Onchocerciasis Control in the Volta River Basin Area: report prepared for the governments of Dahomey, Ghana, Ivory Coast, Mali, Niger, Togo and Upper Volta; annex II-1 chemotherapy of onchocerciasis, prospects and needs

ocPf 73.L ANNEX tI-I ONCHOCERCIASI.S CONTROL IN THE T/OLTA RIYER BASIN AREA Report prepared for the Governments of Dahomey, Ghana, Ivory Coast, Mali, Niger Togo and Upper Volta Al.lNEX II-l: CHEMOTHERAPY OF ONCHOCERCIASIS PRACTICE, PROSPECTS AND NEEDS Geneva t 973 'l Ii l t United Nations Development Programme Food and Agriculture Organization of the United Nations International Bank for Reconstruction and Development World HeaIth Organization @ WORLD HEALTH ORGANIZATIONORGANISATION MONDIALE DE LA SANTE wno/oncno/t2.el Rev.lORTGINAL: H{GLTSH of t5 CHEMOTHERAPY OF ONCHOCERCIASIS PRACTTCE, PROSPECTS AI,ID NEEDS CONTENTS 1. lntroduction Individual treatnent: requirements and results . Adverse reactions to chemotherapy . . Current clinical trials in onchocerciasis . . Mass drug treatment as an adjunct to vector control . . Planning and organization of a mass chemotherapy campaign Needs in experimental chemotherapy Clinical trials and pilot field studies . . Conclusion The issue of this document does not constitute formal publication. lt 6hould not be reviewed, abst?actod or quoted without the agreement of the World Health Organization. Authors alone are responsible for views expresoed in signed articles. Page 2 2 4 7 I IO I2 l4 L4 2 3 4 5 6 7 8 I Annexes I Quantltative methods used in parasitological and clinlcal examinations onchocerciasis patlents . 2. Evaluation of drugs in human onchocerciasis. Design of drug trials 26 Ce document ne constrtue pas une publicatton. ll ne doit faire l'objet d'aucun compte rendu ou rdsum€ ni d'aucune citation sans l'autorisation dc I'Organisation Mondiale de la Sant6. Les opinions exprimdes dans les articles signes n'engaoent que leurs auteurs. lrrHO//ONCHOr2. 91 Rev. I page 2 1. INTRODUCTION Drugs currently used for treating onchocerciasis patients suffer from disadvantages which have so far lrmited their administration on a large scale. As a consequence, onchocerciasis control can only be achieved today by long-term larviciding campaigns aiming to destroy the Simulium vector flies over an ecological zone large enough to prevent reinvasion by the vector from non-treated areas. However, the effects of such campaigns could be greatly enhanced and the duration of the vector control operations shortened if the latter were supplemented by chemotherapeutic measures designed to eliminate the parasite reservoir from the human popula- tion and to prevent the development of serious ocular lesions and blindness in persons already infected. Such a possibility requires careful investigation. IThe present document has been prepared with the object of defining the conditions under which mass chemotherapy could be used as an adjunct to vector control operations. The practical problems encountered in the correct conduct of individual drug treatment in endemic areas are first reviewed, and a brief summary is given of present knowledge of adverse side- effects produced by available drugs and of results obtained in current clinical trials. The obJectives of mass chemotherapy are then considered, together with the various requirements to be met in planning for, and organizing a mass campaign. In the concluding parts, which are devoted to research needs, specific action is proposed, including collaborative prograrnmes to facilitate the screening, evaluation and clinical testing of drugs adapted to onchocerciasis control. 2. INDIVIDUAL TREAITIEIT: REQUIREIVIENTS AND RESULTS 2.r Current druEs Since the use of melarsonyl potassium entails a high risk of death from arsenical encephalopathy, this compound must be ruled out and only two of the currently available drugs can be recommended, namely diethylcarbamazine and suramin. The former is a highly effective microfilaricide with little or no action on adult worms, which can be administered by mouth. The latter is a highly effective macrofilaricide with considerable microfilaricidal properties, which is administered intravenously.. The known characteristics, properties and toxicity of these preparations are described in the second report of the WHO Expert Committee on Onchocerci asi s .2 2.2 Objectives and indications The objective of individual treatment is to eliminate the parasites that cause the signs and symptoms of the disease. Tissues already damaged severely by fibrotic scarring cannot be expected to improve after treatment. The main groups of patients requiring treatment are: (a) those with eye lesions or with a microfilarial invasion of the eye sufficiently serious to render visual impairment or blind- ness a likely sequel; (b) those with severe pruritic skin lesions and onchodermatitis; I Based on a WHO consultation on the chemotherapy of onchocerciasis, which was organized in Geneva, 4-6 September 1972, with financial assistance from the United Nations Development programme. Advisers were: Dr C. B. Cu6tlar, Dr A. Davis, Dr B. O. L. Duke, Dr A. P. Oomen, Dr J. picq, Dr A. Rotland, Dr M. Salazar Ma116n and Professor P. E. Thompson. The WHO Secretariat was represented by: Dr N. Ansari, Dr A. A. Buck, Dr J. Hanon and Dr B. B. Waddy. 2 t/t,ld Hlth techn. Ser., 1966, No. 335, pp. 32-39. henceforth outside an this will rid them of going to be exposed tojustified. wHo/orcro/?2.sL Rev. r page 3 (c) those with very heavy infections whose poor condition, loss of weiBhtr etc. are attributed too volvulus infecti on. It may be desirable to treat also patients who are going to live endemic area or in an area where Simulium control is Carried out, for their parasitesl however, if their disease is not severe and they are , reinfection, the risks and inconvenience of treatment may not be 2.3 Conditions of treatment Most cases of onchocerciasis can be treated on an ambulant outpatient basis or by mobile treatment teams visiting their villages at intervals. ln considering patients for treatment and assessing the risks of its producing adverse reactions, attentionshould be paid to the epidemiological background of the villages from which they come, to obtain an idea of the amount of infection to which they have probably been exposed. A full physical examination and, as far as possible, an adequate parasit- ological examination of the patient should be made before treatment begins so as to determine the lntensity and distribution of the parasites in the body (methods are discussed in Annex l). This examination should include the taking of quantitative skin snips fron the upper and lower parts of the body, an assessment of the numbers of nicrofilariae in the eye, a nodule count and the examination of the urine for microfilariae. Patients with heavy loads of microfilariae are likely to react severely to treatment, but some lightly infected patients may also show severe reactions. Constant, special care may be necessary for certain types of patients (heavy infections, critical eye lesions, poor general state). The condition of patients who are in a poor general state of health or badly nourished should be improved as far as possible before treatment is undertaken. 2.4 Treatment of eye lesions Patients with heavy loads of microfilariae in the ocular tissues should be treated under the supervision of a physician having adequate ophthalmological knowledge and the necessary equipnent for eye examination, including a slit-lamp. Patients with microfilariae and/or lesions in the eye may derive benefit from systeEic treatment whtch eliminates their parasites. Treatnent should not be withheld for fear of reactions in the eye. These reactions, caused by the death of microfilariae in the ocular tissues during treatment, can almost always be controlled by careful administration of local or systenic corticosteroids (especially betamethazone) and atropine. It is also probable that the presence of live microfilariae in the cornea causes irritation of the eye, with injection, watering and photophobia. The death of these parasites after systemic diethylcarbamazine treatment may produce a marked and rapid clinical improvement. According to workers in Mexico, butanolauride of lysergic acid (an anti-serotonin agent) may be useful in checkinB the conjunctivitis and pruritus associated with diethylcarbamazine treatment. Further trials of this preparation are recommended. Where the specialized tissues of the eye have been irreversibly damaged by fibrous reaction, parasitological treatment cannot be expected to improve them, but may, howeve:., arrest further progress of the lesions. Ocular tissue left unscarred and having merely become inflamed as a result of the presence of microfilariae may be expected to undergo resolution. This applies to punctate keratitis and some of the stromal lesions in the cornea, cells and proteinous exudate in the media, and uveal inflanunation. In these particular instances, treatment will therefore contribute to inprovenents in visual acuity as reported by several authors. wHo/ollcHo/l 2.st Rev. t page 4 Surgical intervention for cataract or glaucoma is sometimes necessary rn eyes affected by O. volvulus but it should not be undertaken until the microfilariae have been eliminated from the ocular tissues The use of diethylcarbamazine eye drops (3-5%) may be beneficial in certain onchocercal eye lesions. However, as such drops can provoke extremely severe eye reactions, it is recommended that they be administered only by experienced ophthalmologlsts and that carefully controlled trials be made with this type of medication. For the time being, diethylcarbamazine eye drops should not be made generally available. Nodulectomy as a means of treatment has been considered of value in reducing eye lesions and blindness in Central America where nodules on the head are common. Trials on the effect of nodulectomy alone might be carried out in African areas where Simulium control has been achieved, since its therapeutic value has never been assessed. 2.5 Therapeutic results and Droqnosis Therapeutic results can be checked only some months after completion of treatment when the tissues have had time to reorganize themselves after the death of parasites. The effects of treatment on parasites in the skin and eyes must be assessed by quantitative methods (see Annex I ). Cure may be ascertained by parasitologicat means anafor clinical observations. terms used in this connexion are defined as follows:- The (a) Parasitological cure: After clinical treatnent has been completed parasi.tological cure is achieved when signs and symptoms of active disease have disappeared, no live parasites are detectable, and a negative Mazzotti- test has been recorded at two consecutive examinations made three months apart. (b) Clinical cure: Clinical cure is achieved when symptoms and active clinical signs have disappeared, although parasites may still be present. In endemic areas microfilariae due to reinfections may be detected from one to two years after completion of treatment. The prognosis after treatment wiII depend on the degree of irreversible damage already sustained by the trssues, and on the chances of rernfection. Under conditions of heavy transmission reinfections may build up to pre-treatment levels within five to 1O years; this interval of freedom from microfilarial invasion is however usually sufficient to postpone by several years the onset of serious eye lesions. The effects of various therapeutic measures on all the eye lesions known to be associated with onchocerciasis are sunrmarized in Table I. ADYERSE REACTIONS 10 CHEMOTHERAPY .1 Geographical variations Variations in the reactions of patients to treatment are to be expected from one geographical area to another. These variations probably depend on racial, nutritional and and also on the different O. volvulus - Simulium complexes to whictr they are exposed. Due attention should be paid to such differences when comparing results from several areas. Within any given area the risk of adverse reactions to treatment will also vary according to the intensity of onchocerciasis transmission and to the human infections associated therewith. 