The Qure Study: Q-fever Fatigue Syndrome - Response to Treatment

Study Overview
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Brief Summary
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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).

Detailed Description
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Q fever fatigue syndrome (QFS) is one of the most frequent sequelae of Q fever, and constitutes a significant problem in the current outbreak of Q fever. QFS leads to substantial morbidity and has a high socio-economic burden, related to increased use of healthcare facilities and absence from work. It is envisaged that over 750 patients will become chronically fatigued due to Q fever in The Netherlands (20% of 4000 patients from 2007 until now). Although the outbreak appears to diminish, it is expected that Q fever will remain an endemic disease, and therefore this number will continue to grow. A vast medical consumption can be anticipated, stressing the need for an accessible and effective intervention and clear treatment guidelines. The study will contribute to a better understanding of effective treatment of QFS, providing evidence-based guidelines for general practitioners and medical specialists.

Official Title
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The Qure Study: Q-fever Fatigue Syndrome - Response to Treatment

Conditions
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Q Fever, Fatigue Syndrome, Chronic, Coxiella Infection

Intervention / Treatment
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* Behavioral: Cognitive behavioral therapy
* Drug: Doxycycline
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or non-pregnant, non-lactating females who are 18 years or older Laboratory-proven acute Q fever since the year 2007 and/or positive serology fitting a past infection with Coxiella burnetii; AND being severely fatigued, defined by scoring 35 or higher on the subscale fatigue severity of the CIS; AND being fatigued for at least 6 months; AND disabled because of the fatigue, defined by scoring 450 or higher on the SIP Subjects must sign a written informed consent form. Exclusion Criteria: Fulfilling criteria for chronic Q fever, namely: IFA IgG fase I ≥ 1024, ≥ 3 months after acute Q fever and/or Positive Coxiella burnetii PCR on serum or tissue, 1 month after acute Q fever Acute Q fever in the setting of a prosthetic cardiac valve or aneurysm surgery or stenting necessitating prophylactic use of doxycycline; Pregnancy or unwillingness to use effective contraceptives during the entire study period; Imminent death; Inability to give informed consent; Allergy or intolerance to doxycycline; Somatic or psychiatric illness that could explain the chronic fatigue; Subjects who are currently enrolled on other investigational drug trials or receiving investigational agents; Receiving antibiotics for more than 4 weeks, potentially active against Coxiella burnetii, for any other reason since Q-fever diagnosis; 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); Moderate or severe liver disease (AF, ALAT, ASAT > 3 times the upper limit of normal). 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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cognitive behavioral therapy<br> | Behavioral: Cognitive behavioral therapy<br>* 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).<br>* Other names: Therapy, Cognitive Behavior;|
| Experimental: Doxycycline<br> | Drug: Doxycycline<br>* Antibiotic therapy will consist of doxycycline once daily 200 mg (in 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.<br>* Other names: Tetracycline;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Patients in the placebo group will receive once daily 1 placebo capsule identical in appearance to the doxycycline for 24 weeks and have the same visits and monitoring for side effects as the patients randomized to doxycycline (Patients will be monitored 4, 8, 16 and 26 weeks)<br>* Other names: Sham Treatment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Checklist Individual Strength (CIS) | The primary outcome measure is the fatigue severity measured by the subscale fatigue severity (8 items, 7-point Likert Scale) of the Checklist Individual Strength (CIS questionnaire) with a severity range from 8-56. High scores indicate a high level of fatigue. Patients with a cut-off score of ≥35 are classified as severely fatigued. | 24 weeks after start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sickness Impact Profile (SIP) Total Score | Level of functional impairment measured with the Sickness Impact Profile (SIP). The SIP is an instrument that is used to gauge sickness-related dysfunction. The weighted total score on eight subscales of the SIP8 (SIP8 total score) will be used to assess functional disability in all domains of functioning (range 0-5799). A higher score indicates higher levels of functional impairment. A score of 450 or higher on the SIP is defined as being significant disabled because of fatigue. | 24 weeks after start of treatment | 
| Symptom Checklist 90 (SCL90) | The total score of the Symptom Checklist 90 (SCL90) measures the level of psychological distress. 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. | 24 weeks after start of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Q fever, Cognitive behavioral therapy, Doxycycline, Fatigue, Coxiella