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

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

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 patients in total: pooled data

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

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.

548 VL admissions 16/11/04-26/01/ eligible 61 exclusions: GOT (39%) LFT (26%) Malnourished (13%), Nomad (7%) Refused (5%) Other (10%) 90 randomised SSG 30PM 30SSG/PM 30 1 withdraw 29 finished 0 withdraw 30 finished 2 withdraw 28 finished 397 not eligible

CHARACTERISTICS ON ADMISSION

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recovered, Dx TB Severe anaemia (PM)- on D22, transfused, AmBisome Cardiac failure (SSG/PM)- TB pericarditis, withdrawn SSGPMSSG/PM Malaria683 Pneumonia420 Cough558 Diarrhoea155 Bleeding311 Vomiting366 Other18115

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 (range) SSGPMSSG/PM Urea D0 < < < Creat D0 < < < Urea final follow up < < < Crea final follow up < < <

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

PRIMARY ENDPOINTS n=90, 30 each SSGPMSSG/ PM Withdrawn1 (TB)02 (TB, no FU) Final failures3242 Severe PKDL200 IC and cure 6m236 Slow responder103 Total cured24626 Cure Rate80%20%87% Risk ratio for failure 95%CI (p-value) Ref. (1.00) to 10.0 (p<0.001) to 2.0 (p=0.26)

CLINICAL MARKERS OF IMPROVEMENT SSGPMSSG/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) (-4 to 8) (p=0.13 for SSG/PM vs SSG)

OUTCOMES (Intention to treat) Cure rates (n and %) SSGPMSSG/ PM Um el Kher (Sudan) 24/30 (80%) 10/30 (33%) 26/30 (87%) Kassab (Sudan) 14/15 (93%) 9/15 (60%) 12/15 (80%) KEMRI (Kenya) 10/10 (100%) 11/11 (100%) 10/11 (91%)

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+)

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)

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