3 3 environmental factors affecting the human population, w1o/oNc1o/?2.er Rev. l page 5 o o ti o bo do o +Jq op il + + + E' o o oo il + + o +J 6lr oo o E lt + d6 E .''{ E lt +l d .,{ il o ; o(l o .l{ ct{ +{ q) +{ o b0 '''{ +J(!4 o-r slzl ..{ O = C+)d..{C(!(!(U(l) E O OCotr 6O L -E ,o(Urr6()dO)FIOdO b0 E ..{ .dQ >rkfGr".d O.E6O !rHTitlcooo6O O'aoor.trOb0OdOO(!6eloorrOOFTC0) rr o borr o odtro>r >.o(!().c o cn >a p. oti +)(! C) d +)ao ..{ ol{ b0 .?l P Ioo15c ,oO.dqo Qo F^{ q)do(,(l)>tr>P .d .d +rP>1 o(!(t)tr tdoo!Etr'.{ .l{occ ob0trotro! o () +J .i{i o .'.{ {J .d F{ o >a 8t, .'{ o!(! .i{ .d Eoq) .,{ O o> tiO () o o o 6 !6 o d +r .d +J(, ,{ o ,14 60 .,{oooooti(!O+)d(n o(h o d b0 (gEo, +rdd(l'ooo ,co! Lp o(!t! (JrrEO+rOEO '.'{ d ,,1(!(!r{ lrdob0+rdoc) (! O+{ €..{Otr,ooo!odo o(n .i .Ft +) .d .r{ E +)kooh+{ o .i{ olr>O .,{t+)o6tEACXcto O.H .do P .,{ +r F{ q)do ...{ cao(! A P o o tr o (,) .'{ +J .''{ d o >a cU o .'{ li .'{ o +r o + P o o o q +r .d +J 6L ox b0 tr .'{ o o rr o Fl oth & o 6 ''{oritrokPoc o(! oo +)+) trq .Fl ..{ ooqr([ .r{ .d Lk6(!lrddc) .d .,.{ !qCHE OO6 .JOO ..{ ..{ == >l +{ +{ dq.{ o .'{ +) .l{ +J 6 t{Aoo .YO .FtO+) +) .r{(!() P6op.tro aA ..{ o o d o >l o d(! o! o o o o o CA2 ts ?J) t4 -l 14 frl F1 c)&frl 8 c)zo zH (h FItr CA fi =(J H €-p t4A E 14 F. fro o C) E\fr f.] ,-i frl Fl ra E< o oo o o o o o O'd >+) ..1 6l +|N + 6.'{ +.dF{dad+)(!(,) e .,{ +t o o o I6i{ +, o o t, o .P 6 o do .d o + U €toG+)kclPOc .,.{OEotr .d o o +l o o +l ++ + + Ero6pfrd+)oC '.{o! oq .d o +l o o g tq)6p +J (Jq ',{OEoc .d + + + o + + + + + + U +l o o o d6 o .'{ 60 tr (h .d o o ..1 +rL o C) o r{O +rooo .,{ ti =€ oOE .'.{ .'{EOoo +) ''.{o+r >ti cl.) o o +J c o E +r6 o h P li6 d aI d(u o o Fl C) .d +roq,Q .'{ O ,r f{ o6 >| = + + o + + + + q) P -(!oo ''l(!(, LO+)(lC (.) o +l o o o I .'.{F{N h(lFE .P6 op .r{ lia(! o + N o+ t{:a+oo++rO+{}6 + +l +l o o o o o .,.{ E(E li rJ) + (o Isfo + t{+r+otr +ro(HE (u c o .,{ P .d o tr o o q{ o a0 | '.tc o o ,r o > o Ftp .'{loo oa + + + + + +l +l o o o o wHo/oNcHo/72.sr Rev.l page 6 3.2 Adverse reactions to macrofitaricides (suramin) Adverse reactions to suramin are related either to the toxicity of the druB itself or to tne death of parasites following its r...1 They include a feeling of general weakness continuing for eight to 10 weeks after treatment, fever, itching, swelling, fine or coarse papular eruptions and ensuing desquamation, pain in nodules and tissues around the ioints and over bony prominences, tenderness of the soles of the feet and patms of the hands. When microfilariae in the eye are involved, conjunctivitis and blepharitis may result. The irrrtant action of suramin on the kidneys, revealed by albumin and granular casts in the urine, is probably the most common toxic manifestation. The most severe reactions following suramin treatment are considered to be the exfoliative Iesions affecting the mouth, pharynx and skin, which mey occur early in the course of treatment and appear to be caused by a true drug toxicity. In such instances, administration of the drug must be stopped and corticosteroids as well as other general measures appliecl. Deaths from general wasting, asthenia and chronic diarrhoea some months after completed suramin treatment have always been associated with unnecessarily high and frequent dosage, which may be responsible for suprarenal degeneration. After an initial test dose, dosage wrth suramin on any one course should never exceed ? grams given at weekly intervals and should in most cases be confined to a total of 5-6 grams Biven in I gram doses at weekly intervals. Suramin has been used on a large scale for the treatment of onchocerciasis in Venezuela (where infections are generally light) without any fatalities that could be conclusively attrlbuted to the drug. No adequate autopsy descriptions are avaj.lable for patients who died during or after suramin therapy, so that little is known of the pathotogy of such cases. Careful records extending over several years should be kept of the mortatity figures attributed to the use of suramin in infected African comnunities; comparison should also be made with the mortality observed in similar villages receiving no treatment. 3.3 Adverse reactions to mic rofi laricides (diethylcarbamazine) The reactions commonly encountered during diethylcarbamazine treatment are pruritus, oedema and dermatitis, often accompanled by headache, fever and generalized body pains. They do not, as a ru1e, Iast for more than a few days, and atthough the patient may be in extreme mlsery over this period, he rapidly recovers, without any lasting toxic effects- These allergic reactions can be controlled to some extent by simultaneous administration of 2 corticosteroids, but this should be reserved for those who react severely to the treatment. Fatalities have been reported following administration of diethylcarbamazine to seven Ethiopian onchocerciasis patients who were in a very poor general condition at the time of treatment. Although the drug destroyed the microfilariae in their skins, none of the normal clinical reactions accompanied the death of parasites; the patients lapsed into coma and died on the second or third day of treatment. There was no definite proof that death was due to the drug, but the suspicion of a cause and effect relationship is sufficient to suggest that diethylcarbamazine treatment of patients with severe malnutrition and intercurrent disease should not be undertaken lightly. If in such patients the first dose produces no Mazzotti-type reaction, treatment should be immediately discontinued. ' ,na." reactions have been sununarized on Onchocerciasis (WId Hlt h Org. techn. ReP. in the second report of the WHO Expert Committee Se!., 1966, No. 335, PP. 34-35). , ' Second report of the WHO Expert Committee cn Onchocerciasis 1966, No. 335, P. 33).8., (Wld Hlth Or techn. wHo/oNcHo/12.sL Rev. t page ? 3.4 Contraindicat ions to drug treatment Each case must be iudged on its own merits by the physician in charge of treatment. Particular consideration should be given to the desirability of treating individuals in the following broadly defined groupsr some of which are especially liable to suffer adverse reactions to treatment. (1) Persons with evidence of renal disease (this restriction applies to suramin only) <2) Aged persons (3) Malnourished subjects (until this condition has been redressed) (4) Persons in poor general heatth or with intercurrent disease (until this has been remedied ) (5) Pregnant women (until after delivery) (6) Children under 10 years of age (untess the clinical severity of their infection demands earlier treatment, in which case there need be no limiting age factor) (7) Persons in whom there is evidence of idlosyncrasy or intolerance to the drugs to be used for treatment (8) Persons who are irreversibly blind. CURRENT CLINICAL TRIALS IN ONCHOCERCIASIS 1 Established drugs The possibilities of using new dosage schedules vith already established drugs should be borne in mind, in particular the use of diethylcarbamazine as a microfilarial suppressant. The rationale of such treatnent is first to ellminate the patient's lnitial toad of microfilariae. This may be done by giving an intensive course of diethylcarbamazine working up to 2OO mg ter die sumendum over 5-21 days, or by giving doses of 5O-2OO mg once a week for sone six to eight weeks. Thereafter the nicrofilarial concentrations in the skin may be maintained at low levels by means of a weekly dose of 5o-2oo mg. The second reason for suppressive dosage is that it may help to reduce the numbers of microfilariae reaching the eye. It will also reduce the chances of the patient infectinB Simuliun which feed upon him. Few data are available on the effect of diethylcarbamazine given weekly at very low doses. Field trials of such r6gimes should be stimulated as they nay provide alternative schedules of suppressive treatment of practical value. Schoolchildren would offer suitable target populations. The use of diethylcarbamazine salt has been advocated but the general opinion is that its disadvantages are likely to militate against widespread application. Adninistration of diethylcarbamazine at regular intervals to populations in endemic areas raises practical difficulties, and some doubts have been expressed as to the efficacy of such r6gimes in reducing transnission. 4 4 wHo/oucHo/?2.e1 Rev. page 8 I 4.2 Newer drugs 4.2.L Metrifonate The most promising new drug under investigation is metrifonate, an organophosphorus compound. In Mexico, at a dose of LO ngfkgfday given for six consecutive days and repeated in a similar course after an interval of two weeks, it has been shown to possess a microfilaricidal and a macrofilaricidal action in some patients with onchocerciasis. The clinical reactions to the death of microfilariae were less marked following metrifonate than after diethylcarbamazine. Onchodermatitis improved after metrifonate treatment and microfilariae disappeared from the anterior chamber of the eye. In patients from the West African forest zone treated at a lower dosage (fO mg/l<g given on three occasions separated by intervals of three weeks) a partial microfilaricidal action was observed, but there was no effect on the adult worms. Metrifonate has proved to be free from serious toxic effects when used at the recommended dose of 7.5 ngflrg in a spaced treatment r6gime of three doses at intervals of 14 days in Schistosoma haematobium infections. Depression of red cell and plasma cholinesterases always occurs during treatment. While the recovery of plasma cholinesterase to pretreatment levels is relatively rapid, there is a moderate accumulation of effect on the red cell enzyme after spaced treatments, and the reattainment of pretreatment enzyme levels may take six to eight weeks. Atropine is available for the relief of untoward symptoms and oximes may be given as enzyme reactivators although this has not been necessary in any previous clinical trial. Experimentally, metrifonate has been shown to have both macro- and microfilaricidal effects against Brugia pahangi in cats. Limited and carefully controlled trials of its action on O volvulus should be made using more closely spaced dose r6gimes than have been found to be effective against S. haematobium in man. In the conduct of such trials particular attention should be paid to the incidence and frequency of side effects since there is evidence that adverse reactions are more commonly associated with increasing doses. At present this compound is available only to reconrmend.ed investigators. 4.2.2 Other d rugs Among other new drugs, limited initial studies have been conducted on the following:- (a) Niridazole was found to be ineffective by some workers and of unacceptable toxicity by others. (b) Levanisole, at doses normally used in the treatment of ascariasis, showed no action against o volvulus. tt was suggested that extended dosage schedules should be tested since such r6gimes showed partial activity against animal filariae. (c) Dihyd roemetine was found to have no action on O. volvulus. 5. MASS DRUC TREATMENT AS AN ADJUNCT TO VECTOR CONTROL 5.1 Experience in Americ a and Africa Mass campaigns for the treatment of onchocerciasis with surarnin have been carried out in Venezuela for many years with successful clinical results. However, infections in that country are generally lighter than in Africa. wno/oxcno/l2.sL Rev.I page 9 In Guatemala and Mexico routine nodulectomy has been practised in all endemic areas for many years. Apart from some diethylcarbamazine treatment, this has been the only method of control and no measures have been taken against Simulium. Although nodulectomy has probably reduced the prevalence of blindness, it has had no obvious effect on transnission. In Ghana a treatment campaign was carried out in an area where no vector control measures were applied, using suramin. It was continued for some two years with apparent benefit but was terminated after the sudden occurrence of three deaths associated with treatment. In Mali an attempt to use melarsonyl potassium in a mass campaign conducted rn a vector controlled area was also stopped after a number of deaths occurred in the flrst SOOO patients. These two African experiences illustrate the risks involved in mass chemotherapy. 