The initial searches of PubMed and Cochrane Central Register of Controlled Trials generated 2857 publications (fig 1). We retained 927 publications containing 966 eligible randomised controlled trials. Five publications were added from our literature collection or bibliographies of included publications eventually yielding 971 randomised controlled trials in 932 publications.
Fig 1 Schematic of literature search
Of the 971 trials, 854 dealt with one of the 16 primary diseases and 117 with a complication of one of the diseases (table 1). The most common study sites were Africa (27.6%) and Southeast Asia (26.9%). Only 26 (2.7%) of the trials were multicentre. Less than 3% and 2% of the trials had cluster or crossover designs, respectively. Most trials were either publicly funded or had no funding statement; only 11% reported industry funding. The median number of randomised participants per trial was 89 (interquartile range 42-184).
Table 1 Characteristics of included randomised controlled trials
Randomised evidence and correlation with burden of disease
Figure 2 shows the cumulative number of randomised participants and trials over time. There is an inflection point in the pace of evidence accumulation around 1980 when the growth of evidence accelerates, but growth has remained steady since then. Table 2 shows that for six diseases—Buruli ulcer, cysticercosis, dengue, echinococcosis, human African trypanosomiasis, and leishmaniasis—there were more randomised controlled trials published in the past 12 years than in the preceding 50. For the 10 remaining diseases there have been fewer trials published in the past 12 years than in the preceding 50. The correlation coefficient between the two series was 0.66, indicating there was a modest correlation between the number of trials published before and after 2000 for each of the diseases. Table 3 shows the number of trials, total sample size, and annual global burden for each disease. Leishmaniasis was the most studied disease (184 trials, total sample size 23
039), followed by geohelminth infections (160 trials, total sample size 46
887), and schistosomiasis (142 trials, total sample size 35
026). The least studied diseases were dracunculiasis (nine trials, total sample size 798) and Buruli ulcer (five trials, total sample size 337). There was no strong correlation (Pearson correlation coefficient 0.33, P=0.27 for both analyses) between the global burden of disease and total sample size or number of clinical trials (appendix figure 1) for 13 diseases with available burden of disease estimates. Relative to its global burden of disease (5
000 DALYs), lymphatic filariasis was the least studied disease (73 trials, total sample size 9996). Leprosy was the best studied (120 trials, total sample size 14
772) relative to its fairly low global burden of disease (198
Fig 2 Total sample size and number of clinical trials over time
Table 2 Number of randomised controlled trials published before and after 2000 for each disease
Table 3 Number of trials, total sample size and annual global burden of disease for each disease
Dengue, American trypanosomiasis, the five major foodborne trematode infections, human African trypanosomiasis, dracunculiasis, mucocutaneous leishmaniasis, and Buruli ulcer each had 10 or fewer randomised controlled trials. Few treatment regimens were tested: six for dengue, five for American trypanosomiasis, seven or fewer for each of the foodborne trematode infections, six for dracunculiasis, seven for human African trypanosomiasis and mucocutaneous leishmaniasis, and eight for Buruli ulcer. Diseases with 11-40 randomised controlled trials examining the primary disease included rabies (n=13), strongyloidiasis (n=14), echinococcosis (n=15), tuberculoid/paucibacillary leprosy (n=21), trachoma (n=29), and cysticercosis (n=32). As table 4 shows the evidence for one of the first or second line treatments for Buruli ulcer (all recommended treatments), human African trypanosomiasis (pentamidine), chronic American trypanosomiasis (nifurtimox), cysticercosis (praziquantel plus corticosteroids), rabies (several intramuscular post-exposure vaccine regimens), echinococcosis (percutaneous drainage plus albendazole and watchful waiting/no treatment), New World cutaneous leishmaniasis (pentamidine), and foodborne trematode infections (nitazoxanide for fascioliasis and praziquantel for clonorchiasis, paragonimiasis, and fasciolopsiasis) comes from either a single trial or a total of less than 100 randomised participants. Dengue and dracunculiasis have been investigated in few and primarily small randomised controlled trials, but do not have currently recommended pharmacological treatments. Appendix table 3 shows the amount of evidence for each treatment for each disease and disease complication.
Table 4 Number of trials examining primary disease, number of regimens tested, and amount of evidence from randomised clinical trials supporting first and second line treatments in 16 neglected tropical diseases
Figure 3 shows network diagrams of the tested regimens and comparisons for the 10 disease entities with more than 40 randomised controlled trials—schistosomiasis, ascariasis, hookworm, trichuriasis, lymphatic filariasis, visceral leishmaniasis, Old World cutaneous leishmaniasis, New World cutaneous leishmaniasis, onchocerciasis, and multibacillary leprosy. Appendix figure 2 shows networks for diseases that had 11-40 randomised controlled trials. Figure 3 omits a few trials that used regimens that were not compared with any of those shown in the connected network. This included one trial for Old World cutaneous leishmaniasis, three for visceral leishmaniasis, one for ascariasis, one for schistosomiasis, four for multibacillary leprosy, and one for lymphatic filariasis. Data from these trials are included in tables 3 and 4, but were not used to calculate the probability of interspecific encounter and C scores.
Fig 3 Network diagrams for diseases with more than 40 randomised controlled trials. Node size is proportional to total sample size and line thickness is proportional to number of comparisons. Scale of nodes is different between different networks; see (more ...)
The typical geometry resembled a star or several stars, where star centres were usually first line treatments, sometimes second line treatments, and often placebo. There were some cases where treatments that are not accepted first or second line treatments were star centres, meaning a drug that is not a current first or second line drug has been compared against multiple other treatments. In most cases, this just reflects changes in clinical practice over time. These star centres are either treatments that were recommended treatments at the time of the trial—such as DEC (diethylcarbamazine) for onchocerciasis,78
bephenium for hookworm,80
and dapsone monotherapy for leprosy81
—or a standard of care in the country where the trial was conducted at the time of the trial—such as dapsone-rifampin dual treatment for multibacillary leprosy in Asia.82
Other drugs such as ivermectin and albendazole monotherapy for lymphatic filariasis were shown to be effective in small randomised controlled trials and were used as comparators (often with combination treatment) in subsequent larger trials.84
For nine of the 10 disease networks in figure 3, there was more than one first or second line treatment. In seven of these nine, one or two treatments were most often studied while the other recommended treatments had limited evidence. For example, recommended treatments were compared in fewer than seven clinical trial arms and/or fewer than 1000 patients in onchocerciasis (combination ivermectin-doxycycline), trichuriasis (ivermectin), New World cutaneous leishmaniasis (pentamidine and miltefosine), and visceral leishmaniasis (miltefosine, paromomycin, amphotericin B lipid complex, and liposomal amphotericin).
In many networks, there were few data from head to head comparisons for first and second line treatments, despite them being tested in many trials against multiple comparators. The most extreme examples of this are in the networks for New World cutaneous leishmaniasis, for which there were no head to head comparisons between second line treatments miltefosine and pentamidine, and in visceral leishmaniasis, for which there were few or no head to head comparisons between miltefosine and paromomycin and between miltefosine and either amphotericin B lipid complex or liposomal amphotericin. To a lesser extent, this lack of head to head comparisons between recommended treatments is shown in the geohelminth networks. Trichuriasis and ascariasis networks have few or no comparisons of mebendazole and ivermectin, and the hookworm network shows few comparisons of pyrantel pamoate with albendazole or mebendazole.
All 10 networks had high diversity, with probability of interspecific encounter scores ≥0.82 (table 5). In seven of the 10 networks (Old World leishmaniasis, visceral leishmaniasis, the three geohelminth infections, multibacillary leprosy, and lymphatic filariasis) there was significant co-occurrence, meaning there was a tendency to compare specific pairs of treatments more often and to avoid other comparisons. This could reflect the fact that these networks have multiple star centres and each star centre is compared against a largely non-overlapping set of comparators. Conversely, the networks for New World cutaneous leishmaniasis and schistosomiasis, which mostly have a single star centre (systematic pentavalent antimonials and praziquantel, respectively), do not exhibit significant co-occurrence.
Table 5 Network metrics for 10 disease networks shown in figure 3