Effectiveness of Long-term Doxycycline and CBT in Q Fever Fatigue Syndrome (Qure Study)

[Dolphin]

Free full text:
https://www.researchgate.net/profil...-Qure-Study-A-Randomized-Controlled-Trial.pdf

Effectiveness of Long-term Doxycycline Treatment and Cognitive-Behavioral Therapy on Fatigue Severity in Patients with Q Fever Fatigue Syndrome (Qure Study): A Randomized Controlled Trial

Stephan P. Keijmel
Corine E. Delsing
Gijs Bleijenberg
Jos W. M. van der Meer
Rogier T. Donders
Monique Leclercq
Linda M. Kampschreur
Michel van den Berg
Tom Sprong
Marrigje H. Nabuurs-Franssen
Hans Knoop
Chantal P. Bleeker-Rovers

Clin Infect Dis cix013.
DOI: https://doi.org/10.1093/cid/cix013
Published:
27 February 2017

Abstract
Background.
Approximately 20% of patients with acute Q fever will develop chronic fatigue, referred to as Q fever fatigue syndrome (QFS). The objective of this randomized controlled clinical trial was to assess the efficacy of either long-term treatment with doxycycline or cognitive-behavioral therapy (CBT) in reducing fatigue severity in patients with QFS.

Methods.
Adult patients were included who met the QFS criteria according to the Dutch guideline: a new onset of severe fatigue lasting ≥6 months with significant disabilities, related to an acute Q fever infection, without other somatic or psychiatric comorbidity explaining the fatigue. Using block randomization, patients were randomized between oral study medication and CBT (2:1) for 24 weeks. Second, a double-blind randomization between doxycycline (200 mg/day, once daily) and placebo was performed in the medication group. Primary outcome was fatigue severity at end of treatment (EOT; week 26), assessed with the Checklist Individual Strength subscale Fatigue Severity.

Results.
Of 155 patients randomized, 154 were included in the intention-to-treat analysis (doxycycline, 52; placebo, 52; CBT, 50). At EOT, fatigue severity was similar between doxycycline (40.8 [95% confidence interval {CI}, 37.3–44.3]) and placebo (37.8 [95% CI, 34.3–41.2]; difference, doxycycline vs placebo, −3.0 [97.5% CI, −8.7 to 2.6]; P = .45). Fatigue severity was significantly lower after CBT (31.6 [95% CI, 28.0–35.1]) than after placebo (difference, CBT vs placebo, 6.2 [97.5% CI, .5–11.9]; P = .03).

Conclusions.
CBT is effective in reducing fatigue severity in QFS patients. Long-term treatment with doxycycline does not reduce fatigue severity in QFS patients compared to placebo.

Clinical Trials Registration.
NCT01318356.

cognitive-behavioral therapy, Coxiella burnetii, doxycycline, placebo, Q fever fatigue syndrome.

 

[Dolphin]

The protocol paper is available for free here:
https://bmcinfectdis.biomedcentral.com/articles/10.1186/1471-2334-13-157

It would be interesting to see whether everything has been reported.

 

[Dolphin]

No objective outcome measures were reported for CBT. Subjective improvement has often not led to objective improvement e.g. has measured by actometers.

 

[Dolphin]

Chronic Q fever was excluded based on negative serum polymerase chain reaction (PCR), Q fever serology (immunoglobulin G phase I titers <1:1024), and absence of signs of endocarditis or vascular infection.

 

[alex3619]

If the infection is over then antibiotic therapy should not work, or in other words is a sham treatment. Lack of objective measures means some of the same biases we see in PACE may be present.

 

[Dolphin]

Adverse Events
Safety was assessed by monitoring adverse events (AEs) and concomitant drug use. AEs in the medication condition were recorded during the prescheduled study visits, and, if applicable, during the trial when reported by the patient. For patients allocated to CBT, AEs were monitored at 8 weeks after start of therapy and at EOT.

Doxycycline was reencapsulated and placebo was prepared as capsules with identical appearance. Study visits were at 4, 8, and 16 weeks after start of treatment, including medical history, physical examination, and laboratory investigation.

So patients in the doxycycline and placebo groups were monitored for adverse events more frequently than the CBT group.

