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van CCT (UK)

The Qure study: Q-fever fatigue syndrome - response to treatment.

- candidate number9215
- NTR NumberNTR2797
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR8-mrt-2011
- Secondary IDs205520003-20110307 / 2011-000643-25; ZonMw / EudraCT
- Public TitleThe Qure study: Q-fever fatigue syndrome - response to treatment.
- Scientific TitleThe Qure study: Q-fever fatigue syndrome - response to treatment.
- ACRONYMThe Qure study
- hypothesisSo far no data on effective treatment for Q fever Fatigue Syndrome (QFS) are availabe. At present, it is unclear whether effective treatment for QFS is possible. The objective of this study is to assess the efficacy of two treatment strategies for fatigue and disabilities in QFS: long term treatment with doxycycline or cognitive behavioral therapy (CBT). These treatment modalities will be compared with placebo.
- Healt Condition(s) or Problem(s) studiedAdults, Q fever Fatigue Syndrome
- Inclusion criteria1. Males or non-pregnant, non-lactating females who are 18 years or older;
2. Laboratory-proven acute Q fever since the year 2007 and/or positive serology fitting a past infection with Coxiella burnetii;
3. Being severely fatigued, defined by scoring 35 or higher on the subscale fatigue severity of the CIS;
4. Being fatigued for at least 6 months;
5. Disabled because of the fatigue, defined by scoring 450 or higher on the SIP;
6. Subjects must sign a written informed consent form.
- Exclusion criteria1. Fulfilling criteria for chronic Q fever, namely:
A. IFA IgG fase I ≥ 1024, ≥ 3 months after acute Q fever, and/or;
B. Positive Coxiella burnetii PCR on serum or tissue, 1 month after acute Q fever.
2. Acute Q fever in the setting of a prosthetic cardiac valve or aneurysm surgery or stenting necessitating prophylactic use of doxycycline;
3. Pregnancy or unwillingness to use effective contraceptives during the entire study period;
4. Imminent death;
5. Inability to give informed consent;
6. Allergy or intolerance to doxycycline;
7. Somatic or psychiatric illness that could explain the chronic fatigue;
8. Subjects who are currently enrolled on other investigational drug trials or receiving investigational agents;
9. Receiving antibiotics for more than 4 weeks, potentially active against Coxiella burnetii, for any other reason since Q-fever diagnosis;
10. Subjects who are receiving and cannot discontinue barbiturates, phenytoin, or carbamazepine (these drugs may increase the metabolism of doxycycline and therefore reducing half-life of doxycycline);
11. Moderate or severe liver disease (AF, ALAT, ASAT > 3 times the upper limit of normal);
12. Current engagement in a legal procedure concerning financial benefits (only current involvement interferes with the effectivity of cognitive behavioral therapy. Once the appeal procedure ends, subjects can be included).
- mec approval receivedyes
- multicenter trialno
- randomisedyes
- masking/blindingDouble
- controlPlacebo
- groupParallel
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 1-apr-2011
- planned closingdate1-sep-2015
- Target number of participants180
- InterventionsAllocation will be randomized:
1. CBT for 24 weeks (n=60);
2. Long-term antibiotic therapy using doxycycline 200 mg once daily for 24 weeks (n=60);
3. Placebo for 24 weeks (n=60)).

At first, randomization will occur between CBT or medication (ratio 1:2). If patients are randomized to the medication group, a second double-blinded randomization will be done by the study pharmacist (department of Clinical Pharmacy, Radboud University Nijmegen Medical Centre). Obviously, allocation to the CBT intervention cannot be blinded. However, the assessor performing the post-treatment assessment does not know if the patient has been allocated to CBT as patients will be instructed not to give this information. The double-blinded randomization assignment will be known to the study pharmacist only.

In more detail, the intervention groups consist of:
1. Cognitive Behavioral Therapy (CBT): CBT will consist of a protocolized intervention of 12 sessions during a period of 24 weeks. It starts with goal setting and psycho-education on the possible role of cognitions and behavior in maintaining the fatigue. The maintaining factors will subsequently be addressed (regulation of sleep-wake cycle, gradual increasing activity, reformulating fatigue related cognitions);
2. Doxycycline: Antibiotic therapy will consist of doxycycline once daily 200 mg (1 capsule) for 24 weeks. Patients will be monitored 4, 8, 16 and 26 weeks after start for side effects (rash, liver enzymes). Antibiotics will be stopped in case of side effects or pregnancy;
3. Placebo: Patients in the placebo group will receive once daily 1 placebo capsule identical in appearance to the doxycycline capsules for 24 weeks and have the same visits and monitoring for side effects as the patients randomized to doxycycline.
- Primary outcomeFatigue severity measured with the Checklist Individual Strength (CIS).
- Secondary outcome1. Level of functional impairment measured with the Sickness Impact Profile (SIP) total score;
2. Level of psychological distress measured with the total score of the Symptom Checklist 90 (SCL90). The SCL90 consists of 90 items scored on a 5-point scale. Scores range from 90 to 450. A low total score reflects high psychological well-being. The SCL-90 is a reliable and valid instrument;
3. Coxiella serology and PCR (peripheral blood).
- TimepointsPrimary outcome CIS: At baseline, 8 weeks and 24 weeks after start treatment.

Secondary outcomes:
1. SIP score: At baseline and 24 weeks after start treatment;
2. SCL90: At baseline and 24 weeks after start treatment;
3. Coxiella serology and PCR: At baseline and 26 weeks after start treatment.
- Trial web site
- statusstopped: trial finished
- Sponsor/Initiator Radboud University Medical Center Nijmegen
- Funding
(Source(s) of Monetary or Material Support)
ZON-MW, The Netherlands Organization for Health Research and Development, Q-support
- PublicationsStephan 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; 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. Clin Infect Dis 2017 cix013. doi: 10.1093/cid/cix013
- Brief summaryAbstract publicatie Qure-studie:

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}, 37.344.3]) and placebo (37.8 [95% CI, 34.341.2]; 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, 28.035.1]) than after placebo (difference, CBT vs placebo, 6.2 [97.5% CI, .511.9]; 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.
- Main changes (audit trail)25-Jul-2011: Inclusion criteria changed. Old inclusion criteria: 2. Laboratory-proven acute Q fever in the 3 years before presentation and/or positive serology fitting a past infection with Coxiella burnetii. Exlusion criteria 12 has been added - NM
17-Mar-2013: Planned closingdate has been changed. New approved date is September 2014 - NM
9-Dec-2013: Target number of participants reduced due to low inclusion-rate. Change has been approved by sponsor and METC. - AB
5-Nov-2014: Planned closingdate has been changed into September 2015. Last inclusion planned December 2014. - AB
- RECORD8-mrt-2011 - 8-mrt-2017

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