Plain English Summary
Background and study aims
Lymphatic filariasis is a parasitic disease caused by microscopic, thread-like worms that infect the lymph system, resulting in fluid collection and swelling (lymphedema). Current lymphedema treatment is based on the use of simple measures of hygiene (regular washing with soap and water, skin and nail care), use of topical antibiotics or antifungal agents, exercise and footwear. This is considered the "standard of care" and has been shown to reduce the frequency of acute attacks that drive the progression of lymphedema. In two previous studies doxycycline 200 mg was given to patients with lymphedema for 6 weeks. This oral antibiotic treatment led to improvement or halt of the progression of the lymphedema in most of the treated patients despite active infection with worms that cause lymphatic filariasis. In order to expand the benefits of this observation to more people affected by this disease, similar studies are needed to confirm the earlier results so that doxycycline treatment can be introduced into current treatment programmes. This study takes place in Ghana and is one of five studies that have the aim to confirm the effect of doxycycline 200 mg for 6 weeks. The other four studies are carried out in Mali, Sri Lanka, India and Tanzania. While the three studies in Mali, Sri Lanka and India compare doxycycline 200 mg for 6 weeks versus a placebo (dummy drug) matching doxycycline (both treatments on top of standard methods of hygiene), the two studies in Ghana and Tanzania have the additional aim to find out whether a lower dose of doxycycline of 100 mg is equally beneficial.
Who can participate?
Patients aged 14 – 65 with a lymphedema of the leg
What does the study involve?
Participants with lymphedema stage 1-3 are randomly allocated to be treated with either doxycycline 200 mg, doxycycline 100 mg or a placebo for 6 weeks, and participants with lymphedema stage 4-6 are randomly allocated to receive doxycycline 200 mg or a placebo for 6 weeks. All treatments are given in addition to the standard methods of hygiene and mass drug administration (ivermectin 200 µg/kg plus albendazole 400 mg) in areas where this is still ongoing. At the start of the study and 6, 12, 18 and 24 months later, participants undergo measurements of the leg. A questionnaire about the occurrence of acute attacks is carried out every 2 months after treatment onset. Participants also undergo lymphedema management training at the start of the study and after 4, 6, 12, 18 and 24 months.
What are the possible benefits and risks of participating?
Benefits to the participant include thorough medical evaluation, intensified hygiene training, free supplies for local care of lymphedema and free medical treatment for common illnesses during the treatment period and follow-up. The risks to participants are side effects caused by the licensed study drug doxycycline and infection during blood sampling. In the event of side effects caused by the study drugs or treatments, participants are treated and followed up by the research team until they are resolved.
Where is the study run from?
Kumasi Centre for Collaborative Research (KCCR) (Ghana)
When is the study starting and how long is it expected to run for?
January 2017 to December 2020
Who is funding the study?
Research Networks for Health Innovations in Sub-Saharan Africa sponsored by the Federal Ministry of Education and Research (BMBF) (Germany)
Who is the main contact?
Dr Alexander Yaw Debrah
yadebrah@yahoo.com
Trial website
Contact information
Type
Public
Primary contact
Dr Alexander Yaw Debrah
ORCID ID
Contact details
Faculty of Allied Health Sciences
Kwame Nkrumah University of Science and Technology
Kumasi
00000
Ghana
+233 (0)3220 60351
yadebrah@yahoo.com
Type
Scientific
Additional contact
Prof Achim Hoerauf
ORCID ID
Contact details
Institute for Medical Microbiology
Immunology and Parasitology
University Hospital of Bonn
Sigmund-Freud-Str. 25
Bonn
53105
Germany
+49 (0)228 28715673
achim.hoerauf@ukbonn.de
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
TAKeOFF-4-0117
Study information
Scientific title
Doxycycline 200 mg/d vs 100 mg/d for 6 weeks to improve filarial lymphedema: a multi-national, double-blind, randomized, placebo-controlled trial
Acronym
TAKeOFF - LEDoxy
Study hypothesis
Group A (LE stage 1-3):
1. To confirm the efficacy of a 6-week course of daily doxycycline 200 mg on lack of progression of filarial lymphedema (LE)
2. To reduce the dosage of doxycycline from 200 mg/d to 100 mg/d for 6 weeks for the treatment of filarial LE
Group B (LE stage 4-6):
1. To show efficacy of a 6-week course of daily doxycycline 200 mg on lack of progression of filarial LE
Ethics approval
1. The Committee for Human Research, Publication and Ethics (CHRPE) of the Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana: approval for first submission: 24/10/2017; approval for first amendment: 13/04/2018
2. The Ghana Health Service Ethics Review Committee (GHS-ERC), Accra, Ghana: approval for first submission: 13/12/2017; approval for first amendment: 31/05/2018
3. The Ghana Food and Drug Authority (Ghana FDA), Accra, Ghana: approval for first submission: 15/02/2018; approval for first amendment: 18/06/2018
4. The Ethikkommission an der Medizinischen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn, Bonn, Germany: approval for first submission: December 6, 2017; approval for first amendment: 08/05/2018
Study design
Multi-national interventional randomized double-blind placebo-controlled phase II trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Home
Trial type
Treatment
Patient information sheet
Not available in web format, please use contact details to request a participant information sheet.
