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.
b
tQ.
/rd"r
hhz
The purposes of
2-
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
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$4 million for the deployment of ivermectin in the control of oncho-
cerciasis. 0f this sum, it is 1ike1y thaL US$ one million would go to the OCp for
5.
-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
Skin snip negative children 5-11 years of age>k
Pregnant women Absentees Refusals
Breast feeding
Patient treated in continuing Phase III trial
S ick
2762 L399 640 s66 257 209 L28
4t+
20.27"
LO.2%
4.7%
4.t7"
L.97"
L.57"
0.97"
0.37"
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 RUBBER PIANTATION,
TREATMENT AT THE LAC
LIBERIA
Complaints
following ivermectin treatment
Edema
lower limbs upper limbs face
Pruritis
Body pain
Ocular irritation Arthralgia
Painful ly*ph nodes Headache
Dizzi,n.ess Fever Nausea Weakness
Diarrhea
TOTAL NUMBER
OF PATIENTS SEEN
* ( ) patients seen by Note: Several patients
3e
(28)
19at the day 3 follow-up.
than one complaint.
L-2 days
the team
had more
3
dalzs
8
(s)*e
(s)11 (11)
6 (4)
2 (0) 1 (0)
s
(s)3
(3)4-7 days
7
i
4 1 3 4 1 1 1 1
8-33 days
2
i
10 1 2 2
1 1 18
Total
2L 13 11 25 L2 10
9
8 5 3
t+
1 2 1
101
t+
:
5 10
3
2 2 4
I
2
1
1
(0)1
(0)25
(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
total census population of 13
a high standard and, provided should continue for a further following obj ectives:
(c) To follow ivermectin
(d) To compare
with those
this study, in which 704 were Ereated, had
funds are available, two rounds of annual
7699 persons out of a
been carried out to
recommended that it treatment with the
(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;
the evolution of regression of skin lesions after
treatment;
the reactions to second and third doses of ivermectin 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 eye and in the skin;
(c) to assess the effect of of O. volvulus by parous
of treatment on onchocercal morbidity in the Large-scale treatment in the transmission
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.
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: -
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.
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 (a)
(b)
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;
(ii) that the Cameroon villages on the should be included in the Phase II the expense of delaying treatment villages of Bem, Hom6 and Vogdjom
Mayo Vina below Touboro town
treatment, if necessary at until Phase III in the
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).
(c) The Kara River Basin in Togo/Benin (a reinvasion area).
(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 meeting
results
8
and
of
studies 4 had been carried out by the time of the present the report from the OCP team was based on the combined (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 70,002 (ie 57.8%). As between trial areas the population break down persons treated $ras: -
of of
Bui Asubende Kara
Lower Comoe
1,065 L4,488 L2,531 L2,365
persons persons persons 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
(b) persons who at Ehe time
-15-
were absent from the village or who could not be found
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'
was 1.85/1000 but. in the intenselY
to 3.3911000 and in the other foci
reactions in the four trials combined infected Asubende focus the figure rose it was 0.80-0 .94lLOOl respectively.
After treatment was conducted bY
the follow-up for reactions continued for 72 hours and
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 swelling of lymph nodes ' cutaneous eruptions, irritation of the eyes, 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 reactive s)rmPtoms of headache, itching, pain and limb.
for
the
grading the common sign of a swollen
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
adverse reaction*
Pain Fever Swell. Gland Cutan. Eye
(780) (410) (31s) (2s6) (265)
(83)SSPH Dyspn. OEher
(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
2nd follow-up day
3rd follow-up day
4th follow-up day
5th-8th follow-up d"y
30.37" 28.57" 39 .07.
L5 .6% L3 .2Y" Lt+ .97"
35.57" 28.3% 25.37" 20.0% 23.L%
0.0% L6.67"
0.0% 5 .3%
45.4v" 52.O7" 4L.3% 42.5v" 53 .2% 53.O% 84.8% 40.0% 47 .s7"
18 .0%
3.L%
0.87"
9.L%
5.\7.
0.07"
4.t7"
2.5%
2.9%
L.57"
3.2v"
t.3%
3.87"
2.3%
2.4%
2.47"
8.3% L5.7%
o.o% 20.07" 4.4%
Total
Mean number
of visits
100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0%
1. 30 1. 39 1. 30 1. 38 1. 18 1.48 3
.24
1 .s0
L.44a 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
I
@
I
TABLE IV
MONITORING DURING OCP COMMUNITY STUDIES WITH IVERMECTIN GRADING OF COMMON REACTIONS SYMPTOMS
SEVERITY
SEVERE (3)
MODERATE (2)
Vigorous continuous
Restlessness. Insomnia *
abandonment of bed and
pacing up and down.
Rooted to the sPot (Pillar of salt). Bedridden on
account of anY of these symptoms
Restless, bedridden Obviously recent scratch
marks or excoriations Insomnia, but remained
in bed. Able to carrY Obvious marked limP
or difficult in moving
about
In distress, holding head swiftly
No obviouslY scratching No scratch marks
No discomfort Normal gait
Comfortable
Part of limb onlY No pain or mild Pain
only JOINT PAIN
MUSCLE ACHE GLAND PAIN
SWOLLEN LIMB
(Check for neck stiffness, fever or altered mentation) Involvement of whole limb with extension into adjacent area * loss of use of limb pain
Involvement of whole limbtpain*some
impairment of normal
use
RASH: Note location and approximate extension
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
DROWSINESS BMDYCARDIA
USUALLY RAPID REVERSAL OF SITUATION
MRELY ''SHOCK" ..
3. ON RECUMBENCY:
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.
260 240 220
200 180 160 140 120
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ASUBENDE
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Proportionof
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IVERMECTINPRE_IVERMECTIN POST-IVERMECTIN
10-0ct-87
J 1
-Aug-87
'19-Nov-87 29-Dec-87 07-Feb-BBYY
-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'
