/Rd"R Hhz Btq 2- the Purposes of the Meeeing Were

FINAL DRAFT AND LI},IITED CIRCUII.TION

ocP /ocT/TDR JO]NT MEETTNG REPORT OF THE MONITORING SUB-GROUP FOR IVERMECTIN TRIALS IN ONCHOCERCIASIS

1. INTRODUCT]ON

A meeting of the Monitoring Sub-group for Ivermectin trials in Onchocerciasis was held in Room L50 at the World Health Organization, Geneva on Sunday 20 March 1988.

The meeting was chaired by Professor J.F. Williams (Chairman of SC/TDR/FIL) and was attended by the Clinical Trial Monitor, Professor Herbert M. Gilles and the following members:-

Dr A. Bryceson, TDR

Professor M. Fernex*, TDR

Dr G. De So1e, OCP

Dr H. Remme, OCP

Dr B.O.L. Duke (Rapporteur), OCT

Dr B.M. Greene, OCT

Additional coopted members were: -

Dr K. Awadzi, OCT Dr K.R. Brown, Merck, Sharp and Dohne

and Dr A. Abiose (Nigeria) attended as an observer.

Secretariat: -

Dr T. Godal, Director TDR Dr C. Ginger, OCT Dr R. Le Berre, ECV Dr R. Morrow, TDR Dr C.P. Ramachandran, FIL Dr P. Ranque, FIL Dr P. Smith, TDR Dr B. Thylefors, PBL

unable to attend i-n person but submitted written comments.

. /rd"r hhz btQ 2- The purposes of the meeEing were:

(a) to revi-ew progress in the Phase IV community-based trials of ivermectin that are being supported and carried out by TDR/FIL, OCP and OCT and to make recommendations as to their future conduct,

(b) to review the adverse reactions encountered during these large-scale trials of ivermectin and to provide a statement on the safety and therapeutic use of the drug that would be of assistance to the Mectizan Expert Committee, recenEly established by Merck Sharp and Dohme (MSD) in cooperation with the llorld Health Organization (I,rrHO) for the PurPose of deploying ivermec6in for use in human onchocerciasis by responding to Sovernment-approved requests for supplies of the drug stemming from countries affected by onchocerci.asis.

Opening the meeting, Dr Tore Godal, Director of the UNDP/World Bank/l{HO Special Programme for Research and Training in Tropical Diseases, welcomed the participants and recalled the multiple objectives of the Phase IV community-based trials that had been or were being carried out by TDR and OCP. Not all objectives were being addressed in each tsrial but the major ones lrere as follows:-

1. To assess any short- or long-term adverse effects which may have an incidence lower than that detectable in previous Phase III trials, or are only demonstrated in specific patient groups.

2. To determine the acceptability of the drug when used to treaE Large numbers of infected individuals.

3. To document the effects on disease morbidiEy, particularly with respecE Eo changes in the skin and eye, produced by drug treatment.

4. To determine the effect of wide-scale ivermectin treatment on disease transmission, using entomological parameters for more rapid generation of data, and incidence of new infections in young children as a longer-term index of reduced transmission. -3 5. To evaluate the theory that repeated ivermectin treatments may have macrofilaricidal activity.

The Director then pointed out that over the past year the total number of onchocerciasis patients treated with ivermectin had risen to over 50.000, chiefly as a result of the large numbers treated in the recent OCP trials. In this large series there had been no fatality that could reasonably be attributed to ivermectin and statistically this made it highly unlikely that the trials had failed to detect any rare fatal complication that might occur at a frequency of 1 in 10.000 persons treated.

He felt that WHO and MSD should now be teady to recommend ivermectin as being safe and effective for the large-scale suppressive treaLment of onchocerciasis provided that certain guidelines were adhered to and that the type of medical supervision required in such eampaigns could be clearly defined.

He emphasized that a training exercise of considerable value, which rnight be supported in part by TDR, would be to arrange for meetings between workers who had been involved in large-scale phase rV community-based trials and those who were proposing to undertake large-scale ivermectin treatment of onchocerciasis in their own countries.

He urged the Sub-group to take note of the Mectizan Expert Committee recently established by I,ISD, in collaboration with I.rIHO, to ensure that all necessary safety aspects had been considered and could be put into effect either by Ministries of Health or by their appointed representatives who wished to take advantage of the generous offer of MSD to provide ivermectin free of charge for the treatment of populations living in endemic areas with onchocerciasis. The Mecti-zan Expert Committee would, at least initially, be relying very much on the advice given to it by the sub-group on the basis of its experience in the WHO-supported Phase IV trials.

He also pointed out that the US Congress through US AID had earmarked a sum of US$4 million for the deployment of ivermectin in the control of onchocerciasis. 0f this sum, it is 1ike1y thaL US$ one million would go to the OCp for -4- further ivermectin deployment; US$300,000 would go to TDR as further partial support for its Phase IV Community-based Trial Programme; and the remainder (US$ 2.7 million) would probably be available to support the deplo)rment of ivermectin in the remaining large areas of the world which are endemic for onchocerciasis but which are not covered by OCP.

