Coxiella Infection, Fatigue Syndrome, Chronic, Q Fever
Conditions
Keywords
Q fever, Cognitive behavioral therapy, Doxycycline, Fatigue, Coxiella
Brief summary
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
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.
Interventions
BEHAVIORALCognitive behavioral therapy
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).
DRUGDoxycycline
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.
DRUGPlacebo
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)
Sponsors
ZonMw: The Netherlands Organisation for Health Research and Development
Radboud University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Checklist Individual Strength (CIS) | 24 weeks after start of treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Sickness Impact Profile (SIP) Total Score | 24 weeks after start of treatment | 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. |
| Symptom Checklist 90 (SCL90) | 24 weeks after start of treatment | 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. |
Countries
Netherlands
Participant flow
Pre-assignment details
156 patients signed informed consent and were randomized; of these, 155 started treatment, either doxycycline (n = 52), placebo (n = 52), or CBT (n = 51). One patient refused double-blind randomization after allocation to the medication group, and received no treatment.
Participants by arm
| Arm | Count |
|---|---|
| Cognitive Behavioral Therapy Cognitive behavioral therapy: CBT will consist of a protocolized intervention 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). | 51 |
| Doxycycline Doxycycline: 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. | 52 |
| Placebo Placebo: 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) | 52 |
| Total | 155 |
Baseline characteristics
| Characteristic | Cognitive Behavioral Therapy | Doxycycline | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 43.3 years STANDARD_DEVIATION 13.7 | 43.6 years STANDARD_DEVIATION 10.2 | 44.6 years STANDARD_DEVIATION 12.3 | 43.8 years STANDARD_DEVIATION 12.1 |
| Checklist Individual Strength, subscale fatigue | 49.7 scores on a scale STANDARD_DEVIATION 4.7 | 51.4 scores on a scale STANDARD_DEVIATION 4.7 | 50.2 scores on a scale STANDARD_DEVIATION 4.8 | 50.36 scores on a scale STANDARD_DEVIATION 4.9 |
| Duration of symptoms | 40 months | 36 months | 37.50 months | 39 months |
| Race and Ethnicity Not Collected | — | — | — | 0 Participants |
| Region of Enrollment Netherlands | 51 participants | 52 participants | 52 participants | 155 participants |
| Sex: Female, Male Female | 25 Participants | 29 Participants | 20 Participants | 74 Participants |
| Sex: Female, Male Male | 26 Participants | 23 Participants | 32 Participants | 81 Participants |
| Sickness Impact Profile 8 total score | 1369.4 scores on a scale STANDARD_DEVIATION 646.7 | 1304.9 scores on a scale STANDARD_DEVIATION 537.7 | 1295.1 scores on a scale STANDARD_DEVIATION 593.7 | 1322.8 scores on a scale STANDARD_DEVIATION 591.1 |
| Symptom Checklist 90 total score | 156.4 scores on a scale STANDARD_DEVIATION 35 | 152.2 scores on a scale STANDARD_DEVIATION 31.4 | 159.1 scores on a scale STANDARD_DEVIATION 41 | 155.6 scores on a scale STANDARD_DEVIATION 36 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 50 | 0 / 52 | 0 / 52 |
| other Total, other adverse events | 42 / 50 | 51 / 52 | 45 / 52 |
| serious Total, serious adverse events | 0 / 50 | 0 / 52 | 2 / 52 |
Outcome results
Primary
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.
Time frame: 24 weeks after start of treatment
Population: Intention-to-treat analysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cognitive Behavioral Therapy | Checklist Individual Strength (CIS) | 31.6 score on a scale |
| Doxycycline | Checklist Individual Strength (CIS) | 40.8 score on a scale |
| Placebo | Checklist Individual Strength (CIS) | 37.8 score on a scale |
Secondary
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.
Time frame: 24 weeks after start of treatment
Population: Intention-to-treat analysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cognitive Behavioral Therapy | Sickness Impact Profile (SIP) Total Score | 786.8 score on a scale |
| Doxycycline | Sickness Impact Profile (SIP) Total Score | 1101.5 score on a scale |
| Placebo | Sickness Impact Profile (SIP) Total Score | 963.8 score on a scale |
Secondary
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.
Time frame: 24 weeks after start of treatment
Population: Intention-to-treat analysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cognitive Behavioral Therapy | Symptom Checklist 90 (SCL90) | 127.1 score on a scale |
| Doxycycline | Symptom Checklist 90 (SCL90) | 149.2 score on a scale |
| Placebo | Symptom Checklist 90 (SCL90) | 142.6 score on a scale |