5.2 Objectives and indications of mass drug treatment The main objective of mass drug treatment used in conjunction with Simulium larviciding would be to accelerate the reduction of the parasite reservoir in the human population, thereby interrupting transmission more quickly than would be possible using vector control measures alone. This additional line of attack on the form of the parasi.te available for transmission might indeed increase the chances of successful control in the event that total eradication of the vector cannot be achieved. It is also appreciated that a mass treatment campaign with this end in view could extend over several years. Thus, although at any given moment a considerable proportion of the population might have to be excluded from treatment because they felI into one or the other of the groups in which treatment may be contraindicated (see section 3.4), yet over the years a great many of these people would in the natural course of events move out of the contraindicated groups. In alt, the numbers of persons rn whom treatment ts likely to be contraindicated would probably not be so high as to render unrealistic the goal of parasite elimination. The section of the population in most immediate need of treatment would be persons threatened with blindness. lndeed, in the Kenya foci, where the vector was eradicated some 20 years ago, subsequent observations showed that eye lesions in persons already heavily infected may well progress to blindness despite a complete break in transmission. The highest priorlty should therefore be given to identifying those persons in the population who are particularly at risk of developing severe eye lesions, and to determining suitable schedules for their treatment. It is appreciated that they might be among the most difficult cases to treat, being heavily infected and Iiable to severe reactions, but that, under the threat of blindness (which has been termed a "Iiving death" in Africa), greater risks would be justified. 5.3 Feasibilitv of mass chemotherapy Desp:te the theoretical desirability of mass treatment as an adjunct to vector control, it is considered that, using the drugs available at present, namely suramin and diethylcarba- mazine, the risks of adverse reactions and the incomplete knowledge of the toxicity of thesedrugs in the treatment of onchocerciasis are such that a mass campaign could not immediately be launched with any degree of safety under the conditions obtaining in endemic areas. Specific action required to develop chemotherapeutic measures adapted to onchocerciasis control is outlined in sections 7 and 8 below. lvHo /oNCHo, /72.rJl Rev. I page lO 6. PLANNING AND ORGANIZATION OF A MASS CHEMOTHERAPY CAMPAICN 6.I Neqesg4lJ pIellmlqafy screening procedures (a) As a preliminary to mass treatment it is essential to have full data on the eprclemiological pattern of the disease in the population. Advantage should be taken of improved quantitative techniques to assess the density of infection in skin and eye, and of the most accurate indices of endemicity based on prevalence and intensity of infection. The same standard methods of epidemiological survey must be used throughout the control campar.gn. (b) The establishment of adequate vector control is a necessary prerequisite to mass chemotherapy operations aimed at eliminating transmission. The effect of co.rtrol operations on the vector population and on its transmission potential must be measured throughout the campaign using the same standard methods. (c) The population must be properly screened to determine those persons in whom treatment is contraindicated (see section 3.4). (d) The treatment schedule must be carefully chosen (whether curative or suppressive or a combination of both methods) and priority of treatment given to those groups of persons at greatest risk of developing blindness, and to those contributing most to transmission. The two groups will often overlap to a large extent. (e) Consideration must be given to socio-economic factors in the cornrnunities to be treated. In particular, treatment may have to be undertaken only at certain times of the year, so that there is minimal interference with village agriculture or so that it does not corncide with the hungry season when malnourishment might reduce tolerance of treatment rn the population. 6.2 Statistical aspects and mat hematical models Competent, practical statistical and mathematical advice is essential in all aspects of mass treatment. Mrsleading information may result from routrne health statistics in which aII data are lurnped together according to political or administrative areas. Instead, sampling withrn large endemic areas ("foci") should be done mainly on the basis of epidemiological criteria. Stratification in the sampling design will therefore be related to the intensity of transmission. The vrllages or spatial units of transmissi.on with the highest intensity of transmission should be included in the sampling and preliminary trials may be foreseen, if appropriate. The characteristics of the population and their expected behaviour in regard to drug acceptance and sequential procedures need to be considered. As in any series of mass drug administration cycles, populations tend to divide themselves in three broad groups, each having a different epidemiological significance: Always or nearly alwaYs treated Never or almost never treated Changing behaviour. Operational identification and previous estimates of the size of these groups are important in the development and interpretation of mass drug administration sinulation models. I 2 u wHo/oncHo/72.sL Rev. l page I1 Mathematical oodels with specific objectives are essential for strategical, tactical and early evaluation purposes. [nput to predictive models should include primarily the logistic, operational, geographical and cultural constrai.nts. Data from preliminary trials should also indicate the pattern of acceptance or refusal of mass treatment sequences and other forms of drug administration. With atl such basic information it is possible to construct predictlve models of the effect of drugs on transmission which would be of value when drugs become available for use in an endemic area, ei.ther in formalized mass drug administration cycles or otherwise. Transnission and vector-dynamics mathematical models are equally important for identifying quantifiable determinants of disease transmission even when errors and imperfections cannot be avoided. Preliminary models require a process of constant upgrading and testing. At all times the limitations of modelling should be kept in mind for the reliability of nodels depends on the quallty of the data utilized and of their processing. 6.3 Administrative aspects 6.3.I Population coverase and population novements lt would be highly desirable to call upon medical geographers, sociologists and other behavioural scientists to obtain data on the novements, customs and village economies of the communities in the treatment area. These data would greatly assist the clinicians, parasitologists and ophthalmologists in their tasks. ' The characteristics of the target populations must be well known, including the move- ments of people in their own village environment and from one village to another, emigration of persons in search of work outside the treatment area, and immlgration of people coming in the wake of Simulium control to develop hitherto deserted lands. Efforts must be made to continue adequate surveillance of the population desplte all these movements, since the success of any campaign of mass treatEent will depend in a large measure on the degree offollow-up and on the attendance rates which can be obtained. Cooperation in treatment is likely to be greatest in those villages where the disease is most serious and most feared by the people. The importance of securing the cooperation of the community leaders in any village is emphasized, as well as the considerable difflculties which may be encountered ln obtaining repeated assembly of the population for treatment at regular i.ntervals over a period of some weeks. 6.3.2 Availability of Dersonnel Training ancl use of par.amedical personnel An adequate number of trained medical auxiliaries should be available in order to ensure the success of the project. The services of a willing and authoritative local assistant must also be enlisted in each village treated. Because such a man would be personally known to the inhabitants, his influence would probably be infinitely greater than that of a more highly trained outsider. The importance of having tocally recruited aides in the treatment campaign cannot be overemphasized. Such persons are aware of the particular aspects of the disease of direct concern to the local people and are best able to explain to them the purpose of the treatment, its probable benefits and its risks. 6. 3. 3 Orsanization of treatment and prophylaxis of onchocerciasis ln endemic areas Drug administration must be undertaken mainly on a domiciliary basis. Because o:,the very limited number of medically qualified personnel available, this type of work will have to be entrusted largety to medical auxiliaries. wHo/or'rcHo/z 2.sL Rev. I page 12 As regards the responsibility for drug administration, curative therapy by the use of suramin and administration of suppressive diethylcarbamazine require two different approaches. For suramin administration the ultimate responsibility in determining what a medical auxiliary may do without direct medical supervision rests with the country's Ministry of Health.Subiect to the foregoing, medical auxiliaries can be trained to undertake suramin therapy, but decision on whether or not to treat each individual potential patient must rest with afully qualified doctor. This implies that suramin therapy can be undertaken only to the extent that doctors of suitable temperament, free and willing to travel continuously in rural areas, are available. Each such doctor must be provided with all the necessary facilities, i.e. transport, diagnostic equipment (including a slit-lanp), drugs (including not only suramin but also a general practitioner,s pharmacopoeia), etc. and a team of medical auxiliaries The conditions of service of auxiliaries, In pay and other respects, must be such as to encourage them to spend many years in field work after their training. This may entail the subsidizing of their salaries or allowances. Although suramin therapy must be undertaken on a domiciliary basis, hospital beds should be avairable for any patients suffering from complications. With diethylcarbamazine, the problem is to convince a very high proportion of the totalpopulation to take at regular intervals a drug which has unpleasant after effects. HeaIth education and public relations are therefore vitally important. Preliminary propaganda, and the conducting of general clinics by the campaign teams, are essential in carrying out mass diethylcarbamazine treatment. It is unlikely that fully qualified doctors will be available to 1ead diethylcarbamazine teams. Medical auxiliaries with a very high standard of character and a keen sense of responsibility will have to be found for this task. If the above conditions cannot be net, no such campaign should be envisaged. NEEDS IN EXPERIMM.ITAL CHEMOTHERAPY I The need for alternativ e drugs There are at least 30 million cases of onchocerciasis in the world. The proposed onchocerciasis control project in the Volta River basin area is the first large-scale endeavour to eliminate a serious public health problem with severe social and economicimplications. If successful, it can be anticipated that stmilar control measures will be extended to other parts of Africa and Latin America. Even after the complete elimination of the vector, there will remain a large segment of the lnfected population in which the disease will take its natural course unless specific therapy