Posts
[The exact cost of the PACE Trial is unknown but one of the
co-investigators, Michael Sharpe, has said it would be nearly £4m (=US$6.5m
= 5 Euro. Tom]
http://www.biomedcentral.com/1471-2377/7/6/comments#310638
The dropping of actometers as an outcome measure and other points relating
to the outcome measures being used
Tom Kindlon (22 October 2008)
In their reply to my comments, Peter White and colleagues say they are using
[i]"several objective outcome measures"[/i] [1]. If they think these tests
are useful as objective outcome measures, why is at least one of them not
being used as a primary outcome measure rather than the current situation
where there are only two subjective outcome measures being used. I have
already made some points on the outcome measures but another one is that the
bimodal Chalder Fatigue Scale hardly seems a very good outcome measure for a
"CFS/ME" trial where there is likely going to be so many maximum or near
maximum scoring initially[2]
Also, there are so many (14) secondary outcome measures in this study, along
with so many (18) predictor variables, that it seems unlikely all the
different methods of looking at the secondary outcome measures can be
explored in the final published paper, given authors are encouraged not to
make papers too long (especially journals that have paper editions). The
protocol itself is 20 pages long when all the different aspects of it are
listed! At least some of the information will need to be re-iterated in the
final paper.
It is of course important to take the burden on participants into account
when deciding what outcome measures to use. However I find the following
point very strange:
[i]"Although we originally planned to use actigraphy as an outcome measure,
as well as a baseline measure, we decided that a test that required
participants to wear an actometer around their ankle for a week was too
great a burden at the end of the trial."[/i]
Firstly they clearly don't find it that great a burden that they drop it
altogether as it is being used on patients before the start. If they feel it
was that big of a burden, it should probably have been dropped altogether.
Of course, other studies in the area have used measuring over a similar or
longer period. For example, Bazelmans [3] used an actometer over 14 days,
Black [4] used actigraphy over 14 days, Sisto[5] used actigraphy over 7
days, Vercoulen[6] used an actometer over 12 days and Van der Werf [7] used
an actometer for 12 days.
Also if one wants to reduce the burden on patients, why not take out one or
both of the exercise tests instead. As the clinicians in the study would
know, post-exertional symptoms are part of the condition.
For example, Nijs[8] performed a gentle walking exercise on patients where
they walked on average 558m(+/-340) (range: 120-1620) at a speed of 0.9m/s
(+/-0.2) (range: 0.6-1.1). This resulted in a statistically significant
(p<0.05) worsening of scores in the following areas when comparing
pre-exercise, post-exercise and 24 hour post-exercise scores using ANOVA:
VAS fatigue, VAS musculoskeletal pain, VAS sore throat, SF-36 bodily pain
and SF-36 general health percention. 14 out of 24 subjects experienced a
clinically meaningful change (worsening) in bodily pain (i.e. a minimum
change of the SF-36 bodily pain subscale score of at least 10).
Those results are similar to another study[9] which involved the acute
effects of 10 discontinuous 3-minute exercise bouts on a treadmill in 10 CFS
patients. In between exercise bouts, there was a 3-minute recovery period
between exercise bouts. The participants walked at a comfortable walking
pace self-selected by the subjects. On average, the subjects walked at a
speed of 0.71+/-0.20 m/s. Some patients reported experiencing headaches, leg
pain, fatigue or sore throats.
In another study, Lapp [10] (not to be confused with Clapp[9]) reported on
the effects of 31 patients to his practice who were asked to monitor their
symptoms three weeks before to 12 days after a maximal exercise test. 74% of
the patients experienced worsening fatigue and 26% stayed the same. None
improved. The average relapse lasted 8.82 days although 22% were still in
relapse when the study ended at 12 days. There were similar changes with
exercise in lymph pain, depression, abdominal pain, sleep quality, joing and
muscle pain and sore throat.
