LEDoxy Randomized Controlled Trial

Background: Current treatment practices of lymphedema rely on decreasing the number of acute attacks by improving the hygiene of affected limbs, use of appropriate topical antibiotics and antifungals, exercise, elevation of the limb and use of footwear. While this treatment package has been shown to be effective in halting the progression of lymphedema, it requires sustained access to resources required for limb care and strict adherence to the prescribed procedures.

The anti-Wolbachia effects of doxycycline and its potential role in filarial infections have been well documented. Recent observations have suggested a potential role for lymphatic endothelium-derived VEGF-C and sVEGFR3 and other angiopoetic factors in the pathogenesis of lymphedema that could be lowered by doxycycline. A six-week course of Doxycycline (200 mg daily) prevented progression of lymphedema in patients with active infection of W. bancrofti. More recently, in a trial in Ghana, a similar course of doxycycline decreased severity of mild to moderate lymphedema independent of active filarial infection.

The effect of doxycycline in reversing or stopping the progression of lymphedema of patients with stage 1-3, irrespective of their filarial infections being active, provides an opportunity to include the drug as a new tool in LF morbidity management programs. However, before recommendations can be made regarding the frequency of its usage or alternate dosing patterns the findings of the Ghana study need to be replicated in other settings. This multi-center trial is designed to confirm the findings of the lone study that documented the efficacy of doxycycline treatment in patients with stages 1-3 lymphedema, irrespective of active LF infection, as well people with higher grades of lymphedema.

Objectives: The primary objective of the study was to evaluate the efficacy of a 6-week course of daily doxycycline on changes in the grades of lymphedema.
Secondary objectives were to evaluate the efficacy of a 6-week course of doxycycline in:

changes in the circumference and volume of affected limbs
reducing the skin thickness of affected limbs
reducing the frequency of acute attacks of ADLA and
assessing the tolerability and safety of doxycycline given for 6 weeks.

Methodology:

Geographic Location/Study Sites:

Sri Lanka: Galle and Matara districts and their adjacent suburbs: Unawatuna, Gintota, Bope, Balapitiya, Ambalangoda, Hikkaduwa, Walgama, Pamburana, Madihe, Polhena, Dikwella
Mali: Kolondieba, Sikasso and Kolokani, Koulikoro
India: Ambalappuzha and Cherthala Yaluks of Alappuzha District, Kerala

Eligibility Criteria:
Identification of potential participants:

Sri Lanka: Participants were recruited from Galle and Matara districts and their adjacent suburbs. Participants receiving care at the Filariasis Research Training and Service Unit clinic were invited to participate, and loudspeaker announcements were made in the selected areas. Participants and households contacted by these methods were asked to also to refer other lymphedema patients in their communities.
Mali: Patients with LE in Mali are generally found in rural areas with 1 to 2 cases in a village. Based on a comprehensive survey of LE in 3 health districts of Mali (Kolondieba, Bougouni and Kolokani all those previously identified as having LE were screened for study eligibility.
India: Participants were initially recruited from patients at existing Lymphedema Management Clinics. Snowball sampling was then utilized to capitalize on the patients’ knowledge of other people with lymphedema in their communities.

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

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
Able to give informed consent to participate in the trial (forms to be attached)
Resident in endemic area for five years or more
Body weight >40 kg
Lymphedema of a limb Grade 1-6 measured on a 7-point scale. (Appendix 2 for explanation of the grading system (Dreyer G et al. 2002)
Ability to use established standardized methods of hygiene and effectively applying it prior to the initiation of the drug treatment
No evidence of severe or systemic comorbidities except for features of filarial disease
Normal laboratory profile (Appendix 3 investigations and the maximum or minimum limits in the case of hematological abnormalities – Site Specific)
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:
No lymphedema or lymphedema stage 7
Age < 14 years or > 65 years
Body weight < 40 kg
Pregnant or breastfeeding women
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)
Clinical or laboratory evidence of hepatic or renal dysfunction or CNS disease
Alcohol or drug abuse
History of adverse reactions to doxycycline or other tetracyclines
Patient has any situation or condition that may interfere with participation in the study as judged by the clinical investigator)

Dates of Data Collection:

Sri Lanka: February 2018 – June 2020
Mali: June 2018 – December 2020
India: January 2019 – June 2021

Study Design: Randomized Controlled Trial with longitudinal follow-up for 24 months

Study Arms: Participants were enrolled in three arms: placebo, low- and standard-dose doxycycline.

Data Collection: Data was collected via paper case report forms. These forms were then entered into REDCap by site study staff and validated by site data managers and central data manager.

Data was collected at 56 timepoints. These included a Screening visit, an Enrollment visit, 42 treatment visits, 8 interim follow-up visits to facilitate recall of symptoms and 4 major follow-up visits (at 6, 12, 18 and 24 months) to assess the study outcomes.

Survey data of participant ADL attacks, and concomitant medication was collected at all timepoints. Clinical measurements of affected limbs, quality of life assessment, and observer assessed limb hygiene were conducted at screening, enrollment and major follow-ups. Medical histories were collected at screening. Serum samples were collected at screening, day 22 of treatment and day 42 of treatment to ascertain suitability for the study and monitor liver function during treatment. Urine samples were collected at screening, day 22 of treatment and day 42 of treatment for women under age 55 to assess pregnancy status given the contrindication of doxycycline during pregnancy.

Study Documentation: Coming soon

ClinEpiDB Data Integration: Coming soon

Acknowledgements: The researchers are indebted to the late VK Kumaraswami who was pivotal in developing the early drafts of the protocols. The researchers also acknowledge the input of the following individuals in final design of the study: Joe Schott, Ute Klarmann-Schulz, Achim Hoerauf, Gary Weil, Inge Kroidl, and Drew Deathe. We gratefully acknowledge the many study research assistants, nurses, data managers, and other study staff who contributed to the execution of this study. Thanks in particular to Jennifer Nadal, Brian Plikaytis, Esther Amoakohene, John Shen, Elianna Sinclair, and Jayla Norman for their contributions to data cleaning, management, and analysis. Finally, we thank the study participants and their families without whom this work would not be possible.

Financial Support: This work received financial support from the United States Agency for International Development (USAID) through its Neglected Tropical Diseases Program through their support of the Coalition for Operational Research on Neglected Tropical Diseases (COR-NTD) grant. COR-NTD is funded at The Task Force primarily by the Bill & Melinda Gates Foundation and USAID.

Ethics Statement: This research study has been approved by the following: Western Institutional Review Board (now WCG IRB); Sri Lanka Ethics Review Committee, Faculty of Medicine, University of Colombo; Mali Comité D’Ethique de la Faculte de Medecine et D’Odonto-Stomatologie, Universite des Sciences, des Techniques et des Technologies de Bamako; India Institutional Ethics Committee TD Medical College Alappuzha.

Last Updated: November 17, 2023LEDoxy is a double-blind, placebo-controlled study designed to investigate the impact of six weeks treatment with doxycycline added to standard limb hygiene on early stage filarial lymphoedema in five sites in Africa and the Indian subcontinent.