O. volvulus microfilariae in the anterior chambers of the eye and ocular adverse events after a single dose of 8 mg moxidectin or 150 µg/kg ivermectin: Results of a randomized double-blind Phase 3 trial in the Democratic Republic of the Congo, Ghana and Liberia

doi:10.21203/rs.3.rs-2879768/v1

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Research Article

O. volvulus microfilariae in the anterior chambers of the eye and ocular adverse events after a single dose of 8 mg moxidectin or 150 µg/kg ivermectin: Results of a randomized double-blind Phase 3 trial in the Democratic Republic of the Congo, Ghana and Liberia

https://doi.org/10.21203/rs.3.rs-2879768/v1

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published 15 Mar, 2024

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Background

After ivermectin became available, diethylcarbamazine (DEC) use was discontinued because of severe adverse reactions, including ocular reactions, in individuals with high O. volvulus microfilaridermia. Assuming long-term ivermectin use led to < 5 microfilariae/mg skin (SmfD) with little or no eye involvement, DEC + ivermectin + albendazole treatment a few months after ivermectin was proposed. In 2018, the US FDA approved moxidectin for treatment of O. volvulus infection. The Phase 3 study evaluated ivermectin-naïve individuals with ≥ 10 SmfD for skin and ocular microfilariae and adverse events (AEs) for 12–18 months after a single treatment (8mg moxidectin, n = 978 or 150µg/kg ivermectin n = 494).

Methods

We descriptively analyzed the data from 1463 participants with both eyes evaluated using six (0, 1–5, 6–10, 11–20, 21–40, > 40) categories for microfilariae in the anterior chamber (mfAC) and three pre-treatment (< 20, 20-<50, ≥ 50) and post-treatment (0, > 0–5, > 5) SmfD categories. A linear mixed model evaluated factors and covariates impacting mfAC levels. Ocular AEs were summarized by type and start post-treatment. Logistic models evaluated factors and covariates impacting the risk for ocular AEs.

Results

Moxidectin and ivermectin had the same effect on mfAC levels. These increased from pre-treatment to Day 4 and Month 1 in 20% and 16% of participants, respectively. Six and 12 months post-treatment, mfAC were detected in ≈ 5% and ≈ 3% of participants, respectively. Ocular Mazzotti reactions occurred in 12.4% of moxidectin- and 10.2% of ivermectin-treated participants without difference in type or severity. The risk for ≥ 1 ocular Mazzotti reaction increased for women (OR 1.537, 95% CI 1.096–2.157) and with mfAC levels pre- and 4 days post-treatment (OR 0:>10 mfAC 2.704, 95% CI 1.27–5.749 and 1.619, 95% CI 0.80–3.280, respectively).

Conclusions

The impact of SmfD and of mfAC levels before and early after treatment on ocular AEs needs to be better understood before decisions on the risk-benefit of strategies including DEC. Such decisions should consider interindividual variability in SmfD, mfAC levels and treatment response and risks to even a small percentage of individuals.

Trial registration

The study was registered on 14 November 2008 in Clinicaltrials.gov (ID: NCT00790998).

Onchocerciasis

moxidectin

ivermectin

diethylcarbamazine

ocular microfilariae

microfilariae in the anterior chamber

increase in ocular microfilariae

microfilariae mobilization

ocular Mazzotti reactions

ocular adverse events

Onchocerciasis is a vector-borne parasitic disease caused by the parasite Onchocerca volvulus, transmitted by Simulium black flies. The morbidity, due primarily to immunological reactions of the body to the dead microfilariae in the skin and the eyes, and resulting socio-economic effects, have motivated large scale control and elimination programs in sub-Saharan Africa, Yemen and in the Americas [1, 2, 3, 4, 5, 6, 7]. Today, control and elimination programmes are based on mass drug administration of ivermectin (MDAi).

In 2003, an international consultation concluded that parasite elimination through MDAi was feasible in the six Central and South American countries of the Americas (total population at risk around 0.56 million), but not across the vast and partly hyperendemic areas in Sub-Saharan Africa [8], requiring research for new drugs or drug combinations [9, 10]. Since then, onchocerciasis has been eliminated in the Americas in all but the large endemic area crossing the Venezuela-Brazil border. This was achieved through between 23 and 36 rounds of biannual MDAi, complemented with quarterly MDA in around 300 communities [7, 11, 12, 13]. Data obtained in Africa since 2003 have shown that long term MDAi, implemented as community directed treatment (CDTI) may have eliminated transmission or may be close to doing so in many areas [14, 15, 16]. These data motivated the objective to eliminate O. volvulus transmission in some African countries by 2020 and in 80% of endemic countries by 2025 [17]. These targets have recently been revised to achieve WHO-verified interruption of parasite transmission in 12 countries world-wide and stopping MDAi in at least one focus in 34 countries by 2030 [18].

Expert consultations and data reviews by the African Programme for Onchocerciasis Control (APOC, 1995–2015) concluded that alternative treatment strategies (ATS) are required for onchocerciasis elimination in many areas in Africa [17]. Potential strategies identified include those based on moxidectin which was approved in 2018 for treatment of O. volvulus infected individuals ≥ 12 years of age by the US Food and Drug Administration (FDA) [19, 20, 21, 22, 23, 24, 25, 26, 27]. Discovery, development and implementation research for other ATS [28] is also ongoing including for new or repurposed drugs [10, 29, 30, 31, 32], for effective, affordable, and sustainable complementary vector control strategies [33, 34] and for approaches to safe use of ivermectin in loiasis co-endemic areas (drugs for safe reduction of Loa loa microfilaraemia [35, 36, 37] and ‘test-and-not-treat’ or ‘test-and-treat’ strategies [38, 39, 40, 41, 42]). Furthermore, research for a vaccine is continuing [43].

The triple drug combination ivermectin, albendazole, diethylcarbamazine (IDA) was recommended in 2017 by WHO as an alternative MDA regimen for elimination of lymphatic filariasis in specific areas [44]. Treatment with IDA following treatment with ivermectin (referred to as ‘pretreat and treat’ strategy) has been proposed for onchocerciasis endemic areas with long term CDTI to accelerate onchocerciasis elimination if a single IDA dose sterilizes adult O. volvulus worms and eliminates microfilariae from the skin permanently [45].

Past experience has shown that oral diethylcarbamazine (DEC) treatment of O. volvulus infected individuals can result in very severe Mazzotti reactions, the signs and symptoms of the immunological reaction of the body to dead and dying microfilariae. These include worsening of onchocercal eye disease and new ocular lesions and reactions that resulted in the suggestion to start DEC treatment in the hospital [46, 47, 48, 49, 50]. The severity of the Mazzotti reactions increases with the microfilariae levels in individuals treated with the same oral DEC dose, and increases with the DEC dose when individuals with similar microfilariae burden are compared. These observations resulted in the conclusion that the severity of the Mazzotti reaction after DEC treatment is a function of the number of microfilariae present before treatment and killed [51, 52]. The proposed ‘pretreat and treat’ strategy to use IDA in onchocerciasis endemic areas after long term MDA with ivermectin plus albendazole or long term CDTI [45] is based on the assumption that long-term MDAi will have reduced O. volvulus microfilariae density to ‘usually less than 5 mf/mg skin’ [45] which would reduce the risk of severe Mazzotti reactions. Given data on the percentage of the population that participates in MDAi and long-standing challenge to optimize that percentage [53, 54, 55, 56, 57, 58], the percentage of individuals with skin mf loads above the ‘usually less than 5 mf/mg skin’ warrants consideration.

A clinical study in Ghana to compare the safety and efficacy of single and three daily doses of IDA with the safety and efficacy of ivermectin plus albendazole has completed enrolment and follow up of 154 participants (https://www.clinicaltrials.gov/ct2/show/NCT04188301). Individuals qualifying for enrolment were those with ≤ 3 microfilariae/mg skin and < 5 motile microfilariae in the anterior chamber in either eye among the 231 individuals who participated in a previous trial (https://www.clinicaltrials.gov/ct2/show/NCT03517462 ) [59] and had received a single dose of 150 µg/kg ivermectin in that trial within 6 months before IDA treatment.

We have previously reported results of our randomized, double blind Phase 3 trial comparing the efficacy and safety of a single oral dose of 8 mg moxidectin and 150 µg/kg ivermectin in ivermectin-naïve individuals with ≥ 10 mf/mg skin with or without ocular involvement. The data showed that 1, 6, 12 and 18 months after treatment, skin microfilariae density (mf/mg skin, SmfD) was significantly lower among moxidectin than ivermectin treated participants [20, 60]. In contrast, there was no statistically significant difference between the treatment arms in the level of live microfilariae in the anterior chamber (mfAC) 12 months after treatment among participants with > 10 mfAC pre-treatment [60].