can be given. The main needs in onchocerciasis chemotherapy wourd appear to be for: (a) new macrofilaricides; (b) new microfilaricides that do not give rise to severe reactions associated withthe death of parasites' Possibly compounds acting more srowly than diethyrcarbamazinemight prorluce less reactionl 7 7 (c) chemoprophylactics. ?.2 Screening of compounds for evidence of activity wnofancno/t2.91 Rev.l page 13 Models employed. Alternative test systems The ideal model for the primary screening of drugs would be an infection of Onchocerca volvulus in a small laboratory animal. Such a model does not yet exist, although chimpanzees infected with O. volvulus should fill an important function in the secondary screening of drugs. The only possible alternative approach at this time is to utilize some of the existing animal models of various filariae other than O. volvulus, such as: Litomosoides carinii in cotton rats, Mongolian jirds, or multimammate rats; Brugia pahangi in Mongolian jirds or cotton rats; B. malayi in Mongolian jirds, cats or dogs; Dipetalonema vitae in Mongolianjirds or go lden hamsters; Dirofilaria !mnitis in dogs and Breinlia sergenti in slow lorises. Each of these models has some obvious advantages and disadvantages from the standpoints of convenience for, and feasibility of various types of experimental work, including chemotherapy. It is not possible at this time to say which of these models, if any, could give chemo- therapeutic results that might have relevance to onchocerciasis. Pending the development of a suitable small animal model of onchocerciasi.s, it seems most logical: (a) to conduct primary screening using either L. carinii or B. pahangi ina listedrodent; and (b) to pursue secondary screening in the various other available models above. This approach holds the prospect that drugs showing activity against several types of model infection would be the best candidates for trial in onchocerciasis. This assumption is supported by the fact that the few available antifilarial reference drugs have a broad spectrum of activity against most of the important filariae, although there is much variation among species in their degree of susceptibltity to the reference drugs. Furthermore, much variability in drug susceptibility may exist within the same species among the adult worms, microfllariae and developing larvae. In view of the above, specific drug screening procedures are required to permit assess- ment of each type of action. For practical reasons, priority should be given to the development of safe macrofilaricidal drugs. Research concerned with the cultivation of a view to galning a better understanding of the more rational approach to chemotherapy. filariae in vitro need also be promoted with pa"asit"'ili,ffilism as this might provide a 7.3 Drugs for study The following drugs, which have shown promising activity in various other forms of filariasis in experimental animals, appear at present to be worthy of further investigation aga inst O. volvulus: (a) Potential macrofilaricides Met ri fonate Levamisole Nitrofurantoin (b) Potential microfilaricides Metrifonate Levamisole Nitrofurantoin lvHo,/oNCHo/7 2.sr Rev. I page 14 (c ) Chemoprophylaxis Suramin Levamisole Tetracyc I ine In view of the fact that two drugs (suramin and melarsonyl potassium) effective against adult O..volvulus were ori ginally developed as trypanocides, any new drug with trypanocidal action might be considered for trial against O. volvulus. Current experimental trials of new compounds appear to be limited at present to metrifonate (see section 4.2.L). 8. CLINICAL TRIALS AND PILOT FIELD STUDIES At this stage of drug evaluation carefully designed clinical trials and pilot field studies must be organized not only to develop suitable treatment schedules and to assess their effectiveness and indications but also to investigate acceptance of mass drug administration in populations with different backgrounds as well as the impact made on morbidity and trans- mission of the disease. Recommended procedures for clinical trials are described in Annex 2. Special attention should be given to the following needs (f) Coordinated studies on the pharmaco-dynamics of both established and experimental compounds should be instituted in endemic areas. <2) Various treatment schedules that might make mass chemotherapy more acceptable and less dangerous need to be investigated and evaluated. In this respect prlority tasks are: (a) the determination of the minimum dose of diethylcarbamazine that is effective in onchocerciasis areas of high and medium endemicity; (b) a study of the possibilities of suppressive diethylcarbamazine on the lines described in section 4.1 above; (c) ttre exploration of different schedules of suramin treatment together with a detailed analysis of adverse reactions. (3) Pilot field studies with appropriate drugs are requlred to compare the evolution of the parasite and of the disease in treated and untreated groups of population. The question of the feasibility of the above prograrDrne of work must however be raised. As a rule, clinical trials and pilot field studies are difficult to conduct in endemic areas where resources and facilities for the purpose are either lacking or insufficient. Another essential requisite is that such work, to be meaningful, should be planned, executed and evaluated in a uniform manner. Thought must therefore be given to the possibility of setting up the necessary facilities, with adequate provision being made for specialist and technical staff, equipment and funds. For maximum efficiency, it seems that such facilities would best be located in a central research unit in Africa operating with a well-equipped hospital and associated field stations in various endemic areas. 9. CONCLUSION In view of the magnitude of the public health and economic problems caused by onchocer- ciasis and the inadequacies of the drugs now available for use against this disease, there is a pressing demand for new therapeutic agents suitable for use in mass treatment and prophylaxis. Because of the high costs and other impediments involved in the development and testing of potential drugs, collaborative programmes, assoclating research institutes, drug manufacturerst field stations and professional investigators are required. In continuation of its support to research on the chemotherapy of onchocerciasis, WHO is ready to assist, stlmulate and coordi- nate efforts in the implementation of such collaborative programmes. wHo/oNcHo/z2.er Rev. I page 15 ANNEX I QUANTITATIVE METHODS USED IN PARASITOLOGICAL AND CLINICAL EXAMINATIONS OF ONCHOCERCIASIS PATIEMS 1. Measurement of the lntensity of infection Microfilarial loads generally increase wlth age at a rate which vari.es wlth the amount of transmission. Of aIl available methods for estimating the intensity of infection with Onchoc rca vol lus counting mlcrofilariae ln skin biopsies is the best. Other techniques that have been used on a limlted scale are counts of microfilariae in the anterior chanber or the cornea of the eye and in conjunctival blopsies. Assessment of the intensity of infection by ionuno-diagnostic tests (fluorescent antlbody, indirect haemagglutination, compleDent fixatlon and skin test) is stitl at an experimental stage. Research on immunological methods of diagnosis should be encouraged. Because of its ease, speed and relative convenience, the taking of skin snips with conrmercially available scleral-corneal biopsy punch instruments is the diagnostic nethod preferred in onchocerciasis. For best results, the width of the cutting edge of the punch should measure 2-3 mm. The optimal site for taking biopsies in Africa, is the skin over the iliac crest and, in Central America, the trapezius area. When a high degree of accuracy is required, nultiple skin snips from two to four different sites i'.e. ankle, calf, iliac crest and shoulder are recomnended. The skin snips are transferred to microscope slides. A small drop of O.857o saline solution or distilled water is placed near the snip and then covered with a cover sllp. The specinens, after being alloqred to stand for 30 minutes, are examined under low power of a compound microscope. Some investigators feel that teasing of the snip increases the sensitivity of the method. [f microfilariae are present their number is counted and recorded. Whatever nodifications of the nethod are used by lndividual investigators, it ls important that the same technique be enployed throughout the study to mininize the nagnitude of the method error. Quantiflcation of nlcrofilarial skin concentrations is desirable in order to check the degree of infection of the individual and the results obtained from hls treatment, and also to assess the effect of control Deasures on the density of infection in the human population. It is recognized that there is a lower limit of infection below which detectlon of mlcrofilariae in skin snips is improbable. In such cases a tentative diagnosis of onchocerciasis may be made by adEinistering a dose of 50 mg diethylcarbamazine to provoke a skin reaction (Mazzotti's test), or on the evidence of microfilariae havlng been ingested by Sinulium when fed on the patient. 2. Counting of nicrofilarlae in the eye The presence of live or dead Eicrofilariae in the cornea anafor anterior chamber of the 6ye is not a constant feature of onchocerciasis. It is usually associated with high concentrations of microfilariae in the skin and, although not always acconpanied by ocular lesions, it increases the prospect of such lesions developing subsequently. Using a good joy-stick model sllt-lamp and a high magnification, microfilariae in the cornea can be counted, as well as those visible in the anterior chamber. Separate counts should be made for each eye. Exanination of each anterior chamber requires a fixed period of observatlon (usually one minute), and it may be desirable to increase the numbers of vislble parasites either by massaging the globe of the eye for a flxed perlod or by allowing the patient to slt with his head between his knees for a few mlnutes before the eye is examined. wlofoNc[of72.er Rev. l page 16 Annex I 3. Quantitative assessment of onchocercal eye lesions Onchocercal punctate keratitis, sclerosing keratitis, and other ocular lesions caused by the parasite can also be recorded in a quantitatil'e manner. In all these investigations the exaniner nust record his findings in a detailed protocol. Standardization of protocols is desirable (see nodel appended). Such quantitative studies are likely to prove of considerable help in assessing both the severity of ocular disease 1n infected persons, and the effect of drug treatment. orctle-clAar! atnvn !(nl I rHo/ororcr2.tr i.v.r Pr3. l? Annar I t.l !ao. c."d ,l"at nD ?etlrrt - llu.b. aD Oount", nD Aao 3{ dSr ll_19 5 n ll 12t-t IOs. a. Yaar3 tpan3Plrce of suaYcrr iloDrlcr: l{arlYa glllaaa Ya. Xo ln tha a.aa 20 non€ rn sch@l ta aaer f r shea latrlin t aed. r othca3 qnln@n Yaa - l{o Yoa - No Yo. - l{o Y.! - llo Yoa - No noaa Dra th, lc.rb. Suruln Rorh l6d 2 Ssrulo I +{ 2+t 3 ol Orcth, lca"b. Untnm - 6 .cha - 5yru - )5 yrr rjo - )6 .th. r3o @:: h..d ud nck a[l thorar .OC. q.l palv. loiE 5ro1n 22 23 2,1 25 26 27 6pIm oGhar lrlrrrra l-'l ze l--l zs 30 3l rt. t5 16 32 33 3arT'n .1. 3? 36 39 {o tt 12 {3 aa Er. atlo bloprv: E.!!:..34Ee!: !ts!.!s: YGs Egg: ?9 tr to tr No +h.-i^U.l6^dlalu..l^llo.ordt,,th.|trttr.hI Tn,a for. rhtch tr.i bta dcvaloF'd lot u" tn 'n onehocorcl'ltr dutvoy rpo I.dtcal iet.:aaeh Counall lt alvoo onlr aa tn rr"pl'' ll li not ln lhs P'oc"\r of b'r'18 r'vlt(d' o I 2 3 a s 6 7 e o t 2 I t t6 { _9_ 5 n I _2- 3 a 7 l_ _9_ _9_ -3- _!-i- ;; 3 6 o I o 2 I 3 2 a 3 s a o 5I 7 2 t 7 3 t a s a I o 2 ,3 fa o 3 I I 9 T; 6 2 7 3 a os I 2o 3 2 -!3 6 3I 2 7 I ! 