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Single dose moxidectin versus ivermectin for Onchocerca volvulus infection in Ghana, Liberia, and the Democratic Republic of the Congo: a randomised, controlled, double-blind phase 3 trial

Summary Background The morbidity and socioeconomic effects of onchocerciasis, a parasitic disease that is primarily endemic in sub-Saharan Africa, have motivated large morbidity and transmission control programmes. Annual community-directed ivermectin treatment has substantially reduced prevalence. Elimination requires intensified efforts, including more efficacious treatments. We compared parasitological efficacy and safety of moxidectin and ivermectin. Methods This double-blind, parallel group, superiority trial was done in four sites in Ghana, Liberia, and the Democratic Republic of the Congo. We enrolled participants (aged ≥12 years) with at least 10 Onchocerca volvulus microfilariae per mg skin who were not co-infected with Loa loa or lymphatic filariasis microfilaraemic. Participants were randomly allocated, stratified by sex and level of infection, to receive a single oral dose of 8 mg moxidectin or 150 μg/kg ivermectin as overencapsulated oral tablets. The primary efficacy outcome was skin microfilariae density 12 months post treatment. We used a mixed-effects model to test the hypothesis that the primary efficacy outcome in the moxidectin group was 50% or less than that in the ivermectin group. The primary efficacy analysis population were all participants who received the study drug and completed 12-month follow-up (modified intention to treat). This study is registered with ClinicalTrials.gov, number NCT00790998. Findings Between April 22, 2009, and Jan 23, 2011, we enrolled and allocated 998 participants to moxidectin and 501 participants to ivermectin. 978 received moxidectin and 494 ivermectin, of which 947 and 480 were included in primary efficacy outcome analyses. At 12 months, skin microfilarial density (microfilariae per mg of skin) was lower in the moxidectin group (adjusted geometric mean 0·6 [95% CI 0·3–1·0]) than in the ivermectin group (4·5 [3·5–5·9]; difference 3·9 [3·2–4·9], p<0·0001; treatment difference 86%). Mazzotti (ie, efficacy-related) reactions occurred in 967 (99%) of 978 moxidectin-treated participants and in 478 (97%) of 494 ivermectin-treated participants, including ocular reactions (moxidectin 113 [12%] participants and ivermectin 47 [10%] participants), laboratory reactions (788 [81%] and 415 [84%]), and clinical reactions (944 [97%] and 446 [90%]). No serious adverse events were considered to be related to treatment. Interpretation Skin microfilarial loads (ie, parasite transmission reservoir) are lower after moxidectin treatment than after ivermectin treatment. Moxidectin would therefore be expected to reduce parasite transmission between treatment rounds more than ivermectin could, thus accelerating progress towards elimination. Funding UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases.

Secondary efficacy endpoints 20 Table S 12: Skin microfilariae density 1, 6, 12 and 18 months after treatment: Descriptive statistics and mixed effects model output 20 Table S 13: Percentage SmfD change from baseline of skin microfilariae density 1, 6, 12 and 18 months after treatment: Descriptive statistics 20 Table S   Dependency of Mazzotti reactions on pre-treatment skin microfilariae density 25 Figure  Classification of Response to ivermectin in previous studies 29 Table S

1.1
Eligibility criteria Eligibility criteria were designed to include a population as close to a potential mass treatment population as possible without subjecting participants to higher than necessary unknown risks (exclusion of <12 years in absence of paediatric PK data, pregnant or breastfeeding women, Loa loa co-infection (study areas were not loiasis endemic)), compromising efficacy assessment (exclusion of people with anti-nematodal treatment in last 6 months and plans to move out of the area), confounding adverse event (AE) causality assessment (exclusion of people with acute or uncontrolled disease in the 7 days pre-treatment, treated with an investigational drug or device in the 4 weeks before study drug administration, with lymphatic filariasis (LF) microfilaremia > 100 mf/ml).

Inclusion Criteria
• Male or female subjects ≥ 12 years of age and weighing ≥ 30 kg.
• Subjects with Onchocerca volvulus infection, at least 10 microfilariae/mg by skin snip.
• All female subjects not surgically sterile or postmenopausal had to commit to the use of a reliable method of birth control for 6 months after study drug administration. (Birth control devices / drugs chosen by the woman -and partner, if applicable -was provided by the study)

Exclusion Criteria
• Treatment with the anti-nematodal drugs diethylcarbamazine [DEC], suramin, ivermectin, albendazole or levamisole, within 6 months before planned study drug administration. • Pregnant or breastfeeding women.
• Low probability of residency in the area (based on subject's assessment) over the 20 months following the anticipated date of study drug administration. • Subjects with loiasis.