These are just a small selection of the studies which show patients
experience an exacerbation of their symptoms following exercise testing. So
these are the sorts of symptoms the patients may expect following the
exercise. This reminds me that there seems to be a lot of concentration on
measuring fatigue in this study - there are many other symptoms that are
part of "CFS/ME".
If they had used actometers instead of, say, doing one of the exercise
tests, the response to the exercise could have been followed to see how long
and how severe an effect the exercise had on the patient. Or they could have
dropped both the exercise tests altogether.
As well as "subjective" findings following exercise testing, there have also
been objective findings. Arnold et al[11] found excessive intracellular
acidoss of skeletal muscles with exercise. Jammes[12] found an increase of
damaging oxidative stress following exercise testing. So patients could not
just endure temporary sysptom but possibly also longer-term harm from
exercise testing. There are numerous other exercise abnormalities.
As the clinicians involved in the study probably hear from patients, one of the frustrating things about ME or CFS is that people don't realise the payback that they can have from doing things. This would have been an
opportunity to investigate this as part of the study. But now the effort
patients will put in and the payback they will feel in some ways is being
wasted as the effects won't be measured.
Anyway, to repeat again, given the authors familarity with the literature, I
find it strange that they would decide using an actometer would be worse
than putting patients through two exercise tests.
I also find it surprising that in a study part-funded by the Department of
Work and Pensions (DWP) that the objective outcome measures (not involving
questionnaires) are all once-off exercise tests. It has been established
that patients need to be able to do things on several days during a week
before they can be passed fit for work.
I have mentioned using actometers following exercise tests after an exercise
test above; of course, actometers wouldn't have to be used at that time but
also during a "normal week".
Proponents of pacing methods including APT would say that there is a
"ceiling of activity" that patients can't go above without experiencing a
worsening of symptoms. Black[13] has found evidence of this. Proponents of
CBT or GET for "CFS/ME" would suggest that patients can gradually just
increase how much activity they can do. Actometers would also have tested
the hypothesis. As it stands, the study will not give us information on this
as just because patients answer questionnaires saying they're improved
(which could simply be because they think they're better) or improve their
exercise results (which might simply be because they're willing to push
themselves more) doesn't prove that they don't have an activity ceiling
above which they experience disabling symptoms (esp. when, as in this study,
there is no follow-up period following the exercise testing). [b]This is the
real "heart" of the issue but given the current design, the question won't
be answered.[/b]
[1] PD White, MC Sharpe, T Chalder, JC DeCesare, R Walwyn, for the PACE
trial management group: Response to comments on "Protocol for the PACE
trial" http://www.biomedcentral.com/1471-2377/7/6/comments#306608
[2] Goudsmit EM, Stouten B, Howes S: Fatigue in Myalgic Encephalomyelitis.
Bulletin of the IACFS/ME - Volume 16, Issue 3. http://tinyurl.com/3zcgw8
i.e.
http://www.iacfsme.org/BULLETINFALL2008/Fall08GoudsmitFatigueinMyalgicEnceph/tabid/292/Default.aspx
[3] Bazelmans E, Bleijenberg G, van der Meer JWM, Folgering H. Is physical
deconditioning a perpetuating factor in chronic fatigue syndrome? A
controlled study on maximal exercise performance and relations with fatigue,
impairment and physical activity. Psychol Med 2001; 31: 107–14.
[4] Black CD, O'Connor PJ, McCully KK. Increased daily physical activity and
fatigue symptoms in chronic fatigue syndrome. Dyn Med 2005; 4: 3.
[5] Sisto SA, Tapp WN, LaManca JJ et al. Physical activity before and after
exercise in women with chronic fatigue syndrome. Q J Med 1998; 91:465–73.
[6] Vercoulen JHMM, Bazelmans E, Swanink CMA et al. Physical activity in
chronic fatigue syndrome assessment and its role in fatigue. J Psych Res
1997; 31: 661–73.
