Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202104600961505 Date of Approval: 21/04/2021
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Tylamac phase-II study for the treatment of onchocerciasis
Official scientific title A Phase-II, Randomised, Double-blind, Parallel-group, Proof-of-concept Trial to Investigate ABBV-4083 given for 7 or 14 Days or in Combination with Albendazole in Subjects with Onchocerca volvulus Infection, comprising: Part 1 to Investigate Safety, Tolerability, Efficacy for Dose-Ranging and Pharmacokinetics; Part 2 to Investigate Efficacy of Selected Doses, Safety, Tolerability and Pharmacokinetics
Brief summary describing the background and objectives of the trial Onchocerciasis is a neglected tropical diseases caused by a filarial parasite. Current efforts to eliminate the disease are hindered by a lack of drugs that permanently sterilize the adult worms or provide a macrofilaricidal effect, i.e. kill the adult worms. Antibiotics, including doxycycline, have been shown to deplete Wolbachia, an endosymbiotic bacterium essential to the fertility and development of the parasites, leading to permanent sterilization and macrofilaricidal efficacy. However, contraindications in women of child-bearing age, in breastfeeding women and in children, as well as the long duration of treatment (4-6 weeks) limit the use of these drugs, creating a need for agents with fewer contraindications and a shorter treatment regimen. ABBV-4083 is an anti-Wolbachia agent with demonstrated anti-wolbachial activity in several filarial animal models. ABBV-4083 has also been shown to be synergistic with albendazole in preclinical filarial models, similar to results with doxycycline plus albendazole. The present phase-II study in patients with onchocerciasis will be an adaptive study with two parts. In Part 1, four regimens of ABBV-4083 ± albendazole will be assessed in comparison to albendazole alone with the aim of selecting two regimens having optimal safety and activity to continue into Part 2 using a surrogate endpoint, i.e. the level of Wolbachia depletion at Month 6, which has been shown to correlate with the absence of skin microfilaria at longer-term time-points. The aim of Part 2 is to select the optimal treatment regimen for phase-III studies, based on the safety, tolerability and efficacy of ABBV-4083 compared to placebo using a clinically relevant endpoint, i.e. the percentage of subjects without skin microfilariae at Month 24.
Type of trial RCT
Acronym (If the trial has an acronym then please provide)
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied Onchocerciasis
Purpose of the trial Treatment: Drugs
Anticipated trial start date 30/04/2021
Actual trial start date 22/05/2021
Anticipated date of last follow up 30/06/2022
Actual Last follow-up date 01/10/2022
Anticipated target sample size (number of participants) 444
Actual target sample size (number of participants) 153
Recruitment status Stopped early/ terminated
Publication URL
Secondary Ids Issuing authority/Trial register
DNDi TYL 01 Sponsor
B18 894 Abbvie
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Stratified allocation where factors such as age, gender, center, or previous treatment are used in the stratification Central randomisation by phone/fax Masking/blinding used Care giver/Provider,Outcome Assessors,Participants
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group Part 1 Arm A ABBV 4083 ABBV-4083 400 mg once daily 7 days 7 days of ABBV-4083 400 mg + albendazole placebo followed by 7 days of ABBV-4083 placebo 30
Experimental Group Part 1 Arm B ABBV 4083 ABBV-4083 400 mg once daily 14 days 14 days of ABBV-4083 400 mg + albendazole placebo followed by 7 days of ABBV-4083 400 mg 30
Experimental Group Part 1 Arm C ABBV 4083 and albendazole ABBV-4083 400 mg once daily Albendazole 400 mg once daily 7 days and 7 days 7 days of ABBV-4083 400 mg + albendazole 400 mg followed by 7 days of ABBV-4083 placebo 30
Experimental Group Part 1 Arm D ABBV 4083 and albendazole ABBV-4083 400 mg once daily Albendazole 400 mg once daily 7 days and 3 days 3 days of ABBV-4083 400 mg + albendazole 400 mg followed by 4 days of ABBV-4083 400 mg + albendazole placebo followed by 7 days of ABBV-4083 placebo 30
Control Group Part 1 Arm E albendazole Albendazole 400 mg once daily 7 days 7 days of ABBV-4083 placebo + albendazole 400 mg followed by 7 days of ABBV-4083 placebo 30 Active-Treatment of Control Group
Experimental Group Part 2 Basic Arm K ABBV 4083 plus or minus albendazole plus ivermectin Dose regimen 1 selected from Part 1 Dose regimen selected from Part 1 Same as Arm A, B, C or D from Part 1 with ivermectin at Month 6 84
Experimental Group Part 2 Basic Arm L ABBV 4083 plus or minus albendazole Dose regimen 1 selected from Part 1 Dose regimen selected from Part 1 Same as Arm K with ivermectin placebo at Month 6 84
Experimental Group Part 2 Basic Arm M ABBV 4083 plus or minus albendazole plus or minus ivermectin Dose regimen 2 selected from Part 1 Dose regimen selected from Part 1 Same as Arm A, B, C or D from Part 1 with ivermectin or ivermectin placebo at Month 6 84
Control Group Part 2 Basic Arm N1 Placebo and Ivermectin Placebo Up to14 days depending on regimen selected from part 1 Placebo with ivermectin at Month 6 42 Placebo
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