We are here reporting the number of mfAC before treatment, 4 days and 1, 6, 12 and 18 months after treatment and their relationship to pre- and post-treatment skin microfilariae density (mf/mg skin, SmfD). Our primary objective is to contribute to the evidence base available for review by WHO and countries for a decision whether to include a ‘pretreat and treat’ strategy in control and elimination guidelines and policies for onchocerciasis and/or lymphatic filariasis in onchocerciasis co-endemic areas. While all of our participants had a pre-treatment SmfD at least twice the ‘usually less than 5 mg/skin’, the experience with severe and serious adverse reactions to ivermectin in Loa loa co-endemic areas has shown that decisions on control and elimination strategies need to consider risks for even a very small percentage of individuals [42, 61, 62, 63, 64]. This need drives our emphasis on graphical presentation of individual participant data and presentation of the distribution of participants by mfAC level which facilitate better appreciation of inter-individual differences than the standard statistical measures of variability or statistical models. Our secondary objective is to contribute to the evidence base for review by WHO and countries for decisions on whether to include moxidectin in guidelines and policies for onchocerciasis elimination.

A detailed description of trial conduct and methods and a Consort Flow chart have been published previously [60].

Regulatory Agency and Ethics Committee approval and participant consent

As previously reported [20, 60], the protocol, information documents for potential participants, participant consent and assent forms and study conduct were approved by the Ghana Food and Drugs Authority and the Ghana Health Service Ethics Review Committee, the Liberia Ministry of Health and Social Welfare and the Ethics Committee of the Liberia Institute for Biomedical Research, the Ministère de la Santé Publique of DRC and the Ethics Committee of the Ecole de la Santé Publique Université de Kinshasa in DRC, and the WHO Ethics Review Committee.

Participants documented their informed consent or assent with parental consent to study participation through signature or thumbprint in the presence of a literate witness in their villages. This included consent to publication of summaries of the results. Given lack of consent to sharing individual participant data a large number of summary tables and figures are included in the manuscript or in Additional File 1.

Overview of study conduct

This study was conducted between April 2009 and May 2012. It enrolled individuals ≥ 12 years old with at least ≥ 10 O. volvulus microfilariae/mg skin in four onchocerciasis endemic areas where CDTI had not yet been initiated: Nord Kivu province (current Zones de Santé Kalunguta and Mabalako) in the Democratic Republic of the Congo (DRC), Ituri province in DRC (Zone de Santé Logo in Northern Ituri, subsequently referred to as Nord-Ituri), Lofa county in Liberia (subsequently referred to as Lofa) and the Kpasa subdistrict within the Nkwanta North health district in Ghana (subsequently referred to as Nkwanta). Details on the location of the villages where participants were recruited and the prevalence of infection as determined during screening for the study have been provided previously [20].

Following randomization stratified by sex and ‘level of infection’ (< 20 mf/mg skin vs ≥ 20 mf/mg skin), 978 participants received a single oral dose of 8 mg moxidectin and 494 participants a single oral dose of ≥ 150 µg/kg ivermectin. To ensure double blinding, each participant received four identically looking capsules containing 2 mg moxidectin tablets, 3 mg ivermectin tablets or placebo, as required by treatment allocation and weight. The capsules for each participant had been prepared by a pharmacist not involved in participant evaluation. Participants swallowed the capsules under observation by a study team member.

Participants stayed in the research center from screening to Day 6 (± 1 Day) after treatment for follow up examinations and daily evaluation for adverse events (AEs). ‘Outpatient’ follow up was conducted on Days 14, Month 1, 3, 6 and 12. The study was initiated with 18 months post-treatment as the last follow-up time point. After WHO became the sole study sponsor in July 2011, resource limitations required a protocol amendment eliminating the 18 months follow up. This resulted in 96% of moxidectin-treated and 97% of ivermectin-treated participants with 12 months follow up but only 78% of participants in both treatment arms with month 18 follow up data [60].

Measurement of skin microfilariae densities

Four skin snips (one snip from each iliac crest and calf) were taken pre-treatment and 1, 6, 12 and 18 months post-treatment and SmfD determined as described previously [19, 60].

Ocular examinations

Ocular examinations (detailed history and questioning for symptoms, visual acuity, color vision, visual field examination with FDT perimetry, ocular mobility, pupillary reflex examination, external ocular structures examination, anterior segment examination with a Haag Streit 900 slit-lamp, intraocular pressure and dilated fundus examination by direct and indirect ophthalmoscopy) were conducted pre-treatment, as well as 3 or 4 days (subsequently referred to as Day 4 data), 1, 6, 12 and 18 months after treatment. Microfilariae in the anterior chambers (mfAC) and the cornea (mfCOR), were counted in both eyes with 10x or 16x magnification after participants had been sitting with their head down for at least 5 minutes. If considered necessary by the ophthalmologist, the head down position for at least 5 minutes was repeated before counting of the microfilariae in the second eye.

Grading of ocular adverse events

Any new and clinically significant abnormality or worsening of conditions identified pre-treatment were recorded as an adverse event (AE). Details of AE recording have been provided previously [60]. In brief, AEs were recorded with start and stop date and their severity graded according to the Onchocerciasis Chemotherapy Research Center (OCRC) grading scale. The scale had been developed to quantify signs and symptoms of O. volvulus infection caused by the immunological reaction to dying and dead microfilariae reaching the end of their natural lifespan, and their aggravation following treatment, i.e. Mazzotti reactions [65, 66]. The scale was expanded to include other types of AEs for the moxidectin Phase 2 [19, 27] and Phase 3 study [20, 60] and has been provided previously [60]. All AEs were characterized by the investigators in terms of relationship to study drug and Mazzotti reaction. Before unblinding, all AEs were reviewed centrally by NOO for characterization as Mazzotti reactions. The outcome of that central review forms the basis of the Mazzotti reaction reported here. All AE verbatims were coded using the Medical Dictionary for Regulatory Activities (MedDRA version 13.1). Mazzotti reactions were additionally coded using a Mazzotti reaction specific dictionary since MedDRA codes the same reaction by body system which compromises treatment comparisons [60]. Coding using the Mazzotti reaction specific dictionary is the basis for the Mazzotti reactions reported in the manuscript. Presentation across both Mazzotti reactions and other ocular AEs in Additional File 1 is based on MedDRA coding.

Statistical analysis

Given the focus on changes in mfAC, only the data for the 1463/1472 (99.4%) individuals treated who had both eyes evaluated throughout the study are included (Table 1).

In recognition of the fact that as the number of microfilariae in the eyes increases beyond 10, the accuracy of the counts decreases, individual counts are presented in Figures for illustrative purposes while descriptive statistics are based on the following six mfAC categories: undetected (0), 1–5, 6–10, 11–20, 21–40, > 40). Three pre-treatment SmfD categories (10 to < 20, 20 to < 50, and ≥ 50), referred to as ‘intensity of infection’ (IoI), and three post-treatment SmfD categories (0, > 0–5, > 5) were defined.

A linear mixed model was used to evaluate the marginal means of the number of mfAC pre-treatment, Day 4, months 1, 6, 12 and 18 months after treatment. The model included treatment and sex as factors, age as adjusting variable, and SmfD at baseline as covariate. Study area was included as a random effect. Treatment, sex and IoI adjusted marginal means and 95% Confidence Intervals (CI) by treatment were extracted from the model. A first series of models for each timepoint was run with the raw mfAC values to calculate the arithmetic adjusted marginal means. A second series of models for each timepoint was run with the log transformed mfAC values to calculate the geometric adjusted marginal means.

A linear mixed model was used to evaluate the effect of both SmfD and mfAC at the timepoint of the outcome and previous timepoints on the number of mfAC pre-treatment, Day 4, months 1, 6, 12 and 18 months after treatment. The model included treatment and sex as factors, age as adjusting variable. study area was included as a random effect.

Generalized linear mixed models with a logit link were used to evaluate co-variates and factors impacting the probability of having at least one ocular Mazzotti reaction within the first month after treatment and of having at least one ocular adverse event (whether considered Mazzotti reaction or not) within 6 months after treatment. mfAC levels were included as categorical variable (0, 1–5, 6–10, and ≥ 11) and SmfD levels as defined above. Only four mfAC level categories were considered due to the low number of individuals with mfAC ≥ 11 (n = 135 and n = 76 in the moxidectin and ivermectin treatment group, respectively), The initial model for ocular Mazzotti reactions included treatment, age, sex, SmfD pre-treatment, mfAC levels pre-treatment and on Day4 as fixed effects and study area as random effect. The final model included treatment, sex, and mfAC levels pre-treatment. The initial model for any ocular adverse event during the first 6 months after treatment included treatment, age, sex, SmfD pre-treatment and at Month 1, as well as mfAC pre-treatment, on Day4 and Month 1 as fixed effects and study area as random effect. The final model included treatment, age, sex, and mfAC level at Month 1.

Analyses were conducted with SAS version 9.4 (SAS Institute, Cary, NC, USA). Figures were generated in Excel 365.

Consort diagram and number of participants with both eyes evaluated on Day 4 and months 1, 6, 12 and 18 after treatment

The study CONSORT flow diagram has been reported previously [60].

Table 1 show the number of individuals with data on mfAC obtained from both eyes at day 4 and 1, 6, 12 and 18 months after treatment by pre-treatment mfAC category and treatment arm. The maximum number of mfAC was 102 in the moxidectin and 92 in the ivermectin treatment group.