[7] Van der Werf SP, Prins JB, Vercoulen JHM, van der Meer JWM, Bleijenberg
G. Identifying physical activity patterns in chronic fatigue syndrome using
actigraphic assessment. J Psychosom Res 2000; 49: 373–79.
[8] Nijs J, Almond F, De Becker P, Truijen S, Paul L. Can exercise limits
prevent post-exertional malaise in chronic fatigue syndrome? An uncontrolled
clinical trial. Clin Rehabil. 2008 May;22(5):426-35.
[9] Clapp LL, Richardson MT, Smith JF, Wang M, Clapp AJ, Pieroni RE. Acute
effects of thirty minutes of light-intensity, intermittent exercise on
patients with chronic fatigue syndrome. Phys Ther 1999; 79: 749-56.
[10] Lapp, C (1997). Exercise limits in chronic fatigue syndrome. Am J Med,
103: 83-84.
[11] DL Arnold et al. Excessive intracellular acidosis of skeletal muscles
on exercise in the post viral exhaustion / fatigue syndrome: a 31P-NMR
Study. Proceedings of third Annual Meeting of the Society for Magnetic
Resonance in Medicine, New York, 1984, 12-13.
[12] Jammes Y, Steinberg JG, Mambrini O, Bregeon F, Delliaux S: Chronic
fatigue syndrome: assessment of increased oxidative stress and altered
muscle excitability in response to incremental exercise. Journal: J Intern
Med., 2005 Mar;257(3):299-310.
[13] Black CD, McCully KK: Time course of exercise induced alterations in
daily activity in chronic fatigue syndrome. Dyn Med. 2005 Oct 28;4:10.
Competing interests
No competing interests
* * *
co-investigators, Michael Sharpe, has said it would be nearly £4m (=US$6.5m
= 5 Euro. Tom]
http://www.biomedcentral.com/1471-2377/7/6/comments#310638
The dropping of actometers as an outcome measure and other points relating
to the outcome measures being used
Tom Kindlon (22 October 2008)
In their reply to my comments, Peter White and colleagues say they are using
[i]"several objective outcome measures"[/i] [1]. If they think these tests
are useful as objective outcome measures, why is at least one of them not
being used as a primary outcome measure rather than the current situation
where there are only two subjective outcome measures being used. I have
already made some points on the outcome measures but another one is that the
bimodal Chalder Fatigue Scale hardly seems a very good outcome measure for a
"CFS/ME" trial where there is likely going to be so many maximum or near
maximum scoring initially[2]
Also, there are so many (14) secondary outcome measures in this study, along
with so many (18) predictor variables, that it seems unlikely all the
different methods of looking at the secondary outcome measures can be
explored in the final published paper, given authors are encouraged not to
make papers too long (especially journals that have paper editions). The
protocol itself is 20 pages long when all the different aspects of it are
listed! At least some of the information will need to be re-iterated in the
final paper.
It is of course important to take the burden on participants into account
when deciding what outcome measures to use. However I find the following
point very strange:
[i]"Although we originally planned to use actigraphy as an outcome measure,
as well as a baseline measure, we decided that a test that required
participants to wear an actometer around their ankle for a week was too
great a burden at the end of the trial."[/i]
Firstly they clearly don't find it that great a burden that they drop it
altogether as it is being used on patients before the start. If they feel it
was that big of a burden, it should probably have been dropped altogether.
Of course, other studies in the area have used measuring over a similar or
longer period. For example, Bazelmans [3] used an actometer over 14 days,
Black [4] used actigraphy over 14 days, Sisto[5] used actigraphy over 7
days, Vercoulen[6] used an actometer over 12 days and Van der Werf [7] used
an actometer for 12 days.
Also if one wants to reduce the burden on patients, why not take out one or
both of the exercise tests instead. As the clinicians in the study would
know, post-exertional symptoms are part of the condition.
