A 24 Month Study, to Compare the Efficacy of Doxycycline vs. Placebo for Improving Filarial Lymphedema in Mali
Condition: Lymphedema; Lymphatic Filariasis; Filariasis
MeSH terms: Filariasis; Elephantiasis, Filarial; Lymphedema; Elephantiasis
Study type: Interventional
Phase: Phase 3

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Doxycycline; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Once daily tablet for 6 weeks:
Active comparator: Doxycycline hyclate 200 mg per day x 6 weeks for patients >50 kg or 100 mg per day for patients <50 kg); Once daily tablet for 6 weeks. Placebo comparator: matching tablets containing no active ingredients
Other intervention name(s): Doxycycline hyclate
Intervention MeSH terms: Doxycycline
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Lymphedema; Lymphatic Filariasis; Filariasis; Doxycycline