Table 1

Participants with both eyes evaluated by treatment arm, pre-treatment mfAC category and time point
	Moxidectin
PreTx mfAC	Any	0	1–5	6–10	11–20	21–40	> 40	Any	0	1–5	6–10	11–20	21–40	> 40
Time	N	n	n	n	n	n	n	N	n	n	N	n	n	n
PreTx	973	596	183	59	67	52	16	490	289	96	29	45	18	13
D4	973	596	183	59	67	52	16	490	289	96	29	45	18	13
M1	967	592	181	59	67	52	16	488	287	96	29	45	18	13
M6	956	586	179	58	65	52	16	487	287	95	29	45	18	13
M12	941	574	180	57	63	51	16	476	281	93	28	43	18	13
M18	758	449	145	49	56	46	13	382	223	69	28	36	15	11

D4 Day 4 post-treatment, M1, M6, M12, M18 Month 1, 6, 12 and 18 post-treatment, mfAC live microfilariae in the anterior chamber of the eye, PreTx pre-treatment, percentage calculated for each timepoint by treatment arm

Table 2

Participants with both eyes evaluated by pre-treatment SmfD and mfAC category and sex
PreTx SmfD	PreTx mfAC	Women		Men
		n	%	n	%
< 20	0	113	38	187	62
	1–5	20	47	23	53
	6–10	9	47	10	53
	11–20	12	36	21	64
	21–40	11	46	13	54
	> 40	5	63	3	38
	Any	170	40	257	60
20-<50	0	126	31	276	69
	1–5	46	38	74	62
	6–10	17	46	20	54
	11–20	14	35	26	65
	21–40	9	35	17	65
	> 40	4	40	6	60
	Any	216	34	419	66
≥ 50	0	51	28	132	72
	1–5	46	40	70	60
	6–10	18	56	14	44
	11–20	16	41	23	59
	21–40	6	30	14	70
	> 40	4	36	7	64
	Any	141	35	260	65

Number of live microfilariae in the anterior chambers 4 days and 1, 6, 12 and 18 months after treatment

Figure 1 and Fig. 2 illustrate the mfAC levels 4 days and 1, 6, 12 and 18 months after treatment relative to pre-treatment levels for each participant. Figure 3 shows the arithmetic means and the linear model derived adjusted geometric mean mfAC pre-treatment, 4 days, 1, 6, 12 and 18 months post-treatment.

Increases in the number of mfAC detected sufficient to change the mfAC category occurred from pre-treatment to Day 4 and from pre-treatment to Month 1, respectively, in 21% and 16% in the moxidectin treatment arm and 19% and 15% in the ivermectin treatment arm. Furthermore, in 10% of participants in both treatment arms mfAC levels increased from Day 4 to Month 1 (Table 3). The mean, standard deviation, minimum and maximum mfAC levels pre-treatment, on Day 4 and at Month 1 for participants with mfAC increases from pre-treatment to Day 4 or Month 1 and from Day 4 to Month 1 are provided in Table 4.

Table 5 shows the distribution of participants by mfAC category at Day 4 and Month 1 relative to their distribution pre-treatment and on Day 4 resulting from increases in mfAC levels in some participants and decreases or changes not affecting the mfAC category in others.

Table 3

Number (%) of participants with mfAC number increases from pre-treatment to Day 4 or Month 1 and from Day 4 to Month 1 resulting in mfAC levels in a higher mfAC category
	Moxidectin																Ivermectin
mfAC category	Nf	1–5 mfAC		6–10 mfAC			11–20 mfAC		21–40 mfAC			> 40		Any mfAC increase			Nf		1–5 mfAC		6–10 mfAC		11–20 mfAC		21–40 mfAC			> 40 mfAC			Any mfAC increase
		n	%	n	%	n		%	n	%	n		%		n	%			N	%	n	%	n	%	n	%	n		%	n		%
PreTx		Day 4																	Day 4
0	596	135	22.7	11	1.8	3		0.5	1	0.2					150	25.2		289	49	17.0	4	1.4	1	0.3	2	0.7				56		19.4
1–5	183			16	8.7	13		7.1	3	1.6	4		2.2		36	19.7		96			15	15.6	3	3.1	4	4.2				22		22.9
6–10	59					3		5.1	4	6.8	2		3.4		9	15.3		29					2	6.9	2	6.9	3		10.3	7		24.1
11–20	67								1	1.5	2		3.0		3	4.5		45							5	11.1	2		4.4	7		15.6
21–40	52										4		7.7		4	7.7		18
Sum	957	135	14.1	27	2.8	19		2.0	9	0.9	12		1.3		202	21.1		477	49	10.3	19	4.0	6	1.3	13	2.7	5		1.0	92		19.3
PreTx		Month 1																	Month 1
0	592	113	19.1	5	0.8	2		0.3	1	0.2					121	20.4		287	45	15.7	6	2.1			1	0.3				52		18.1
1–5	181			9	5.0	9		5.0	5	2.8	2		1.1		25	13.8		96			3	3.1	6	6.3			1		1.0	10		10.4
6–10	59					4		6.8	3	5.1	1		1.7		8	13.6		29					1	3.4	2	6.9				3		10.3
11–20	67								1	1.5					1	1.5		45							5	11.1	1		2.2	6		13.3
21–40	52										2		3.8		2	3.8		18
Sum	951	113	11.9	14	1.5	15		1.6	10	1.1	5		0.5		157	16.5		475	45	9.5	9	1.9	7	1.5	8	1.7	2		0.4	71		14.9
Day 4		Month 1																	Month 1
0	533	68	12.8	9	1.7	2		0.4							79	14.8		263	37	14.1	4	1.5								41		15.6
1–5	237			4	1.7	4		1.7	3	1.3	1		0.4		12	5.1		105			3	2.9	1	1.0			1		1.0	5		4.8
6–10	71					2		2.8	3	4.2					5	7.0		42					2	4.8						2		4.8
11–20	72								2	2.8					2	2.8		34							2	5.9				2		5.9
21–40	32										2		6.3		2	6.3		29
Sum	945	68	7.2	13	1.4	8		0.8	8	0.8	3		0.3		100	10.6		473	37	7.8	7	1.5	3	0.6	2	0.4	1		0.2	50		10.6

mfAC live microfilariae in the anterior chamber, PreTx pre-treatment, Nf number of participants with data at relevant follow up time points, % calculated based on Nf.

Table 4

Mean (SD), minimum and maximum mfAC levels among participants with increases from pre-treatment to Day 4 or Month 1 and from Day 4 to Month 1 resulting in mfAC levels in a higher mfAC category
					1–5 mfAC
mfAC	AM	SD	Min	Max	AM	SD	Min	Max	AM	SD	Min	Max	AM	SD	Min	Max	AM	SD	Min	Max	AM	SD	Min	Max
	Moxidectin
	PreTx				Day 4
0	0	0	0	0	1.60	0.96	1	5	7.09	1.04	6	9	15.67	2.52	13	18	23.00	0	23	23
1–5	2.39	1.50	1	5					7.88	1.54	6	10	13.85	2.41	11	19	27.67	6.43	23	35	50.25	13.99	41	71
6–10	7.67	1.50	6	10									12.67	2.08	11	15	26.50	6.45	22	36	51.00	5.66	47	55
11–20	15.00	3.00	12	18													30.00	0	30	30	52.00	8.49	46	58
21–40	26.00	5.94	21	34																	53.50	12.26	45	71
All	1.50	4.39	0	34	1.60	0.96	1	5	7.56	1.4	6	10	13.95	2.41	11	19	26.89	5.42	22	36	51.75	10.29	41	71
	PreTx				Month 1
0	0	0	0	0	1.87	1.18	1	5	7.40	1.34	6	9	16.50	3.54	14	19	26.00	0	26	26
1–5	2.40	1.53	1	5					6.78	1.30	6	10	13.33	2.92	11	19	30.40	7.64	22	39	55.00	1.41	54	56
6–10	7.25	1.49	6	10									14.75	2.87	11	17	25.67	2.08	24	28	75.00	0	75	75
11–20	12.00		12	12													40	0	40	40
21–40	28.00	9.90	21	35																	48.00	4.24	45	51
All	1.18	3.78	0	35	1.87	1.18	1	5	7	1.30	6	10	14.13	2.97	11	19	29.5	6.77	22	40	56.2	11.3	45	75
	Day 4				Month 1
0	0	0	0	0	1.81	1.18	1	5	6.78	0.97	6	9	12.50	2.12	11	14
1–5	2.50	1.17	1	5					7.50	1.29	6	9	11.00	0	11	11	25.67	2.52	23	28	54	0	54	54
6–10	8.40	0.89	7	9									12.50	0.71	12	13	28.67	9.87	22	40
11–20	17.00	2.83	15	19													37.50	2.12	36	39
21–40	35.50	0.71	35	36																	60	21.21	45	75
All	1.77	5.72	0	36	1.81	1.18	1	5	7	1.08	6	9	11.75	1.16	11	14	29.75	7.42	22	40	58	15.39	45	75
	Ivermectin
	PreTx				Day 4
0	0	0	0	0	1.71	1.12	1	5	6.50	0.58	6	7	11.00		11	11	24.50	2.12	23	26
1–5	2.45	1.37	1	5					8.00	1.36	6	10	16.00	1.73	15	18	27.75	6.65	22	37
6–10	8.86	0.90	7	10									16.00	2.83	14	18	32.50	9.19	26	39	49.00	6.56	42	55
11–20	13.29	1.60	11	15													28.40	4.72	22	35	78.50	31.82	56	101
21–40
All	2.27	4.06	0	15	1.71	1.12	1	5	7.68	1.38	6	10	15.17	2.64	11	18	28.23	5.6	22	39	60.80	23.15	42	101
	PreTx				Month 1
0	0	0	0	0	1.76	0.91	1	4	7.33	1.21	6	9					24.00		24	24
1–5	2.80	1.62	1	5					8.00	2.00	6	10	14.33	2.88	12	19					55.00	0	55	55
6–10	9.00	0.00	9	9									12.00		12	12	28.50	4.95	25	32
11–20	14.17	1.17	12	15													26.60	6.80	21	37	51.00	0	51	51
21–40
All	1.97	4.28	0	15	1.76	0.91	1	4	7.56	1.42	6	10	14	2.77	12	19	26.75	5.65	21	37	53.00	2.83	51	55
	Day 4				Month 1
0	0	0	0	0	1.59	0.86	1	4	7.25	1.5	6	9
1–5	2.80	1.79	1	5					7.00	1.00	6	8	12.00	0	12	12					55.00	0	55	55
6–10	9.00	0	9	9									13.5	2.12	12	15
11–20	15.00	4.24	12	18													30.00	9.90	23	37
21–40
All	1.24	3.51	0	18	1.59	0.86	1	4	7.14	1.21	6	9	13.00	1.73	12	15	30.00	9.90	23	37	55.00	0	55	55