MD value is negative AND
The probability is <5% that the overall sensitivity of the subject is in the range of ≥95% of the people with normal vision of that age (P<5% indicated after the MD value) 2 (moderate) MD value is negative AND The probability is <2% that the overall sensitivity of the subject is in the range of ≥95% of the people with normal vision of that age (P<2% indicated after the MD value) 3 (severe) MD value is negative AND The probability is <1% that the overall sensitivity of the subject is in the range of ≥95% of the people with normal vision of that age (P<1% indicated after the MD value) 4 (very severe) MD value is negative AND The probability is <0.5% that the overall sensitivity of the subject is in the range of ≥95% of the people with normal vision of that age (P<0.5% indicated after the MD value)

Overview of Mazzotti reactions
Common systemic clinical manifestations of the Mazzotti reaction include pruritus, rash, lymphadenitis, headache, myalgia, arthralgia, hypotension, fever, and swelling of the face and limbs. 1 Ocular events include epiphora, photophobia, conjunctival injection, limbitis, anterior uveitis, chorioretinitis, and optic neuritis. 2 The clinical laboratory changes involve the peripheral blood leukocytes, AST, ALT and sometimes LDH, and GGT; microfilariae also appear in blood, urine, and other body fluids. The eosinophils exhibit the most prominent changes. There may be an initial eosinopenia followed several days later by a marked increase above pretreatment levels. A complete disappearance of eosinophils from the peripheral blood is the laboratory hallmark of a severe reaction. Lymphocyte counts may fall initially, followed by lymphocytosis, but not to the same extent as with eosinophils. Leukocytosis with neutrophilia is less common. Elevations in liver enzymes occur, but rarely exceed grade 2 and usually normalize by day 30. Levels of bilirubin and AP are usually unchanged. Proteinuria may occur. Although the laboratory changes per se have little clinical significance, they give indirect evidence of the death of microfilariae and may even indicate the speed and severity of the reaction to the event. 3 The factors that govern the Mazzotti reaction include the intensity of infection, 4 the dose regimen, and the microfilaricide used. These determine the onset, evolution, reaction severity, extent of the laboratory changes, and whether the reaction is mono-or biphasic. A notable exception occurs in subjects with hyperreactive onchodermatitis (Sowda), 5 where severe, predominantly cutaneous adverse effects occur even with very low skin microfilarial counts. For a given intensity of infection, the severity of the Mazzotti reaction to ivermectin is independent of dose within the range of 150 to 800 μg/kg (approximately 9 mg to 48 mg for weights between 45 kg and 64 kg). 6 Dangerous and alarming reactions result from the simultaneous occurrence of severe reactions in multiple systems. 7 This phenomenon is rare with ivermectin. Biphasic reactions, characterized by a marked recrudescence of cutaneous or lymph node symptoms or the development of an acute febrile polyarthritis, 8 several days after the initial reaction, have also not been observed with ivermectin.

Coding of adverse events characterized as Mazzotti reactions
The Medical Dictionary for Regulatory Agencies (MedDRA), the standard for coding of investigator verbatims of adverse events (AE) into 'preferred terms' and their assignment to system organ classes, results for common types of Mazzotti reactions (e.g. swelling, pruritus, pain) into distribution across different system organ classes and preferred terms. This does not facilitate comparison of the frequency of Mazzotti reactions after different treatments. Therefore, AEs characterized as Mazzotti reactions were coded and grouped into reaction clusters and reaction groups with a dictionary specifically designed for Mazzotti reactions based on the experience at OCRC (Table S 6). CS -clinically significant.

