Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01192789 |
| Other study ID # |
665-Ped/ERC-06 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
August 31, 2010 |
| Last updated |
May 19, 2017 |
| Start date |
February 2008 |
| Est. completion date |
May 2010 |
Study information
| Verified date |
May 2017 |
| Source |
Aga Khan University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Two-arm cluster randomized controlled trial located in Hala district, Pakistan to determine
the impact of using Lady Health Workers (LHW) of National Program for Family Planning and
Primary Health Care to diagnose and manage severe pneumonia with oral amoxicillin on
treatment failure rates at day 6 among 2-59 month old children. LHWs in the control arm
receive a refresher in standard pneumonia case management. LHWs in the intervention arm
receive standard training that is enhanced to include training in the recognition of severe
pneumonia and its home management with oral amoxicillin. Clusters are by Union Council (UC),
administrator units consisting of 7 to 25 LHWs; each UC is randomized to either enhanced
pneumonia case management with oral amoxicillin therapy (intervention) for severe pneumonia
or standard case management and referral to the nearest health facility for treatment
(control). Process indicators reflecting the LHW's ability to assess, classify and treat
pneumonia in the intervention group and cost-effectiveness data is also being collected.
Primary Hypothesis:
Enhanced pneumonia case management and oral amoxicillin therapy for severe pneumonia
delivered by LHWs in the community will result in a reduction in treatment failure among
children 2 - 59 months of age with severe pneumonia who are treated by the LHW compared with
those referred for care by the LHW.
Secondary Hypotheses:
1. The proportion of treatment failure, [persistence of lower chest indrawing (LCI) or
need for second line treatment between day 3 and day 14], will be less in the
intervention arm compared with the control arm.
2. LHWs can adequately assess, classify, and treat severe pneumonia in 2 - 59 month old
children, and adequately recognize and refer children who present with danger signs
during initial antimicrobial therapy.
Description:
Acute respiratory infection (ARI) is one of the leading causes of morbidity and mortality in
children less than five years of age, and is responsible for over 2 million annual deaths in
this age group. Of the 10.8 million global child deaths estimated in 2000, 34% were in South
Asia and 21% of the total deaths were attributed to pneumonia. Inclusion of all deaths for
which acute lower respiratory infections (ALRI) are an associated cause would increase these
estimates by two to threefold. The ARI mortality burden is principally constituted by
pneumonia. The median incidence of pneumonia in under-five children in developing countries
is estimated to be 0.29 episodes (interquartile range 0.21-0.71) per child year. It is
estimated that in the developing countries 150.7 million new pneumonia cases occur each
year, of which 11-20 million (7-13%) are severe enough to require hospital admission. The
region of the world with the highest incidence of pneumonia is South and South East Asia
with an estimated 55.2 million episodes occurring in children under five years old. In the
developed world, an estimated 14.7 million cases occur each year.
Recent trends indicate that Pakistan has begun to lag behind many regional countries in
major indicators such as infant mortality rates (IMR). Currently, Pakistan has an IMR of
81/1000 live births and under-five mortality rate of 103/1000 live births. Annual number of
child deaths in Pakistan is estimated at 565,000, giving Pakistan 4th ranking after India,
Nigeria and China. Of more than 560,000 under-five deaths reported in Pakistan in 2001, 19%
were due to pneumonia.
At the community level WHO guidelines recommend that trained health workers treat non-severe
pneumonia with an oral antibiotic and refer children with severe pneumonia (i.e. lower chest
wall indrawing [LCI] present) to a local health facility to be treated by injectable
antibiotic (and oxygen, as required). A series of WHO sponsored randomized controlled trials
and a subsequent meta-analysis of results demonstrated that these guidelines implemented by
community-based health workers (CHWs) resulted in a 24-27% reduction in total child
mortality and a 36-42% reduction in pneumonia mortality in these research settings.Pandey et
al. have shown 28% reduction in total under-five mortality using locally trained community
health workers to detect and treat pneumonia.
It has been previously shown that oral amoxicillin is an effective treatment for
(WHO-defined) severe pneumonia in children. More recently a multi-centre randomized
controlled trial (RCT) conducted in eight countries has shown that oral amoxicillin is as
effective as injectable penicillin for the treatment of severe pneumonia in a hospital
setting. For non-severe pneumonia two large multicentre RCTs in Pakistan and India have
shown that three-days' treatment with oral amoxicillin therapy was equivalent to five-days'
treatment. Non-adherence was the most important risk factor for treatment failure in these
studies and was also significantly related to longer duration of therapy. In addition, it
has been shown in studies from India and Bangladesh/Indonesia that the three-days'
antibiotic therapy resulted in lower prevalence of resistant organisms 15 days after
initiation of therapy, when compared with a five-days' therapy.