AM Arithmetic Mean, SD Standard Deviation, Max maximum, mfAC live microfilariae in the anterior chambers, Min minimum, PreTx pre-treatment

Table 5

Number (%) of participants by mfAC category on Day 4 or Month 1 after treatment by pre-treatment and Day 4 mfAC category and treatment arm
	Moxidectin													Ivermectin
		0 mfAC		1–5 mfAC		6–10 mfAC		11–20 mfAC		21–40 mfAC		> 40 mfAC			0 mfAC		1–5 mfAC		6–10 mfAC		11–20 mfAC		21–40 mfAC			> 40 mfAC
mfAC	N	n	%	n	%	n	%	n	%	n	%	n	%	N	n	%	n	%	n	%	n	%	n	%	n		%
PreTx		Day 4													Day 4
0	596	446	74.8	135	22.7	11	1.8	3	0.5	1	0.2			289	233	80.6	49	17.0	4	1.4	1	0.3	2	0.7
1–5	183	65	35.5	82	44.8	16	8.7	13	7.1	3	1.6	4	2.2	96	31	32.3	43	44.8	15	15.6	3	3.1	4	4.2
6–10	59	15	25.4	16	27.1	19	32.2	3	5.1	4	6.8	2	3.4	29	1	3.4	9	31.0	12	41.4	2	6.9	2	6.9	3		10.3
11–20	67	5	7.5	3	4.5	25	37.3	31	46.3	1	1.5	2	3.0	45			3	6.7	11	24.4	24	53.3	5	11.1	2		4.4
21–40	52	1	1.9	4	7.7	1	1.9	23	44.2	19	36.5	4	7.7	18			1	5.6			4	22.2	13	72.2
> 40	16	2	12.5		0.0		0.0		0.0	4	25.0	10	62.5	13									3	23.1	10		76.9
All	973	534	54.9	240	24.7	72	7.4	73	7.5	32	3.3	22	2.3	490	265		105	21.4	42	8.6	34	6.9	29	5.9	15		3.1
PreTx		Month 1													Month 1
0	592	471	79.6	113	19.1	5	0.8	2	0.3	1	0.2			287	235	81.9	45	15.7	6	2.1			1	0.3
1–5	181	92	50.8	64	35.4	9	5.0	9	5.0	5	2.8	2	1.1	96	51	53.1	35	36.5	3	3.1	6	6.3			1		1.0
6–10	59	34	57.6	10	16.9	7	11.9	4	6.8	3	5.1	1	1.7	29	18	62.1	3	10.3	5	17.2	1	3.4	2	6.9
11–20	67	48	71.6	7	10.4	5	7.5	6	9.0	1	1.5		0.0	45	24	53.3	11	24.4	2	4.4	2	4.4	5	11.1	1		2.2
21–40	52	37	71.2	6	11.5	1	1.9	3	5.8	3	5.8	2	3.8	18	15	83.3	1	5.6	2	11.1
> 40	16	9	56.3	2	12.5			2	12.5	1	6.3	2	12.5	13	4	30.8			2	15.4			3	23.1	4		30.8
All	967	691	71.5	202	20.9	27	2.8	26	2.7	14	1.4	7	0.7	488	347	71.1	95	19.5	20	4.1	9	1.8	11	2.3	6		1.2
Day 4		Month 1													Month 1
0	533	454	85.2	68	12.8	9	1.7	2	0.4		0.0		0.0	263	222	84.4	37	14.1	4	1.5
1–5	237	129	54.4	96	40.5	4	1.7	4	1.7	3	1.3	1	0.4	105	62	59.0	38	36.2	3	2.9	1	1.0			1		1.0
6–10	71	39	54.9	18	25.4	9	12.7	2	2.8	3	4.2		0.0	42	26	61.9	10	23.8	4	9.5	2	4.8
11–20	72	45	62.5	12	16.7	4	5.6	9	12.5	2	2.8		0.0	34	20	58.8	6	17.6	4	11.8	2	5.9	2	5.9
21–40	32	18	56.3	5	15.6	1	3.1	4	12.5	2	6.3	2	6.3	29	15	51.7	4	13.8	3	10.3	3	10.3	4	13.8
> 40	22	6	27.3	3	13.6		0.0	5	22.7	4	18.2	4	18.2	15	2	13.3			2	13.3	1	6.7	5	33.3	5		33.3
All	967	691	71.5	202	20.9	27	2.8	26	2.7	14	1.4	7	0.7	488	347	71.1	95	19.5	20	4.1	9	1.8	11	2.3	6		1.2
mfAC live microfilariae in the anterior chambers

Six, 12 and 18 months post-treatment, the percentage of participants with 0 mfAC and 1–5 mfAC detected was 94.8% and 4.3%, 98.1% and 1.5%, and 98.7% and 1.2%, respectively, in the moxidectin treatment arm and 95.5% and 4.1%, 95.6% and 3.6%, and 95.8% and 3.1% in the ivermectin treatment arm. With two exceptions, the remaining participants had mfAC levels in the 6–10 or 11–20 mfAC category and maximum mfAC levels at six, 12 and 18 months follow-up were 20, 12 and 6 in the moxidectin treatment group and 11, 12 and 19 in the ivermectin treatment group, respectively (Table 6). One participant from Nord Ituri treated with ivermectin had mfAC levels of 56, 120, 100, 49, 54 and 77 pre-treatment and on Day 4, Month 1, 6, 12, and 18, respectively, with SmfD levels of 53, 53, 32, 49 and 72 pre-treatment and at Month 1, 6, 12, and 18, respectively, qualifying for suboptimal microfilariae response and suboptimal response [20]; one participant from Nkwanta treated with moxidectin had mfAC levels of 100, 100, 45, 0 and 22 pre-treatment and on Day 4, Month 1, 6, and 12, respectively, with SmfD levels of 44, 0, 0 and 0.4 pre-treatment and at Month 1, 6 and 12, respectively. That participant did not have a Month 18 evaluation due to the protocol amendment abolishing the Month 18 visit.

Table 6

Number (%) of participants by mfAC category 6, 12 and 18 months after treatment by pre-treatment mfAC category and treatment arm
PreTx	Moxidectin													Ivermectin
mfAC	Any mfAC	0 mfAC		1–5 mfAC		6–10 mfAC		11–20 mfAC		21–40 mfAC		> 40 mfAC		Any mfAC	0 mfAC		1–5 mfAC		6–10 mfAC		11–20 mfAC		21–40 mfAC			> 40 mfAC
	N	n	%	n	%	n	%	n	%	n	%	n	%	N	n	%	n	%	n	%	n	%	n	%	n		%
		Month 6													Month 6
0	586	571	97.4	15	2.6		0.0							287	279	97.2	8	2.8
1–5	179	164	91.6	12	6.7	1	0.6	2	1.1					95	89	93.7	6	6.3
6–10	58	51	87.9	6	10.3	1	1.7							29	26	89.7	3	10.3
11–20	65	61	93.8	2	3.1	1	1.5	1	1.5					45	43	95.6	2	4.4
21–40	52	45	86.5	5	9.6	1	1.9	1	1.9					18	18	100.0
> 40	16	14	87.5	1	6.3	1	6.3							13	10	76.9	1	7.7			1	7.7			1		7.7
All	956	906	94.8	41	4.3	5	0.5	4	0.4					487	465	95.5	20	4.1			1	0.2			1		0.2
		Month 12													Month 12
0	574	570	99.3	3	0.5	1	0.2							281	276	48.1	4	0.7	1	0.2
1–5	180	175	97.2	5	2.8									93	91	50.6	2	1.1
6–10	57	53	93.0	4	7.0									28	26	45.6	2	3.5
11–20	63	61	96.8	1	1.6	1	1.6							43	37	58.7	6	9.5
21–40	51	50	98.0	1	2.0									18	18	35.3
> 40	16	14	87.5		0.0			1	6.3	1	6.3			13	7	43.8	3	18.8	1	6.3	1	6.3			1		6.3
All	941	923	98.1	14	1.5	2	0.2	1	0.1	1	0.1			476	455	48.4	17	1.8	2	0.2	1	0.1			1		0.1
		Month 18													Month 18
0	449	444	98.9	5	1.1									223	220	49.0	2	0.4	1	0.2
1–5	145	143	98.6	2	1.4									69	65	44.8	3	2.1	1	0.7
6–10	49	48	98.0	1	2.0									28	25	51.0	3	6.1
11–20	56	55	98.2			1	1.8							36	35	62.5	1	1.8
21–40	46	45	97.8	1	2.2									15	15	32.6
> 40	13	13	100.0											11	6	46.2	3	23.1			1	7.7			1		7.7
All	758	748	98.7	9	1.2	1	0.1							382	366	48.3	12	1.6	2	0.3	1	0.1			1		0.1

mfAC live microfilariae in the anterior chambers, % calculated based on all participants with data in the specified PreTx mfAC category (N)