Sample size calculation
The distribution and mean pre-treatment skin microfilariae levels which impact the skin microfilariae levels 12 months after ivermectin treatment could not be predicted during study planning since they depend on a number of unknown factors including the level of endemicity in the villages from which participants would be recruited as well as the age and thus life time risk of infection of each participant and area and individual treatment history. Consequently, sample size calculations to show a 50% difference in arithmetic mean SmfD 12 months after treatment between the two treatment arms took into account data obtained 12 months after ivermectin treatment from two different historical scenarios: the first community study of ivermectin 9 (raw data provided by Dr. H. Remme, 32·49 ± 2·35 mf/snip ) and a study conducted at the OCRC (4·01 ± 2·41 mf/mg skin). We assumed that the Month 12 mean values in the ivermectin arm would be one or the other, with the Month 12 value in the moxidectin arm being half that in the ivermectin arm (16.24 mf/snip and 2.0 mf/mg, respectively) and with the estimate of the common standard deviation being that in the historical scenario (2.35 mf/snip or 2.41 mf/mg, respectively). Sample size calculation was conducted for both scenarios for the case of a 2-sided test, type I error of 0.05 and power of 90% based on a student t-test and log e (y+1) transformed data, taking into account the randomization ratio of 2:1 moxidectin to ivermectin, previously decided upon in view of safety data collection. For the two historical scenarios this yielded a total sample size of 159 (106:53, moxidectin:ivermectin) and 276 (184:92), respectively. Assuming that only 65% of enrolled participants would be available for the 12 months visit and taking into account the planned block size of 6 for randomization, the sample sizes were 246 and 426, respectively. This was judged not to provide a sufficient number of participants for the safety-related part of the primary study objective. The planned sample size was increased to approximately 1000 moxidectin : 500 ivermectin treated participants, which, assuming 65% evaluability (650 moxidectin treated, 325 ivermectin treated participants having Month 12 SmfD data), yielded >99% power to detect a ≥50% treatment difference.

Statistical methods for primary efficacy endpoint
SmfD were logarithmically transformed (y=log e (SmfD+1)) before analysis. Back transformation was carried out by directly exponentiating least squares means (LSM) as well as the lower and upper confidence limit and subtracting 1. SmfD 12 months post-treatment was compared with a mixed-effects model as described in the manuscript including sex*treatment and LoI*treatment interactions. When no interactions were detected (p > 0.05), the interaction term was not considered and the main effects model was used for the primary analysis. When an interaction was detected, adjusted (least square) means were calculated for each combination of the treatments and the sex and LoI categories and compared pairwise to evaluate for which level of the stratification variable there was a statistically significant difference between treatments. For this analysis, no imputations for missing data were made. The mixed model is valid in the presence of missing data, if the missing data can be considered missing at random which was the case: in each treatment group 3% of treated participants did not have a month 12 evaluation. The model fit was assessed in 2 ways: (1) comparison with a model with intercept only. Here the log-likelihood ratio test was used.
(2) choice of the variance-covariance matrix for random effects and for repeated effects was performed by using AIC and BIC. The lower AIC represented the best matrix to choose. An R-square can be approximated by focusing on percent reduction in variability due to the model where R-square=1-SSE/SSTOT with SSE the sum of the squared residuals from the model and SSTOT the sum of squared residuals from an intercept only model: By default the structure of the variance -covariance matrix for the repeated measurements part of the model was unstructured (UN). When UN failed to converge, other variance -covariance matrix structures including Toeplitz (TOEP) compound symmetry (CS), variance components (VC) and first-order autoregressive (AR (1)) were considered. Akaike Information Criteria (AIC) was used to choose between them. Two-way interactions were evaluated and analysed when necessary as described for the primary efficacy variable.
As per protocol, a non-parametric model was fitted to the data. It was performed by first transforming the outcome data to Savage ranks and analyzing these transformed data with the same mixed model described in the manuscript for the primary efficacy outcome. As per peer reviewer recommendations, sensitivity analyses were conducted: • a linear fixed effects model with baseline SmfD, treatment, sex, LoI, treatment*sex and treatment*LoI interactions, and site as fixed effects, • a linear mixed model with % change in skin microfilarial density at 12 months from baseline the outcome variable. Baseline SmfD, treatment, sex, LoI, treatment*sex, and treatment*LoI interactions were fixed effects and site the random effect.

Analysis populations
The modified intent-to-treat (mITT) population (population for primary efficacy and secondary SmfD based analysis and safety analysis) was defined as all participants who received a single dose of study drug. The secondary population for efficacy analysis was the efficacy-modified intent-to-treat (e-mITT) population defined as all participants who received treatment and for whom skin microfilariae counts were obtained at baseline and month 12. Since the e-mITT population constituted around 98% of the mITT population, only the results for the mITT population are provided.

