Sodium Stibogluconate (SSG) & Paromomycin Combination Compared to SSG for Visceral Leishmaniasis in East Africa: A Randomised Controlled Trial

Visceral leishmaniasis (VL) is a parasitic disease with about 500,000 new cases each year and is fatal if untreated. The current standard therapy involves long courses, has toxicity and there is evidence of increasing resistance. New and better treatment options are urgently needed. Recently, the antibiotic paromomycin (PM) was tested and registered in India to treat this disease, but the same dose of PM monotherapy evaluated and registered in India was not efficacious in Sudan. This article reports the results of a clinical trial to test the effectiveness of injectable PM either alone (in a higher dose) or in combination with sodium stibogluconate (SSG) against the standard SSG monotherapy treatment in four East African countries—Sudan, Kenya, Ethiopia and Uganda. The study showed that the combination of SSG &PM was as efficacious and safe as the standard SSG treatment, with the advantages of being cheaper and requiring only 17 days rather than 30 days of treatment. In March 2010, a WHO Expert Committee recommended the use of the SSG & PM combination as a first line treatment for VL in East Africa

Geographical Variation in the Response of Visceral Leishmaniasis to Paromomycin in East Africa: A Multicentre, Open-Label, Randomized Trial

Visceral leishmaniasis (VL) is a fatal parasitic disease with 500,000 new cases each year according to WHO estimates. New and better treatment options are urgently needed in disease endemic areas due to the long courses, toxicity and development of resistance to current treatments. Recently, the antibiotic paromomycin was tested and registered in India to treat this disease. The current study describes a clinical trial to test the effectiveness of injectable paromomycin, either alone or in combination with the standard drug sodium stibogluconate in three East African countries—Sudan, Kenya and Ethiopia. The study showed that at the same paromomycin dose that was successfully used and registered in India, a far poorer outcome was obtained, particularly in Sudan, suggesting that there are either differences in the patients ability to respond to the drug or in the susceptibility of parasites in East Africa compared with those in India. However, no major safety concerns were noted with the treatment. Further research was initiated to see if a higher dose of paromomycin would perform better, especially in Sudan. The results of this and the performance of the combination arm will be reported later. Our study highlights the importance of considering geographical differences to treatment responses

All Serious Adverse Events (non-related events and related adverse drug reactions) by System Organ Class (bold) and Preferred Term according to MedDRA.

<p>MedDRA, Medical Dictionary of Regulatory Activities; SSG, sodium stibogluconate (20 mg/kg/day for 30 days); PM paromomycin sulphate (20 mg/kg/day for 21 days); SSG & PM (SSG 20 mg/kg/day & PM at 15 mg/kg/day for 17 days); NR, non-related Serious Adverse Events; SADR, Serious Adverse Drug Reaction.</p>a<p>Death due to an unknown cause.</p>b<p>Raised bilirubin/jaundice.</p>c<p>Abdominal sepsis and malaria were considered as unlikely related to the drug by the investigators.</p>d<p>2 PM patients withdrew consent after 4 and 6 days on treatment and 1 SSG & PM patient after 6 days on treatment, no SAE reported prior to withdrawal.</p

CONSORT Patient Flowchart – SSG <i>vs.</i> PM.

<p>SSG, sodium stibogluconate; PM, paromomycin sulphate; SAE, serious adverse event; LTFU, loss to follow-up; ITT, intention-to-treat; PP, per protocol. Patients included in the SSG (20 mg/kg/day for 30 days) vs. PM (20 mg/kg/day for 21 days) arms; <b>^a</b> data from these patients were previously reported <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001674#pntd.0001674-Musa1" target="_blank">[14]</a>.</p

Paromomycin (PM) monotherapy versus Sodium Stibogluconate (SSG): Efficacy Data.

<p>CI = confidence interval, ITT = Intention-to-Treat, PP = Per-Protocol.</p>a<p>205 patients were originally recruited to the PM arm, 386 to the SSG arm.</p>b<p>Treatment effect: difference in efficacy between SSG and PM, percent scale with exact binomial 95% CI. Adjustment for centre was not possible due to only one failure in one centre.</p>c<p>p-value from likelihood ratio test comparing binomial regression models with and without treatment.</p>d<p>Complete-case analysis: patients with missing outcome data excluded from analysis.</p>e<p>Worst-case analysis: missing outcomes assumed to be treatment failures.</p

Sodium Stibogluconate (SSG) & Paromomycin (PM) versus SSG: Efficacy Data.

<p>CI = confidence interval, ITT = Intention-to-Treat, PP = Per-Protocol.</p>a<p>381patients were originally recruited to the SSG&PM arm, 386 to the SSG arm.</p>b<p>Treatment effect: difference in efficacy between SSG and SSG & PM combination treatment, percent scale with exact binomial 95% CI.</p>c<p>p-value from likelihood ratio test comparing binomial regression models with and without treatment.</p>d<p>p-value from likelihood ratio test comparing binomial regression models with and without factor of interest, after adjustment for treatment allocation.</p>e<p>Complete-case analysis: patients with missing outcome data excluded from analysis.</p>f<p>Worst-case analysis: missing outcomes assumed to be treatment failures.</p

Baseline Data.

<p>SSG = sodium stibogluconate (20 mg/kg/day for 30 days); PM = paromomycin sulphate (20 mg/kg/day for 21 days); SSG & PM Combination treatment (SSG at 20 mg/kg/day plus PM at 15 mg/kg/day for 17 days);</p>a<p>Patients 4–17 years old were classified as children and patients 18–60 years old were classified as adults.</p>b<p>These are presented as mean (SD).</p>c<p>Classification based on World Health Organization child growth standards in patients ≤19 years or using body mass index in those ≥20 years.</p>d<p>340 out of 386, 203 out of 205, and 335 out of 381 patients were tested for HIV in the SSG, PM and SSG & PM arms respectively.</p

CONSORT Patient Flowchart – SSG <i>vs.</i> SSG&PM.

<p>SSG, sodium stibogluconate; PM, paromomycin sulphate; SAE, serious adverse event; LTFU, loss to follow-up; ITT, intention-to-treat; PP, per protocol. Patients included in the SSG (SSG at 20 mg/kg/day for 30 days) vs. SSG & PM combination (SSG at 20 mg/kg/day & PM at 15 mg/kg/day for 17 days) arms; <b>^a</b> patient was diagnosed with tuberculosis and was removed from the study before the end of treatment; <b>^b</b> patient died from non-VL causes; <b>^c</b> patient with deviation also had a missing outcome value and was already excluded from the ITT analysis.</p

Serious and non-serious adverse events occurring during the study.

<p>SSG = sodium stibogluconate; PM = paromomycin sulphate; SSG & PM = combination treatment;</p><p>AE, adverse event; SAE, serious adverse event; TEAE, treatment emergent adverse event;</p>a<p>There were two consent withdrawals in the PM arm (after 4 and 6 days on treatment) and 1 withdrawal in the SSG & PM arm (after 6 days on treatment) - data were therefore collected only up to the day of withdrawal for these patients.</p>b<p>Treatment emergent adverse event is defined as onset being between day 1 of treatment and 30 days post end of treatment, inclusive.</p>c<p>No patient experienced more than one SAE.</p>d<p>Adverse drug reaction is defined as any adverse event the investigator recorded as having a probable, possible or unlikely relationship to the study drug.</p>e<p>Cause of deaths were as follows: SSG: unknown (1), Acute Renal Failure (2), cardiotoxicity (1); PM: VL; SSG & PM: Pericarditis tuberculosis (1), malaria (1).</p>f<p>Person-days at risk is defined as the treatment period per study drug regimen plus an additional 30 days post end of treatment.</p