / 6 |
| serious Total, serious adverse events | 0 / — | 1 / — |
Outcome results
Primary
Detection of Plasma Venom Levels During the Post Acute Treatment Period.
Time frame: Follow up after Maintenance doses were completed. Two Weeks.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Anavip Crotalinae (Pit Viper) Equine Immune F(ab)2 Antivenom | Detection of Plasma Venom Levels During the Post Acute Treatment Period. | Detectable venom | 0 participants |
| Anavip Crotalinae (Pit Viper) Equine Immune F(ab)2 Antivenom | Detection of Plasma Venom Levels During the Post Acute Treatment Period. | Undetectable venom | 6 participants |
| CroFab Crotalidae Polyvalent Immune Fab, Ovine Antivenom | Detection of Plasma Venom Levels During the Post Acute Treatment Period. | Detectable venom | 4 participants |
| CroFab Crotalidae Polyvalent Immune Fab, Ovine Antivenom | Detection of Plasma Venom Levels During the Post Acute Treatment Period. | Undetectable venom | 2 participants |
Secondary
>50,000 Platelets/mm3
Thrombocytopenia during follow up period. Two weeks
Time frame: Follow up after maintenance dose
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Anavip Crotalinae (Pit Viper) Equine Immune F(ab)2 Antivenom | >50,000 Platelets/mm3 | Thrombocytopenia present | 0 participants |
| Anavip Crotalinae (Pit Viper) Equine Immune F(ab)2 Antivenom | >50,000 Platelets/mm3 | Thrombocytopenia absent | 6 participants |
| CroFab Crotalidae Polyvalent Immune Fab, Ovine Antivenom | >50,000 Platelets/mm3 | Thrombocytopenia present | 3 participants |
| CroFab Crotalidae Polyvalent Immune Fab, Ovine Antivenom | >50,000 Platelets/mm3 | Thrombocytopenia absent | 3 participants |