Condition category
Infections and Infestations
Date applied
21/07/2017
Date assigned
25/07/2017
Last edited
25/07/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

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 200mg was given to patients with lymphedema for six 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 Tanzania and is one of five studies that have the aim to confirm the effect of doxycycline 200mg for 6 weeks. The other four studies are carried out in Mali, Sri Lanka, India and Ghana. While the three studies in Mali, Sri Lanka and India compare doxycycline 200 mg for six weeks versus a placebo (dummy drug) matching doxycycline (both treatments on top of standard methods of hygiene), the two studies in Tanzania and Ghana have the additional aim to find out whether a lower dose of doxycycline of 100mg 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 200mg, doxycycline 100mg or a placebo for six weeks, and participants with lymphedema stage 4-6 are randomly allocated to receive doxycycline 200mg or a placebo for six weeks. All treatments are given in addition to the standard methods of hygiene and mass drug administration (ivermectin 200µg/kg plus albendazole 400mg) in areas where this is still ongoing. At the start of the study and six, 12 and 24 months later, participants undergo measurements of the leg and the skin thickness at the ankles. A questionnaire about the occurrence of acute attacks is carried out every two months after treatment onset. Participants also undergo lymphedema management training at the start of the study and after four, six, 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?
The National Institute of Medical Research (NIMR) (Tanzania)

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. Upendo Mwingira, NIMR, Tanzania
umwingira@yahoo.com

Trial website

Contact information

Type

Public

Primary contact

Dr Upendo Mwingira

ORCID ID

Contact details

The National Institute of Medical Research (NIMR)
3 Barak Obama Drive
P.O.Box 9653
Dar es Salaam
11101
Tanzania
+255 783 276 177
umwingira@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
+49 228 28715673
achim.hoerauf@ukbonn.de

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

TAKeOFF-4-0117-TZ

Study information

Scientific title

Doxycycline 200mg/d vs 100mg/d for 6 weeks to improve filarial lymphedema: A multi-national, double-blind, randomized, placebo-controlled trial

Acronym

TAKeOFF - LEDoxy

Study hypothesis

Hypotheses for Group A (LE stage 1-3):
1. To confirm the efficacy of a 6-week course of daily doxycycline 200mg on lack of progression of filarial lymphedema (LE).
2. To reduce the dosage of doxycycline from 200mg/d to 100mg/d for 6 weeks for the treatment of filarial LE.

Hypothesis for Group B (LE stage 4-6):
1. To show efficacy of a 6-week course of daily doxycycline 200mg on lack of progression of filarial LE.

Ethics approval

Submission pending, documents will be submitted in August/September 2017 to the following boards for approval:
1. National Health Research Ethics Sub-Committee (NatHREC) of the Medical Research Coordinating Committee (MRCC),Dar es salaam, Tanzania
2. Tanzania Food and Drug Authority, Dar es salaam,Tanzania
3. The Ethikkommission an der Medizinischen Fakultaet der Rheinischen Friedrich-Wilhelms-Universitaet Bonn, Bonn, Germany

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 200mg for 6 weeks, doxycycline 100mg for 6 weeks or placebo matching doxycycline for 6 weeks (42 days). Participants with lymphedema stage 1-3 are randomised using block randomisation to one of the three treatment regimens, participants with lymphedema stage 4-6 receive either doxycycline 200mg or placebo matching doxycycline.

1. DOX 200: Doxycycline 200mg/d for six weeks (2 100mg tablets/day orally) on top of standard MDA (ivermectin 200µg/kg plus albendazole 400mg once a year)

2. Placebo (control): Placebo matching Doxycycline for six weeks (2 tablets/day orally) on top of standard MDA (ivermectin 200µg/kg plus albendazole 400mg once a year)

3. DOX 100 (additional arm for group A [LE stage 1-3]): Doxycycline 100mg/d for six weeks (1 tablet 100mg doxycycline/day plus one tablet placebo matching doxycycline orally) on top of standard MDA (ivermectin 200µg/kg plus albendazole 400mg once a year)

Treatment is administered ad personam by the trial clinician directly in the villages in the form of daily observed treatment (DOT). All treatment regimens is administered on top of the standardized methods of hygiene ("standard of care") and on top of standard mass drug administration (MDA; ivermectin 200µg/kg plus albendazole 400mg) in areas where MDA is still ongoing. Treatment is carried out in a blinded manner, meaning that neither the patients nor the caregiver know to which treatment arm the patients belong.

At baseline as well as six, 12 and 24 months after treatment onset, participants 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) is carried out every two months after treatment onset. Participants also undergo lymphedema management training at baseline and after four, six, 12, 18 and 24 months.

Intervention type

Drug

Phase

Phase II

Drug names

Doxycycline

Primary outcome measures

Lack of progression of lymphedema (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 or 12 months after treatment onset
2. Improvement of LE, i.e. stage reduction (at least one stage compared to pre-treatment), examined 6, 12 and 24 months after treatment onset
3. Change of LE stages (reduction or increase) compared to baseline, assessed at 6, 12 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
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

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 <2 000/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

01/01/2018

Recruitment end date

30/09/2018

Locations

Countries of recruitment

Tanzania

Trial participating centre

The National Institute of Medical Research (NIMR)
3 Barak Obama Drive P.O.Box 9653
Dar es Salaam
11101
Tanzania

Sponsor information

Organisation

The National Institute of Medical Research (NIMR)

Sponsor details

3 Barak Obama Drive
P.O. Box 9653
Dar es Salaam
11101
Tanzania

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)

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

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes