A 24 Month Study, to Compare the Efficacy of Doxycycline vs. Placebo for Improving Filarial Lymphedema in Mali

A Multi-center, Double-blind, Randomized, 24-month Study, to Compare the Efficacy of Doxycycline Once Daily for 6 Weeks Versus Placebo in Improving Filarial Lymphedema Independent of Active Filarial Infection

Current lymphedema management protocols are 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" in most endemic countries in the absence of any structured treatment programs. Previous controlled clinical trials and extensive field experience have shown the benefit of these measures in reducing the frequency of attacks of acute dermato-lymphangio-adenitis (ADLA) that drive the progression of lymphedema.

In the present study, the progression of lymphedema in a group of patients who receive a six-week course of doxycycline will be compared with that of a group who receives doxycycline "look-alike" placebo tablets. However, both groups will be enrolled into a standardized "regimen of hygiene" described above. Thus, patients enrolled in the "placebo" group also will receive the current standard of care, and the placebo used in the study will help to identify the benefits of doxycycline on a background of simple hygiene measures. The regimens will be explained to all participants who will be trained to use established standardized methods of hygiene and be effectively applying it prior to the initiation of the drug treatment. In addition, patients will be evaluated at 3, 6, 12 and 24 months.. A common, generic SOP with handouts that describes methods and the training schedule will be used so that similar methods are employed across all sites.

This (LEDOXY) trial is designed as a randomized, controlled, observer-, provider- and patient-blinded multicenter superiority trial with two parallel groups and a primary endpoint of change in grade of lymphedema at 24 months. The population will be stratified according to the Grade (Early Grade 1-3; Late Grade 4-6). Randomization will be performed as block randomization within each center in blocks of (N=4-10) for each of the groups (Early and Late).

The effect of a 6-week course doxycycline on lymphedema without active filarial infection has been demonstrated in a single setting in Africa (Ghana). In order to expand the benefits of this observation, similar studies need to be carried out in other endemic settings. Lymphatic filariasis is endemic in many countries of Africa and Asia that are yet to implement morbidity management programmes. In addition, the components of the proposed hygiene package are likely to vary depending on the availability of material and human resources. The conduct of this trial as a multi-center study will not only allow the evaluation of the efficacy of the drug in a variety of settings but also facilitate its rapid adoption by the respective control programmes of endemic countries, if proven to be useful.

The choice of study sites in endemic countries has been made based on the availability of a) adequate numbers of patients with various grades of lymphedema and b) clinical trial teams familiar with lymphedema management procedures and past experience with similar trials.

All screened patients will be enrolled into a programme of hygiene (described below) and will be required to demonstrate ability to use established standardized methods of hygiene and effectively applying it prior to the initiation of the drug treatment. Eligible patients will be randomized to receive either daily doxycycline or placebo. Doxycycline and placebo will be provided by Medopharm (India). Re-labeling and packaging of the drug and the placebo will be done by Piramal Healthcare, Morpeth, UK

Additionally, after un-blinding and data analysis, the placebo group will be offered doxycycline treatment if the intervention proves to be more effective in ameliorating LE.

Both doxycycline and placebo will be administered under supervision (directly observed treatment) for 6 weeks. The first dose of doxycycline (two 100 mg tablets for those over 50kg body weight and one 100 mg tablets for those between 40 and 50 kg body weight) or placebo will be given after all the investigations have been completed and informed consent has been obtained and the patient has been initiated into the programme of basic hygiene (Appendix 2 and 3, Study Schedule). Patients will be encouraged to eat before swallowing the tablets whole with a glass of water. Vomited doses will be replaced.

Ideally, patients will be required to come every day to the closest community health center to take their drugs under supervision. Subjects living in villages at a distance from any health center will be treated by the community health care provider or the local caregiver living in this village who will be informed and trained in the possible adverse events related to the drug.

Since some study sites may be village based without a health centre, patients may be treated in their village and required to attend daily at a fixed meeting point. The trial clinician and the research team with the help of trained community health workers will normally administer the treatment. They should come to the clinic every week with the patient and collect the drugs for one week. The provider will keep a diary where he or she will mark down the time of intake of the drug. A health worker may make surprise checks at the patient's residence by looking at the diary and also by counting the remaining drugs to estimate compliance.

Inclusion Criteria:

Patients eligible for the trial must comply with all of the following at randomization:

1. Age ≥ 14 years and <65 years, male or non-pregnant women of childbearing-potential using an approved, effective method of contraception before, during and for at least 2 weeks after the completion of the active intervention with doxycycline or placebo
2. Able to give informed consent to participate in the trial (forms to be attached)
3. Resident in endemic area for five years or more
4. Body weight >40 kg
5. Lymphedema of a limb Grade 1-6 measured on a 7-point scale. (Appendix 1 for explanation of the grading system (Dreyer G et al. 2002).
6. Ability to use established standardized methods of hygiene and effectively applying it prior to the initiation of the drug treatment
7. No evidence of severe or systemic comorbidities except for features of filarial disease
8. Normal laboratory profile (Appendix 3 investigations and the maximum or minimum limits in the case of hematological abnormalities - Site Specific)
9. Consent to storage of blood samples for study

Exclusion Criteria:

Patients are ineligible to participate in the trial, if they have any of the following:

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. (A pregnancy test will be conducted as part of the screening process to exclude pregnancy and repeated at 3 and 8 weeks. In addition, women of childbearing potential will be counseled against pregnancy during the treatment period)
6. Clinical or laboratory evidence of hepatic or renal dysfunction or CNS disease
7. Alcohol or drug abuse
8. History of adverse reactions to doxycycline or other tetracyclines
9. Patient has any situation or condition that may interfere with participation in the study as judged by the clinical investigator