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MSF H (Um el Kher site) DNDi, IEnD (Sudan), KEMRI (Kenya), MoH (Ethiopia)

MSF H (Um el Kher site) DNDi, IEnD (Sudan), KEMRI (Kenya), MoH (Ethiopia).

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MSF H (Um el Kher site) DNDi, IEnD (Sudan), KEMRI (Kenya), MoH (Ethiopia)

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  1. MSF H (Um el Kher site)DNDi, IEnD (Sudan), KEMRI (Kenya), MoH (Ethiopia) A MULTICENTRE COMPARATIVE TRIAL OF EFFICACY AND SAFETY OF SODIUM STIBOGLUCONATE (SSG) VERSUS PAROMOMYCIN (PM) VERSUS COMBINATION OF SSG AND PM AS THE FIRST LINE TREATMENT FOR VISCERAL LEISHMANIASIS IN ETHIOPIA, KENYA AND SUDAN

  2. BACKGROUND • Parasitic disease 500,000 new cases/ yr • Leishmania donovani (Kala Azar) in East Africa • Spread by sandfly (Phlebotomus orientalis) • Promastigote form lives in sandfly gut • After bite, invades monocyte/ tissue macrophage, divides to amastigote form then spread to RES • Spectrum: sub-clinical, acute, chronic • Wasting illness fatal in 95% if untreated • Fever, weight loss, enlarged spleen/ lymph nodes

  3. BACKGROUND (2) • Few therapeutic options in Africa: SSG/ AmpB • Paromomycin (with SSG) has been shown to be safe and effective (5 studies: Kenya, India, Sudan) • Use in combination offers potential for shorter, safer, more efficacious regimen • LEAP Goal: multi-centre study with aim of PM registration in East Africa • 5 sites, 5 partners: DNDi, Sudan IEnD (1), KEMRI (1), Ethiopia MoH (2), MSF (1) • Plan for 700 + patients in total: pooled data

  4. METHODOLOGY • SSG: 20mg / kg IM for 30 days • PM: 15mg/ kg IM for 21 days • SSG & PM (doses as above) for 17days • Inclusion: 4-60 yrs, LNA positive, Clinical signs & symptoms, consent • Exclusion: Poor condition, malnourished, pregnant/ lactating, Hb<5, Abnormal LFTs (x3) or Renal function or ECG • Safety monitoring: Clinical assessment, Hb, Renal/ Liver F, ECG- D0, 7, 14, end, 6m post Rx

  5. METHODOLOGY (2) • Primary end point= Cure at 6 months: clinically well, LNA –ve, no further anti-VL treatment needed. • Secondary endpoint= cure at end of treatment: clinically well for discharge. • If LNA 1+ve at initial discharge but well, then was followed up at 1M.

  6. 548 VL admissions16/11/04-26/01/05 397 not eligible 151 eligible 90 randomised 61 exclusions: GOT (39%) LFT (26%) Malnourished (13%), Nomad (7%) Refused (5%) Other (10%) SSG 30 PM 30 SSG/PM 30 1 withdraw 29 finished 0 withdraw 30 finished 2 withdraw 28 finished

  7. CHARACTERISTICS ON ADMISSION

  8. MAIN ADVERSE EVENTS (n=106) SEVERE ADVERSE EVENTS (n=3) • Severe epistaxsis (SSG) – transfused, recovered, Dx TB • Severe anaemia (PM)- on D22, transfused, AmBisome • Cardiac failure (SSG/PM)- TB pericarditis, withdrawn

  9. MONITORING TOXICITY • No clinically observed ototoxicity • No serious clinical/ biochemical nephrotoxicity: only 1 case with 1 grade shift in toxicity (SSG) Normal range: Urea< 50mg/dl Creatinine<1.0mg/dl

  10. MONITORING TOXICITY: LFTS LFTs generally raised above normal values Transient rise in all LFTs by D7 (mean values shown here) GOT & GPT tend to normalise EXCEPT in PM gp Not accompanied by any clinical manifestations

  11. PRIMARY ENDPOINTS

  12. SSG PM SSG/PM Hb gain (g/dl) (median, range) Weight gain 2.8 (-1.1 to 4.9) 2 (-4 to 5) 1.7 (-4.8 to 4.7) (p=0.03 for PM vs SSG) 1 (-1 to 6) 2.0 (-0.1 to 4.1) (p=0.22 for SSG/PM vs SSG) 2 (-7 to 8) Spleen regression (cm) (median, range) 3 (0 to 8) 2 (-4 to 8) (p=0.02 for PM vs SSG) 4 (0 to 10) (p=0.29 for SSG/PM vs SSG) Liver regression (cm) (median, range) 0 (-9 to 4) 0 (-2.5 to 4) (p=0.15 for PM vs SSG) -1 (-4 to 8) (p=0.13 for SSG/PM vs SSG) CLINICAL MARKERS OF IMPROVEMENT

  13. OUTCOMES (Intention to treat)

  14. LIMITATIONS/ KEY ISSUES • Sample size: multi-centre approach • Difficulty in excluding TB on inclusion • Decision to treat if LNA + but well at discharge • Use of LNA to define cure (could not use splenic aspirate) • HIV status (19 adults, 14 tested, 1 HIV+)

  15. CONCLUSION • High failure rate to PM in Um el Kehr • High rates also seen in other Sudan site • Dosing based on Indian data: appropriate? • Importance of robust data to ensure adequate new regimens are implemented • DNDi trial now moving forward to a phase II trial of PM (dose escalation)

  16. Acknowledgements • MSF team (Um el Kher) • HQ: Koert Ritmeijer, Dr RN Davidson • Partners (DNDi, Sudan MoH) • PATIENTS

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