 

[Esther12]

By the standards of most CBT trials, good to have a placebo group.

Not sure how big the difference between CBT and placebo was... less than their own standards for a clinically meaningful improvement from baseline:

The primary endpoint in the intention-to-treat analysis, fatigue
severity at EOT adjusted for baseline fatigue severity, did not
significantly differ between doxycycline (40.8 [95% CI, 37.3–
44.3]) and placebo (37.8 [95% CI, 34.3–41.2]; difference, doxycycline
vs placebo, −3.0 [97.5% CI, −8.7 to 2.6]; P = .45), and
was significantly lower after CBT (31.6 [95% CI, 28.0–35.1])
than after placebo (difference, CBT vs placebo, 6.2 [97.5% CI,
.5–11.9]; P = .03) (Table 2; Figure 2). Clinically meaningful
improvement, that is, a reduction of 9 points on the CIS subscale
Fatigue Severity plus a score of <35, was reached by 44%
of patients: doxycycline, 31%; placebo, 46%; CBT, 56% (P = .04;
Supplementary Table 4).

None of the
treatment regimens showed a significant effect on functional
impairment.

Functional impairment measured by Sickness Impact Profile (SIP8) questionnaire total score.

The do mention the potential for bias:

As masking for CBT was not possible, this trial
was partly blinded. CBT was directly compared to placebo
plus usual care, which might explain some of the differences
observed as patients in the CBT group clearly know they
are being treated.

In this study, the observed placebo effect is
remarkably high. This can be explained by the regular follow-up
visits during the treatment course, which included standard
advice on how to manage chronic fatigue (eg, regulation of bedtimes,
quitting sleeping during the day, and maintaining mental
and physical activities as much as possible). For several years no
standard care was available for QFS patients, and this study, the
initiation of which was partly patient-driven, provided support
for patients.

So even the gains of the placebo group are taken to show the benefits of expert management?

To evaluate
the long-term beneficial effects of CBT, as has been shown
for CBT for CFS [41], patients are currently surveyed by
poststudy questionnaires 12–15 months posttreatment.

I've not been pulling out annoying/misleading references to CFS, but [41] is the null PACE LTFU paper.

 

[Dolphin]

From the flowchart in Figure 1:

8 discontinued allocated treatment prematurely
1 withdrew consent
7 refused further treatment

During CBT, 1 patient withdrew informed consent, and the other 7 patients discontinued treatment because they could not adhere to the therapy for various reasons.

 

[Dolphin]

At EOS [end of study], the majority of patients had stable or declining antibody titers compared to baseline, and the number of patients with declining titers was similar in all groups (Supplementary Tables 3 and 5). Coxiella burnetii PCR remained negative in all patients.

 

[Dolphin]

The mean number of AEs [Adverse Events] per patient was lowest in the CBT group, and no SAE [Severe Adverse Event] occurred in this group. Therefore, patients need not be concerned about safety if CBT is performed by qualified and trained therapists [35].

However:

During CBT, 1 patient withdrew informed consent, and the other 7 patients discontinued treatment because they could not adhere to the therapy for various reasons.

If you can't adhere to a therapy, that may mean one is suffering adverse events and so it is not necessarily safe.

 

[Dolphin]

I would be interested in seeing the supplemental files on the journal's website if anyone wishes to post them or private message them to me.

 

[Sean]

To evaluate the long-term beneficial effects of CBT, as has been shown for CBT for CFS [41],...

...[41] is the null PACE LTFU paper.

How is their grossly misleading claim anything but straight fraud?

SNAFU

 

[user9876]

I think what this shows is that using CBT you can get people to change the way they mark fatigue by telling them to ignore symptoms and be positive. That is not surprising and is backed up by PACE where there were subjective improvements for people who had interventions aimed at changing "illness beliefs" and were told if they did that they could get better. Of course no evidence is given of real improvements in any case.

Such trials are just a waste of money, effort since the way they are designed will give no useful information.

 

[Valentijn]

CBT is effective in reducing fatigue severity in QFS patients. Long-term treatment with doxycycline does not reduce fatigue severity in QFS patients compared to placebo.

Now if only the patients gave a fuck about their fatigue scores