5 6 q a 7 s -q7 t I Cornea paBe 18 Annex I I. Praktrca camera - Frame (frlm rdentlflcatlon): 2. Drawlngs l)up t I h'un(lus 3. Kowa camera (fundus photograplry) t'rame (f rlm rdenttf rcatron) wao/oxcao/tz.sr page 19 Annex I Rev. I I = male 2 = female 11-12 Place of survey or vllIage of survey (each village being allocated a number Ol, 02, etc.) 13 Area CoI s. I -4 5 6-7 8-9 10 l4-r5 t6-17 t8-19 20 2L CODINC INSTRUCTIOT.IS Serial number Card number Month of survey Year of survey Sex I = rain forest 2 = SaVAnna 3 = borderline, between savanna and raln forest Tribe, each major tribe being allocated a number: Ol, 02, erc. Age 1n years Years spent at place of survey or withln 2 miles of it Occupation Treatment O= t 2 3 4 5 6 7 I I never dlethylcarbamazlne or suranln any anount of dlethylcarbamazlne wlthin the past 6 months 2 or nore suranin lnjectlons wlthln the past 5 years land2 2 or more suranln inJectlons more than 5 years ago land4 2 and. 4 3and4 any anount of diethylcarba^mazine mor€ than 6 months ago unknown 22-26 Nunber of nodules 9 = 9 or more nodules no vislble swellings vislble lngrinal swelllng, excluding hernla, of any size and number - uni- or bilateral vlslble femoral swelllng, gxcludlng hernia, of any size and number - unl- or bilateral Iand2 hydrocele of any degree, uni- or bllateral Iand4 2and4 3and4 not exanlned 27 Groin O= l= ,- a- 4= 5= 6= 9= wHo/oncHo/?2.9r Rev.l page 20 Annex 1 Col s. 28 Spleen O= I= ,- normal or .negative'. spleen not palpable even on deep inspiration spleen patpable only on deep or at least more than normal inspiration spleen palpable on normal breathing but not proiected below a horizontal line tf2-way between the costal margin and the umbilicus, measured along a line dropped vertically from the left nipple spleen with lowest palpable point proiected more than tf2-wa-v between the costal margin and the umbilicus, but not beyond the Ilne drawn horizontally through it spleen with lowest palpable point betow the umbilical level but not proiected more than tf2-way towards a horizontal Iine through the symphysis pubis spleen with lowest palpable point betow the lower limit of class 4 not examined o- 4= o- 2,J Other filariae Q = Do other filariae streptocerca present (diurnal blood mf absent) = loa-1oa present =land2 = perstans present =Iand4 -2and4 =3and4 = g!1g.1!ry present (capillary blood not examined) = not known or not examined Weight of shoulder bropsy in mg to one decimal point Number of volvulus microfilariae geen 1n shoulder biospy Welght of buttock biospy in mg to one decimal point Number of volvulus microfilariae seen in buttock bi'ospy Skin pigment changes no shin depigmerrtation of either leg unilateral shin depigmentation of any degree bilateral shin depigmentation of less then^3 cmz on either side bilateral shi.n depigmentation of from 3 cm2 to half the shin bilateral shin depigmentation of more than half the shin shin depi6;mentation with depigmentation of any other area macular dyspigmentation without depigmentation macular dyspigmentation combined with l, 2, or 3 macular dyspigrnentation combined with tI, or 5 I 2 3 4 5 6 7 8 I 30- 3r 32-34 35- 36 37- 3!) 40 4I Skin atroPhY o= l- 2= n_ 4= 5= 6= n- 8= Q= l= 2= 3= 4= 5= 6= 7= 8= absent acute papular onchodermatitrs of any extent pachydermia of buttocks and thighs land2 2 and elsewhere slight presbvdermia of buttocks and thighs severe presbydermia of buttocks and thighs 6 and elsewhere skin reaction to diethylcarbamazine wno/oNcuo/t2.er Rev.r page 2l Annex I Col s. 42 Lymphoedema O - absent I = lymphoedema of the extremities, of any degree or extent 2 = p€4u d'orange of the trunk, of any degree or extent 3=land2 4 = lynphoedema of the scrotum or vulva 5rIand4 6=2and4 7=3and4 43 Groln 44 45-46 47-48 O = ho skin changes I = skin atrophy present 2 = skin folds less than I cm 3 = hanging groin more than I cm 4 = hernia, or hernia scar, unilateral or bilateral 5=land4 6=2and4 7=3and4 9 = not examlned Leprosy O = absent I = tuberculoid 2 = lepromatous 3 = borderline 4 = ? leprosy, includlng cases without signs but with a history of leprosy treatment Visual acuity, right and left eye o=6f6 r = 6fL2 2 = 6f24 3 = 6f6O or counting fingers at 6 m 4 = counting fingers at 3 m 5 = counting fingers at I m 6 = hand movements 7 = perception of light 8 = no perception of light 9 = unrecordable due to age or mental inability Conjunctiva, rlght and lelt eye O r normal I = hyperaemia of any degree 2 = pinguecula (no corneal involvement) 3 - any heaping up or irregularity of nasal or temporal limbal tissue with or without encroachment on to the cornea up to I rnm 4 = pterygium (corneal encroachnent to be more than I mn) 5=land2 6rland3 7=land4 9 = eye so shrunken that conJunctival condition of no importance wno^NcHo/?2.el Rev.r page 22 Annex I CoIs. 49-50 Microfilariae in the anterior chamber, right and left eye O = absent I = I nicrofilaria present 2 = 2 to 5 microfilariae present 3=6to20mf 4=2lto50mf 5-50+mf 9 = not visible due to corneal opacities 51-52 'Cornea', right and left eye O= l- 2- 3= 4= 5= 6= l= a- (t- normal (i.e. the other conditions in this column are absent) mild trachoma (vessels not encroaching qore than 2 run) severe trachoma (vessels encroaching more than 2 mm) any dense corneal opacity of 3 or more rnm diameter corneal epithelial oedema Ior2and3 lor2and4 3and4 lor2and3and4 cornea unrecognizable due to phthisis bulbi 53-54 Corneal opacities, right and left eye absent (conditions in cols. 51-52 may still be present) opacities within 2 mm of the limbus opacities outside the Iimbal zone, or limbal + outside a clear cornea with five or less mf without reaction limbal opacities + five or less mf (mf without reaction may here be scattered, but those with reaction must be limbal) 2 and five or less mf in the cornea a clear cornea with six or more mf without reaction as for 4 above, but with six or more mf in the cornea 2 and six or more mf in the cornea not visible due to causes such as phthlsis, corneal oedema, total leucoma, etc. O= l= ,- 2- '1 = 5= 6= 7= 8= 9= 55-56 Type of corneal opacitles, right and left eye O = absent (only when cols. 53-54 equals O, 3, or 6) I = I white non homogeneous opacity at the level of Bowman,s zone, the diameter lf4 - Sf+ mn 2 = any round opacity of less than 2 mm diameter with a cLear edge 3 = opacities not covered in I or 2, e.E. reactions round mf, small opaci ties the edges unclear, and 2 and 3 and 3 and 2 and 3 = as cols. 53-54 N.B.: corneal scars and nebulae are not coded, but are recorded separately round stromal 4 5 6 7 !) =1 =l -o =l CoI s. 57-58 Scleroslng keratltls, rlght and left eye O = absontI = nasal encroachDent 2 = temporal encroachnent 3 - lnferlor encroachnent 4 5 6 ? = confluent, pupll free 8 = part or whole of the puptl covered 9 = as cols. 53-54 59-60 Rrpll, right and left eye y.rlo/o$cPloh2.et Rev.l page 23 Annex I nith or without keratie no K.P. andfor old K.P. =I =1 =2 and {rnd and 2 3 3 O= I= ,- e- 4= 6= l= o- nornal pupll diameter more than 5 m, poorly reactlng a snalt pupll bound down by posterlor synechiae pear shaped defornation sllght defornatlon in any dlrectlon posterlor synechlae 3andS 4and5 as cols. 49-50 61-62 lrls, right and left eye O = rlOrmAII = disappearance of puplllary ruff of any degree 2 = complete absence of crypts 3 = visibility of whlte lris strona of any degree, excluding visibility at the bottom of crypts 4=land2 5=1and3 6--2and3 ?=land2and3 9 = as cols. 49-50 63-64 lritls, rlght and left eye O = absentI = scattered cells only 2 = acute irltis slth lniection, flare, and cells'preclpltates (K.P. ) 3 = a quiet looklng eye' but wlth flare and cells' 4 = 8s 3, but wlth K.P. 5 = pigrent on posterlor corneal surface6 r lrregrlar pignent on the ahterlor lens capsule, 7-Aands 8-5and6 9 = 8s cols. 49-50 Lens - Vitreous' rlght and left eYe O = clear lensI = early cataract, fundus detalls Eost1y vislble 2 = advanced cataract, tundus details largely obscured 3 = nature cataract, no fundus vleg{ = ah Df between the lens and the vltreous (c1ear'lens) 5 = Btr mf in the vltreous (clear tens) 6 = as 4, but slth early cataract 65-66 wHo/oNCHo/12.sL Rev. I page 24 Annex I Col s. 65-66 Lens - Vitreous (contd. ) ?=4and5 8 = 6 and mf in the vitreous I -- as cols. 49-50 67-68 Optic disc, right and left eye O = nOrm&l I = ? early optic atrophy 2 = primary optic atrophy J = post-neuritic optic atrophy 4 = features of 2 and 3 combined 5 = pink disc 6 - papillitis 7 = physiological cupping 8 = pathological cuppinB I = not visible due to opaque media 'Ridley' fundus, right and left eye O = absent I = irregular granularity of retinal pigment (stippling) 2=?I 3 = a clearly circumscribed area of retinal degeneration, with irregular pig-ment distribution and choroidal sclerosis 4 = ? early stages of 3 !) = as cols. 67-68 7t-72 Vesse1s, right and left fundus O = normal I = any obvious fibrous reaction around an artery 2 - any obvious fibrous reaction around a vein 3 - pathological narrowing of arteries 4-land2 5=Iand3 6=2and3 7=Iand2and3 g = as cols. 67-68 73-74 rTigroid' fundus, right and Left eye 69-70 Q= l= o- a_ 4= 5= (t- absent mild peripheral, i present below mild diffuse, i.e. marked periPheral marked diffuse gross central as cols. 67-68 e. not seen when viewing the immediate disc surrounds' but seen when viewing the immediate disc surrounds 75-76 Colloid bodies, right and left eye O = absent I = 4 group of discrete yellowlsh-white spots with clear margins, temporal to the macu I a 2 - similar spots scattered in the temporal fundus 3 = similar spots elsewhere in the fundus 4=Iand2 5=1and3 6-2and3 wHo/or.rcHo/7 2.sL Rev. I page 25 Annex I CoI s. 7 5-76 77 -78 Colloid bodies, right and left eye (contd.) 7=Iand2and3 9 = 8s cols. 67-68 Choroiditis, right and left fundus O = absentI = isolated pigment mass, the surroundings belng normal 2 = one patch of choroiditls3 = more than one patch of choroiditis 4 = several irregularly placed pigment masses 5=2and4 6=3and4 9 = 8s cols, 67-68 7-q Hour of skin biopsy O = skin biopsy taken between O7-OB I = skin biopsy taken between O8-O9 2 = skin biopsy taken between O9-lO 3 = skin biopsy taken between lO-11 4 = skin biopsy taken between 11-12 5 = skin biopsy taken between 12-13 6 = skin biopsy taken between 13-14 7 = skin biopsy taken between 14-15 8 = skln blopsy taken between t5-17 9 = hour of biopsy unknosn 80 Number of microfilariae seen rn the hrs. hrs. hrs. hrs. hrs. hrs. hrs. hrs. hrs. R cornea O= l= ,- 3= 4= 5- 6= ?= o- none lmf 2-5 mf 6-20 mf 21-5O mf 5l - IOO mf 1O1-5OO ml 5OO + mf as cols. 53-54 w{ofoNc{of72.el Rev.1 page 26 ANNEX 2 EVALUATION OF DRUGS IN HT.III,IAN ONCHOCERCIASIS DESIGN OF DRUG TRIALS 1. GENERAL The methodology of drug evaluation in onchocerciasis is complicated in that available drugs are differentially effective against larval and adult forms of the parasite. In addition, re-exposure to infection in endemic areas may be constant. Standardized methodology woutd minimize variation in the reported results of drug efficacy. These variations may be due to: (a) Variation in criteria of diagnosis (clinical diagnosis only, parasitological diagnosis only, combined clinico-immunological diagnosis, immunological diagnosis only, etc. ) . (b) Variatlon in methods and times of assessment of patients, both lndividually and in groups. (c) Variation ln criteria of cure andfor lmprovement. (d) Variation of strain response to the same drug. Given such problems there are two fruitful methods of approach: (1) Agreement on techniques, methodology, criteria and times of assessment. statistical methods of(2) Reduction of data to permit the application of efficient analysis. The reports of trlals conducted by standardized methods can then be compared with increased validity and speciflcity. Furthermore the questton whether or not a varying strain responso to the same drug occurs can be resolved and perhaps quantified. Neither eosinophilia nor the use of immunological tests are specific enough to aid the assessment of drugs used in onchocerciasis. The only two remaining objective measurements of use are the number of skin microfilariae (mf) at agreed sites and the body weight.(Within a given geographical area, other variables such as race, socio-economic class, physical activity, species and strain of infection, risk of exposure, and re-exposure after treatment, can reasonably be considered similar, providing of course a vector control campaign ls not being undertaken in the area during the perlod of drug trials.) 