Finally, the Director pointed out that uhe beginning of large-sca1e deployments of ivermectin by no means implied that everything relevant was known abouE the drug, and he emphasized that any unresolved research problems already recognized or arising in the future would be candidates for research support from TDR/FIL.

Following the Director's introductory remarks the Chairman reminded the members of the Sub-group of the recent sad death of Dr l{ohammed AzLz who had done so much to advance iwermectrin from its Phase I clinical trials to the stage of registration for human onchocerciasis in France. The Sub-group then observed one-minute's silence in respect of the memory of the late Dr Aziz.

2. REVIEW OF PHASE ]V COMMUNTTY-BASED TRIALS

2.1 LIBERIA (TDR) data based on reports from Dr Hugh Taylor, presented by Dr B.M. Greene.

This trial was taking place on the Liberian Agricultural Company (LAC) Plantation. The tot.al census population on this rubber plantation, living in a large number of labour camps, amounted to L3,704. Of them 7699 (56.2%) had been treated with -a single dose of ivermectin at L50 mcg/kg.

Those excluded from treatment were grouped as follows: -

Children under 5 years of age 2762 20.27" Skin snip negative children 5-11 years of age>k L399 LO.2% Pregnant women 640 4.7% Absentees s66 4.t7" Refusals 257 L.97" Breast feeding 209 L.57" Patient treated in continuing Phase III trial L28 0.97" S ick 4t+ 0.37" .5-

The main purpose of this study in a high-prevalence, low-intensiuy W. African forest community \^ias to assess adverse reactions. Detection of adverse reactions was achieved by (a) passive surveillance by the treatment teams during the first 4 days after treatment in each camp; (b) surveillance by special monitoring teams, which visited each camp routinely every two weeks, starting the month before treatment and continuing after treatment; these teams recorded reactions, migrations and deaths; and (c) surveillance by rnobile teams from the plantation hospital which visit all camps on a regular basis to give general health service. In addition in 5 camps a 7.7% sampLe of the whole population was specially monitored by the medical team.

The main adverse reactions eneountered in this trial are given in Table I. Of the 15 persons who died on the plantation during the 5 months taken up by treatment, none could be related t,o ivermectin dosage.

Among the subsidiary objectives of this trial was an attempt to assess whether ivermectin treatmenE might induce changes in the eleetrocardiogram recordings of patients in whom there was already some evidence of cardiac disease or irregularity. Of 35 men with mild cardiac abnormality each submitted to 2 baseline ECG examinations followed by another on Day 1 just after treatment and five subsequent examinati-ons. No significant changes were recorded following the ivermectin treatment. O.ther conti-nuing objectives were as follows:-

(a) A study of the changes induced by microfilariae ard suppressive ivermectin treatment in the acute dermatitis lesions characteristic of onchocerciasis. Photographic evidence of improvement in several cases of hyperpigmented lesions was observed. On the other hand one of the rarer late adverse reactions to treatment consi-sted of the appearance of large bullae on the feet.

(b) To assess the numbers of skin snip negative children in the 5-11 age group before the large-scale treatment began and to assess changes in the prevalence and incidence of infection in this age group following the treatment campaign. Indirectly this could give a measure of any change in transmission that has been achieved. -6- TABLE 1

COMPI.AINTS FOLLOWING IVERMECTIN TREATMENT AT THE LAC RUBBER PIANTATION, LIBERIA

Complaints following ivermectin L-2 3 4-7 8-33 treatment days dalzs days days Total

Edema lower limbs t+ 8 (s)* 7 2 2L upper limbs e (s) 13 face : 11 (11) i i 11

Pruritis 5 6 (4) 4 10 25

Body pain 10 1 1 L2

Ocular irritation 3 2 (0) 3 2 10

Arthralgia 2 1 (0) 4 2 9

Painful ly*ph nodes 2 s (s) 1 8

Headache 4 1 5

Dizzi,n.ess 3 (3) 1 3

Fever 2 1 I t+

Nausea 1 1 (0) 1

Weakness 1 (0) 1 2

Diarrhea 1 1

TOTAL NUMBER 25 3e (28) 19 18 101 OF PATIENTS SEEN

* ( ) patients seen by the team at the day 3 follow-up.

Note: Several patients had more than one complaint. 7- (c) The sub-group was also shown a recent letter from Dr Taylor in which he provided good evidence that the Liberian Crial, if continued, would have sufficient analytical power to detect any significant increase i-n adverse outcomes of pregnancy in women who had inadvertently received ivermectin during the first trimester.

After discussing the findings reported from this triar, the sub-group made the following recomrnendations to the TDR/FIL Steering Committee:

Conclusions and Recommendations on the Liberian Phase IV Trial

The sub-group considered that this study, in which 7699 persons out of a total census population of 13 704 were Ereated, had been carried out to a high standard and, provided funds are available, recommended that it should continue for a further two rounds of annual treatment with the following obj ectives:

(a) To assess the incidence of patent infection in children in this area of rain-forest and any change in incidence following large-scale i.vermecEin treatment;

(b) To detect possible adverse outcomes of pregnancy in women inadvertentry reeeiving ivermectin during the first trimester;

(d) To compare the reactions to second and third doses of ivermectin with those obtained on the first round of treatrment; and

(e) To detect any unexpected and infrequent adverse reactsions following repeat challenge with ivermectin, e.g. halothane hepatitis only occurs after repeat challenge.

