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

• Sponsor: Radboud University Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01318356
• Collaborator: ZonMw: The Netherlands Organisation for Health Research and Development (Other)
• Enrollment: 156
• Location: 1
• Arms: 3
• Duration (Months): 53
• Patients Per Site Per Month: 2.9

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Q Fever; Fatigue Syndrome, Chronic; Coxiella Infection	Behavioral: Cognitive behavioral therapy; Drug: Doxycycline; Drug: Placebo	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 156 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: The Qure Study: Q-fever Fatigue Syndrome - Response to Treatment
• Study Start Date: Apr 1, 2011
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cognitive behavioral therapy	Behavioral: Cognitive 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).; Other Names: Behavior Therapy, Cognitive Cognition Therapy Cognitive Behavior Therapy Cognitive Psychotherapy Psychotherapy, Cognitive Therapy, Cognition Therapy, Cognitive Therapy, Cognitive Behavior
Experimental: Doxycycline	Drug: 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.; Other Names: Doxycycline Monohydrate Tetracycline
Placebo Comparator: Placebo	Drug: 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); Other Names: Sham Treatment

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Radboud university medical center	Nijmegen	Gelderland	Netherlands	6500 HB

Sponsors and Collaborators

• Radboud University Medical Center
• ZonMw: The Netherlands Organisation for Health Research and Development

Investigators

• Study Director: Chantal P Bleeker-Rovers, MD PhD, Radboud University Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

• Keijmel SP, Delsing CE, Sprong T, Bleijenberg G, van der Meer JW, Knoop H, Bleeker-Rovers CP. The Qure study: Q fever fatigue syndrome--response to treatment; a randomized placebo-controlled trial. BMC Infect Dis. 2013 Mar 27;13:157. doi: 10.1186/1471-2334-13-157.

• Responsible Party: Stephan Keijmel, S.P. Keijmel, MD, Radboud University Medical Center
• ClinicalTrials.gov Identifier: NCT01318356
• Other Study ID Numbers: 205520003-20110307; 2011-000643-25
• First Posted: Mar 18, 2011
• Last Update Posted: Jun 23, 2021
• Last Verified: Jun 1, 2021

• Keywords provided by Stephan Keijmel, S.P. Keijmel, MD, Radboud University Medical Center: Q fever; Cognitive behavioral therapy; Doxycycline; Fatigue; Coxiella
• Additional relevant MeSH terms: Fatigue Syndrome, Chronic; Q Fever; Syndrome; Fatigue; Fever; Doxycycline; Tetracycline

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	Cognitive Behavioral Therapy	Doxycycline	Placebo
Arm/Group Description	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).	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.	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)
Period Title: Overall Study
STARTED	51	52	52
COMPLETED	43	49	50
NOT COMPLETED	8	3	2

Baseline Characteristics

Arm/Group Title	Cognitive Behavioral Therapy	Doxycycline	Placebo	Total
Arm/Group Description	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).	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.	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)	Total of all reporting groups
Overall Participants	51	52	52	155
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.3 (13.7)	43.6 (10.2)	44.6 (12.3)	43.8 (12.1)
Sex: Female, Male (Count of Participants)
Female	25 49%	29 55.8%	20 38.5%	74 47.7%
Male	26 51%	23 44.2%	32 61.5%	81 52.3%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Netherlands	51 100%	52 100%	52 100%	155 100%
Sickness Impact Profile 8 total score (scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [scores on a scale]	1369.4 (646.7)	1304.9 (537.7)	1295.1 (593.7)	1322.8 (591.1)
Checklist Individual Strength, subscale fatigue (scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [scores on a scale]	49.7 (4.7)	51.4 (4.7)	50.2 (4.8)	50.36 (4.9)
Symptom Checklist 90 total score (scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [scores on a scale]	156.4 (35.0)	152.2 (31.4)	159.1 (41.0)	155.6 (36.0)
Duration of symptoms (months) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [months]	40	36	37.50	39

