Transcript MSF H Um el Kehr

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
MSF H (Um el Kher site)
DNDi, IEnD (Sudan), KEMRI (Kenya), MoH (Ethiopia)
BACKGROUND
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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 700 + patients in total: pooled data
METHODOLOGY
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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
16/11/04-26/01/05
397 not eligible
151 eligible
90 randomised
61 exclusions:
GOT (39%)
SSG 30
PM 30
SSG/PM 30
1 withdraw
0 withdraw
2 withdraw
29 finished
30 finished
28 finished
LFT (26%)
Malnourished (13%),
Nomad (7%)
Refused (5%)
Other (10%)
CHARACTERISTICS ON ADMISSION
SSG
PM
SSG/ PM
Age (yrs)
10.0 (4-50)
11.0 (4- 50)
9.5 (4-36)
M: F sex ratio
1.30 (17/13)
2.75 (22/8)
1.90 (19/10)
Weight (kg)
23.5 (10- 63)
24.5 (12-66)
22.0 (10- 58)
Moderate malnour.
14 (46.7%)
10 (33.3%)
11 (63.3%)
Not malnourished
16 (53.3%)
20 (66.7%)
19 (36.7%)
Spleen size (cm)
6.0 (0- 14)
6.0 (0-17)
5.0 (0- 14)
Liver sixe (cm)
2.5 (0-5)
2.3 (0-8)
3.0 (0- 8)
Hb (g/dl)
8.4 (6-12.7)
9.1 (5.2-14)
8.4 (5.7- 13)
LNA (log scale)
2.0 (1-6)
2.0 (1-6)
2.0 (1-6)
Malaria on arrival
2 (7%)
2 (7%)
1 (3%)
Pneumonia on arrival
2 (7%)
0
1 (3%)
Malaria (at any time)
8 (26.7%)
10 (33.3%)
4 (13.3%)
Pneumonia (at any
6 (20.0%)
2 (6.7%)
1 (3.3%)
Nutritional status
time)
Moderate malnourished: BMI 16- 18 kg/m2 or W/H 70-80%; severe malnourishment: BMI <16 kg/m2
or W/H <70%.
For age, weight, spleen, liver, Hb, LNA: median and range
MAIN ADVERSE EVENTS (n=106)
SSG
PM
SSG/PM
Malaria
6
8
3
Pneumonia
4
2
0
Cough
5
5
8
Diarrhoea
1
5
5
Bleeding
3
1
1
Vomiting
3
6
6
Other
18
11
5
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
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)
SSG
PM
SSG/PM
Urea D0
<20-38.8
<20-35.8
<20-48.8
Creat D0
<0.5-1.1
<0.5-1.2
<0.5-0.9
Urea final follow up
<20-24.3
<20-28.2
<20-33.7
Crea final follow up
<0.5-0.9
<0.5-1.0
<0.5-0.8
MONITORING TOXICITY: LFTS
100
90
80
70
60
SSG
50
PM
70
40
SSG/ PM
60
30
50
20
GOT
10
0
0
7
14
18-22
31
SSG
40
PM
30
600
500
SSG/ PM
400
20
GPT
10
0
0
7
14
18-22
31
SSG
300
PM
SSG/ PM
200
ALP
100
0
0
7
14
18-22
31
• 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
SSG
PM
SSG/ PM
Withdrawn
1 (TB)
0
2 (TB, no FU)
Final failures
3
24
2
Severe PKDL
2
0
0
IC and cure 6m
23
6
23
Slow responder
1
0
3
Total cured
24
6
26
Cure Rate
80%
20%
87%
Risk ratio for
failure
95%CI (p-value)
Ref. (1.00)
4.5
2.0 to 10.0
(p<0.001)
0.4
0.1 to 2.0
(p=0.26)
CLINICAL MARKERS OF IMPROVEMENT
SSG
PM
SSG/PM
Hb gain (g/dl)
(median, range)
2.8
1.7
2.0
(-1.1 to 4.9)
(-4.8 to 4.7)
(p=0.03 for PM vs
SSG)
(-0.1 to 4.1)
(p=0.22 for SSG/PM
vs SSG)
Weight gain
2 (-4 to 5)
1 (-1 to 6)
2 (-7 to 8)
Spleen regression
(cm)
(median, range)
3
2
4
(0 to 8)
(-4 to 8)
(p=0.02 for PM vs
SSG)
(0 to 10)
(p=0.29 for SSG/PM
vs SSG)
Liver regression
(cm)
(median, range)
0
0
-1
(-9 to 4)
(-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 %)
Um el Kher
(Sudan)
Kassab
(Sudan)
KEMRI
(Kenya)
SSG
PM
SSG/ PM
24/30
(80%)
14/15
(93%)
10/10
(100%)
10/30
(33%)
9/15
(60%)
11/11
(100%)
26/30
(87%)
12/15
(80%)
10/11
(91%)
LIMITATIONS/ KEY ISSUES
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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
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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
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MSF team (Um el Kher)
HQ: Koert Ritmeijer, Dr RN Davidson
Partners (DNDi, Sudan MoH)
PATIENTS