2.2 CAI'IEROON (TDR) data based on reports from Dr J. Prodhon, presented by Dr B.O.L. Duke

This trial, which is taking place in a series of heavily infected West African savanna villages spread out along the valley of the Vina du Nord in north cameroon, is designed to continue for 3 years. All persons not 8- falling within the present exclusion criteria for ivermectin will receive an initial dose of the drug at 150 mcg/kg followed by regular annual treatment. The trial will be extended along the valley in a series of annual phases. The main objectives are:-

(a) to assess adverse reactions to, and the acceptability of ivermectin; (b) to document the effects of treatment on onchocercal morbidity in the eye and in the skin; (c) to assess the effect of Large-scale treatment in the transmission of O. volvulus by parous S. damnosum s. e. flies.

In the original protocol provision was made to study a group of untreated control subjects living in onchocerciasis-infected villages along the Mayo Rey, over 200 km away and near the town of Tchol1ir6. However, for ethical reasons and at the request of the Cameroonian Ministry of Health it may not prove possible to maintain this group, which had been considered essential if the positive beneficial effects of ivermectin on the development of eye lesions was to be assessed in a reliable manner.

The first Phase of treatment had included the first 5 willages on the road running west from Tonboro in the direction of Ndok. A total of 2253 persons had received treatment in Phase I estimated as representing 80% of the total population (although some doubt was expressed that the 807. might refer to the whole treatable population - this must be ehecked).

A group of 1502 persons had been selected for special clinico parasitological monitoring in the treated villages. 87.7% of these were mf positive and the mean loads of mf per snip were 445 in the positive men and 264 mf/snip in positive women - both high figures by comparison with subjects in other trials. A group of 354 men from the treated villages had also been selecEed to form a group for repeated opthalmological monitoring. 18% of them showed one or more serious lesions of ocular onchocerciasis.

In the untreated control zone villages, which are somewhaE more lightly infected, a clinicoparasitological monitoring group of L373 had been established, of which 5L.3% were mf positive with mean mf loads per snip of 185 (men) and 134 (women) . An ophthalmic monitoring group of 234 men had also been selected, 9.4% of which showed a serious ocular lesion. 9- No fatalities directly attributable to i.vermectin were recorded and adverse side effects, although frequent, were usually mild - itching, joint pains, headache, abdominal pains, oedema, lymph adenopathy, muscle pains, dizziness, papular emphitis and fever were all recorded, mostly during the first 4 days after treatment.

Entomological observations were made to assess the amount of transmission of Q. vo1vulus, by dissecting the S. damnosum s.e. (almost eertainly $. sirbanum and f. damnosum s.s.) caught at 3 stations on the Mayo Vina every day from 1 month before treatment until 2 months after treatment. The fly population at this season was thought not to be subject to long-distance immigration of infective f1ies. Hovrever, no significant change was observed in the numbers of infecEed or i-nfective flies per 100 parous flies before and after treatment, nor in the numbers of developing or infective larvae indistinguishable from those of O. volvulus in the same flies.

It is eoncluded that the first round of treatment of these 5 villages did not reduce the overall microfilarial reservoi.r in the Mayo Vina walley sufficiently to bring about a detectable reduction in transmission.

Conclusions and Recommendations on the Cameroon Phase IV Trial

The Sub-group congratulated the Cameroon team on the progress achieved and made the following recommendations with regard to the future execution of this study: -

(a) The methods of assessing the CMFL and of reporting resulcs should be unified with those used in other similar projects, notably those in OCP. To assist in this task a suitable computer(s) should be provided for data storage.

(b) To ensure the quality of the ophthalmological data, follow-up examinations should be made as far as possible, by the same ophthalmologist(s)'vho made Ehe initial examination. If this is not possible, then adequate quality control checks between observers must be instituted. This is the only Phase IV study in which an 10- ophthalmological assessment of the effects of ivermectin treatment is being made and it must be done well.

(c) If it becomes necessary on ethical grounds, or at the request of the Cameroon Ministry of health, to abolish the untreated control group of patients in the villages around Tchollir6 and to provide them with treatment, then it is essential that a second exami-nation of the ophthalmological cohort in these villages should be made immediately before treatment in order to assess any changes in eye lesions that may have taken place since the initial examination'

(d) A follow-up examination of the already-treated ophthalmological cohort from the villages west of Touboro should be made before these patients are re-treated in June. This is particularly important in order to make certain that the original ivermectin treatmenthasnothadanyadverseeffectontheeyes.

(e) Included in the next report should be:

(i) information on how many patients with adverse reactions received s)rmPEomatic or palliative treatment:

(ii) information on the skin lesions studied and their progression after treatment.

