Randomized double blind comparative trial of two new antivenoms for the treatment of patients enveno

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Randomized double blind comparative trial of two
new antivenoms for the treatment of patients
envenomed by the saw-scaled or carpet viper
(Echis ocellatus) in northern Nigeria

• 1Abubakar SB, 2Abubakar IS, 3Nasidi A, 3Durfa N,
  2Habib AG, 1Yusuf PO, 1Larnyang S, 5Garnvwa J,
  6Sokomba E, 5Theakston RDG, 3Salako L, 7Warrell
  DA, for the EchiTab Study Group Nigeria UK
• 1Kaltungo General Hospital, Kaltungo, Gombe
  state, Nigeria 2Faculty of Medicine, Bayero
  University Kano, Aminu Kano Teaching Hospital,
  PMB 3452, Kano, Nigeria3EchiTab Study Group,
  Federal Ministry of Health, Abuja, Nigeria 5
  Alistair Reid Venom Research Unit, Liverpool
  School of Tropical Medicine, UK 6Faculty of
  Pharmaceutical Sciences, University of Jos,
  Nigeria 7Nuffield Department of Clinical
  Medicine, University of Oxford, UK

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Most important venomous snake in Nigeria Echis
ocellatus (saw scaled or carpet viper)
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Nigeria and Echis ocellatus (bite) map
Study site Kaltungo
Yellow spots have published reports of E.
ocellatus bites
Shaded area is E. ocellatus habitat
High prevalence states
Low prevalence states
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Echis ocellatus habitat Hilly savanna terrain
in NE Nigeria Kaltungo Town viewed from Tangale
Peak (Kilang)
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Plan

• Objectives
• To compare the efficacy and safety of two
• antivenoms, using initial doses derived from the
• following
• Pre-clinical testing of candidate antivenoms (at
  Liverpool School of Tropical Medicine)
• Preliminary dose-finding/safety study in
  envenomed patients

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Study site duration

• Kaltungo General Hospital
• Gombe State
• Nigeria

Site of several previous studies of Echis bite
(1972-1994)
Warrell et al,
1974, 1980
Daudu and Theakston, 1988
Meyer et al,
1997
Study duration 2005 2008 (30mths)
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Kaltungo Hospital Compound
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Front of Snake bite ward, Kaltungo General
Hospital
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Pre-clinical tests of candidate antivenoms
Echis ocellatus max venom yield 24.8 mg
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Preliminary open dose-finding/safety study

• Study of 3 antivenoms that passed pre-clinical
  testing
• Continual Reassessment Method (CRM) with "33"
  dose escalation design
• Efficacy assessed by restoration of blood
  coagulability 6 hr after a dose of antivenom
• Patients treated in groups of 3, repeating or
  increasing dose according to fixed
  efficacy/safety criteria
• Initial dose (d) determined by pre-clinical
  testing

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20 minute whole blood clotting test (20WBCT)

• Take 2-3 ml venous blood without
  
  anti-coagulant into new, clean,
  
  dry, glass vessel
• Leave undisturbed at ambient
  temperature
  for 20 min
• Tip vessel once
• If blood runs out like water consumptive
  coagulopathy from systemic envenoming
• If in doubt, compare with normal control blood in
  same type of tube
• Repeat test 6 hr after antivenom treatment (until
  permanent restoration is achieved), then daily

image
Warrell et al QJM19774633-62 Sano-Martins et
al Toxicon 1994321045-1050
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Dose-finding by Continual Re-assesment Method
(CRM) with 33 dose escalation design
     
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Efficacy/Safety criteria

• Never increase dose to dd (double initial dose)
  if 2 or more (out of 3 or 6) reactions have
  occurred with dose d
• Never de-escalate to a dose at which 1 out of 3
  or fewer patients were cured

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Preliminary dose finding/safety study results

• ET-Plus initial dose of 3 vials (30ml) restored
  blood coagulability in 5 of 6 by 6 hours
  (pruritic early reactions in 2 of 6)
• ET initial dose of 1 vial (10ml) restored blood
  coagulability in 5 of 6 by 6 hours (pruritic
  early reactions in 2 of 6)
• Vacsera initial dose of 5 vials (50mls) restored
  blood coagulability in 0 of 3 by 6 hours
  (pruritic reactions in 2 of 3)
• Therefore ET-Plus and ET were selected for RCT

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Patients inclusions

• Patients of either sex and any age, provided
  that
• Incoagulable blood (20WBCT)
• Venous access for 6-hourly blood sampling
• Bitten within the previous 72 hours
• Informed consent to admission, treatment and
  investigation (patient, relative)