For example, Nijs[8] performed a gentle walking exercise on patients where
they walked on average 558m(+/-340) (range: 120-1620) at a speed of 0.9m/s
(+/-0.2) (range: 0.6-1.1). This resulted in a statistically significant
(p<0.05) worsening of scores in the following areas when comparing
pre-exercise, post-exercise and 24 hour post-exercise scores using ANOVA:
VAS fatigue, VAS musculoskeletal pain, VAS sore throat, SF-36 bodily pain
and SF-36 general health percention. 14 out of 24 subjects experienced a
clinically meaningful change (worsening) in bodily pain (i.e. a minimum
change of the SF-36 bodily pain subscale score of at least 10).
Those results are similar to another study[9] which involved the acute
effects of 10 discontinuous 3-minute exercise bouts on a treadmill in 10 CFS
patients. In between exercise bouts, there was a 3-minute recovery period
between exercise bouts. The participants walked at a comfortable walking
pace self-selected by the subjects. On average, the subjects walked at a
speed of 0.71+/-0.20 m/s. Some patients reported experiencing headaches, leg
pain, fatigue or sore throats.
In another study, Lapp [10] (not to be confused with Clapp[9]) reported on
the effects of 31 patients to his practice who were asked to monitor their
symptoms three weeks before to 12 days after a maximal exercise test. 74% of
the patients experienced worsening fatigue and 26% stayed the same. None
improved. The average relapse lasted 8.82 days although 22% were still in
relapse when the study ended at 12 days. There were similar changes with
exercise in lymph pain, depression, abdominal pain, sleep quality, joing and
muscle pain and sore throat.
These are just a small selection of the studies which show patients
experience an exacerbation of their symptoms following exercise testing. So
these are the sorts of symptoms the patients may expect following the
exercise. This reminds me that there seems to be a lot of concentration on
measuring fatigue in this study - there are many other symptoms that are
part of "CFS/ME".
If they had used actometers instead of, say, doing one of the exercise
tests, the response to the exercise could have been followed to see how long
and how severe an effect the exercise had on the patient. Or they could have
dropped both the exercise tests altogether.
As well as "subjective" findings following exercise testing, there have also
been objective findings. Arnold et al[11] found excessive intracellular
acidoss of skeletal muscles with exercise. Jammes[12] found an increase of
damaging oxidative stress following exercise testing. So patients could not
just endure temporary sysptom but possibly also longer-term harm from
exercise testing. There are numerous other exercise abnormalities.
As the clinicians involved in the study probably hear from patients, one of the frustrating things about ME or CFS is that people don't realise the payback that they can have from doing things. This would have been an
opportunity to investigate this as part of the study. But now the effort
patients will put in and the payback they will feel in some ways is being
wasted as the effects won't be measured.
Anyway, to repeat again, given the authors familarity with the literature, I
find it strange that they would decide using an actometer would be worse
than putting patients through two exercise tests.
I also find it surprising that in a study part-funded by the Department of
Work and Pensions (DWP) that the objective outcome measures (not involving
questionnaires) are all once-off exercise tests. It has been established
that patients need to be able to do things on several days during a week
before they can be passed fit for work.
I have mentioned using actometers following exercise tests after an exercise
test above; of course, actometers wouldn't have to be used at that time but
also during a "normal week".
Proponents of pacing methods including APT would say that there is a
"ceiling of activity" that patients can't go above without experiencing a
worsening of symptoms. Black[13] has found evidence of this. Proponents of
CBT or GET for "CFS/ME" would suggest that patients can gradually just
increase how much activity they can do. Actometers would also have tested
the hypothesis. As it stands, the study will not give us information on this
as just because patients answer questionnaires saying they're improved
(which could simply be because they think they're better) or improve their
exercise results (which might simply be because they're willing to push
themselves more) doesn't prove that they don't have an activity ceiling
above which they experience disabling symptoms (esp. when, as in this study,
there is no follow-up period following the exercise testing). [b]This is the
real "heart" of the issue but given the current design, the question won't
be answered.[/b]
[1] PD White, MC Sharpe, T Chalder, JC DeCesare, R Walwyn, for the PACE
trial management group: Response to comments on "Protocol for the PACE
trial" http://www.biomedcentral.com/1471-2377/7/6/comments#306608
[2] Goudsmit EM, Stouten B, Howes S: Fatigue in Myalgic Encephalomyelitis.