(f) In Phase II of the operation, in order that the study on the effect of large-sca1e ivermectin treatment on the transmission of e. volwulus by S. damnosum shall have the best chance of detecting any change in the infection rate in parous flies it is recommended:

(i) that the first round of treatment i-n the Phase II vi11ages, and the second round of treatment in the Phase I villages, should be carried out as soon as possible in order that the post-treatment entomological assessment (lasting two months) can be completed by the end of June and before the risk of wind-assisEed invasion by infective flies from distant breeding sites becomes high at the beginning of the rains; -11 - (ii) that the Cameroon villages on the Mayo Vina below Touboro town should be included in the Phase II treatment, if necessary at the expense of delaying treatment until Phase III in the villages of Bem, Hom6 and Vogdjom higher up the Vina; and

(iii) that catching points additional to those already in use along the Mayo Vina and its tributaries should be manned on the stretch between Kouman and Konmbo during the period of Phase II transmission assessment. Additional funds may be necessary for this.

(S) Every effort should be made by the Secretariat to send the funds for Phase II to the PI, as he has already requested, immediately after the SC meeting. If the present timetable of treatment cannot be adhered to, ihe Phase If transmission study may be hopelessly j eopardized.

2.3 MALI (OCT) data based on reports from Dr G. Soula, presented by Dr P. Ranque.

Albeit relatively smal1, thi-s community-based trial, funded by OCT and originally aiming mainly to detect possible changes in the transmission potential of O. volvulus by S. sirbanum in the northern savanna zone of Mali, turned out to be the model on which OCP based its own subsequent and much Larger scale trials of community-based ivermectin treatment.

The two adjacent but isolated valleys of the Koba and Dlaka rivers both contain villages where savanna onchocerciasis is hyperendemic but with a relatively short transmission season.

During 1985 baseline data on the transmission potential and other transmission parameters in the Simulium population were collected throughout the transmission season (July to December). In 1987 a complete census of all villages in both valleys was made, along with a thorough onchocerciasis survey recording, skin snip densities nodule counts, eye lesions and skin lesions. In lttay L987, before the 1987 transmission season, the whole "non-excluded" populations of the 8 villages in the Koba valley were treated with ivermectin, observations were made on the adverse reactions encountered; and the effect in transmission by the S. sirbanum population was followed from t2- July-December 1987. Follow-up examinaEions on mf densities, skin and eye lesions were made in December L987, at which time 90% of the original 1463 persons were reexamined.

There were no fatalities that could be directly associated with ivermectin treatment. Adverse reactions, studied by means of passive reporting affecred 130 out of 856 (L5.27") persons treated. They included headache, itching, joint pain, muscle pains, painful lyrph nodes, fever and rash. Only 8 persons suffered temporary invalidity being obliged Eo remain in their huts for 1-3 days. The frequency of reactions was related to the pre-treatment microfilarial load and to the patient,s age but not to the dose of ivermectin over the range included (f00-200 mcg/kg) or to sex.

The pre- and post- treatment seasons fly dissection results are still being analyzed. Their interpretation is rendered difficult by the relatively smal1 numbers of flies caught (especially in 1987) and the high proportion of type D (non-O. volvulus) larvae encountered, which is an indication of a high degree of zoophily among E. airbanum.

Conclusions and Recommendations on the Mali Phase IV Trial

It was concluded that the Mali trial had been well carried out but that the analysis was not yet complete. The Sub-group recommended as follorus : -

(a) The analysis of the entomological results for 1986 and 1987 should be made and reported as soon as possible.

(b) OCT should provide funds for a second round of treatment in the Koba Valley villages in 1988 with a repeat (comparative) assessment of the frequency of severity of adverse reactions on the second round. For ethical reasons the 2 v|Llages in the Dlaka valley should receive their first round of treatment at the same time.

(c) Since this is one of the few Phase IV trials with a good ophthalmological component, a complete clinico-parasitological and ophthalmic survey of the populations in both valleys should be made before the new round of treatment. 13- (d) If OCP does not start spraying the area with insecticide in 1988, a further year's study of the parasite in the fly population should be made.

2.4 GI{ANA (Asubende and Bui). TOGO/BENIN and COTE D'IVOIRE (OCP) presented by Dr K. Awadzi, Dr G. De SoIe and Dr H. Remme.

The community-based trials planned by uhe OCP are 8 in number. Their objectives are: -

(a) to determine the risk of rare, but severe, adverse reactions, and of moderate reactions which, nevertheless, might be inimical to the acceptability of i-vermectin treatment in mass campaigns;

(b) to determine the potential of ivermectin mass treatment as a method for transmission control under the differing conditions prevailing in OCP; and

(c) to develop the most appropriate and cost-effective ivermectin delivery systems in collaboration with the national onchocerciasis teams.

The eight studies planned are:-

(a) Bui on the Black Volta River in Ghana (an area of partial failure in 1oca1 vector control).

(b) Asubende on the Pru River in Ghana (an isolated focus of hearry savanna onchoeerciasis in the Southern Extension).

(d) Comoe River Basin in C6te d'Ivoire (on the southern edge of the prograrnme area and not normally under vector control).