2. TRIALS IN MAN For the evaluation of drugs in onchocerciasis two separate stages are envisaged: (1) Initial studies in man. (2) A formal trial or multiple trials. In most cases field trials are envisaged and there is no reason why they should not conform to the principles generally accepted for the formal therapeutic trial. wHo/oNcHo/?2.sL Rev. l page 2? Annex 2 2.1 Inltial studies in man These trials are concerned with the confirmatlon of a suspected parasiticidal effect, studies of the absorption, distribution, metabolism and excretion of the drug, and above arr, with the safety of the drug. studles should be conducted on smarl numbers of adult patients,in hospltal, under as strict supervision as is possible under local conditions. There is noplace for control studies or the use of control drugs at this stage. If the effect of the drug is promising and undue toxicity has not been encountered, thenthese prelininary studies are extended to larger groups of patients, under strlct supervision. 2.I.L Essential conditions before star inltial studies There must be justification for a new drug as in onchocerciasis where the available drugs are either limited in efficacy to one stage of the parasite life-cycle, or toxicity precludestheir use ln Eass treatment. There must be dlscussion between the origlnators of the drug and the physiclan performingthe triars. The physician must satisfy himself that the pre-clinical experiments and the animal data are adequate in scope. Detailed methodology of pre-clinlcal work and the resurtsof studies in healthy volunteers or patient-volunteers must be made avallable to him. Thiswill be difficult in onchocerciasis drug trials due to the lack of a suitable antmal moder forscreening. The prlnclples for the acceptance of any new drug for triars must however be adhered to as far as possible, to the extent of requesting further experlmentation shourd this appear necessary after revlery and discussion of the pre-clinical work. 2.1.2 Choice of subjects for lnitlal s tudies P.referably thesa should be young adult males wlth a high count of skin mf (at 1east25 nf./ng) who are accessible and cooperative. They shourd have some parpabre nodules whlch can be exclsed after treatment to assess the effect of the drug on adult worms. Chlldren,females of child-bearing age, and older peopre are best avoided at thls stage. The number of subjects will be small, five to lO. 2.1.3 Dosase of d rug The dose to be used may pose problems. There is no scientiflc method for predlcting a correct dose level for man, and often a particular dose is suggested by the originators ofthe drug on evldence derived from animar experiments. rf avairable, the resurts of studles of different dosas given to volunteersareof vital importance. Whatever dose ls decided rrpon,and this declsion should preferably be one by an informed group rather than one by an individualphysician, the physiologlcal implications to man must be appreclated. Background informatlon on this aspect may be avallable from studies on drugs similar in bompositlon or action to the new drug. At this stage interaction with other compounds, including alcohol, food, anti-pyretics and analgesics should be consldered. 2.1.4 Choice of measuremen t of variables Durlng the initial studies the choice of variables to be measured will give rlse todifficultles. rt wlll be possible only to measure whatever is compatibte with the efficiencyof a rural parasitology laboratory. The clinical measurements of temperature, resplratton, urine and bowel functlon, dallypulse and blood pressure readings will be made. Futl pre-treatment and post-treatmentphysical examlnation, plus supplementary ones 1f indicated and general parasitorogicar surveys wlHofoNclofT2.sL Rev. 1 page 28 Annex 2 (stools, urines, blood films) are mandatory. Chest X-ray and urinalysis are part of a normal physical examination as they may reveal unsuspected conditions which may exclude the patient from the trial. Daily.olectrocardiograms are considered normal practice in the investigation of new drugs in other parasitic infections. If no abnormalities occur durlng the treatment of the flrst dozen cases then the examination is restricted to a tracing before and after treatment in the next two dozen cases. tf there is still no overt abnormality then the examination can be omitted. The purpose of the examination is to uncover any changes which may make an investigator wary of proceeding to wider groups of subjects. In addition, the appearance of abnormalities may lead to further animal experimentation, directed specifically towards the cardiovascular system. tn short, the examination is a function of safety rather than an investigation which will produce significant findings. 2.1.5 Pharmocodynamics armacokinetics Biochemical monitorlng during initial studies on drugs may be considered in three groups: (a) Monitoring of the effects of the new drug. (b) Monitoring of the effect on other organ/system function known to occur wlth drugs similar in composition to the new drug, e.g. estimation of cholinesterase inhibition during the use of different organo-phosphorus compounds. (c) Routine monitoring of organ or system dysfunction. (a) The pharmacokinetic studies associated with the use of a new drug will depend on the state of general knowledge in that particular field. [n antlparasitic chemotherapy such knowledge is rarely extensive. Radiochemical studies are excluded under African field conditlons, and accurate and specific methods of estimating levels of parasiticidal drugs (and/or metabolites) are often lacking. Furthermore, chemical methods requiring expensive or complex reagents (possibly needing special storage conditlons or critical modes of preparation) or the use of spectrophotometers (perhaps operating in the infra- red or ultra-violet spectra and dependent on a static voltage) or the employment of a complicated physicochemical technique, are also impracticable in the field. Pharmacokinetic information will rely heavily on the data available from the pre- clinical experiments of the originators of the drug. Herein lies the importance of volunteer studies performed in a centre where the appropriate methods and means of investigation are used. In the absence of a reasonably sinple m€thod of estimating the amount of drug (or metabolite) present in biological flulds, the best that can be attempted is the regular withdrawal of blood and the collection of 24 hour urine or stool speclmens (ttris is possible even in field hospital practice). They should be transferred to a centre for the estimations. At this point 1t should be stressed that the use of a new compound should not be contemplated unless the following infornatlon is made available by the manufacturers: the formula of the compound (where known), its chemical and physical properties, methods of estimatlon of the drug or metabollte(s) in biological fluids (if such exist), relationship to other compounds in therapeutic use, pharmacodynamics and pharmacokinetics in normal and infected animals, acute, subacute and chronic toxicity data ln three species including the experinental model and if possible primates. wHo/oN}toh2.sr Rev. I page 29 Annex 2 (b) During initial trials, any change in, for example, enzyme levels as a by-product of the new drug's parasiticidal action, or as a result of metabolic change, should be followed. It may or may not be necessary to continue this monitorlng as trial groups enlarge. (c) Routine nonitoring of organ/system function during initiat studies should probably, in the tropics, be kept as simple as posslble for two reasons. There may be doubts of the efficiency of the methods used in African field hospital laboratories, and more information is needed on the effectiveness of routine monitorlng of hepatic, renal andperipheral blood functton as early indications of organ damage. The accepted range of liver function tests are probably within the capabllities of a 2OO-bedded hospital laboratory. It is preferable to keep routine biochemical monitoring as slmple as possible and perform the tests in a parasitology laboratory where strict control over methodology can be exercised, €.8. SGOI and SGpI for livei function(kits are available commercially for simple estimations); regular haemoglobin estimations, WBC and differential counts; blood ureas. Additional tests are added when indlcated if within the laboratory facilities. The above routlne for initial studies may appear formidable but in practice there are few itens which cannot be attempted in any well-equipped field parasitology laboratory,given technical personnel. 2.2 Extenslon of initial studies to wlder groups Many new drugs, after initial studies in man, will be referred back to the manufacturers for further experimentatlon, or even rejected because of toxic side effects. Those showingpromise, i.e. parastticidal effect combined with reasonable tolerance, will be extended tolarger groups of subjects. The conduct of trials at thls stage will remain largely that of the initial studies. The treatment of further two to four dozen patients is envisaged. They should be In groups of, say, six' treated in hospital under close supervision. If this is imposslble then out-patients in small groups may be treated, provided they can visit the laboratory daily, or be visited, during and immediately after the administration of the new drug. Information m.11g. be available from the primary studles which suggests a need for the nonitorlng of pariicular function(s). These witt then recelve extended observation andinvestigation during this period of wider application. opportunities should not be lostto collect sera/urine/stoots for drug or metabolic estlmations. The selection of patients at this stage can be profitably broadened, i.o. those withheavy, meditrm and light infections, particutar note being taken of any subjective or objectivetoxic effects and their relation to the degree of infection; or to the presence of murtiprelnfections, etc. A cautious extension of dosage range may be attempted. If the doseinitially used was effectlve, then smaller total doses or smaller daity doses may beadministered until it becomes obvious that no response has occurred. If the dose inltialry used was only partially effective yet relatively non-toxlc, then the effects of cautiousincrements cf the total dose or the daily dose may be tried. The purpose is to acquire dataon the therapeutic dose-response curve. The appearance of undue toxic effects will indicatecessation of treatment, and in these earry stages any unexpected symptom or sign should beregarded as due to the new drug, until otherwise proven. wHo/oNCHo/12.sr Rev. l page 30 Annex 2 It is necessary to ensure that patlents in hospital during these early trials receive only the drug under test and prescribing other than by the investigating physician must be forbidden. This fact complicates the use of out-patients for extended studies as such patients have opportunities for the consumption of other drugs, or may have a variety of other substances given to them by witch doctors or other unqualified practitloners. It may be possible, at this stage, to acquire information on the natural variation of skin microfilarial content. For example, patients diagnosed on primary survey who failed to attend for treatment, can be contacted aBain in six to L2 weeks and offered treatment. If they agree, then exactly the same diagnostic procedure (skin snip, weigh, count) is repeated.