Pre- and post-treatment mfAC levels relative to pre-treatment skin microfilariae density (IoI)

Additional File 1 Fig S1 and Fig S2 illustrate for participants with < 10 mfAC and ≥ 10 mfAC pre-treatment, respectively, the mfAC counts before and 4 days, 1, 6, 12 and 18 months after treatment by IoI.

Table 7 provides the corresponding distribution of participants in the defined pre-treatment mfAC categories by IoI. The data indicate that as the IoI increases the % of individuals with undetected mfAC decreases. Table 8 presents the distribution by mfAC categories at Day 4 and Month 1 of the participants with an increase in mfAC levels from pre-treatment to Day 4 and Month 1 and from Day 4 to Month 1 that resulted in a higher mfAC category by pre-treatment SmfD category. The data suggest that a higher pre-treatment SmfD is associated with a higher percentage of treated individuals who experienced a transient increase in mfAC from pre-treatment to Day 4 and Month 1 post-treatment.

Table 7

Number (%) of participants by mfAC category pre-treatment and on Day 4 and Month 1, 6, 12 and 18 post-treatment by intensity of infection
IoI	Moxidectin
	All	0 mfAC		1–5 mfAC		6–10 mfAC		11–20 mfAC		21–40 mfAC		> 40 mfAC		All	0 mfAC		1–5 mfAC		6–10 mfAC		11–20 mfAC		21–40 mfAC		> 40 mfAC
	N	n	%	n	%	n	%	n	%	n	%	n	%	N	N	%	n	%	n	%	n	%	n	%	n	%
	Pre-Treatment
< 20	279	197	70.6	27	9.7	14	5.0	21	7.5	18	6.5	2	0.7	148	103	69.6	16	10.8	5	3.4	12	8.1	6	4.1	6	4.1
20-<50	454	299	65.9	77	17.0	25	5.5	25	5.5	20	4.4	8	1.8	181	103	56.9	43	23.8	12	6.6	15	8.3	6	3.3	2	1.1
≥ 50	240	100	41.7	79	32.9	20	8.3	21	8.8	14	5.8	6	2.5	161	83	51.6	37	23.0	12	7.5	18	11.2	6	3.7	5	3.1
All	973	596	61.3	183	18.8	59	6.1	67	6.9	52	5.3	16	1.6	490	289	59.0	96	19.6	29	5.9	45	9.2	18	3.7	13	2.7
	Day 4
< 20	279	170	60.9	59	21.1	17	6.1	21	7.5	8	2.9	4	1.4	148	98	66.2	18	12.2	10	6.8	8	5.4	10	6.8	4	2.7
20-<50	454	259	57.0	113	24.9	30	6.6	33	7.3	12	2.6	7	1.5	181	108	59.7	39	21.5	13	7.2	13	7.2	7	3.9	1	0.6
≥ 50	240	105	43.8	68	28.3	25	10.4	19	7.9	12	5.0	11	4.6	161	59	36.6	48	29.8	19	11.8	13	8.1	12	7.5	10	6.2
All	973	534	54.9	240	24.7	72	7.4	73	7.5	32	3.3	22	2.3	490	265	54.1	105	21.4	42	8.6	34	6.9	29	5.9	15	3.1
	Month 1
< 20	278	233	83.8	39	14.0	2	0.7	2	0.7	2	0.7			148	120	81.1	18	12.2	4	2.7	2	1.4	4	2.7
20-<50	450	332	73.8	86	19.1	16	3.6	13	2.9	2	0.4	1	0.2	181	136	75.1	39	21.5	4	2.2	1	0.6	1	0.6
≥ 50	239	126	52.7	77	32.2	9	3.8	11	4.6	10	4.2	6	2.5	159	91	57.2	38	23.9	12	7.5	6	3.8	6	3.8	6	3.8
All	967	691	71.5	202	20.9	27	2.8	26	2.7	14	1.4	7	0.7	488	347	71.1	95	19.5	20	4.1	9	1.8	11	2.3	6	1.2
	Month 6
< 20	273	269	98.5	4	1.5									148	144	97.3	3	2.0			1	0.7
20-<50	446	424	95.1	20	4.5	2	0.4							179	170	95.0	9	5.0
≥ 50	237	213	89.9	17	7.2	3	1.3	4	1.7					160	151	94.4	8	5.0							1	0.6
All	956	906	94.8	41	4.3	5	0.5	4	0.4					487	465	95.5	20	4.1			1	0.2			1	0.2
	Month 12
< 20	268	265	98.9	2	0.7	1	0.4							146	140	95.9	4	2.7	1	0.7	1	0.7
20-<50	437	426	97.5	9	2.1	1	0.2			1	0.2			175	172	98.3	3	1.7
≥ 50	236	232	98.3	3	1.3			1	0.4					155	143	92.3	10	6.5	1	0.6					1	0.6
All	941	923	98.1	14	1.5	2	0.2	1	0.1	1	0.1			476	455	95.6	17	3.6	2	0.4	1	0.2			1	0.2
	Month 18
< 20	224	223	99.6	1	0.4									115	111	96.5	2	1.7	1	0.9	1	0.9
20-<50	334	327	97.9	6	1.8	1	0.3							138	137	99.3	1	0.7
≥ 50	200	198	99.0	2	1.0		0.0							129	118	91.5	9	7.0	1	0.8					1	0.8
All	758	748	98.7	9	1.2	1	0.1							382	366	95.8	12	3.1	2	0.5	1	0.3			1	0.3

PreTx pre treatment, IoI pre-treatment skin microfilariae density (microfilariae/mg skin).

Table 8

Number (%) of participants by mfAC category on Day 4 and Month 1 and pre-treatment IoI for participants with mfAC number increases from pre-treatment to Day 4 or Month 1 and from Day 4 to Month 1 resulting in mfAC levels in a higher mfAC category
	Moxidectin													Ivermectin
		1–5		6–10		11–20		21–40		> 40		Any increase			1–5			6–10			11–20			21–40			> 40			Any increase
IoI	N	n	%	n	%	n	%	n	%	n	%	n	%	N	n	%	n		%	n		%	n		%	n		%	n		%
	Day 4 mfAC category of participants with mfAC increase from preTx to Day 4
< 20	279	38	13.62	1	0.36	1	0.36	1	0.36	2	0.72	43	15.41	148	38	13.62	1		0.36	1		0.36	1		0.36	2		0.72	43		15.41
20-<50	454	68	14.98	13	2.86	7	1.54	2	0.44	2	0.44	92	20.26	181	68	14.98	13		2.86	7		1.54	2		0.44	2		0.44	92		20.26
≥ 50	240	29	12.08	13	5.42	11	4.58	6	2.5	8	3.33	67	27.92	161	29	12.08	13		5.42	11		4.58	6		2.5	8		3.33	67		27.92
All	973	135	13.87	27	2.77	19	1.95	9	0.92	12	1.23	202	20.76	490	135	13.87	27		2.77	19		1.95	9		0.92	12		1.23	202		20.76
	Month 1 mfAC category for participants with mfAC increase from preTx to Month 1
< 20	278	24	8.63		0	1	0.36		0		0	25	8.99	148	10	6.76	1		0.68	2		1.35	2		1.35			0	15		10.14
20-<50	450	56	12.44	8	1.78	8	1.78	1	0.22		0	73	16.22	181	16	8.84			0	1		0.55			0			0	17		9.39
≥ 50	239	33	13.81	6	2.51	6	2.51	9	3.77	5	2.09	59	24.69	159	19	11.95	8		5.03	4		2.52	6		3.77	2		1.26	39		24.53
All	967	113	11.69	14	1.45	15	1.55	10	1.03	5	0.52	157	16.24	488	45	9.22	9		1.84	7		1.43	8		1.64	2		0.41	71		14.55
	Month 1 mfAC category for participants with mfAC increase from Day 4 to Month 1
< 20	278	13	4.68		0	1	0.36		0		0	14	5.04	148	9	6.08	1		0.68	1		0.68	1		0.68			0	12		8.11
20-<50	450	32	7.11	9	2	3	0.67	1	0.22		0	45	10.00	181	20	11.05			0	1		0.55			0			0	21		11.60
≥ 50	239	23	9.62	4	1.67	4	1.67	7	2.93	3	1.26	41	17.15	159	8	5.03	6		3.77	1		0.63	1		0.63	1		0.63	17		10.69
All	967	68	7.03	13	1.34	8	0.83	8	0.83	3	0.31	100	10.34	488	37	7.58	7		1.43	3		0.61	2		0.41	1		0.2	50		10.25

mfAC live microfilariae in the anterior chamber, PreTx pre-treatment, N Number of participants with mfAC data at Day 4 and Month 1, respectively, % calculated based on total number of participants with mfAC data on Day 4 or Month 1 within each IoI category.