The non-severe pneumonia and severe pneumonia studies mentioned above were all hospital
based clinical efficacy studies (several conducted by members of this project team) so that
close monitoring and follow-up could be assured. There is now a need to demonstrate the
effectiveness of these management strategies for severe pneumonia in the community when
implemented by CHWs. If the findings of the hospital-based RCTs can be replicated in
community settings then this may have a very significant impact on global policy in
community-based management of ARI in young children. Children with very severe pneumonia or
very severe disease (such as those who have danger signs) will continue to be referred for
hospital treatment following current WHO IMCI guidelines. The use of oral antibiotic for
treating severe pneumonia at the community level has many potential benefits. This case
management strategy, if shown to be effective, could:
- simplify treatment of severe pneumonia;
- minimize the need for referral or hospitalization;
- decrease treatment administration costs;
- reduce transport, food and lost income costs for the family;
- reduce the pressure on already overburdened hospitals;
- reduce the risk of needle-associated complications such as needle-borne infections; and
- reduce the risk of nosocomial infection during hospital stay.
LHWs in Pakistan are very well placed in the community and, in Hala district comprise the
mainstay of the primary health care system. LHWs are trained in standard ARI case management
based on WHO's guidelines and the program has an active health education component.
Management of pneumonia through standard case management, part of IMCI - an approach
developed by the WHO and UNICEF - is the principal strategy for reducing ARI mortality.LHWs
employing the IMCI approach classify the severity of respiratory infections by observing a
child for the key signs of pneumonia: chest in-drawing and fast breathing. With the help of
the refresher course recently developed by the LHW program - based on the IMCI algorithm -
LHWs will be additionally trained in identifying and managing severe pneumonia at the
community level and improve their skills in promotion of care-seeking for ANA.While it is
hoped that these measure will markedly reduce overall childhood mortality and pneumonia
related mortality in the community, the study being proposed here will measure the effect of
enhanced case management of ANA by LHWs in reducing the clinical treatment failure rate
among children 2-59 months of age.
DEFINITION OF TREATMENT FAILURE
Suspected treatment failure will be determined by the LHW on subsequent home visits after
the child has been enrolled. The LHW will immediately contact the Lady Health Worker
Supervisor (LHS) who will independently confirm each case of failure. The provision of
clinical care (i.e. arranging referral) will not be delayed should there be a delay between
the identification of suspected treatment failure and confirmation by the LHS.
Clinical Treatment Failure through day 5 for children 2-59 months will be defined as:
1. Clinical deterioration through day 5 or death occurring within 14 days of enrollment,
prior to change in primary antibiotic therapy.
2. Persistence of fever (>or=100 F) and lower chest indrawing on day 3 (after 48 hours of
initiation of therapy)
3. Fever(>or=100 F)or lower chest indrawing or appearance of any danger sign on day 6
4. Secondary treatment failure or relapse is defined as appearance of any danger sign or
lower chest indrawing or fast breathing (>or= 50 breaths/min) between day 7 and 14.
Case management in Control Arm:
The standard of care and training for LHWs in the control clusters will be the current
curriculum and training workshops. All LHWs in the control clusters will receive a refresher
in management of ARI through LHW supervisors. They will continue to treat non-severe
pneumonia and other cases of ARI with oral co-trimoxazole. Skills in recognition of severe
pneumonia will be reinforced in the refresher course and LHW will be instructed to continue
to evaluate and refer these cases to the Rural Health Center (RHC) or district general
hospital for admission and treatment (with injectable chloramphenicol or ampicillin) as per
current policy. Patients who refuse to go to any health facility for treatment (either
public or private), will not be offered enhanced home treatment with amoxicillin but will be
provided oral co-trimoxazole as per GoP policy. These children will not be included in final
analysis for treatment failure, but will be recorded in the overall epidemiological data
from the area. Oral cotrimoxazole is provided free of cost per GOP policy. Any compensation
for research related injury including hospitalizations and transportation to and from the
health clinic will be borne by the study. Subjects who develop signs of penicillin allergy
will be treated with an antihistamine at no cost and transported to the local health
facility at the cost of project.