(Snips should be at a site in close proximity to the originals.) This gives a series of paired observations and the precision of comparison is increased by the fact that the samples are related. Instead of expressingoneexamination data as a percentage of the other, a more refined method is to consider only the differences between the two measurements, some of which will be positive and some negative. The variation between patients is thus eliminated and the distribution of differences only considered. If the distribution of the differences between the two observations is normal, or if a transformation to a normal distribution can be used, then the t test can be applied in order to detect a significant difference between the mean of the population of differences and a population with zero mean. Alternatively the variances of each set of data could be compared by an F test, would be applied to the raw colurnn figures, to geometric means of multiple counts or figures arising from an appropriate transformation. which to the When the distributions of counts are abnormal and when they cannot be transformed into a normal distribution, a distribution-free method can be used for comparison of such paired data, e.B. a non-parametric two way analysis of variance (Friedmann, 193?, 1940).1 This is essentiatly the comparison of sums of ranks and the statistic computed follows the chi- squared distribution under certain conditions. Details can be found in Siegel (f956).2 A variety of non-parametric tests for related samples are available. The collection and anatysis of "within-patient" data at this stage not only helps to define natural variabitity in parasitic larval output but may assist in the more efficient design of later field trials. 2.3 The formal trial (field trial) The purpose of this stage of drug evaluation is (a) To confirm the validity of the original studies in respect of ttrerapeutic efficacy. (b) To examine the problems raised by the use of the drug in a population representative of that which will be treated in ordinary clinical practice, or during mass treatment campaigns. (c) To detect further toxic manifestations. The reactions of the snall sample of patients studied to date cannot be accepted as representative of those of the population as a whole. ( 1937 ) J. Amer. Statist. Ass. 9, als.(1940) Ann. Math. Statist , 11, 86. 2 Siegel , S. (1956) Nonparametric statistic t Friedmann, M Friedmann, M Book Company Inc., New York, Torontor London. s for the behavioural sciences, Mccraw-Hi11 wuofoncnofzz.sr Rev. I page 31 Annex 2 (d) To make as specific, and as precise comparisons as possible betweon the new and reference drugs, treated and untreated patients, etc. This raises peculiar problems, statistical and otherf,,ise, and the question of controls will be deferred to a later section (see 2.3.4). In trials at this stage, which will be conducted under field conditions, the extent of direct supervision of patients silI diminish considerably. Providing the trials are designed and analysed in accordance with efficient and acceptable statistical principles, the conclusions andfor the comparisons wilt be specific and precise for the drug, the parasite and the area concerned. As a first step thequestions to b€ answered by means of the trial must be considered. These questions should be few, and as precise as possible. Numerous questlons may only lead to i.nconclusive answers. There is a great deal of merit, in antiparasltic chemotherapy trials, in limiting such questions to: (a) Is this drug effective curatively/suppressively in reducing a larva1 transmission reservoir? (b) [f so, how effective is it? (quantification of response) (c) Is it acceptable or not to a population representative of the general population at risk? (toxicity) (d) If a new drug can be glven by the same route as a reference drug, over the same time period (dose adjustment may be necessary here), the further question, "how effective, and toxic, is it in comparison wtth standard drug X?", can be posed. (see section 2.3.5 for elaboration) It is wise, before a trial beglns, to prepare a written statement, enurerating: (1) The questton(s) asked. <2) The treatment used - fixed or varlable dose. (3) The measurements required. (4) The details of methodology. 2.3.1 Selectlon of patients The results of inltlal trlals, performed on selected patients with high parasite loads, under close clinical supervision may not be representative of the results obtained when the drug is introduced to the general populatlon at risk. This applies to both therapeutlc efficacy and toxicity. It is wise to restrict the first field trial to groups of patlents who will not provide undue anxiety for the investigator, i.e. males aged 15 to 50 years.(As antiparasitic drugs, once marketed, nay be used for mass or semi-mass treatnent, often administered by partlally skilled personnel under sub-optimal conditions, it is necessary to assess their advantages and disadvantages in field trials at a relatively early stage of their evaluation. ) 2.3.2 Cholce of variables to be measured For obvious reasons these should be kept as simple as possiblo, €.8. repeated Larval/egg counts in blood films, skin snips, stool, urine, etc., body weiBht, and the recording of the presence or absence of side effects (without direct questioning). !{ilHofoNclof72.9l Rev. l page 32 Annex 2 2.3.3 Construction of s of patients This will be necessary to compare different doses of a drug, new drug versus reference drug and drug versus placebo, etc. An essential step is to utilize a random method of allocation, commonly by the use of a table of random numbers. If relevant background infor- mation is avaitable on the trials population, the population can be stratified (sub-divided) into more homogenous sub-groups. From each sub-group a random sample is withdrawn for allocation to treatment, then reassembled into their original groups, all being treated simultaneously. After follow-up and during the evaluation of results, the individuals of the treatment groups can be reallocated back to their appropriate strata and examination of cure rates in relation to pre-treatment microfilarial count (and hence parasite load), performed by the appropriate statistical technique. The importance of randomization in clinical trials cannot be over-emphasized. essential: It is (i) To provide the scientific justification for the application of significance tests. (ii) To ensure the presence of strictly comparable groups for different treatments or doses in respect to all variables other than the treatments used. (iii) To avoid both the conscious and unconscious bias which inevitably occurs when a method of assigning treatments is used which is dependent on a physician's choice. There is no justification for applying tests of significance or probability to non- randomized data, a practice only too common. It is always wise to compare two (or more) the proportions of variables contained in each, No. in each group male female age above 15 years age below 15 years length of history (5 years length of hlstory )5 years randomized pre-treatment groups in respect of e. g. ym yf Ya yb xI Xs y1 Ye vx xm xf xa xb This form can be extended to numerous variables. During the course of multiple trials there may be occasions when ono group is significantly loaded in respect of one or more variables. The purpose of comparing recipient groups is to detect these occurrences and acquire information on the presence of different variables which might influence the results of treatment, e.g. subsequent analysis of trials results may reveal that, at a certain dose level children (or adults) gave significantly greater cure rates than the alternative group(the explanation may of course be in factors other than age). The essential point is the reduction of data in sub-groups, followed by appropriate classification, to give leads as to why a certain drug, or dose, was associated with a higher (or lower) cure rate, reduction of larval count, etc. iw$ofcIr,Ic\ofT2. 91 Rev. 1 page 33 Annex 2 2.3.4 Controls In drug evaluation in temperate climates this subject causes more controversy than any other aspect of clinical trials. In antiparasitic chemotherapy the question of controls is Iess controversial. Two main factors are responsible: (a) In many parasitic diseases there is a retrospective fund of knowledge on the natural history of the parasite in man. Information on the variation of level, over a perlod of time, of parasite larvae, or products within the body is commonly available. Thus comparisons between these untreated variations and the variations induced by experimental interference are possible. (b) In the assessment of the effect of drugs on parasites, objective methods of measurement and enumeration are usually used. These factors, combined with an investigator's knowledge that reduction of larvae after treatment will be of a gross degree (exceeding all natural variation), if caused by an exhibited drug, render the question of controls of less importance than, for example, the subjective assessment of changes in symptomatology induced by drugs. Controls may be concurrent or retrospectivei they may be between patients or within patients, and they may be via a standard treatment or by placebo. No detailed discusslon will be attempted here as the problems vary with different parasitic diseases. Many parasite larva1 outputs, €.8. egg excretion, microfilarial deposition, are subject to a wide range of natural variation. Where such outputs do not spontaneously cease in the absence of treatment, then, even without controls, continued absence of eggs or microfllariae in replicated post-treatment material can reasonably be attributed to the treatment. If circumstances are such that concurrent controls can either be non-treated, or given a placebo (by the same route of administration and at the same time as the test drug), then this is alI the more satisfactory for precise evaluation of drug effect. Occasionally within-patient control studies are used to estimate variation of parasite load in the absence of treatment, e.g. the comparison of paired observati.ons at different time intervals for similarlty or dissimilarity. If, after treatment, the same measurements are made (at the same time interval) then the degree of reduction of parasite load can be quantifled with confidence. 2.3.5 Blind trials Since measurements are objective and since random allocation to treatment schedulesprotect agalnst bias, bllnd trials are of lesser importance in antiparasitic chemotherapy than in diseases where measurement of drug effect is targely subjective. It should be noted that some "obJective" measurements may not produce objective findings, and the orrors, confidence limits and limitations (human and technical) of any "objective" method of measurement should be appreciated by investigators. Double blind trials may be attempted when physical formulations of drugs are identical. Usually, however, a lack of experienced personnel will renrler this desirable goal unattainable. But the paucity of preparations available ln many parasitic conditlons will frequently make a double blind approach impracticable. A drug adminlstered intravenously obviously cannot be compared with one given by mouth, on a double btind basis, unless four groups of recipients are formed, two to receive the drugs being tested, and the other two to receive a placebo administered by the intravenous and oral route respectively. In thls situation many would wHo/oNcHof 2. el Rev. I page 34 Annex 2 argue that it is ethlcally unjustifiable to give an lntravenous placebo, yet, if there is genuine doubt of efficacy, this may be the quickest method of arriving at a decision. Usually, for statistical validity, like must be conpared with Iike. When different physical formulations are encountered and a comparison is needed, then the proportions of cures or failures, and the proportions of those with or without side effects in randomized comparable groups can be elucidated. Even so, the ultimate crlterion of comparison, i.e. the relative ratio of benefit and safety, can be extremely dlfficult to assess. Extra- polation of such data should recall the truism that a route of administration of a drug to a partlcular community may neither be desirable nor acceptable to other communities. Many trials of drugs in tropical climates are I'single-blind" in that the subject is unaware of the specific nature of a treatment although this is known to the investigator. To summarize, concurrent controls are essential in diseases of short duration, or in environments subject to rapid change, e.g. vector control measures taken during a trial period. In many other instances retrospective control, or within-patient concurrent control can be substituted. In antiparasitic trials there is hardly ever a place for "cross-over designs" unless the duration of the trial is measured in terms of years. 