(e) Tienfala on the Niger River in Mali (a hyperendemic savanna focus in the Western Extension - possibly suitable for trial dosage at 75 ncg/kg). L4- (f) Milo River Basin in Guinea (a hyperendemic savanna focus in the WesEern Extension and a source of reinvading flies - again possibly suitable for trial dosage ax 75 mcg/kg.

(g) Pendie on the Dienkva River in Burkina Faso (an isolated focus of 1ocaI transmission which appears to have persisted in the main control area).

(h) Mako on the Gambia River in Senegal (a hyperendemic savanna focus in the Western Extension).

Of these 8 studies 4 had been carried out by the time of the present meeting and the report from the OCP team was based on the combined results of (a)-(d) above.

Before beginning the studi-es, a "Manual of Procedure" for the Simple Epidemiological Evaluations carrj-ed out had been drawn up by a number of contributors and edited by Dr De So1e. An appendix to this document entitled "Community Ivermectin Trial - Guidelines for Monitoring" had also been prepared, along with Individual Record Forms, Adverse Event Report Forms and Forms for Monitoring Adverse Reactions.

The four trials reported by OCP contain by far the largest numbers of patients treated to date.

A total of 40,449 persons was treated out of an estimated population of 70,002 (ie 57.8%). As between trial areas the population break down of persons treated $ras: -

Bui 1,065 persons Asubende L4,488 persons Kara L2,531 persons Lower Comoe L2,365 persons

The major reasons for non-treatment (including all the current exclusion criteria applying to ivermecEin use) were:-

(a) children under 5 years or below 15 kg in weight (45% of the non-treated population) ; and -15- not be found (b) persons who were absent from the village or who could at Ehe time of treatment ( 307. of the non treated population) '

Single-scored 6 mg ivermectin tablets were available permitting L/2 tablet (3 mg) intervals in dosage. The average dose given was about 160 mcglkg.

Data were presented from the Asubende focus showing that the intensity of microfilarial skin infection fell markedly following treatment and that an immediate effect in lowering the prevalence rate (as assessed on 2 skin snips) was also detectable' However, the prevalence rate (perhaps not surprisingly) had bounced back by 2 months after treatment'

The average occurrence of 'severe' reactions in the four trials combined was 1.85/1000 but. in the intenselY infected Asubende focus the figure rose to 3.3911000 and in the other foci it was 0.80-0 .94lLOOl respectively.

After treatment the follow-up for reactions continued for 72 hours and was conducted bY nurses supervised by rnedical officers '

Symptomsandsignsofanyreactionwerevolunteeredbythepatientsin the first instance and were not actively sought by the follow-up team' In general, reactions were classified into mild (causing no disability), moderate and severe (the latter two classes implying some degree of

disabiliuy) .

Table II classifies the adverse reacti-ons encountered in the four trials dividing them into pain, fever, swelling of the skin' tenderness and eruptions, irritation of the eyes, swelling of lymph nodes ' cutaneous severe symptomatic postural hypotension (SSPH)' dyspnoea and others' ForeachmanifestationthepercentagesofPatientsshowingthat manifestation on each day from the day of treatment onwards to the 5th-8th day are given.

Table III outlines the basic approach to monitoring adverse reactions used in Ehe OCP trials.

Table IV gives the classification system adopted for grading the common reactive s)rmPtoms of headache, itching, pain and the sign of a swollen limb. 15

TABLE II Day of first reporting for each of the various adverse reactions in villages with resident monitoring. number of cases per reacEion is given between brackets)

Day of first reporting of Pain Fever Swell. Gland Cutan. Eye SSPH Dyspn. OEher adverse reaction* (780) (410) (31s) (2s6) (265) (83) (33) (s) (320)

Day of treatment o .6% L.O% 0.07. 0 .0% L.97" 0.0% 0 .0% 20 .0% 0 .97" lst follow-up day 45.4v" 52.O7" 4L.3% 42.5v" 53 .2% 53.O% 84.8% 40.0% 47 .s7"

2nd follow-up day 30.37" 28.57" 39 .07. 35.57" 28.3% 25.37" 9.L% 20.0% 23.L%

3rd follow-up day L5 .6% L3 .2Y" Lt+ .97" 18 .0% 8.3% L5.7% 5.\7. 0.0% L6.67"

4th follow-up day 4.t7" 2.9% 3.2v" 3.L% 3.87" 2.4% 0.07" 0.0% 5 .3%

5th-8th follow-up 2.5% L.57" t.3% 0.87" 2.3% 2.47" o.o% 20.07" 4.4% d"y

Total 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0%

Mean number 1. 30 1. 39 1. 30 1. 38 1. 18 1.48 3 .24 1 . s0 L.44 of visits

a day of first reporting missing for 10 cases -I7-

TABLE II]

OCP COMMUNTTY BASED STUDIES WITH IVERMECTIN

MONITORING - BASIC APPROACH

1. A SIMPLIFIED OCRC PROTOCOL ADDRESSED TO NURSES AS THE PRINCIPAL EXECUTING AGENTS OF THE STUDY SUPERVISED BY MED]CAL OFFICERS