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Typical patient recruited into study
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Patients exclusions

• Already received antivenom
• Pregnant
• Clinical features of severe envenoming (shock,
  massive bleeding, lateralising signs suggesting
  intracerebral haemorrhage, etc) who require
  urgent resuscitation and treatment with a large
  dose of rescue antivenom (SAVP)
• Obvious severe unrelated medical condition (e.g.
  advanced AIDS Slim disease/tuberculosis

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Type of patient excluded from study (coma with
lateralising signs of cerebral haemorrhage)
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Clinical methods

• Diagnosis patients with incoagulable blood
  assumed to have been envenomed by E. ocellatus
  (valid assumption in this region, based on
  studies since 1972) confirmed by identifying
  dead snake when brought in 160 (40) patients
• History and the results of physical examination
  recorded on standard proforma on admission and at
  least daily thereafter
• General management (analgesia, wound care,
  reactions etc) according to guidelines

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Design and Method

• Design Randomized double blind comparative trial
  (RCT) of 2 new antivenoms
• Ethics approval Ministry of Health, Gombe State,
  Ethics committee
• Informed consent after discussion of patient
  information sheet in English and local vernacular
  language - Hausa
• Block randomization from table treatment
  allocation hidden in sealed envelopes kept by the
  hospital pharmacist (who was not involved in the
  study)
• Blinded antivenoms provided by hospital
  pharmacist after reconstituting to 40mls with
  sterile water for injection in syringe

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Study design Non-inferiority

• The RCT was designed to demonstrate 10
  non-inferiority of ET-Plus compared to ET with
  predicted efficacy of 80 for ET, i.e., ET-Plus
  efficacy of 70 is defined as non-inferior
• Sample size for non inferiority N 2 p (1
  p)(Z2a Z2ß)/d2
• p estimate of overall probability of response
  0.8
• Z2a a one sided 95 confidence interval should
  exclude a difference of 0.05, giving 2a
  equivalent to 0.1 1.645
• Z2ß power of 80 if there is no efficacy
  difference, giving 2ß equivalent to 0.40 0.842
  
• d set at 0.1
• N sample size required in each of the
  comparison group for non inferiority trial
• Substituting, N 198 in each group or approx 400
  patients in both groups
• - Armitage, Berry Mathews (2002). Statistical
  Methods in Medical Research, 4th ed. pp 638-9
• - STATA Software version 7 (Texas, USA)

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Results recruitment

• Background In 2007, a full calendar year during
  the study
• Total patients seen 1803 (26 fatal cases)
• Echis ocellatus bites 1623 (90)
• Naja spp bites 21
• Bitis arietans bites 4
• Atractaspis spp.
• non-venomous (e.g. Telescopus variegatus)
• Of gt3000 patients snake-bitten patients admitted
  during the study period (2005-2008, 30 months),
  400 were recruited into and completed the (RCT)
  per criteria

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Baseline characteristics of 400 Carpet viper
envenomed victims by administered antivenoms
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Anatomic site of bite and clinical features by
administered antivenom
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Outcomes among 400 envenomed carpet viper victims
by antivenom administered I
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Outcomes among 400 envenomed carpet viper victims
by antivenom administered II
There were no fatalities in either intervention
arm
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Echis ocellatus envenoming results of previous
comparative studies

• Average dose of antivenom needed permanently to
  restore blood coagulability (double-blind RCT)
  Warrell et al 1974
  
  SAIMR
  (SAVP) Echis mono-specific 15.2ml
• Behringwerke polyspecific antivenom
  37.9ml
• Daudu Theakston 1988 studied Pasteur
  polyspecific Ipser Afrique and found it modestly
  effective
• Proportion of patients whose blood coagulability
  was permamently restored by initial dose of
  antivenom (open RCT) Meyer et al 1997
  
  EchiTAb monospecific Fab (10mls)
  36 (reactions 15)
  
  Ipser Afrique polyspecific
  (40mls) 35 (reactions 10)
• Proportion of patients whose blood coagulability
  was restored by initial dose of antivenom
  (historical comparison, Ghana) Visser et al
  2008FAV-Afrique 30 (case fatality 2)
  
  
  Bharat Asna (BSI) polyspecific 12 (case
  fatality 12)
• ET was used successfully in pregnant women Habib
  et al 2008

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Conclusion

• Both ET-Plus and ET antivenoms proved effective
  and acceptably safe and both can be recommended
  for the treatment of E. ocellatus envenoming in
  Nigeria and probably elsewhere in Africa.

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EchiTab Study Group Nigeria-UK
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