Post-treatment mfAC levels relative to post-treatment skin microfilariae density

Table 9 shows the distribution of participants in each treatment arm by mfAC category and SmfD category 6, 12 and 18 months post-treatment. Additional File 1 Fig S3 and Fig S3 illustrate the data for each individual participant for those with < 10 mfAC and those with ≥ 10 mfAC pre-treatment, respectively. As the SmfD increases, the percentage of participants with undetectable mfAC decreases slightly.

Table 9

Number (%) of participants by mfAC category 6, 12 and 18 months after treatment by post-treatment SmfD and treatment
	Moxidectin
	Any	0		1–5		6–10		11–20		21–40		> 40			Any		0		1–5		6–10		11–20		21–40			> 40
SmfD	N (%)¹	n	%²	n	%	n	%	n	%	n	%	N	%	N (%)¹		n		%²	n	%	n	%	n	%	n	%	n		%
Month 6	Month 6
0	875 (91.5)	830	94.9	37	4.2	4	0.5	4	0.5					54 (11.1)		54		100
> 0–5	81 (8.5)	76	93.8	4	4.9	1	1.2							339 (69.6)		325		95.9	13	3.8			1	0.3
> 5	0 (0)													94 (19.3) ⁴		86		91.5	7	7.4							1		1.1
All	956 (100)	906	94.8	41	4.3	5	0.5	4	0.4					487 (100)		465		95.5	20	4.1			1	0.2			1		0.2
Month 12	Month 12
0	436 (46.3)	434	99.5	2	0.5									24 (5.0)		24		100
> 0–5	431 (45.8)	422	97.9	6	1.4	2	0.5			1	0.2			212 (44.5)		208		98.1	2	0.9	1	0.5	1	0.5
> 5	74 (7.9)³	67	90.5	6	8.1			1	1.4					240 (50.4) ⁴		223		92.9	15	6.3	1	0.4					1		0.4
All	941 (100)	923	98.1	14	1.5	2	0.2	1	0.1	1	0.1			476 (100)		455		95.6	17	3.6	2	0.4	1	0.2			1		0.2
Month 18	Month 18
0	212 (28.0)	211	99.5	1	0.5									15 (3.9)		15		100
> 0–5	376 (49.6)	374	99.5	1	0.3	1	0.3							130 (34.0)		128		98.5	2	1.5
> 5	170 (22.4)³	163	95.9	7	4.1									237 (62.0) ⁴		223		94.1	10	4.2	2	0.8	1	0.4			1		0.4
All	758 (100)	748	98.7	9	1.2	1	0.1							382 (100)		366		95.8	12	3.1	2	0.5	1	0.3			1		0.3

¹% calculated across SmfD categories, ²% calculated by SmfD category. ³ Maximum SmfD of 27.9 and 70.5 at Month 12, respectively, ⁴ maximum SmfD 43.1, 76.5 and 101.3 at Month 6, 12 and 18, respectively (for further details see Additional FileFig S3 and Fig S4).

Participant characteristics impacting mfAC levels before and after treatment

As previously reported for mfAC levels at month 12 in participants with at least 10 mfAC [60], there was no statistically significant difference at any time point between the mfAC levels in the moxidectin and the ivermectin treatment arm. Age and sex were not a significant covariate and factor, respectively. Table 10 provides an overview of the impact of the other covariates emerging from the linear model. Additional file 1 Table S1 shows the full output.

Table 10

Impact of SmfD and mfAC levels up to the relevant time point on mfAC levels pre-treatment and at different time points post treatment
mfAC at time	Covariates in the final model	p value ≤ 0.05	p value > 0.5
PreTx	SmfD preTx	< 0.0001
Day 4	SmfD preTx	0.0006
	mfAC preTx	< 0.0001
Month 1	SmfD preTx	< 0.0001
	SmfD Month 1	0.0058
	mfAC preTx		0.1469
	mfAC Day 4	< 0.0001
Month 6	SmfD preTx		0.9828
	SmfD Month 1	0.0002
	SmfD Month 6		0.1561
	mfAC preTx		0.6150
	mfAC Day 4	0.0419
	mfAC Month 1	< .0001
Month 12	SmfD preTx	0.0015
	SmfD Month 1		0.0544
	SmfD Month 6		0.8066
	SmfD Month 12	0.001
	mfAC preTx	0.0015
	mfAC Day 4		0.2651
	mfAC Month 1	< .0001
	mfAC Month 6	< .0001
Month 18	SmfD preTx		0.1763
	SmfD Month 1		0.9814
	SmfD Month 6		0.3455
	SmfD Month 12		0.2232
	SmfD Month 18		0.7997
	mfAC preTx		0.2282
	mfAC Day 4		0.6282
	mfAC Month 1		0.8748
	mfAC Month 6	0.0001
	mfAC Month 12	< .0001

mfAC live microfilariae in the anterior chambers, SmfD Skin microfilariae density (microfilariae/mg skin)

Microfilariae in the cornea

Live microfilariae in the cornea were detected pre-treatment in the majority of participants from Lofa (count range 3–42), but in only few participants in the other study areas. Similarly, dead microfilariae in the cornea were more frequently seen in participants from Lofa (count range 2–25) than in participants from the other study areas (count range 0–18). Six, 12 and 18 months after treatment, live microfilariae in the cornea were detected only in five (count range 1–9), zero and one (count = 2) participants from Lofa, respectively. Dead microfilariae in the cornea at Month 6, 12 and 18 were found in one (count = 6), zero and zero participants from Nord Kivu, two (counts = 2), zero and one (count = 1) participants from Nord-Ituri, 18 (count range 1–29), two (count = 1) and 1 (count = 2) participants from Lofa and in zero, one (count = 1) and zero participant from Nkwanta, respectively.

Ocular Mazzotti reactions and other ocular adverse events

As previously reported across all participants treated [60], a higher percentage of participants treated with moxidectin (121/973, 12.4%) than with ivermectin (50/490, 10.2%) had at least one ocular Mazzotti reaction, but the type of reactions did not differ (Table 11). Among those with ocular Mazzotti reactions, a higher percentage of moxidectin treated (26/121, 21.5%) than ivermectin treated (6/50, 12%) participants had more than one ocular Mazzotti reaction, but there was no trend towards higher severity of the ocular Mazzotti reactions after moxidectin than ivermectin treatment (Table 12). The vast majority of Mazzotti reactions occurred between the day of treatment up to 2nd day after treatment with a trend towards earlier start after moxidectin than after ivermectin treatment(Table 13), a trend also seen for non-ocular Mazzotti reactions.

Table 11

Participants with ocular Mazzotti reactions starting within 1 Month of treatment among participants with both eyes evaluated by treatment
	Moxidectin	N = 973¹	Ivermectin	N = 490¹
Mazzotti sign/ symptom	n	%	n	%
Eye pruritus	45	4.62	12	2.45
Conjunctivitis	41	4.21	15	3.06
Eye pain	29	2.98	8	1.63
Eyelid oedema	20	2.06	5	1.02
Ocular discomfort²	9	0.92	5	1.02
Tearing/watery eyes	7	0.72	7	1.43
Blurred vision	3	0.31	3	0.61
Photophobia	2	0.21	1	0.20
Peripheral Sensory Phenomena³	1	0.10	2	0.41
Visual acuity⁴	1	0.10		0
Total number of participants with at least 1 ocular Mazzotti reaction	121	12.4	50	10.2
Total number of Mazzotti reactions	158		58

¹ Among the nine participants who did not have both eyes evaluated at all visits they attended, one had an ocular Mazzotti reaction (pain in right eye, 26 days after ivermectin treatment).

² Verbatims for ‘Ocular discomfort’ included in the moxidectin group: ‘ocular discomfort’ (n = 5), ‘foreign body sensation in eyes’ (n = 3) and ‘sandy sensation of eyes’ (n = 1) and in the ivermectin group ‘ocular discomfort’ (n = 2), ‘foreign body sensation in eyes’ (n = 2) and ‘cumbersome upper eyelids’ (n = 1).

³ Verbatims for ‘Peripheral Sensory Phenomena’ included ‘heavy sensation of the eyelids’ (moxidectin, duration 1 day), ‘sandy sensation in eyes’ (ivermectin, duration 7 days) and ‘burning sensation in the eyes’ (ivermectin, duration 132 days).

⁴ Verbatim: ‘reduced vision’ (moxidectin, duration 1 day).