2. SIMPLE GUIDELINES AND CR]TERIA IN THE RECOGN]TION AND QUANTIF]CATION OF REACTIONS (SYMPTOMS AND SIGNS)

3. FOUR GRADES OF REACTIONS O, 1, 2, 3

4. GRADING SYSTEM HEAVILY CONDITIONED BY F'I]NCTIONAL DISABILITY

1. MILD NONE

2. MODERATE +MODEMTE DISABILITY (SYMPToMS AND SIGNS)

3. SEVERE +SEVERE DISABILITY (SYMPTOMS AND SIGNS)

5. EXCEPTIONS TO 4 ]NCLUDE GMDING FOR

FEVER - AN ARBITRARY AGE DEPENDENT SCALE USED IRRESPECTIVE OF DISAB]LITY

RASH - GMDE 3 NOT FEASIBLE

6. CERTAIN PHYSICAL SIGNS I^IITH NO F'T'NCTIONAL DISABILITY WERE NOT SCORED

EG. TACHYCARDIA

ASYMPTOMATIC HYPOTENS ION

ASYMPTOMATIC RASH

7. SYMPTOMS WERE VOLUNTEERED AND NOT SOUGHT

8. MONITORING OF REACTIONS FOR AT LEAST 72 HOURS AFTER I^A,ST DOSE ADM]NISTERED AT TREATMENT CENTRE TABLE IV

MONITORING DURING OCP COMMUNITY STUDIES WITH IVERMECTIN

GRADING OF COMMON REACTIONS SYMPTOMS

SEVERITY

MODERATE (2) SEVERE (3)

No obviouslY scratching Obviously recent scratch Vigorous continuous Insomnia * No scratch marks marks or excoriations Restlessness. Insomnia, but remained abandonment of bed and in bed. Able to carrY pacing up and down.

Rooted to the sPot (Pillar JOINT PAIN No discomfort Obvious marked limP I on Normal gait or difficult in moving of salt). Bedridden @ MUSCLE ACHE account of anY of these GLAND PAIN about I symptoms

Comfortable In distress, holding head Restless, bedridden swiftly

(Check for neck stiffness, fever or altered mentation)

whole Involvement of whole limb SWOLLEN LIMB Part of limb onlY Involvement of pain or mild limbtpain*some with extension into adjacent No Pain use of limb only impairment of normal area * loss of use pain

RASH: Note location and approximate extension 19- The most common severe reaction encountered was SSPH, which occurred in 49 patients out of the 40448 treated, an incidence of about 1 in 1000, but of these only 9 (or about 1 in 5000) were graded as severe and eonsidered in Ehe trial as requiring medical intervenEion.

The clinical aspects of SSPH are sunmarized in Tabre v. The syndrome comes on mosE commonly within the first L2-24 hours of creatment; and is accompanied by a fall of 25 mm Hg or more in the pre-tsreatment systolic and diastolic blood pressure. Most cases responded rapidly within 24 hours to simple bed-rest and intake of non alcoholic fluids, but in the Asubende trial it was considered necessary to give intravenous fluids and hydrocortisone to four patients.

TABLE V

SSPH

CLINICAL ASPECTS

1. PATIENT UNABLE TO STAND FOR TWO MINUTES FOR BLOOD PRESSURE RECORDING

2. COM},ION ASSOCIATES: DIZZINESS

FAINTNESS

SWAYING

EXCESSIVE YAWNING

PROFUSE SWEATING

TACHYCARDIA

RARELY, CONFUSION

3. ON RECUMBENCY: DROWSINESS

BMDYCARDIA

USUALLY RAPID REVERSAL OF SITUATION

MRELY ''SHOCK" .. other very rare causes of reactions classed as severe in the ocp trials were 2 attacks of asthma which developed in 2 patients known to be asthmatic and one attack of laryngeal oedema requiring treatmenE with adrenaline. 20- Finally there were a small number of delayed reactions of uncertain pathogenesis but possibly related causally to the treatment. These reactions occurred 1-3 weeks after treatment in 13 patients at Asubende. In 5 cases one or more abscesses developed in the muscles or around ly*ph nodes, one patient had a pyoarthrosis ' In the remainder there was i-nduration, swelling and pain in the hip, groin or lower limbs.

In a series of 515 patients iU was shown that the occurrence and severity of adverse reactions was related to microfilarial skin density over the range of 0-128 mf/snip. The dangerous 1evel being above 32 mf/snip. The incidence of reactions also correlated positively with age and with the male sex i-n meso and hypoendemic villages, but there was no correlation with dose level over the observed range of 130-200 ncg/kg.

Transmission studies in the Asubende trial

During the Asubende trial there was a deliberate interruption of larvicidal control which permitted substantial population of biting flies to build up. The infection and infectivity rates in this population were recorded for l+ weeks before ivermectin treatment and for 3 months after treatmenE, when larviciding was again resumed. Following ivermectin treatment, transmission, as measured by L3 larvae indisUinguishable from O. volwulus in the heads of the man-biting S. damnosum s.e. population, declined byTO-75%, these figures holding good by comParison with reliable observations on infected and infective fly rates obtained in previous years.

