Doxycycline to improve lymphedema due to podoconiosis

• Register: ISRCTN
• Last refreshed on: 30 January 2023
• Main ID: ISRCTN11881662
• Date of registration: 25/07/2017
• Prospective Registration: Yes
• Primary sponsor: University of Buea
• Public title: Doxycycline to improve lymphedema due to podoconiosis
• Scientific title: Doxycycline for treatment of non-filarial lymphedema due to podoconiosis (PodoLE): a randomized, placebo-controlled trial
• Date of first enrolment: 01/05/2019
• Target sample size: 200
• Recruitment status: Completed
• URL: https://www.isrctn.com/ISRCTN11881662
• Study type: Interventional
• Study design: Interventional randomized double-blind placebo-controlled phase II trial (Treatment)
• Phase: Phase II

Countries of recruitment

Cameroon

Contacts

• Name: Achim Hoerauf

• Name: Samuel Wanji

Key inclusion & exclusion criteria

Inclusion criteria:
Current participant inclusion criteria as of 07/05/2019:
1. Lymphedema of at least one leg grade 2-3 measured on a 5-point scale (Tekola et al, 2008)
2. Age = 18 years and = 60 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 endemic area for podoconiosis 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
9. Negative test for lymphatic filariasis (LF)


Previous participant inclusion criteria:
1. Lymphedema of at least one leg grade 2-4 measured on a 5-point scale (Tekola et al, 2008)
2. Age = 18 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 endemic area for podoconiosis 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
9. Negative test for lymphatic filariasis (LF)

Exclusion criteria:
Current participant exclusion criteria as of 07/05/2019:
1. No lymphedema
2. Stage 1, 4 or stage 5 lymphedema due to podoconiosis
3. Lymphedema due to lymphatic filariasis (LF)
4. Age < 18 years or > 60 years
5. Body weight < 40 kg
6. Pregnant or breastfeeding women
7. Women of childbearing potential not using an agreed method of contraception (including abstinence; oral contraceptives are not allowed because of interaction with trial drugs)
8. Clinical or biologic evidence of hepatic or renal dysfunction or disease of the central nervous system (CNS)
9. Evidence of severe comorbidities except for features of filarial disease
10. Alcohol or drug abuse
11. History of adverse reactions to doxycycline or other tetracyclines
12. 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
13. History of photosensitivity reactions after taking drugs.
14. Concomitant medication with antacids containing aluminium, magnesium or sucralfate and not able to discontinue
15. Concomitant medication with other antibiotics than doxycycline and not able to discontinue
16. Concomitant medication with diuretics or sulfonylurea
17. Concomitant medication with coumarin
18. Haemoglobin < 8 gm/dL
19. Neutrophil count <1 100/mm3
20. Platelet count <100 000/mm3
21. Creatinine > 2 times upper limit of normal
22. AST (GOT) > 2 times upper limit of normal
23. ALT (GPT) > 2 times upper limit of normal
24. Gamma-GT > 2 times upper limit of normal
25. Positive urine pregnancy test
26. Positive test for W. bancrofti


Previous participant exclusion criteria:
1. No lymphedema, stage 1 or stage 5 lymphedema due to podoconiosis
2. Lymphedema due to lymphatic filariasis (LF)
3. Age < 18 years or > 65 years
4. Body weight < 40 kg
5. Pregnant or breastfeeding women
6. Women of childbearing potential not using an agreed method of contraception (including abstinence; oral contraceptives are not allowed because of interaction with trial drugs)
7. Clinical or biologic evidence of hepatic or renal dysfunction or disease of the central nervous system (CNS)
8. Evidence of severe comorbidities except for features of filarial disease
9. Alcohol or drug abuse
10. History of adverse reactions to doxycycline or other tetracyclines
11. 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
12. History of photosensitivity reactions after taking drugs.
13. Concomitant medication with antacids containing aluminium, magnesium or sucralfate and not able to discontinue
14. Concomitant medication with other antibiotics than doxycycline and not able to discontinue
15. Concomitant m

Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

Podoconiosis (Podo)
Injury, Occupational Diseases, Poisoning
Lymphoedema, not elsewhere classified

Intervention(s)

Current interventions as of 07/05/2019:
The study involves daily observed treatment with either doxycycline 200mg for 6 weeks or placebo matching doxycycline for 6 weeks (42 days). Participants with lymphedema due to pododconiosis (PodoLE) stage 2-3 will be randomized (block randomisation) to one of the two treatment regimens:
1. DOX 200: Doxycycline 200mg/d for 6 weeks (2 100mg tablets/day orally)
2. Placebo (control): Placebo matching Doxycycline for 6 weeks (2 tablets/day orally)

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").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 measurements (circumference measurements of the leg, volume measurement of the legs). A questionnaire regarding the occurrence of acute attacks (ADLA) will be carried out every 2 months after treatment onset. Participants will also undergo lymphedema management training at baseline and after 4, 6, 12, 18 and 24 months.


Previous interventions:
The study involves daily observed treatment with either doxycycline 200mg for 6 weeks or placebo matching doxycycline for 6 weeks (42 days). Participants with lymphedema due to pododconiosis (PodoLE) stage 2-4 will be randomized (block randomisation) to one of the two treatment regimens:
1. DOX

Primary Outcome(s)

Lack of progression of lymphedema due to podoconiosis (PodoLE) (stage reduction or same stage as pre-treatment using the 5-point scale staging according to Tekola et al, 2008), examined 24 months after treatment onset

Secondary Outcome(s)

Current secondary outcome measures as of 07/05/2019:
1. Lack of progression of PodoLE (stage reduction or same stage as pre-treatment using the 5-point scale staging according to Tekola et al, 2008), examined 6, 12 or 18 months after treatment onset
2. Improvement of PodoLE, 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 PodoLE 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, 18 and 24 months after treatment onset
5. Changes of the circumference of the affected limbs compared to baseline circumferences, measured with an infrared scanner (LymphaTech®) at 6, 12, 18 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 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

Assessment of safety:
Adverse events (AE) assessed and described in the scope of the daily observed treatment (DOT). This involves:
1. Occurrence of AE
2. Intensity of AE (Grade 0 [none], Grade 1 [mild], grade 2 [moderate] grade 3 [severe])
3. SAE
4. Relation to treatment (definite, probable, possible, remote, not related)
5. Outcome of AE (restored, improved, unchanged, deteriorated, death, unknown, overcome with sequelae)
6. Intervention


Previous secondary outcome measures:
1. Lack of progression of PodoLE (stage reduction or same stage as pre-treatment using the 5-point scale staging according to Tekola et al, 2008), examined 6 or 12 months after treatment onset
2. Improvement of PodoLE, i.e. stage reduction (at least one stage compared to pre-treatment), examined 6, 12 and 24 months after treatment onset
3. Change of PodoLE stages (reduction or increase) compared to baseline, assessed at 6, 12 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
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

Assessment of safety:
Adverse events (AE) assessed and described in the scope of the daily observed treatment (DOT). This involves:
1. Occurrence of AE
2. Intensity of AE (Grade 0 [none], Grade 1 [mild], grade 2 [moderate] grade 3 [severe])
3. SAE
4. Relation to treatment (definite, probable, possible, remote, not related)
5. Outcome of AE (restored, improved, unchanged, deteriorated, death, unknown, overcome with sequelae)
6. Intervention

Secondary ID(s)

TAKeOFF-5-0517

Nil known

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 07/05/2019: 1. Approved 03/05/2019, Comite Ethique de la Recherche pour la Sante Humaine (CNERSH), Yaounde, Cameroon, ref: 2018/05/1002/CE/CNERSH/SP. 2. Approved 04/05/2018, The Ethikkommission an der Medizinischen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn, Bonn, Germany, ref: 139/18. Previous ethics approval: Documents will be submitted in Septem

Results

• Results available: Yes
• Date Completed: 22/01/2022