A randomized, single-ascending-dose, ivermectin-controlled, double-blind study of moxidectin in Onchocerca volvulus infection

Abstract

Background: Control of onchocerciasis as a public health problem in Africa relies on annual mass ivermectin distribution. New tools are needed to achieve elimination of infection. This study determined in a small number of Onchocerca volvulus infected individuals whether moxidectin, a veterinary anthelminthic, is safe enough to administer it in a future large study to further characterize moxidectin's safety and efficacy. Effects on the parasite were also assessed.

Methodology/principal findings: Men and women from a forest area in South-eastern Ghana without ivermectin mass distribution received a single oral dose of 2 mg (N = 44), 4 mg (N = 45) or 8 mg (N = 38) moxidectin or 150 µg/kg ivermectin (N = 45) with 18 months follow up. All ivermectin and 97%-100% of moxidectin treated participants had Mazzotti reactions. Statistically significantly higher percentages of participants treated with 8 mg moxidectin than participants treated with ivermectin experienced pruritus (87% vs. 56%), rash (63% vs. 42%), increased pulse rate (61% vs. 36%) and decreased mean arterial pressure upon 2 minutes standing still after ≥5 minutes supine relative to pre-treatment (61% vs. 27%). These reactions resolved without treatment. In the 8 mg moxidectin and ivermectin arms, the mean±SD number of microfilariae/mg skin were 22.9±21.1 and 21.2±16.4 pre-treatment and 0.0±0.0 and 1.1±4.2 at nadir reached 1 and 3 months after treatment, respectively. At 6 months, values were 0.0±0.0 and 1.6±4.5, at 12 months 0.4±0.9 and 3.4±4.4 and at 18 months 1.8±3.3 and 4.0±4.8, respectively, in the 8 mg moxidectin and ivermectin arm. The reduction from pre-treatment values was significantly higher after 8 mg moxidectin than after ivermectin treatment throughout follow up (p<0.01).

Conclusions/significance: The 8 mg dose of moxidectin was safe enough to initiate the large study. Provided its results confirm those from this study, availability of moxidectin to control programmes could help them achieve onchocerciasis elimination objectives.

Trial registration: ClinicalTrials.gov NCT00300768.

Figure 1. Number of participants by cohort screened, randomized, treated and analyzed.

1. Cohorts were screened for and eligible participants randomized and treated in sequential order. 2. In each dose group, subjects were randomized 3∶1 to the dose of moxidectin (Moxi) specified and ivermectin (IVM). 3. Mild: <10 microfilaria/mg skin, no ocular involvement, Moderate: 10–20 mf/mg skin, ocular involvement with sum of microfilariae in both eyes ≤10, Severe: >20 mf/mg skin without or with any level of ocular involvement. 4. Screen failure reasons: not meeting criteria for intensity of infection of the cohort for which screening was conducted (56%), laboratory values outside the protocol specified range (26%), ocular disease inconsistent with the eligibility criteria of the cohort for which screening was performed (7%), hypertension (6%) and others (5%, including age outside protocol specified range, orthostatic hypotension, pregnancy, weight below the limit specified in the eligibility criteria, history of neurologic/neuropsychiatric disorder/epilepsy). 5. All participants received the treatment they had been randomized to and completed the intervention (single dose study). 6. mITT modified intent to treat population including all treated participants. Safety analysis population. 7. e-mITT efficacy modified intent to treat population, including all participants who completed the study. Efficacy analysis was conducted for the e-mITT and the mITT population. 6 participants did not complete the study: 1 who died due to a snake bite, 1 who decided to withdraw from the study and 4 who were lost to follow up, i.e. could not be located despite several attempts.

Figure 2. Cohort enrolment, treatment and follow up and decision making for progression to screening of the next intensity of infection cohort within one dose group (A) and for progression to screening for the mildly infected cohort at the next higher dose level (B).

Figure 3. Map of Ghana showing the location of some towns/villages in the area from which participants were recruited.

The boundaries and names shown and the designations used in this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.

Figure 4. Percentage reduction from pre-treatment in skin microfilariae density (mean, standard deviation) 8 days, 1, 2, 3, 6, 12 and 18 months after treatment by treatment group.

A Total e-mITT population, B Severely infected in the e-mITT population treated with ivermectin or 8 mg moxidectin. For the ivermectin treatment group, means and standard deviations are shown across all severely infected and without the suboptimal microfilariae responders (Ivermectin - SOMR). Tx – treatment, SD – standard deviation shown in one direction. Marker positions for different treatment groups have been placed around the measurement time point to allow, to the extent possible, differentiation between overlapping means and SD.

Figure 5. Skin microfilariae density in individual participants pre-treatment (0) and at the different times post-treatment (e-mITT population) in the four treatment groups.

A Ivermectin. The data for the three participants treated with ivermectin whose decrease in skin microfilariae levels did not meet the criteria of ‘adequate response’ are indicated by markers at the evaluation time points. B 2 mg moxidectin, C 4 mg moxidectin, D 8 mg moxidectin.

Figure 6. Percentage of participants with undetectable levels of skin microfilariae by treatment group and time post-treatment.

A total e-mITT population, B Severely infected in the e-mITT population treated with ivermectin or 8 mg moxidectin.

Figure 7. Time of nadir and start of sustained increase in skin microfilariae levels by treatment.

A Time of nadir among participants with any intensity of infection, B Time of nadir among severely infected participants, C Time of start of sustained increase (time of two subsequent measurements above the nadir) among participants with any intensity of infection, D Time of start of sustained increase among severely infected participants. Data analyzed are those of participants who completed the study excluding participants with a decrease in skin microfilariae levels not meeting the criteria for ‘adequate response’ (SOMRs).

Figure 8. A. Number of excised onchocercal nodules by age and sex of participants.

B. Pre-treatment skin mf density by age and sex of participants. Participants with 0 excised onchocercal nodules either had no palpable nodules or all excised nodules were non-onchocercal based on histological evaluation.

Figure 9. A. Skin microfilaria density pre-treatment by sex of participant and number of onchocercal nodules.

B. Skin microfilaria density pre-treatment by number of live female macrofilariae and sum of live (LI) and dead, non-calcified female macrofilariae (LIDD). Only data from participants who had not more palpable nodule sites at month 18 than at pre-treatment and who had agreed to excision of all palpable nodules or who had no palpable nodules are included. For display reasons, the×axis maximum in Figure B was set to 9. The data from the man with 8 nodules in Figure A who had 13 live female macrofilariae and 3 dead, non-calcified female macrofilariae and 50.2 mf/mg skin pre-treatment are thus not displayed.

Figure 10. Number of live female macrofilaria, live young female macrofilaria and live male macrofilaria in excised nodules vs skin mf density 18 months after treatment by treatment.

A. Ivermectin, B. 2×axis maximum was set to 7. The data for one participant treated with 2 mg moxidectin who had 13 live female macrofilaria and a skin mf density of 8.2 mf/mg are thus not displayed. Participants with 0 macrofilaria in excised nodules either had no palpable nodules or all excised nodules were non-onchocercal based on histological evaluation. Abbreviations: LI FM – live female macrofilariae, Y FM – live young female macrofilariae, LI MW – live male macrofilariae.