The remarkable results of this experiment are shown in Fig 1. This is the first time that a convineing drop in transmission has been demonstrated following ivermectin treatment of a community, and although the residual rate of transmission post-ivermeetin was still unacceptably high, the results argue well for the use of this drug to control transmission, provided adequate coverage of the human population can be obtained and maintained. FIG.1

ASUBENDE

Chonges in Proportion of lnfected Flies following lvermectin Distribution 260

240

@ a) 220

a :l 200 IVERMECTIN o oL- q) I o_ (I 180 5b o YY ro 160 I be N o- .: 140 oO I qrtr - 120 -oo

.Po'o O- 100 .oU PRE_IVERMECTIN POST-IVERMECTIN .= c) E \-/tJ) BO t- a) 60 _o c z:) 40

0 '19-Nov-87 J 1 -Aug-87 10-0ct-87 29-Dec-87 07-Feb-BB -22- 2.5 GUATEMAI-A (TDR)

No written report was available on this trial for which funding has not yet been received by the Principal Investigator (Professor E.W. Cupp). Nevertheless Dr Duke, who is involved in this projecL, was able to report EhaC the field manager of the proiect had been in Guatemala since December 1987 making administrative preparations for the trial, selecting the fincas for investigation and carrying out the pre-treatment census. In all Ehese aspects he had received much help and cooperation from Dr G. Lea Hoves and the staff of the Servicio de Oncocenosj-s. The clinicio-parasitological surveys of the fincas in the trial witl begin in Aprit 1988 and it is hoped to start treatmenE in May.

The principal aim of this trial is to assess the effect of community-based ivermectin treatment on transmission, in this case, by S. ochraceum.

2.6 MALAWI

No report was available from Dr Burnham as this trial is not due to start before May 1988.

3. .iHE MECTIZAN EXPERT COMMITTEE

An unofficial oral report on the progress of this Committee was given by Dr Bruce Greene who is one of its members.

The Committee was established by Merck Sharp and Dohme, in cooperat.ion with WHO, for the purpose of considering applications and making recommendations for the distribution of ivermectin on a large-scale in countries where onchocerciasis is endemic. IL works in close associati-on with both MSD and WHO.

The Committee is chaired by Dr W.Foege, who is based in the Carter Center in Atlanta, Georgia, USA and held its first meeting in February 1988. Dr Greene informed the Sub-group of some of the Committee's initial decisions concefning ivermectin delivery' -23- (a) The Ministry of Health of the country concerned must agree to any application to distribute i-vermectin in that eountry.

(b) Applications may come from Governments or NGO,s but must be accompanied by a satisfactory protocol. Copies will be sent to MSD and l{HO for comment before they are considered. If the Committee approves the protoeol, MSD will ship the drug on a cost-free basis.

(d) Areas where there is a prevalence of onchocerciasis exeeeding 40% will be considered suitable for blanket treatment with ivermectin. Inlhere the prevalence is less than 10% the drug will not be supplied free. No decision has yet been reached on prevalence levels between these two figures.

tunong problem areas in which the committee has got to make up its mind are: -

(i) Should the recommended L50 ng/kg dose of ivermecrin be reduced initially in heavily infected areas?

(ii) I^Ihat degree of medical supervision i-s needed, and will this vary with the intensity of infection in the area to be treated?

(iii) Should the Committee endeavour to obtain monetary support for purchase of vehicles or other supplies and equipmenE required by distribution teams?

4. RESEARCH NEEDS

The Sub-grouP was of the opinion that although ivermectin had reached the stage of large-scale distribution there were still many aspects of its use which required further research. Among these were:- -24- (a) investigation of the physiological basis, pharmacological mediators and causes of the hypotension which appears to be associated with death of microfilariae under ivermectin (or DEC) treatment; and of the best means of treatment of the sSPH syndrome;

(b) investigations into the rate at which microfilariae disaPpear from the skin after different doses of ivermectin and the mechanism and site of their destruction;

(d) investigations into the relationships between microfilariae 1oads, reacEions to treatment and dosage with ivermectin lower than that currentlY recommended;

(e) investigati-ons to determine whether repeated doses of ivermectin or simultaneous treatment with ivermectin and other filaricides might have a macrofilaricidal or permanent sterilizing action on Q. volvulus.

5. RECOMMENDATIONS

5.1 In order to have a Ereater degree of uniformity in the reporting of Phase IV trials the following should be unified throughout:

(a) Reaction reporting forms. (b) Assessmenr of the CMFL (which may imply unification of, or adjustments to the results of, presently used skin snip

techniques) .

5.2 A monitor (or monitors) should be appointed to supervise the eonduct of the trials and make field visits.

5.3 Regular meetings of the l"lonitoring Sub-group should take place to review progress. -25- 5.4 Training meetings or workshops should be organized whereat those with experience in large-scale ivermectin community based trials can impart their knowledge and experi-ence to those who are about to undertake large-sca1e onchocerciasis control operations using the drug. -26 ANNEX II

TNFORMATION AND COMMENTS TO BE CONVEYED BY DR BRUCE GREENE TO THE MECTIZAN EXPERT COMMITTEE FOLLOWING THE MEETING OFTHEMoNIToRINGSUB-GRoUPFoRIVERMECTINTRIALSIN ONCHOCERCIASIS (20 Mareh 1988)

1. As a result of the Phase IV community-based trials of ivermectin against onchocerciasis conducted by the OCP, OCT and TDR/FIL, - trials which observed all the current ivermectin exclusion criteria - the total number of patients who have received a single dose of ivermectin in rhe range of 100 -2oo ncg/kg (mainly 150 mcg/kg) no\'I exceeds 50,000.