Outcome Measures

1. Primary Outcome

Title	Checklist Individual Strength (CIS)
Description	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

Outcome Measure Data

Analysis Population Description

Intention-to-treat analysis

Arm/Group Title	Cognitive Behavioral Therapy	Doxycycline	Placebo
Arm/Group Description	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).	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.	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)
Measure Participants	50	52	52
Mean (95% Confidence Interval) [score on a scale]	31.6	40.8	37.8

2. Secondary Outcome

Title	Sickness Impact Profile (SIP) Total Score
Description	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

Outcome Measure Data

Analysis Population Description

Intention-to-treat analysis

Arm/Group Title	Cognitive Behavioral Therapy	Doxycycline	Placebo
Arm/Group Description	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).	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.	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)
Measure Participants	50	52	52
Mean (95% Confidence Interval) [score on a scale]	786.8	1101.5	963.8

3. Secondary Outcome

Title	Symptom Checklist 90 (SCL90)
Description	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

Outcome Measure Data

Analysis Population Description

Intention-to-treat analysis

Arm/Group Title	Cognitive Behavioral Therapy	Doxycycline	Placebo
Arm/Group Description	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).	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.	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)
Measure Participants	50	52	52
Mean (95% Confidence Interval) [score on a scale]	127.1	149.2	142.6

Adverse Events

Time Frame	Safety was assessed by monitoring adverse events (AEs) and concomitant drug use. For patients allocated to the medication condition, AEs were monitored at 4 weeks, 8 weeks, and 16 weeks after start of therapy, and at EOT (= up to approximately 26 weeks after start of therapy). Furthormore, 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 (up to 26 weeks after start of therapy).
Arm/Group Title	Cognitive Behavioral Therapy		Doxycycline		Placebo
Arm/Group Description	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).		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.		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)
All Cause Mortality
	Cognitive Behavioral Therapy		Doxycycline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/50 (0%)		0/52 (0%)		0/52 (0%)
Serious Adverse Events
	Cognitive Behavioral Therapy		Doxycycline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/50 (0%)		0/52 (0%)		2/52 (3.8%)
Cardiac disorders
Cardiological symptoms	0/50 (0%)		0/52 (0%)		1/52 (1.9%)
Renal and urinary disorders
Urosepsis	0/50 (0%)		0/52 (0%)		1/52 (1.9%)
Other (Not Including Serious) Adverse Events
	Cognitive Behavioral Therapy		Doxycycline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	42/50 (84%)		51/52 (98.1%)		45/52 (86.5%)
Gastrointestinal disorders
Gastointestinal	5/50 (10%)	5	31/52 (59.6%)	51	27/52 (51.9%)	33
General disorders
Other	18/50 (36%)	21	24/52 (46.2%)	34	13/52 (25%)	15
Immune system disorders
Allergic reaction	0/50 (0%)	0	0/52 (0%)	0	0/52 (0%)	0
Infections and infestations
Infection	29/50 (58%)	54	22/52 (42.3%)	33	26/52 (50%)	46
Investigations
Laboratorial	0/50 (0%)	0	14/52 (26.9%)	16	7/52 (13.5%)	8
Musculoskeletal and connective tissue disorders
Muskuloskeletal	14/50 (28%)	18	22/52 (42.3%)	28	17/52 (32.7%)	22
Bone and teeth	1/50 (2%)	1	3/52 (5.8%)	4	2/52 (3.8%)	2
Nervous system disorders
Neurological	6/50 (12%)	8	13/52 (25%)	13	10/52 (19.2%)	11
Skin and subcutaneous tissue disorders
Skin	5/50 (10%)	5	20/52 (38.5%)	29	10/52 (19.2%)	12

Limitations/Caveats

It was not designed to compare doxycycline and CBT directly, due to the limited number of available patients. As masking for CBT was not possible, this trial was partly blinded. CBT was directly compared to placebo plus usual care. Due to the maximum number of vailable patients, it was not possible to include a control group without any form of treatment. Finally, it is unclear whether the detected effects will be sustained over time.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.