Efficacy, Safety, and Dose of Pafuramidine, a New Oral Drug for Treatment of First Stage Sleeping Sickness, in a Phase 2a Clinical Study and Phase 2b Randomized Clinical Studies

被引：18

作者：

Burri, Christian ^{[1
,2
]}

Yeramian, Patrick D. ^{[3
]}

Allen, James L. ^{[4
]}

Merolle, Ada ^{[5
]}

Serge, Kazadi Kyanza ^{[6
]}

Mpanya, Alain ^{[7
]}

Lutumba, Pascal ^{[8
,9
]}

Ku Mesu, Victor Kande Betu ^{[9
,10
]}

Mia Bilenge, Constantin Miaka ^{[11
]}

Fina Lubaki, Jean-Pierre ^{[12
]}

Mpoo Mpoto, Alfred ^{[12
]}

Thompson, Mark ^{[13
]}

Fungula Munungu, Blaise ^{[7
]}

Manuel, Francisco ^{[14
]}

Josenando, Theophilo ^{[14
]}

Bernhard, Sonja C. ^{[1
,2
]}

Olson, Carol A. ^{[15
]}

Blum, Johannes ^{[1
,2
]}

Tidwell, Richard R. ^{[15
,16
]}

Pohlig, Gabriele ^{[1
,2
]}

机构：

[1] Swiss Trop & Publ Hlth Inst, Basel, Switzerland

[2] Univ Basel, Basel, Switzerland

[3] Vaccine & Gene Therapy Inst Florida, Port St Lucie, FL USA

[4] Immtech Pharmaceut Inc, Vernon Hills, IL USA

[5] QED Grp, Luanda, Angola

[6] Med Sans Frontieres Suisse, Geneva, Switzerland

[7] Lisumbi Hlth Ctr, Kinshasa, DEM REP CONGO

[8] Kinshasa Univ, Inst Natl Rech Biomed, Kinshasa, DEM REP CONGO

[9] Kinshasa Univ, Dept Trop Med, Kinshasa, DEM REP CONGO

[10] Minist Sante Publ Kinshasa, Programme Malad Trop Negligees, Kinshasa, DEM REP CONGO

[11] Minist Hlth, Kinshasa, DEM REP CONGO

[12] Hosp Evangel Vanga, Vanga, DEM REP CONGO

[13] Federally Qualified Community Hlth Ctr, Elgin, IL USA

[14] Inst Combate & Controlo Tripanossomiases, Luanda, Angola

[15] PPD, Infect Dis, Global Prod Dev, Rockville, MD USA

[16] Univ N Carolina, Sch Med, Dept Pathol & Lab Med, Chapel Hill, NC USA

来源：

PLOS NEGLECTED TROPICAL DISEASES | 2016年 / 10卷 / 02期

关键词：

TRYPANOSOMA-BRUCEI; PRODRUG DB289; DIAMIDINE; THERAPY; MONKEY; DB75;

D O I：

10.1371/journal.pntd.0004362

中图分类号：

R51 [传染病];

学科分类号：

100401 ;

摘要：

Background Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT. Methods The Phase 2a study was an open-label, non-controlled, proof-of-concept study where 32 patients were treated with 100 mg of pafuramidine orally twice a day (BID) for 5 days at two trypanosomiasis reference centers (Angola and the Democratic Republic of the Congo [DRC]) between August 2001 and November 2004. The Phase 2b study compared pafuramidine in 41 patients versus standard pentamidine therapy in 40 patients. The Phase 2b study was open-label, parallel-group, controlled, randomized, and conducted at two sites in the DRC between April 2003 and February 2007. The Phase 2b study was then amended to add an open-label sequence (Phase 2b-2), where 30 patients received pafuramidine for 10 days. The primary efficacy endpoint was parasitologic cure at 24 hours (Phase 2a) or 3 months (Phase 2b) after treatment completion. The primary safety outcome was the rate of occurrence of World Health Organization Toxicity Scale Grade 3 or higher adverse events. All subjects provided written informed consent. Findings/Conclusion Pafuramidine for the treatment of first stage HAT was comparable in efficacy to pentamidine after 10 days of dosing. The cure rates 3 months post-treatment were 79% in the 5-day pafuramidine, 100% in the 7-day pentamidine, and 93% in the 10-day pafuramidine groups. In Phase 2b, the percentage of patients with at least 1 treatment-emergent adverse event was notably higher after pentamidine treatment (93%) than pafuramidine treatment for 5 days (25%) and 10 days (57%). These results support continuation of the development program for pafuramidine into Phase 3.

引用

页数：18

共 29 条

[21] Efficacy of the diamidine DB75 and its prodrug DB289, against murine models of human African trypanosomiasis [J].