Table 12

Participants with ocular Mazzotti reactions starting within 1 Month of treatment by severity and treatment among participants with both eyes evaluated
Mazzotti sign/ symptom	Grade	Moxidectin	N = 973	Ivermectin	N = 490
		n	%	n	%
Eye pruritus	1	35¹	3.6	7	1.4
	2	8¹	0.8	4	0.8
	3	2	0.2	1	0.2
Conjunctivitis	1	38²	3.9	14	2.9
	2	2	0.2
	3	1	0.10	1	0.2
Eye pain	1	25	2.6	8	1.6
	2	4	0.4
Eyelid oedema	1	18	1.8	5	1.0
	2	2	0.2		0.0
Blurred vision	1	3	0.3	2	0.4
	2			1	0.2
Ocular discomfort	1	8	0.8	4³	0.8
	2	1	0.1	1	0.2
Tearing/watery eyes	1	6⁴	0.6	5⁵	1.0
	2	1⁴	0.1	2	0.4
Photophobia	1	2	0.2	1	0.2
Peripheral Sensory Phenomena	1	1	0.1	2	0.4
Visual acuity⁶	1	1	0.1

¹ Moxidectin treatment: One participant had eye pruritus grade 3 starting one day after treatment which lessened to grade 2 on day 2 and resolved 2 days later.

² Moxidectin treatment: One participant had conjunctivitis grade 1 starting on the day of treatment, which worsened to grade 3 on the day after treatment before resolving three days later..

³ Ivermectin treatment: One participant had ocular discomfort grade 1 starting on the day of treatment which resolved the next day, reappeared on Day 3 and resolved the next day.

⁴ Moxidectin treatment: One participant had watery eyes starting on the day of treatment which resolved 2 days later and reappeared on Day 11 to resolved 6 days later. One participant had grade 2 watery eyes starting on the day of treatment which resolved the next day and experienced grade 1 watery eyes starting 8 days after treatment which resolved 43 days later.

⁵ Ivermectin treatment: One participant had watery eyes starting on the day of treatment which the next day, and again from 2–3 days after treatment.

⁶ Moxidectin treatment: One participant complained about ‘reduced vision’ starting on Day 2 after treatment which resolved on Day 3 after treatment.

Table 13

Participants with ocular Mazzotti reactions starting within 1 Month of treatment by start day and treatment among participants with both eyes evaluated
		Moxidectin			Ivermectin
Mazzotti sign/ symptom	Start after treatment (days)	n	% of N (973)	% of participants with that ocular Mazzotti reaction	n	% of N (490)	% of participants with that ocular Mazzotti reaction
Eye pruritus	0	21	2.2	46.7	3	0.6	25.0
	1	17	1.7	37.8	6	1.2	50.0
	2	2	0.2	4.4	1	0.2	8.3
	3				1	0.2	8.3
	4	1	0.1	2.2
	8	1	0.1	2.2
	11				1	0.2	8.3
	15	1	0.1	2.2
	21	2	0.2	4.4
Conjunctivitis	0	24	2.5	58.5	3	0.6	20.0
	1	11	1.1	26.8	4	0.8	26.7
	2	3	0.3	7.3	8	1.6	53.3
	3	2	0.2	4.9
	5	1	0.1	2.4
Eye pain	0	8	0.8	27.6	1	0.2	12.5
	1	14	1.4	48.3	2	0.4	25.0
	2	2	0.2	6.9	5	1.0	62.5
	3	2	0.2	6.9
	4	2	0.2	6.9
	10	1	0.1	3.5
Eyelid oedema	0	8	0.8	40.0
	1	7	0.7	40.0	4	0.8	80.0
	2	4	0.4	40.0
	3	1	0.1	40.0	1	0.2	20.0
Ocular discomfort	0	7	0.7	77.8	1	0.2	20.0
	1	1	0.1	11.1	1	0.2	20.0
	3	1	0.1	11.1	2	0.4	40.0
	9				1	0.2	20.0
Tearing/watery eyes	0	3	0.3	0.4	2	0.4	28.6
	1	1	0.1	0.1	3	0.6	42.9
	2			0.00	2	0.4	28.6
	4	1	0.1	0.1
	8	1	0.1	0.1
	11	1	0.1	0.1
Blurred vision	0	2	0.2	66.7
	1				3	0.6	100
	21	1	0.1	33.3
Photophobia	1				1	0.2
	2	2	0.2
Peripheral Sensory Phenomena	0	1	0.1		1	0.2
	1				1	0.2
Visual acuity	2	1	0.1

The logistic model identified women as at higher risk for ocular Mazzotti reactions (OR Male:Female 1:1.537, 95% CI 1.096–2.157, p = 0.0128) and detected pre-treatment mfAC levels as impacting the risk for ocular Mazzotti reactions (OR for 0 mfAC : >10 mfAC 2.704 with 95% CI 1.272–5.749, p = 0.0608). The OR for treatment with moxidectin : ivermectin was 1:0.76 (95% CI 0.519–1.072, p = 0.1127). Additional file 1 Table S2 shows the output of the final model.

At least one ocular adverse event (i.e. considered Mazzotti reaction or not) was recorded for 23/973 (22.9%) and 92/490 (16.7%) of participants within the first month and for 92/973 (9.5%) and 43/490 (8.8%) of participants between the end of the 1st and the end of the 6th months after treatment with moxidectin and ivermectin, respectively. An overview of participant incidence and total number of ocular AEs is provided in Additional file 1 Table S3 and Table S4. Grade 3 ocular AEs not considered a Mazzotti reaction included in the moxidectin treatment group were eye pruritus in three participants (starting 64, 86 and 159 days after treatment, respectively), eye pain starting 173 days after treatment and cyclitis starting 174 days after treatment. One ivermectin treated participant experienced a grade 3 ocular AEs not considered a Mazzotti reaction: increased lacrimation starting 10 days after treatment. The logistic model showed a higher risk at least one ocular AE for women than men (p = 0.015, OR Male:Female 1:1.404 with 95% CI 1.068–1.845) and a significant impact of mfAC levels at Month 1 (p = 0.0005, OR 0mfAC : >10 mfAC 2.918 with 95% CI 1.737–4.9). The OR for moxidectin : ivermectin was 1 : 0.709 (95% CI 0.536–0.939, p = 0.0165). Additional file 1 Table S5 shows the output of the final model.

In our study population from CDTI-naïve areas, selected to have at least 10 mf/mg skin, around 60% of participants had undetectable mfAC levels pre-treatment while approximately 19% and 6% had mfAC levels between 1–5 and 6–10, respectively, and around 2% had more than 40 mfAC across both eyes (Table 1). Pre-treatment SmfD significantly impacted pre-treatment mfAC levels (Table 10).

Higher mfAC levels 4 days and 1 month after treatment than pre-treatment were identified in 21% and 16% of moxidectin treated and 19% and 15% of ivermectin treated participants, respectively, and this increase was not restricted to individuals with low mfAC levels pre-treatment (Table 3, Table 8). A transient increase in mfAC levels in some individuals early after ivermectin as well as after DEC treatment has been shown previously, including during the clinical studies that supported regulatory approval of ivermectin [67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78]. The peak mfAC increase around Day 4 after treatment determined in these studies informed mfAC measurement on Day 3 or 4 in the moxidectin Phase 2 and 3 studies [19, 60]. An mfAC increase was not mentioned and cannot be deduced from the data provided in other publications of the early ivermectin studies [79, 80, 81]. Additional File 1 Table S6 provides an overview of the data reported. The way mfAC data are quantified in the publications (frequency of detectable mfAC levels, geometric means, descriptive text) makes it impossible to determine the frequency and extent of the mfAC increases for comparison with our data.

The lack of evaluation of mfAC changes early after treatment in subsequent studies of the efficacy and safety of ivermectin may be due to the fact that once the concern that ivermectin may have a similar risk of severe ocular reactions as DEC had been alleviated, quantifying changes in the number of ocular microfilariae early after ivermectin treatment was not considered important anymore. In the context of the proposed introduction of DEC as part of a triple drug therapy (IDA) into onchocerciasis elimination strategies [45], attention to mfAC levels before and increases early after treatment with DEC will become important until a better understanding of the relationship between ocular mfAC before and early after treatment and the ocular safety of treatment with DEC has been achieved. In our study, pre-treatment mfAC levels > 10 significantly increased the risk of having at least one ocular Mazzotti reactions (occurring primarily within the first few days after treatment (Table 13)) and mfAC levels > 10 one month after treatment significantly increased the risk of at least one ocular adverse event within the first 6 months after treatment relative to 0 mfAC at these time points (Additional file 1 Table S2, Table S5). In light of the fact that in our study women had a higher risk of having at least one ocular Mazzotti reaction and at least one ocular AE of any type than men (Additional file 1 Table S2, Table S5), sex disaggregated analyses of the safety data of further studies of the ocular safety of ivermectin, DEC or moxidectin is indicated.