Bulletin of the IACFS/ME - Volume 16, Issue 3. http://tinyurl.com/3zcgw8
i.e.
http://www.iacfsme.org/BULLETINFALL2008/Fall08GoudsmitFatigueinMyalgicEnceph/tabid/292/Default.aspx
[3] Bazelmans E, Bleijenberg G, van der Meer JWM, Folgering H. Is physical
deconditioning a perpetuating factor in chronic fatigue syndrome? A
controlled study on maximal exercise performance and relations with fatigue,
impairment and physical activity. Psychol Med 2001; 31: 107–14.
[4] Black CD, O'Connor PJ, McCully KK. Increased daily physical activity and
fatigue symptoms in chronic fatigue syndrome. Dyn Med 2005; 4: 3.
[5] Sisto SA, Tapp WN, LaManca JJ et al. Physical activity before and after
exercise in women with chronic fatigue syndrome. Q J Med 1998; 91:465–73.
[6] Vercoulen JHMM, Bazelmans E, Swanink CMA et al. Physical activity in
chronic fatigue syndrome assessment and its role in fatigue. J Psych Res
1997; 31: 661–73.
[7] Van der Werf SP, Prins JB, Vercoulen JHM, van der Meer JWM, Bleijenberg
G. Identifying physical activity patterns in chronic fatigue syndrome using
actigraphic assessment. J Psychosom Res 2000; 49: 373–79.
[8] Nijs J, Almond F, De Becker P, Truijen S, Paul L. Can exercise limits
prevent post-exertional malaise in chronic fatigue syndrome? An uncontrolled
clinical trial. Clin Rehabil. 2008 May;22(5):426-35.
[9] Clapp LL, Richardson MT, Smith JF, Wang M, Clapp AJ, Pieroni RE. Acute
effects of thirty minutes of light-intensity, intermittent exercise on
patients with chronic fatigue syndrome. Phys Ther 1999; 79: 749-56.
[10] Lapp, C (1997). Exercise limits in chronic fatigue syndrome. Am J Med,
103: 83-84.
[11] DL Arnold et al. Excessive intracellular acidosis of skeletal muscles
on exercise in the post viral exhaustion / fatigue syndrome: a 31P-NMR
Study. Proceedings of third Annual Meeting of the Society for Magnetic
Resonance in Medicine, New York, 1984, 12-13.
[12] Jammes Y, Steinberg JG, Mambrini O, Bregeon F, Delliaux S: Chronic
fatigue syndrome: assessment of increased oxidative stress and altered
muscle excitability in response to incremental exercise. Journal: J Intern
Med., 2005 Mar;257(3):299-310.
[13] Black CD, McCully KK: Time course of exercise induced alterations in
daily activity in chronic fatigue syndrome. Dyn Med. 2005 Oct 28;4:10.
Competing interests
No competing interests
* * *
I wonder if the refusal to include the actimeter readings was because they proved the patients aren't "lazy" -- many of us live alone (divorced because husbands couldn't/wouldn't put up with the added burdens of a disabled wife), so no matter how much the doctors would like to believe that CFS patients are lying in bed all day with a full staff of servants waiting on them hand and foot, the reality is, if you have 2 good hours per day, you're going to spend that time getting groceries, doing laundry, putting together meals...
I'll agree with Tom that most people don't understand the after-effects of doing things. At my worst, it took me a week to do a single load of laundry, because I needed to rest the next day after each step. To this day, people see that I can go out to run an errand, but don't understand why the ability to go out on Monday does not mean I also have the ability to go out on Tuesday. Most of the time, I'm limited to 2 days a week -- sometimes I can push it to 3, but they cannot be 3 consecutive days.
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