Safety and Effectiveness of PANAF-Premium TM Snake Venom Antiserum As Standard Treatment for Snakebites

The Safety and Effectiveness of PANAF- Premium TM Snake Venom Antiserum-Pan Africa Administered As a Standard Treatment for Cases of Snakebites- a Phase IV Open Label Trial

Snakebite envenomation (SBE) is a major public health problem in many developing countries. Standard snake antivenom (SA) remains the primary treatment and has been shown to reduce mortality in observational studies conducted in several sub-Saharan African (SSA) countries. Although it is relatively available in other endemic contexts such as Asia and Latin America, there have been major challenges with the reliable supply of effective products in sub-Saharan Africa for many years. Premium Serums & Vaccines Pvt. Ltd. (PSVPL) recently introduced its SA brand, namely PANAF-Premium TM, manufactured to address unmet treatment needs in the local context. This serum has received WHO approval for use in sub-Saharan Africa and is used in Cameroon with neutralizing efficacy for 24 species represented in Africa.

This is an open-label, Phase IV post-marketing surveillance study to collect safety and effectiveness data systematically following the administration of PANAF-Premium TM. The study will describe the types, severity, and number of adverse events recorded following the administration of PANAF-Premium TM and its effectiveness for snakebite management. Epidemiological data will also be collected, along with information on the snake species typically responsible for bites in the North region of Cameroon, the type of envenomation, the total dose of SA required for reversal of envenomation, and the total time required for clinical recovery. This will complement the international and national pool of pharmacovigilance data.

Background: Snakebite envenomation (SBE) is a major public health problem in many developing countries. Conventional snake antivenom (SA) remains the primary treatment and has been shown to reduce mortality in observational studies conducted in several sub-Saharan African (SSA) countries. Although it is relatively available in other endemic contexts such as Asia and Latin America, there have been major challenges with the reliable supply of effective products in sub-Saharan Africa for many years. Premium Serums & Vaccines Pvt. Ltd. (PSVPL) recently introduced its SA brand, namely PANAF-Premium TM, manufactured to the latest standards, providing a solution to address unmet treatment needs in the local context. This serum has received WHO approval for use in sub-Saharan Africa and is used in Cameroon with neutralizing efficacy for 24 species represented in Africa. Since antivenom is of animal origin, it can cause adverse reactions ranging from mild itching to fatal anaphylaxis; therefore, patients should be treated appropriately or given prophylactic premedication. Approximately 20% of cases may develop early (within a few hours) or late (five days or more) allergic reactions after administration of snake antivenom. This open-label, Phase IV post-marketing surveillance study aims to collect safety and effectiveness data systematically following administration of PANAF-Premium TM. The study will describe the types, severity, and number of adverse events recorded following administration of PANAF-Premium TM and its effectiveness for snakebite management. Additionally, epidemiological data will be collected regarding the snake species typically responsible for bites in the North Cameroon region, the type of envenomation, the total dose of SA required for reversal of envenomation, and the total time required for clinical recovery. This will also contribute to the international and national pool of pharmacovigilance data.

Method: An open-label, Phase IV post-marketing surveillance trial will be conducted to describe the types, severity, and number of adverse events recorded during snakebite management. The average dose of SA used will be identified, and the duration of recovery, as well as the type of snakes prevalent in the area, will be explored. Eligible patients will be admitted to the hospital, and case management will be in accordance with the standard protocol followed in Cameroon and adapted from the guidelines of the African Society of Venomology. Any medication or procedure necessary to save the patient will be permitted. If antivenom serum is needed, the study drug to be used is PANAF-Premium TM (Snake Venom Antiserum-Pan Africa), manufactured by Premium Serums & Vaccines Pvt. Ltd. Any suspicious or unexpected serious adverse events (SAEs) will be recorded immediately and reported to the sponsor/ethics committee for further action. There will be no restrictions on the use of any concomitant medication or other interventions or investigations mandated by the patient's clinical condition.

Inclusion Criteria:

Patients of both sex and of any age, with history of snakebites/unknown bites received in study sites

• Willingness to participate in the study by signing the Informed Consent Form (ICF)
• Presence of one or more signs of envenomation detected by clinical examination including positive clot test. Patient may present with one or more of following visible clinical signs and symptoms of snake envenomation being local or systemic -

Defining local and systemic envenomation

1. Local envenomation- (I) Presence of bite marks with or without oozing of blood, blistering and change in color of skin.

   (ii) Rapidly progressive or massive swelling involving more than half of the bitten limb within few hours of bite (without tourniquet) (iii) Development of enlarged tender lymph nodes draining the bitten part within couple of hours after bite

2. Systemic envenomation- (i) Neurotoxic syndrome- signs of neuro-paralysis like blurring of vision, double vision, difficulty in swallowing, sleepy feeling, drooping of head, slurring of speech and the voice may become indistinct with shallow breathing, ptosis, ataxia, respiratory paralysis and generalized flaccid paralysis.

(ii) Hemotoxic syndrome- spontaneous systemic bleeding, nausea, vomiting, abdominal pain and abdominal tenderness suggestive of gastro-intestinal or retro-peritoneal bleed and/or renal damage, coagulopathy detected by 20 min WBCT with or without external bleeding and shock and a clinical condition/envenomation serious enough to administer SA will be eligible for enrolment

Exclusion Criteria:

• Participants not able to give consent
• Participants who are unable to understand the nature, scope, significance and consequences of this clinical trial
• Pre-existing renal disease, uncontrolled chronic obstructive airway disease, congestive heart failure or previous myocardial infarction and consumption of diuretics, anticoagulants and antiplatelet drugs have been causes for exclusion in a few earlier studies as these illnesses and medications could have altered the clinical and laboratory profile of patients with envenomation.
• Known history of hypersensitivity to the investigational drug or to drugs with a similar chemical structure
• Simultaneous participation in any clinical trial involving administration of an investigational medicinal product within 30 days prior to clinical trial beginning
• Participants with a physical or psychiatric condition which at the investigator's discretion may put the subject at risk, may confound the trial results, or may interfere with the subject's participation in this clinical trial
• Known or persistent abuse of medication, drugs or alcohol Others conditions may include evidence of clinically significant neurological, cardiac, pulmonary, hepatic or renal disease as far as can be assessed by history of participants, physical examination, and/or laboratory examinations.

NB: Patient previously sensitized with equine antiserum such as Tetanus or Diphtheria antitoxin or patients having received treatment with adrenaline, antihistamine, or steroids as a part of treatment at primary health care center and pregnancy will not be excluded. Since this is a post-marketing study, these patients will be included, and this information will be factored in while collating and analyzing data.