1.7
Overview of protocol amendments Study initiation occurred under Amendment 1. Amendment 2 incorporated clarifications provided previously to the investigators via sponsor memoranda, i.e.
• prohibited prior and concomitant anthelminthics were anti-nematodal drugs, should be used only in the absence of functioning sponsor-provided equipment when the investigator needs the results for safety reasons • randomization of participants with 20 mf/mg. • biological samples should be destroyed only after verification of the protocol-specified data by the laboratory head and investigator or designate. and added immunochromatographic tests during follow up for participants with positive tests for LF at baseline.

Amendment 3 was instituted after completion of enrolment in all sites and completion of follow up of all participants enrolled in Liberia to
• update sponsor and sponsor-related information • eliminate the Month 18 visit for all participants whose Month 18 visit occurred after 31 December 2011 or approval of the amendment by the Ethics Committees in DRC and Ghana and update or clarify all related information and provisions Furthermore, Amendment 3 • included clarifications which investigators been previously provided with via Sponsor Memoranda (provision of best estimate for number of punctate opacities when ophthalmologists considered accurate counting impossible, application of adverse event criteria to laboratory and ECG findings) • updated the section on Clinical Experience with moxidectin to include the results of analyses completed for the healthy volunteer studies and the Phase 2 study. There were no changes in the objectives, or planned sample size or endpoints or the planned analysis of the primary efficacy outcome, i.e. mixed effect models including baseline skin microfilariae density, treatment group, visit, treatment by visit, and stratification variables sex and center. Before unblinding, center was selected as the random effect for the mixed effect model and the level of infection added to the factors in the mixed effect model. Liberia: 30/299 tested were ICT positive. None had detectable levels of microfilariae in the blood.   2.2.2 Protocol-planned non-parametric analysis of primary efficacy endpoint (SmfD 12 months posttreatment) P value of non parametric model for treatment difference: p<0.0001. Interaction treatment * Sex: p=0.4250, Interaction treatment * level of infection at baseline: p <0.0001.  Table S      Odds for undetectable SmfD after ivermectin treatment relative to odds for undetectable SmfD after moxidectin treatment obtained from the mixed effects logistic regression, see below. 2 Odds for undetectable SmfD after moxidectin treatment relative to odds for undetectable SmfD after ivermectin treatment obtained from the mixed effects logistic regression, see below.

Adverse events reported as resulting in Death (MedDRA coding)
Among moxidectin treated participants 2/978 (0·2%) and among ivermectin treated participants 2/494 (0·4%) died within 6 months of treatment. None of the AEs resulting in death (Table below) were assessed as related to study drug or Mazzotti reactions by the investigator. The relevant medical history of this 65 year old woman included flank pain on exertion, right atrial dilatation, epigastric pain and peptic ulcer syndrome She received ivermectin on 20 August 2010. On 22-Oct-2010, she experienced abdominal pain and asthenia and self medicated with an unspecified herbal therapy.
On 31-Oct-2010, the patient died. The cause of death was reported as septicemia.
The investigator considered there was not a reasonable possibility that the event was related to the study medication.
The past medical history of this 70 year old man included bronchial asthma.
He started productive cough with dyspnoea on 07-Aug-2010. Physical examination on 07-Aug-2010 found presence of crackles and rhonchi all over the lung associated with tachycardia, fever and conjunctival hyperemia. Acute asthmatic attack (asthma) was diagnosed.
On 09-Aug-2010, the patient was hospitalized in the reference hospital.
He died on 11-Aug-2010. The cause of death was reported as asthma.
The investigator considered there was not a reasonable possibility that the event was related to the study medication.
The reported past medical history of this 60 year old woman did not include urinary incontinence and existence of a vesico vaginal fistula. She gave birth to the last child approximately 5 years before her death.
She underwent a vesico-vaginal fistular surgical repair on 19-Jan-2010. Bloody urine was observed following the procedure which continued until 21-Jan-2010. Abdominal distension was observed proceeded by difficulty breathing, gasping and finally death. The patient's blood pressure declined during this period. The patient received ampicillin IV (post operative) starting on 19-Jan-2010, and chloramphenicol IV and flagyl IV were started on 21-Jan-2010.
The patient died on 21-Jan-2010. The cause of death was reported as peritonitis and cardiac arrest.
The investigator considered there was not a reasonable possibility that the event was related to the study medication.  see Figure S4, Any other ocular MAZ includes ocular discomfort, tearing/watery eyes, blurred vision, photophobia and visual acuity. The relatively high prevalence of other ocular MAZ among those with ≥80 mf/mg treated with ivermectin is due to tearing/watery eyes.