Condition
Lymphatic filariasis (LF)
Intervention
The study involves daily observed treatment with either doxycycline 200 mg for 6 weeks, doxycycline 100 mg for 6 weeks or placebo matching doxycycline for 6 weeks (42 days). Participants with lymphedema stage 1-3 will be randomized (block randomisation) to one of the three treatment regimens, participants with lymphedema stage 4-6 will receive either doxycycline 200 mg or placebo matching doxycycline.
1. DOX 200: doxycycline 200 mg/d for 6 weeks (2 100 mg tablets/day orally) on top of standard MDA (ivermectin 200 µg/kg plus albendazole 400 mg once a year)
2. Placebo (control): placebo matching doxycycline for 6 weeks (2 tablets/day orally) on top of standard MDA (ivermectin 200 µg/kg plus albendazole 400 mg once a year)
3. DOX 100 (additional arm for group A [LE stage 1-3]): doxycycline 100mg/d for 6 weeks (1 tablet 100 mg doxycycline/day plus 1 tablet placebo matching doxycycline orally) on top of standard MDA (ivermectin 200 µg/kg plus albendazole 400 mg once a year)
Treatment will be administered ad personam by the trial clinician directly in the villages in the form of daily observed treatment (DOT). All treatment regimens will be administered on top of the standardized methods of hygiene ("standard of care") and on top of standard mass drug administration (MDA; ivermectin 200 µg/kg plus albendazole 400 mg) in areas where MDA is still ongoing. Treatment will be carried out in a blinded manner, meaning that neither the patients nor the caregiver will know to which treatment arm the patients belong.
Current as of 03/08/2018:
At baseline as well as 6, 12, 18 and 24 months after treatment onset, participants will undergo lymphedema-specific measurements (circumference measurements of the leg, volume measurement of the legs. A questionnaire regarding the occurrence of acute attacks (ADLA) will be carried out every 2 months after treatment onset. Participants will also undergo lymphedema management training at baseline and after 4, 6, 12, 18 and 24 months.
Previous:
At baseline as well as 6, 12 and 24 months after treatment onset, participants will undergo lymphedema-specific measurements (circumference measurements of the leg, volume measurement of the legs, ultrasound measurement of the skin thickness at the ankles). A questionnaire regarding the occurrence of acute attacks (ADLA) will be carried out every 2 months after treatment onset. Participants will also undergo lymphedema management training at baseline and after 4, 6, 12, 18 and 24 months.
Intervention type
Drug
Phase
Phase II
Drug names
Doxycycline, ivermectin, albendazole
Primary outcome measure
Lack of progression of LE (stage reduction or same stage as pre-treatment using the 7-point scale staging according to Dreyer et al, 2002), examined 24 months after treatment onset
Secondary outcome measures
1. Lack of progression of LE (stage reduction or same stage as pre-treatment using the 7-point scale staging according to Dreyer et al., 2002), examined 6, 12 or 18 months after treatment onset
2. Improvement of LE, i.e. stage reduction (at least one stage compared to pre-treatment), examined 6, 12, 18 and 24 months after treatment onset
3. Change of LE stages (reduction or increase) compared to baseline, assessed at 6, 12, 18 and 24 months after treatment onset
4. Changes (reduction or increase) of the circumference of the affected limbs compared to baseline circumferences, measured by tape measure at 6, 12 and 24 months after treatment onset
5. Changes of skin thickness of the affected limbs compared to baseline values, measured by ultrasound at 6, 12 and 24 months after treatment onset (outcome measure removed as of 03/08/2018)
6. Changes of the circumference of the affected limbs compared to baseline circumferences, measured with an infrared scanner (LymphaTech®) at 6, 12 and 24 months after treatment onset
7. Changes of the volume of the affected limbs compared to baseline volume, measured with an infrared scanner (LymphaTech®) at 6, 12 and 24 months after treatment onset
8. Changes in the duration of acute attacks compared to pre- treatment, as assessed with a questionnaire every two months after treatment onset and evaluated at 6, 12 and 24 months after treatment onset
9. Changes in the frequency of acute attacks compared to pre-treatment, as assessed with a questionnaire every two months after treatment onset and evaluated at 6, 12 and 24 months after treatment onset
10. Absence of acute attacks, as assessed with a questionnaire every two months after treatment onset and evaluated at 6, 12 and 24 months after treatment onset
11. Changes of the hygiene level compared to pre-treatment, assessed by using a hygiene survey especially developed for this study at 6, 12 and 24 months
12. Changes of the quality of life (QoL) compared to pre-treatment, assessed using the 12-item version of the WHODAS 2.0 at 12 and 24 months after treatment onset
