Phase III evaluation of the insecticidal efficacy and durability of a deltamethrin-treated polypropylene long-lasting net LifeNet®, in comparison with long-lasting nets made from polyester and polyethylene: study protocol

A recent WHO consultation to review the evidence on the fabric strength of LNs concluded that the current data on the durability of LNs are inadequate, variable and poor quality, and that direct prospective trials to compare different brands of net in a variety of field settings are necessary [37]. To our knowledge the present proposed trial is the first to compare three types of LN polymer – polyester, polyethylene and polypropylene – in the same location using a prospective randomized controlled trial design.

WHOPES Phase III bioefficacy guidelines for LNs are currently based on retention of bioefficacy rather than physical durability. To obtain a WHOPES full recommendation at least 80% of the LNs surviving 3 years of household use in malaria endemic countries must retain sufficient insecticidal activity to induce 80% mosquito mortality in bioassay tests [28]. Four brands of LN have already achieved this criteria: polyester nets, PermaNet 2.0® and Interceptor® [35, 40], and polyethylene nets, Olyset® and DuraNet® [41, 42]. A further four LNs have obtained WHO full recommendations on the basis of equivalence to the aforementioned brands, and a further eight have obtained WHO interim recommendation after demonstrating bioefficacy in Phase II experimental hut trials [25]. While most brands of LN may achieve the requisite levels of bioefficacy, it is much less clear whether all types of net can physically withstand the wear and tear of 3 years of household use. LN survival will depend on the environment and household conditions of use. A LN stretched over a rustic wooden bed in a cramped traditional mud house will not last as long as a properly fitted LN draped over a bespoke net frame in a rodent free home. The duration of the mosquito season will also affect LN longevity and usage, and this will differ between the tropics and subtropics, highlands and lowlands, and coastal and plain areas [4, 15]. In practice, few brands of LN have undergone rigorous longitudinal monitoring. The first LNs to obtain WHOPES full recommendation – polyester PermaNet 2.0® LN and polyethylene Olyset® LN – were the subject of annual cross-sectional surveys of random samples of nets [35, 42] across a number of countries after 1–3 years of use rather than longitudinal monitoring of a documented cohorts of nets [28]. In these surveys it was noted that net integrity (hole index) reached a steady state after 2 years of use indicating that LNs with higher hole indexes were being discarded and not surviving to 3 years. In these countries only one brand of net had been distributed. Unless different types of LNs are tested in the same location, in parallel, in household randomized trials, it will be difficult to determine their relative durability under field conditions. Few LN brands have been evaluated against one another in this way. A recent exception was a household randomized trial in Cambodia between polyethylene Netprotect® LNs and polyester PermaNet 2.0® LNs [43]. Net survivorship exceeded 90% in the first 2 years but after 3 years decreased to ~60% for both LNs, indicating that nets of either material were unable to last much longer than 2 years. It is therefore appropriate that the proposed trial of a longer lasting polypropylene LN is assessed alongside and against polyester and polyethylene LNs over 3 years of field use.

A standard WHOPES phase III trial of a LN normally compares the candidate LN to a reference LN (positive control) made from the same material to determine insecticide bioefficacy after 3 years of field use [28]. While the proposed field trial uses the WHOPES phase III guidelines and may ultimately lead to a WHO recommendation for LifeNet® LN, it is primarily designed as a randomized controlled trial to compare the relative field durability of three types of LN polymer. Increasing the current average lifespan of LNs is a priority for the WHO. LNs with longer life cycles would need to be replaced less frequently, thus reducing the unit cost of LN distribution and replacement [6, 37]. A WHOPES evaluation criterion based on durability would also create a stimulus for manufacturers to improve performance of their products [6]. Based on current data, WHOPES has been unable to set a fabric durability threshold that a candidate LN should meet. The WHO Technical Expert Group on malaria vector control has proposed the setting of a median LN survival time based on functional LN survival at a given time after distribution. It is hoped that the present comparative study of polypropylene, polyester and polyethylene LNs would provide evidence to help calculate that criterion for different types of LN. Looking forward beyond current pyrethroid LNs to a future of nets treated with alternative insecticides to combat pyrethroid resistant mosquitoes, more durable fabrics may be necessary to maintain LN unit costs to a reasonable level [44, 45].

It is not clear whether the physical durability of LNs in the field can be anticipated by laboratory tests of fabric strength. The WHO consultation that recently reviewed the utility of fabric strength tests concluded that their usefulness for predicting LN durability in the field has yet to be determined, and recommended comparative prospective studies with various types of LN in a single study environment [37]. It is intended that the present study will match the indicators of field durability (hole index and functional survival) with those of laboratory strength tests to predict the durability of LNs in operational settings.

Experience has demonstrated that net attrition can be due to a variety of reasons other than loss of integrity. In the trial of Netprotect® and PermaNet 2.0® LNs in Cambodia, twice as many nets were lost or stolen, sold or given away, than were no longer used due to loss of integrity [43]. In the WHOPES funded evaluation of ICON® Maxx in Tanzania from 2011 to 2014, only 17% of nets survived 3 years of monitoring [46]. While 32% of nets failed due to loss of integrity, 52% were absent for other reasons, including families moving home, seasonal absences, selling or giving nets away. Such losses reduced power to detect an effect from the intervention, and should be discouraged provided the right to withdraw from the trial remains paramount. To encourage responsible net use, study participants/families were requested before recruitment to the cohort component of the trial not to give away or sell the study LNs. They were afforded the freedom to stop using the LNs at any time but to let investigators know the reasons during the next follow up survey. Study participants were informed that LNs would be replaced after 3 years (at the end of the trial period and not before) regardless of net condition but only on production of the trial net. If participants stopped using the LN for any reason, including accumulation of holes, they were to store the net for replacement, or give it to the investigators who would replace it after the trial period has elapsed. These revisions to Phase III guidelines were approved by the WHO and reported by the WHOPES working group in 2014 [46]. Such consent by participants would fulfil the needs of the trial and potentially reduce non-attrition losses, but would not affect participants’ right to stop using their net at any time with impunity.