Doxycycline to improve filarial lymphedema (LEDoxy Ghana)

• Register: ISRCTN
• Last refreshed on: 30 January 2023
• Main ID: ISRCTN14042737
• Date of registration: 17/07/2017
• Prospective Registration: Yes
• Primary sponsor: Kumasi Centre for Collaborative Research (KCCR)
• Public title: Doxycycline to improve filarial lymphedema (LEDoxy Ghana)
• Scientific title: Doxycycline 200 mg/d vs 100 mg/d for 6 weeks to improve filarial lymphedema: a multi-national, double-blind, randomized, placebo-controlled trial
• Date of first enrolment: 12/03/2018
• Target sample size: 420
• Recruitment status: Completed
• URL: https://www.isrctn.com/ISRCTN14042737
• Study type: Interventional
• Study design: Multi-national interventional randomized double-blind placebo-controlled phase II trial (Treatment)
• Phase: Phase II

Countries of recruitment

Ghana

Contacts

• Name: Alexander Yaw Debrah

• Name: Achim Hoerauf

Key inclusion & exclusion criteria

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

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 <2000/mm3 - Updated 03/08/2018: Neutrophil count < 1100/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


Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

Lymphatic filariasis (LF)
Infections and Infestations
Filariasis

Intervention(s)

Current intervention as of 25/11/2021:
The study involves daily observed treatment with either doxycycline 200 mg for 6 weeks, doxycycline 100 mg for 6 weeks or placebo matching doxycycline for 6 weeks (42 days). Participants with lymphedema stage 1-3 will be randomized (block randomisation) to one of the three treatment regimens, participants with lymphedema stage 4-6 will receive either doxycycline 200 mg or placebo matching doxycycline.
1. DOX 200: doxycycline 200 mg/d for 6 weeks (2 100 mg tablets/day orally) on top of standard MDA (ivermectin 200 µg/kg plus albendazole 400 mg once a year)
2. Placebo (control): placebo matching doxycycline for 6 weeks (2 tablets/day orally) on top of standard MDA (ivermectin 200 µg/kg plus albendazole 400 mg once a year)
3. DOX 100 (additional arm for group A [LE stage 1-3]): doxycycline 100mg/d for 6 weeks (1 tablet 100 mg doxycycline/day plus 1 tablet placebo matching doxycycline orally) on top of standard MDA (ivermectin 200 µg/kg plus albendazole 400 mg once a year)

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

At baseline as well as 6, 12, 18 and 24 months after treatment onset, participants will undergo lymphedema-specific mea

Primary Outcome(s)

Current primary outcome measure as of 25/11/2021:
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 at 24 and 36 months


Previous primary outcome measure:
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 24 months after treatment onset

Secondary Outcome(s)

Current secondary outcome measures as of 25/11/2021:
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 at 6, 12, 18, 24, and 36 months
2. Improvement of LE, i.e. stage reduction (at least one stage compared to pre-treatment), examined at 6, 12, 18, 24, and 36 months
3. Change of LE stages (reduction or increase) compared to baseline, assessed at 6, 12, 24, and 36 months
4. Changes (reduction or increase) of the circumference of the affected limbs compared to baseline circumferences, measured by tape measure at 6, 12, 24, and 36 months
5. Changes in the circumference of the affected limbs compared to baseline circumferences, measured with an infrared scanner (LymphaTech®) at 6, 12, 24, and 36 months
6. Changes of the volume of the affected limbs compared to baseline volume, measured with an infrared scanner (LymphaTech®) at 6, 12, 24, and 36 months
7. 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, 24, and 36 months
8. 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, 24, and 36 months
9. Absence of acute attacks, as assessed with a questionnaire every two months after treatment onset and evaluated at 6, 12, 24, and 36 months
10. Changes of the hygiene level compared to pre-treatment, assessed by using a hygiene survey especially developed for this study at 6, 12, 24, and 36 months
11. Changes of the quality of life (QoL) compared to pre-treatment, assessed using the 12-item version of the WHODAS 2.0 at 12, 24, and 36 months
12. 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, 24, and 36 months
13. 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, 24, and 36 months
14. Symptoms related to COVID-19 and history of infection and vaccination with SARS-CoV-2 assessed using participant questions at 36 months

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


Previous 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, 12 or 18 months after treatment onset
2. Improvement of LE, i.e. stage reduction (at least one stage compared to pre-treatment), examined 6, 12, 18 and 24 months after treatment onset
3. Change of LE stages (reduction or increase) compared to baseline, assessed at 6, 12, 18 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 (outcome measure removed as of 03/08/2018)
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

Secondary ID(s)

TAKeOFF-4-0117

Source(s) of Monetary Support

Research Networks for Health Innovations in Sub-Saharan Africa sponsored by the Federal Ministry of Education and Research (BMBF), Germany

Ethics review

Status:
Approval date:
Contact:

Current ethics approval as of 25/11/2021: 1. Approved 24/10/2017; approval for first amendment: 13/04/2018; approval for 3 year-follow up 10/11/2021; The Committee for Human Research, Publication and Ethics (CHRPE) of the Kwame Nkrumah University of Science and Technology (KNUST) (Kumasi, Ghana), ref: CHRPE/AP/535/21 2. Approved 13/12/2017; approval for first amendment: 31/05/2018; The Ghana Health Service Ethics Review Committee (GHS-

Results

• Results available: Yes
• Date Completed: 20/08/2020