2.3.6 Withdrawals from treatment groups This is almost inevitable during field trials, either due to non-attendance, incomplete attendance or the occurrence of side effects. In the analysis of results non-attenders can be omitted providing there is a valid reason for non-attendance which is unconnected urith the trial. A record of these patients should be included in the report. Incomplete attenders can be categorized and their results treated separately - useful information may be gained. Withdrawals through side effects must be included in the analysis of results and if not cured be regarded as drug failures. 2.3.7 Losse s durins follow-uD Losses during follow-up should be tabulated and dealt with by allocation to extreme ends of the distribution under test, e.g. in a contingency table (the customary way of expr€ssing results), one may have the following: Cure Non-cure (i.e. failure) Lost TotaI Treatment A Treatment B xa X6 Ya Yg za Z6 2 XaYaza 2 X6Y5Z5 Total ax EY 2Z EN(TotaI No. cases) o Step I. Remove Z^and 26. Analyse the 4 celI table. wno/oncHo/?2.er Rev. page 35 Annex 2 Cure Fai I ure TotaI Treatment A Treatment B xa X6 Ya Y6 TotaI Step 2. Add Za to X., add ZO to Y6, and reanalyse the new tab1e. Step 3. Add Zb to Xb, add Za to Ya, and reanalyse the new 4 cell table. If an observed difference between treatments remains statistically significant throughout loading, then there is no problem and the difference is a real one, significant at whatever level the data produce. The problem arises when there is a statistically significant difference in inltial analysis which becomes non-signlficant on analysis after one of the loading procedures. In a large trial with an appreciable follow-up loss ln those completing treatment, it may be possible to calculate probabilities of cureffailure in the lost cases by assuming that these probabillties are similar to those in the observed data. Then such probabilttles, expressed as figures, can be added to the observed data and loaded again. But this may be a tenuous proposition, depending on the arrays of results, and may be imprac- ticable in small-scale trials. The answer is to avoid at all costs any degree of loss during follow-up or to adopt another method of analysisr €.8. analysls of a contlnuous varlable where missing observatlons may be theoretically easier to deal with. 2.3.8 Fixed sample, sample size The completion of a therapeutic trial must bear no relationship to the observers' impression of what the results should be or might be. A decision is made in advance that a fixed sample shall be used, i.e. a certaln nurnber of patients or all suitable patients presenting wlthtn a specific period shall be treated. In tropical practlce all suitable patients found during a survey extendlng over a given time or over a glven population are utilized. Analysis of observations made on a fixed sample, or sequential analysis, can be employed. The latter needs expert statistical aid as the confldence limits of the amount of a difference may be wide. It is not possible to tabulate the number of patients to include in a flxed sample trial unless some knowledge of the size of the difference expected between two treatments is available. WHO has issued various tables of sample si.zes appropriate to degrees of rnagnitude of differences in "."pon"".1 Generally statistlcal aid should be sought. I a t Adequacy of sample size, November 1961. Unpublished document MHo/PAf22o.63. :v{:HofoNclofT2.sr Rev. I page 36 Annex 2 2,3.9 Fixed dose or variable dose In antiparasitic drug trials commonly one dose level of a compound is used. This is satisfactory when the dose has been shown to be curative yet non-toxic regardless of individual variation. Furthermore, generalization of fixed dose results is rather more reliable than those from variable dose regimes. Dose regimes varying with the individual will mean complicated trial design and statistical advice is necessary. Of greater value is the comparison of two or more fixed doses in randomized comparable groups. Multicentre trials under a standardized protocol may relieve some of these difficulties. 3. PARASITOLOCICAL CRITERIA FOR ASSESSMET.IT OF DRUG ACTION 3.1 Basic remises 1. The only variable on which to base a criterion of success or failure is the presence or absence of skin mf on replicated snips. If mf positive then a count of mf must be made after weighing the snip and the result expressed as mf per mg of tissue. (Whether or not the tissue should be teased during counting is a matter best left to the experts to argue about and produce a decision. Whichever method is decided upon then it obviously must be retained in its entirety throughout trials.) I 2 3 4 5 The normal life span of the adult female O. volvulus is 10-16 years. The life span of mf is around two years. The pre-patent period of O. volvulus is 1O-2O months.l (a) Where moderate transmission exists, reinfection does not lnfluence analysis of therapeutic results before 24 months (b) Where heavy transmission exists, reinfection may influence analysis of results after I5 months. (c) A follow-up of six to 12 months gives aII information requlred on the filaricidal properties of a drug. 6. The four main types of drug action are (1) Drug kills or sterilizes all adult females and mf. Zero mf counts found immediately after treatment. Reinfection gives iZi mt population in 15-24 months. (2) Drug kills or sterilizes all adult females. No effect on mf. Mf found post- treatment. If mf eliminated then with diethylcarbamazine (DEC), skin remains negative until reinfection produces new mf population in 15-24 months. (3) Drug kills mf. No effect on adult females. Mf negative on post-treatment examination. Mf positive after, say one year, deriving from remaining adults. t ,ha"" is recent evidence that infections in children may show much shorter pre-patent intervals. a ai wlofoNc{of72.el Rev. r page 37 Annex 2 (4) Drug ineffective versus adults and mf. Mf positive at all post-treatm€nt examina- tions, whether or not mf eliminated by DEC after completion of treatment with new drug. 3.2 Timins of parasitological examlnations and drug administration Before treatment the concentration of microfilariae should be measured using either weighed skin snips or a punch technique in at least four skin snips taken from different areas of the body where their concentration is high (e.g. left and right buttocks and left and right calvesl or from the upper parts of the body if the infection is centred there). A11 palpable nodules are recorded on a body chart. The drug under investigation is then given, and its microfilaricidal action is assessed by repeating the skin snip examination a few days after the drug is expected to have been excreted or broken down in the body. If microfilariae are still present at this examination it is advisable to wait for about a month and then give a course of diethylcarbamazine sufficient to kill the microfilariae remaining in the skin (e.g. 2oo mg b.d. for five days). A further skin snip examination is then done, which will be almost, if not quite, negative. Two months later a further skin snip examination is made to see whether microfilarial concen- trations are building up again. Failure of microfilariae to reappear indicates that the drug has elther killed or sterilized the adult female worms, and this may be confirmed by excising nodules at this stage, opening them, and observing the condition of the male and female worms and their state of embryogenesis, etc. If, on the other hand, microfllariae are found again in the skin in considerable numbers, a further course of diethylcarbamazine should be given, and another examlnation should be made two months later. It sometlmes happens that the action of drugs on adult worms is slow, and that live microfilariae continue to emerge from the uteri of moribund worms for a consideiable period after treatment, and then make their way slowly to the skin. Prolonged observation is therefore needed lest a macro- filaricidal action be missed. tt is also possible that a drug may have a temporary action on embryogenesis without killing the adult worms, and that the females can recover their fertility after some months. AII these posslbilities must be borne in mind when conducting trials, and the timing of the skin examinations may have to be modified in the light of the results obtained. The assessment of the effects of drugs on adult O. volvulus cannot be rushed and, in particular, nodules should not be excised too early for a clear assessment of the condltion of their contained worms to be made. Given time it is not difficult to recognlze a drug which is a realIy effective macrofilaricide, for microfilariae will decline to zero and remain at that level, and the patient will develop a negative Mazzotti test. Ideally trials should be done in areas where Simulium control has conslderably reduced or eliminated the risk of reinfection, but this is often impossible and experience has shown that, in view of the long pre-patent period of new infections (15-18 months), adequate informa- tion on the action of new drugs can be obtained even in patients living under conditions of high exposure to reinfection. 4. EFFECTS OF DRUCS ON MICROFII,,ARIAB IN THE EYE AND ON ONCHOCERCAL EYE LESIONS This aspect of treatment, which is a most lmportant one, has received little attention. This may be partly because the areas where heavy microfilarial invasion of the eye occurs are limited in extent and often remote. Obviously it is desirable to know to what extent parasitocidal treatment can prevent or halt the progress of the blinding eye lesions of onchocerciasis. a wHo/oNCHo/12.sL Rev. r page 38 Annex 2 Investigations on these lines require careful assessment of the effects of drugs(particularly microfilaricides) on parasites in the cornea and anterior chamber, which in turn calls for skilled examination with a joy-stick model slit lamp and skilled ophthalmoscopy. The most pressing need is to clarify the effects of treatment, immediate and long-term, beneficial or detrimental, on patients with microfilariae in the cornea and anterior chamber who receive suramin, ana/or diethylcarbamazine (systemic or local). Careful observations are needed on selected patients to determine whether it is the presence of live or dead micro- filariae whlch contribute most to the pathology of ocular onchocerciasis; to assess the reality or otherwise of the potential dangers associated with the use of drugs to kiI1 parasites in the ocular tlssues; to assess the effects.of corticosteroids in reducing adverse reactions; and to decide upon the stage of development of the disease at which treatment should be instituted in order to avoid the development of blinding lesions. These remarks apply particularly to parasites in the anterior segment of the eye, for it ls the sclerosing keratitis of onchocerciasis which is the most dangerous blinding lesion in the disease. However, more informatlon is likewise needed on the natural history and development of the posterior segment lesions associated with onchocerciasis (i.e. optic atrophy and the "Ridley fundus"), for at present it cannot be foretold who will develop such lesions, nor do we know how rapidly they progress. Therapeutic experiments may show whether they can be prevented or halted once they have started. Once again, trials of this nature could be done to best advantage ln areas whore Simulium control has been established. 5. PROPHYLACNIC DRUGS Chemoprophylactics against filarial infections could be of great use in the field, but little effort appears to have been devoted to investigating drugs for such action in laboratory infections. Should any promising candidates be discovered they could be tested for action against O. volvulus in chimpanzees, or perhaps by the use of biopsy techniques in human volunteers. Later, controlled field trials could be undertaken. Although assessment would not be easy, this is a field which has been sadly neglected to date. t o a