13. Levels of angiogenic, lymphangiogenic, pro-fibrotic or pro-inflammatory biomarkers (such as VEGF, CECAM-a, MMPS) in blood and/or urine as a measure for prognostic effects, measured using ELISA and/or Luminex Multiplex Assay technique at baseline, 6, 12 and 24 months after treatment onset
14. T cell activation and differentiation markers in the blood such as HLADR, Ki67 and CD38 (activation), PD-1, CTLA-4, Eomes (exhaustion), CD45RA, CD27, CCR7 (differentiation) on CD4 and CD8 T cells, assessed using unstimulated whole blood which will be added to fluorochrome-conjugated antibodies that specifically detect the above mentioned factors. The percentage of positive cells is measured using flow cytometry at baseline, 6, 12 and 24 months after treatment onset
Assessment of safety:
Adverse events (AE) assessed and described in the scope of the daily observed treatment (DOT). This involves: a) occurrence of AE, b) intensity of AE (Grade 0 [none], Grade 1 [mild], grade 2 [moderate] grade 3 [severe], c) SAE, d) relation to treatment (definite, probable, possible, remote, not related), e) outcome of AE (restored, improved, unchanged, deteriorated, death, unknown, overcome with sequelae, f) intervention
Overall trial start date
01/01/2017
Overall trial end date
31/12/2020
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Lymphedema of at least one leg grade 1-6 measured on a 7-point scale [3]
2. Age ≥ 14 years and ≤ 65 years
3. Men or non-pregnant women. If women of childbearing-potential, they must use an approved, effective method of contraception (including abstinence) before, during and for at least 2 weeks after the completion of the active intervention with doxycycline or placebo
4. Negative pregnancy test
5. Body weight ≥ 40 kg
6. Resident in LF endemic area for ≥ 2 years
7. Able and willing to give informed consent/ to provide assent to participate in the trial
8. Ability to use established standardized methods of hygiene and effectively applying it prior to the initiation of the drug treatment
Participant type
Patient
Age group
Mixed
Gender
Both
Target number of participants
Group A (LE stage 1-3): n = 360, Group B (LE stage 4-6): n = 60
Participant exclusion criteria
1. No lymphedema or lymphedema stage 7
2. Age < 14 years or > 65 years
3. Body weight < 40 kg
4. Pregnant or breastfeeding women
5. Women of childbearing potential not using an agreed method of contraception (including abstinence; oral contraceptives are not allowed because of interaction with trial drugs)
6. Clinical or biologic evidence of hepatic or renal dysfunction or disease of the central nervous system (CNS)
7. Evidence of severe comorbidities except for features of filarial disease
8. Alcohol or drug abuse
9. History of adverse reactions to doxycycline or other tetracyclines
10. Any significant condition (including medical and psychological/ psychiatric disorder) which in the opinion of the study investigator might interfere with the conduct of the study
11. History of photosensitivity reactions after taking drugs.
12. Concomitant medication with antacids containing aluminium, magnesium or sucralfate and not able to discontinue
13. Concomitant medication with other antibiotics than doxycycline and not able to discontinue
14. Concomitant medication with diuretics or sulfonylurea
15. Concomitant medication with coumarin
16. Haemoglobin < 8 gm/dL
17. Neutrophil count <2000/mm3 - Updated 03/08/2018: Neutrophil count < 1100/mm3
18. Platelet count <100 000/mm3
19. Creatinine > 2 times upper limit of normal
20. AST (GOT) > 2 times upper limit of normal
21. ALT (GPT) > 2 times upper limit of normal
22. Gamma-GT > 2 times upper limit of normal
23. Positive urine pregnancy test
Recruitment start date
12/03/2018
Recruitment end date
21/07/2018
Locations
Countries of recruitment
Ghana
Trial participating centre
Kumasi Centre for Collaborative Research (KCCR)
Kwame Nkrumah University of Science and Technology
Kumasi
00000
Ghana
Sponsor information
Organisation
Kumasi Centre for Collaborative Research (KCCR)
Sponsor details
Kwame Nkrumah University of Science and Technology
Kumasi
00000
Ghana
Sponsor type
Research organisation
Website
Funders
Funder type
Research organisation
Funder name
Research Networks for Health Innovations in Sub-Saharan Africa sponsored by the Federal Ministry of Education and Research (BMBF), Germany
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
The publication of the study results is planned in a high-impact peer reviewed journal.
IPD sharing statement
The current data sharing plans for the current study are unknown and will be made available at a later date.
Intention to publish date
31/12/2021
Participant level data
To be made available at a later date
Basic results (scientific)
Publication list
2020 protocol in https://www.ncbi.nlm.nih.gov/pubmed/32228663 (added 02/04/2020)