The recent study of the tolerability and effect of ivermectin on skin and ocular microfilariae in primarily ivermectin-naive individuals from hypoendemic villages in the Nkwanta North district of Ghana (pre-treatment SmfD 3 to 86.3 mf/mg) included mfAC measurement pre-treatment (64/231 with mfAC, mfAC range 1-150) and on Day 7, Month 3 and Month 6 post-treatment. The study identified a higher number of individuals with mfAC on Day 7 (73/231, mfAC range 1–82). The presentation of the data (frequency of detectable mfAC levels, geometric means, ranges and graphical presentation of individual participant data excluding the Day 7 data) [59] limit comparison with our data but the findings presented are consistent with our data and those of the early ivermectin studies. The lack of more detailed presentation of the mfAC data by Opoku et al. may be due to the fact that they attributed the mfAC increases to insensitivity of a single slit-lamp examination for detecting mfAC when counts are low, day to day variation in mfAC and easier detection of mfAC after they have been paralyzed by ivermectin [59]. The motility of mfAC during the first days after ivermectin treatment was found to be abnormal (transient immobility for 0.5-1 second, movement in extended rather than coiled configuration, motion in which mfAC bent only in the middle suggesting spams) [79, 82] but paralysis facilitating counting has to our knowledge not been described previously. We observed in our study that mfAC were more mobile and difficult to count 3–4 days after treatment than at any other time in the study, resulting in frequent requests to participants to take again a head down position for at least 5 minutes before counting of the mfAC in the second eye.

While we do not consider the increase in mfAC we observed early after treatment in around 20% of participants as due to methodological issues, we do recognize the limitations of the accuracy of mfAC counts and that it is thus important not to overinterpret ‘0 mf counted’ as indicating that there are no mfAC in the eyes or a small change in mfAC counted as representing a real increase or decrease. However, we do think that the data available support the hypothesis that a ‘mobilization of microfilariae’ into the anterior chamber can occur. This term has been used in some of the publications of the early ivermectin studies (e.g. [68, 69]). Mobilisation of microfilariae after DEC and ivermectin treatment into the urine and blood has been described previously as has appearance of microfilariae in other body fluids after DEC treatment [68, 69, 83, 84, 85, 86, 87]. We also observed mobilisation of microfilariae into blood and urine in some participants in the moxidectin Phase 2 study (unpublished data, summary statistics provided in Additional File 1 Table S7).

Six and 12 months after treatment, no mfAC were detected, respectively, in 95% and 98% of participants who had received a single dose of moxidectin and in 95% and 96% of participants who had received a single dose of ivermectin. At these time points, more than 10 mfAC were detected in 0.2% and 0.2% of moxidectin and in 0.4% and 0.2% of ivermectin treated participants, respectively (Table 6, Table 7). The above referenced study by Opoku and co-workers identified mfAC 6 months after ivermectin treatment in a comparable percentage of participants (12/212 (5.7%), mfAC range 1–35), including ‘low mfAC counts’ in three participants who had no mfAC detected pre-treatment (but two had mfAC detected on Day 7). In our study, covariates impacting Month 6 mfAC levels significantly were Month 1 SmfD and Day 4 and month 1 mfAC. Covariates with significant impact on Month 12 mfAC levels were SmfD pretreatment and at Month 12 as well as mfAC levels at pretreatment, Month 1 and 6 (Table 10).

Among our ivermectin-naïve study participants from onchocerciasis meso- or hyperendemic villages with at least 10 mf/mg skin, there was no statistically significant difference in the effect of a single dose of 8 mg moxidectin or 150 µg/kg ivermectin on mfAC levels on day 4 or Month 1, 6, 12 or 18 after treatment. Ocular Mazzotti reactions occurred in 12.4% of moxidectin and 10.2% of ivermectin treated participants without a difference in the type of these reactions or their severity between the treatment groups.

The extent to which findings on the efficacy and safety of ivermectin, moxidectin and DEC in ivermectin-naïve individuals are relevant for decisions on including DEC into strategies for elimination of onchocerciasis in areas with a long history of MDAi needs to be determined. Assuming the benefit of IDA for elimination of O. volvulus transmission is demonstrated, the role of SmfD and mfAC levels pre-treatment and of mobilisation of microfilariae into the anterior chambers early after treatment on the safety of DEC needs to be further investigated to provide the data that can inform decisions on the risk-benefit of inclusion of DEC in onchocerciasis elimination strategies. Such decisions should consider interindividual variability in skin and/or ocular microfilariae levels and response to treatment as well as possible differences between onchocerciasis endemic areas [20] and carefully weigh any projected population-based benefits vs. the risks to even a small percentage of individuals.

Ethics approval and consent to participate

Participants documented their consent or assent with parental consent to study participation through signature or thumbprint in the presence of a literate witness in their villages.

Availability of data and materials

Participants consented to publication of summaries of the results, not to sharing of their individual data. Consequently, the Sponsor (WHO) and the authors do not have the participants’ permission to make individual participant data publicly available. Individuals wanting to analyze the data should contact the Sponsor ([email protected] ) and Medicines Development for Global Health to which WHO has licensed the data (via mark. [email protected] or https:// www.medicinesdevelopment.com/contact). Requests should include the objectives, data analysis plan and plans to obtain applicable Ethics Committee approvals and involve the investigators (co-authors on this manuscript) and commitment to not share the data with anybody else.

Competing interests

ACK and CMH are staff of WHO which funded the work of all co-authors on the study whose data are analysed here through its department UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR). ACK retired from WHO in March 2023.

Funding

WHO/TDR funded this study, utilizing contributions from the WHO African Programme for Onchocerciasis Control (APOC), 6.3 million $US from Wyeth and following its acquisition by Pfizer, Pfizer, and WHO/TDR donor countries. Wyeth provided drug for this study and contributed to the study protocol. Wyeth prepared the submissions to the Ministries of Health and provided data management services until July 3, 2011. Pfizer was not further involved in this study in any way, including data verification or analysis and has not commented on this manuscript.

Authors’ contributions

NOO, DKB, EMK, and HH were the principal investigators responsible for site preparation, community engagement, participant recruitment, study implementation, data review, and data query resolution in Ghana, Nord Ituri and Nord-Kivu (Democratic Republic of the Congo), and Liberia, respectively. EMK, AN, and JPL did the ophthalmological examinations in Nord-Kivu, Nord Ituri and Liberia, respectively. GLM, MMN, DRU, FN, KKK, KK, KMP, SKA, GO, SA, and MM were co-investigators responsible for recruiting, examining, and following up participants, and collecting data. MV was responsible for data management after WHO became sole study sponsor, co-designed the statistical analysis, and conducted the statistical analyses. CMH participated in site training and study initiation, managed conduct, supervised study monitoring and close-out, and supported investigators and MV in data management after TDR became sole study sponsor. ACK was involved in study design and protocol finalization with input from the late Dr K Awadzi, TDR staff, TDR external advisors, and advice from the European Medicines Agency. ACK managed research center creation in Liberia and the Democratic Republic of the Congo, study preparation and set up, did staff training and study initiation, managed study conduct, co-designed the statistical analysis, reviewed the data analyses, drafted the manuscript, and finalized it with co-author input. All authors reviewed the manuscript and approved the submitted version.

Acknowledgements

We acknowledge the contribution to data collection in Liberia of Mr. Mawolo Kpawor, who died in October 2016. We acknowledge Dr Fatorma Bolay who directed study center creation and preparation, community engagement, parasitologist training and management of the Liberian study site (see [60]). He died in March 2021. We also gratefully acknowledge Dr Safari L Masembe, a co-investigator in the study team in Nord Kivu. He passed away on 13 January 2022. We furthermore acknowledge the contribution of Jean-Pierre Lotsima who contributed to the data from Ituri. He passed way in March 2023. For others whose contribution to the study we want to acknowledge, see [60].

We are particularly grateful to all study participants for their co-operation.

The authors alone are responsible for the views expressed which do not necessarily represent the views, decisions or policies of the institutions with which the authors are affiliated.

Copyright

World Health Organization 2023. This article is published under the CC BY 3.0 IGO license (https://creativecommons.org/licenses/ by/3.0/ igo) which permits use, sharing, adaptation, distribution, and reproduction in any medium or format, as long as the original work is properly cited, appropriate credit is given to the IGO, a link is provided to the Creative Commons licence, and any changes made are indicated. In any use of this article, there should be no suggestion that WHO endorses any specific organization, products, or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article’s original URL.

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Competing interest reported. ACK and CMH are staff of WHO which funded the work of all co-authors on the study whose data are analysed here through its department UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR). ACK retired from WHO in March 2023.

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O. volvulus microfilariae in the anterior chambers of the eye and ocular adverse events after a single dose of 8 mg moxidectin or 150 µg/kg ivermectin: Results of a randomized double-blind Phase 3 trial in the Democratic Republic of the Congo, Ghana and Liberia

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Abstract

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Introduction

Methods

Regulatory Agency and Ethics Committee approval and participant consent

Overview of study conduct

Measurement of skin microfilariae densities

Ocular examinations

Grading of ocular adverse events

Statistical analysis

Results

Pre- and post-treatment mfAC levels relative to pre-treatment skin microfilariae density (IoI)

Post-treatment mfAC levels relative to post-treatment skin microfilariae density

Participant characteristics impacting mfAC levels before and after treatment

Microfilariae in the cornea

Ocular Mazzotti reactions and other ocular adverse events

Discussion

Conclusions

Abbreviations

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Ethics approval and consent to participate

Availability of data and materials

Competing interests

Funding

Authors’ contributions

Acknowledgements

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References

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