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Randomized Controlled Trial
. 2024 Oct 1;111(4_Suppl):83-93.
doi: 10.4269/ajtmh.24-0337. Print 2024 Oct 1.

Efficacy and Safety of Adding 6 Weeks of Doxycycline to the Essential Package of Care to Treat Filarial Lymphedema: A Double-Blind, Randomized, Controlled Trial in Southern India

Suma Krishnasastry  1 , Anuja Ashok  1 , Ammu Devidas  1 , Sarah Sullivan  2 , Mariana Stephens  2 , Jayla Norman  2 , Elianna Paljug  2 , Andrew Deathe  2 , Andrew Majewski  2 , John Horton  3 , Joseph P Shott  4 , Ute Klarmann-Schulz  5 , Achim Hoerauf  5 , Eric Ottesen  2 , Charles D Mackenzie  2   6
Affiliations
Randomized Controlled Trial

Efficacy and Safety of Adding 6 Weeks of Doxycycline to the Essential Package of Care to Treat Filarial Lymphedema: A Double-Blind, Randomized, Controlled Trial in Southern India

Suma Krishnasastry et al. Am J Trop Med Hyg. .

Abstract

Finding additional ways to manage lymphedema due to lymphatic filariasis (LF) is a primary concern for the Global Program to Eliminate Lymphatic Filariasis. The WHO-recommended Essential Package of Care (EPC) consists of skin hygiene, elevation of affected limbs, exercise, protective shoe ware, wound care, and supportive therapy for acute phases. The care program has been successful but often hard to maintain. A double-blind study reexamined previous findings that doxycycline treatment could improve the lymphedematous changes in LF patients. The present study was carried out in a semi-urban location of Kerala, southern India, where Brugia sp. is the predominant parasite, and LF mass drug administration had ceased in many areas. Two hundred individuals (aged 14-65 years; 142 females and 58 males) with lymphedema of stages 1-3 were instructed in the EPC and were randomly administered either 200 mg doxycycline or an identical-appearing placebo daily for 6 weeks. Data were collected at 0, 3, 6, 12, 18, and 24 months and included the state of the lymphedema (size, cleanliness, skin thickness and changes), occurrence of adenolymphangitis (ADL) attacks, and patients' quality of life (QOL). The results demonstrated no difference over time between the two arms of the study; virtually all patients of both groups showed either improvement or "no worsening" in the parameters during the 2-year study period. Importantly, this rigorous trial confirmed that the EPC is of substantial benefit to lymphedema patients by reducing acute ADL and improving their QOL and clinical condition.

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Conflict of interest statement

Disclosures: The core protocol was approved by Western Institutional Review Board (Olympia, Washington). This study site was registered on Clintrials.gov (India: NCT 02929121). The approval for the study in India was obtained from Health Ministry Screening Committee (HMSC) of the India Council of Medical Research, India, and also the Institutional Ethics committee of Government TD Medical College, Alappuzha, Kerala. Approval from the HMSC, Ministry of Health (GOI) was obtained for study drug importation and for the trial implementation. A separate Data Safety Monitoring Committee (DSMC) composed of independent scientists was established to monitor the safety aspects of the study; data were reviewed by the PI, Safety Officer, and the DSMC quarterly, or immediately if required in cases where serious adverse experiences occurred. Informed written consent was obtained from all individuals.

Authors’ contributions: Study design and protocol: S. Krishnasastry, C. D. Mackenzie, A. Deathe, J. Horton, J. P. Shott, U. Klarmann-Schultz, A. Hoerauf, and E. Ottesen. Study management: S. Krishnasastry, M. Stephens, A. Majewski, A. Deathe, E. Ottesen, and C. D. Mackenzie. Study implementation: S. Krishnasastry, A. Ashok, A. Devidas, and J. P. Shott. Analysis and interpretation: S. Krishnasastry, S. Sullivan, J. Norman, E. Paljug, C. D. Mackenzie, and E. Ottesen. Manuscript production: C. D. Mackenzie, E. Ottesen, S. Sullivan, and S. Krishnasastry. Manuscript review: S. Krishnasastry, C. D. Mackenzie, E. Ottesen, J. Horton, A. Deathe, A. Ashok, A. Devidas, S. Sullivan, J. Norman, and A. Majewski.

Figures

Figure 1.
Figure 1.
Study settings, Alappuzha, Kerala, India.
Figure 2.
Figure 2.
Study flow chart: Enrollment and follow-up of participants. GGT = gamma-glutamyl transferase; GI = gastro intestinal.
Figure 3.
Figure 3.
Sankey plots: Improvement of lymphedema stages during follow-up.
Figure 4.
Figure 4.
Lymphedema improvement: Multivariate logistic analysis. ADL = adenolymphangitis; DOX = doxycycline; Mo. = month(s); OR = odds ratio; Ref = reference.
Figure 5.
Figure 5.
WHODAS 2.0 score metrics. Error bars shown depict the 95% confidence interval associated with the WHODAS point estimate.
Figure 6.
Figure 6.
WHODAS disability assessment schedule: Regression analysis. ADL = adenolymphangitis; DOX = doxycycline; LE = lymphoedema; Mo. = month(s); Ref = reference. Error bars shown depict the 95% confidence interval of the odds ratio for the corresponding independent variable.
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