Case management in Intervention Arm:
LHWs in the intervention clusters will have specific training to enhance their ability to
evaluate and treat ARI. This will include post-training evaluation of their ability to
assess and classify non-severe and severe pneumonia and manage non-severe pneumonia. This
will consist of an improved training module for the LHWs (respiratory care component) with
an amended treatment plan for severe pneumonia with oral amoxicillin. The enhanced
respiratory training module for LHWs will include prompt recognition and referral of study
treatment failures (including very severe disease) by day 3, based on objective criteria of
fever and lower chest indrawing. In the intervention arm LHWs who diagnose severe pneumonia
will not refer the patient to the nearest facility (RHC with admitting facility or district
general hospital), but instead will offer treatment with oral amoxicillin (90 mg/kg/day
divided BID) at home for 5 days with close follow-up. Additionally, these LHWs will continue
to treat non-severe pneumonia entirely in the community with a 3 days course of oral
amoxicillin as per standard of practice. The study drug (oral amoxicillin) is provided free
of cost per GOP policy. Any compensation for research related injury including
hospitalizations and transportation to and from the health clinic will be borne by the
study.
For severe pneumonia, oral amoxicillin will be provided as a suspension at a total dose of
90 mg/kg per day for 5 days
Patients who vomit within a half an hour of oral treatment will receive a repeat dose of
amoxicillin. This will be attempted three times over 30 minutes. If the patient fails three
attempts they will be considered a treatment failure.
Sample Size Calculation - Primary Objective
The investigators have calculated a sample size that will allow us to test the following
null hypothesis:
Null hypothesis: The proportion of children who fail treatment in the treatment group will
not be greater than the proportion of those who fail in the control group.
The method of Hayes and Bennett21, which employs the following equations, was used to
calculate the number of clusters. The sample size calculation was then repeated using PASS
software using procedures for cluster randomized equivalency trial Because the number of
clusters was fixed, the investigators calculated the sample size for the trial by solving
for the number of participants required given a set of assumptions.
c =2 + (Zα/2 + Zβ)2 * [π0*(1-π0)/n +π1*(1-π1)/n+k2*(π02+π12)]/(π0-π1)2
where π0 = prop int, π1=prop control, n=number per cluster, k=coefficient of variation
Below the investigators detail the assumptions used in sample size calculations and provide
justifications for these assumptions:
1. Failure proportion in control group: The investigators anticipate that the proportion
of children 2-59 months who fail standard of care therapy by day 6 will be 15%. This is
based on the 15% failure proportion found in the APPIS I trial.(11) A consensus among
investigators determined that failure proportion will be lower in this trial because
the definition of failure in APPIS I was overly conservative.
2. Failure proportion in intervention group: The investigators anticipate that the
proportion of children who fail therapy by day 6 in the intervention arm will be 10%.
The null hypothesis is that the proportion of children 2-59 months who fail treatment
in the intervention group will not be greater than the proportion of those who fail in
t control group. Based on a consensus of the investigators, if a difference of 5% or
less is observed in treatment failure between the groups, then the two treatments will
be considered equivalent. This equivalence was considered clinically equivalent.
3. Number of clusters: The investigators have based the sample size determination on a
total of 18 available clusters (9 per arm).
4. Power: The investigators have used a power of 0.9, setting the Type II error level at
0.1, or a 10% chance of not being able to detect a difference in treatment failure if
it truly existed. This was based on a consensus among the investigators. Power was set
high because this was an equivalency trial, and more emphasis should be placed on
making sure any lack of difference was not based on an underpowered study.
5. Alpha: Based on a consensus of the principal investigators, the null hypothesis will be
rejected based on a one-sided test (because the study focuses only on whether the
intervention is not equivalent to the control), with a p=0.05 level of significance.
6. Coefficient of variation (k): Inherent correlations between observations in homogeneous
clusters are accounted for in cluster-randomized trials through the coefficient of
variation. The investigators have used an estimate of 0.20 for the study. Hayes and
Bennett21 note that k is typically less than 0.25 for health studies. In this case the
outcome is the proportion of children failing treatment and the investigators therefore
assume that variation in failure rates between clusters will not exhibit great
variation. A coefficient of variation of 0.2 would be equivalent to no cluster in the
control arm having a failure rate below 0.06 or above 0.18.
Based on these assumptions, the investigators conclude that they will need to enroll 290
cases of severe pneumonia per cluster among 9 clusters per arm (total 18 clusters) over two
years, for a total of 5,233 cases of severe pneumonia.