2. In this large series there were no deaths or permanently disabling reacti-ons recorded which could be causally related to ivermectin treatment. On statistical probabilities it is virtually certain that a series of 50,000 patients would reveal any serious adverse reaction that occurs with a frequency of 1 in 10,000 or less.

3. None of the adverse reacti-ons encountered, most of which were mi1d, could be attributed to direct toxicity on the part of ivermectin.

4. Most of the adverse reactions encountered occurred during the first 3 days after treatment and could be attributed to the effect of the drug in killing rnicrofilariae (eg. itching, rash, oedema of the skin, swollen painful lymph glands and fever). They were rarely incapacitating and in no way comparable in severity to what would have been expecced following DEC.

5. The few late adverse reactions (joint manifestations and abscesses) occurring 1-3 weeks after treatment are of uncertain pathogenesis but may have been due to the effect of the drug on other coincidental parasitic infections (eg W. bancrofti, Dracunculus etc.)

6. It is probable that none of the reactions 'l{as life-threatening but medical intervention was considered necessary in a few cases during the trials. _27-

7. The most severe adverse reactions were seen in a few patients who developed a serious degree of postural or orthostatic hypotension beginning within L2-24 hours of treatment and lasting for up xo 24 hours. The main complaint was dizziness and an inability to stand without fainting and falling. The occurrence rate was about 1 in 1000 patients treated but most of these responded to the simple measures of lying down and taking non-alcoholic oral fruids. rn about 1 in 5 of the patients so affected (or 1 in 5000 of the treated population) treatment with intravenous fluid and hydrocortisone was considered necessary by the M.O,s in charge of the present trials.

The exaet physiologic.al- and/or pharmacological basis of this syndrome which has come to be referred to as severe s)rmptomatic postural Hypotension or ssPH, is unknown, but it also occurs much more frequently and severely after DEC treatment of onchocerciasis. patients and it is probably associated in some way with microfilarial death or destruction.

The syndrome occurs most often in patients with high microfilarial skin concentrations and its incidence rate in a severe degree is likely to reach 1 in 5000 in persons having more than 30 mf/skin snip, especially where the community microfilarial load (ie the geometric mean of skin snip densities in the population over 20 years of age) exceeds 32.

The sub-group considers that for the time being in any large-scale ivermectin campaign, particularly in heavily infected areas, alr persons complaining of post-treatment dizziness should be instructed to: -

(i) lie down; and (ii) drink non-alcoholic fluids

They should not be asked to try and stand up while their blood pressure is taken or until they faint, they should be warned of the danger of falling and injuring themselves if they do try to stand or move about before the period of dizziness has passed. -28- Lf these simple measures do not result in symptomatic and eventual permanent improvement, local medical help should be called to assess whether intravenous fluids or hydrocorti-sone are necessary.

8. In the present trials a single patient in the early stages of cerebro-spinal meningitis was inadvertently treated without mishap' Nevertheless the Sub-group considers that the ban on giving ivermectin during the course of a meningitis outbreak or of an outbreak of sleeping sickness should be maintained'

9. Although 2 patients with a history of asthma, developed asthmatic attacks soon after treatment there are not yet sufficient data available to take an intelligent view on whether or not to include a history of asthma among the exclusion criteria'

10. In none of the Phase IV trials was pregnancy testing carried out and hence a number of women in the first trimester have been inadvertently treated. So far no abnormalities have been reported in the children born to the few moLhers so treated. One of the Phase IV trials (that in Liberia) should have the statistical power to detect Lhe significance of possible adverse outcomes of pregnancy in such women.

11 It should be noted that the supervision, medical and otherwi-se, of the present Phase IV trials was such that all patients were weighed before treatment and the dose was adjusted in steps of L/2 a tablet to approximate as closely as possible to 150 mcg/kg. The supervision and record-keeping were such that the risk of over dosage was excluded and there was normally no possibilitY* of a patient receiving more than one dose either from those carrying out the trial or from any outside source. Ensuring these two safety factors may be one of the more difficult aspects in campaigns to deploy ivermecti-n on a large scaIe.

L2. The Sub-group considered thaL the minimum degree of medical follow-up supervision for large-scale treatment would be the presence of a nurse with ability to give intravenous fluids (+ hydrocortisone) during the period 48-78 hours after treatment. This would be performed in any area but would be essential in areas with high microfilarial dens ities

As the exception which proves the rule one child received two doses by accident ie. l+O0 mcg/kg without adverse effects. 29- 13 Some symptomatic relief for reactions to the death of microfilariae in the skin can be achieved by dosage with antihistami-nes and/or aspirin but no trial as to the relati-ve efficacy of these two drugs has yet been done.