1. Written, signed (or thumb-printed) and dated informed consent. 2. Men and women with Onchocerca volvulus infection, 18 to 65 years of age inclusive at time of Screening: i. Presence of at least one excisable subcutaneous nodule/onchocercoma detected on palpation; ii. O. volvulus infection diagnosed by skin snip method: documented mf-positivity on skin assessment on at least 2 out of 4 skin snips. 3. Body weight > 40 kg at Screening. 4. For women of child-bearing potential, acceptance of requirement to use highly effective birth control from Day 0 until at least 1 month after the final intake of IMP. Main exclusion criteria 1. Administration of medication or herbal preparations as follows: i. Any medication or herbal preparation within 14 days prior to IMP administration; ii. Strong CYP3A inhibitors or inducers within 14 days or 10 half-lives, whichever is longer, prior to IMP administration. iii. Other drugs known to interact with albendazole, within 14 days or 10 half-lives, whichever is longer, prior to IMP administration; iv. The following antifilarial therapies, or medication that may have an antifilarial effect: • ivermectin; ≤ 6 months prior to IMP administration; and/or • doxycycline, ≤ 1 year prior to IMP administration: more than 2-week course; and/or • any other anti-Wolbachia treatments, ≤ 1 year prior to IMP administration: more than 2-week course; and/or • moxidectin, ≤ 2 years prior to IMP administration; v. Other preventive chemotherapy, e.g. as part of an MDA program, within 14 days prior to IMP administration; 2. Requirement for albendazole during the first 28 days after IMP administration or more than one dose per year thereafter given in MDA; 3. Presence of any of the following at Screening: i. Abnormal physical and/or neurological examination or laboratory findings; ii. Any clinically significant medical condition including, significant acute or chronic liver or kidney condition or cardiovascular disease, active infection, current or previous epilepsy, known human immunodeficiency virus (HIV) infection, disclosed by review of medical history or concomitant medication; 4. Ophthalmological history or conditions that could interfere with the objectives of the trial or the safety of the subject. 5. Clinically significant history of cardiac abnormality, and/or relevant pathological abnormalities on the ECG at Screening. 6. Known hypersensitivity to any ingredient of the IMPs, including the active ingredient of ABBV-4083, macrolides, albendazole or to ivermectin or to any medication used during the study (e.g. for eye examination). 7. Coincidental infection with other endemic filarial parasite (Loa loa > 8 000 mf/mL, Mansonella species or Wuchereria bancrofti), based on positive laboratory test at Screening. 8. Current hyperreactive onchodermatitis or severe manifestation due to onchocerciasis. 9. For women of child-bearing potential: pregnant or breastfeeding. Adult: 19 Year-44 Year,Middle Aged: 45 Year(s)-64 Year(s) 18 Year(s) 65 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 02/01/2021 National Health Ethics Committee
Ethics Committee Address
Street address City Postal code Country
1er niveau, Local 5 Kinshasa 14094 Congo
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Part 1. Status of each live female adult worm as without Wolbachia endobacteria or not, as assessed by immunohistology of nodules Month 6
Primary Outcome Part 2. Status of each subject as without skin microfilariae or not, as assessed across all skin snips in subject Month 24
Secondary Outcome Part 1. Proportion of live female adult worms with only degenerated embryos in the uterus per subject Month 6
Secondary Outcome Part 1. Proportion of live female adult worms out of all female adult worms per subject Month 6
Secondary Outcome Part 1. Absence of microfilariae in nodular tissue per subject Month 6
Secondary Outcome Part 1. Status of each subject as without skin microfilariae or not Month 3 and 6
Secondary Outcome Part 1. Reduction in skin microfilarial density (defined as mean number of microfilariae/mg per subject) as compared to baseline Month 3 and 6
Secondary Outcome Part 1. Status of each live adult worm as without Wolbachia endobacteria or not, as assessed by PCR Month 6
Secondary Outcome Part 2. Proportion of live female adult worms per subject Month 24
Secondary Outcome Part 2. Proportion of live female adult worms with only degenerated embryos in uterus per subject 24 Months
Secondary Outcome Secondary efficacy Part 2. Status of each subject as without skin microfilariae or not at all All time points other than Month 24
Secondary Outcome Secondary efficacy Part 2. Reduction in skin microfilarial density as compared to baseline All time points
Secondary Outcome Secondary efficacy Part 2. Absence of microfilariae in nodular tissue per subject Month 24
Secondary Outcome Secondary efficacy Part 2. Status of each live adult female worm as without Wolbachia endobacteria or not, assessed by immunohistology Month 24
Secondary Outcome Secondary efficacy Part 2. Status of each live adult worm as without Wolbachia endobacteria or not, as assessed by PCR Month 24
Secondary Outcome Exploratory Parts 1 and 2. Absence of Wolbachia in skin microfilariae per subject, as assessed by PCR All time points
Secondary Outcome Exploratory Parts 1 and 2. Decline in number of Wolbachia in skin microfilariae per subject compared to baseline, as assessed by PCR All time points
Secondary Outcome Exploratory Parts 1 and 2. Microfilaria levels in cornea and anterior chamber per subject All timepoints when ophthalmological assessments are performed
Secondary Outcome Exploratory Parts 1 and 2. Presence, severity and clinical evolution of onchocerciasis ocular disease and onchocerciasis skin disease in each subject All time-points when ophthalmological or skin examinations are performed
Secondary Outcome Safety Parts 1 and 2. Adverse events, physical and skin examination findings, vital signs, ECG, clinical laboratory parameters including haematology, biochemistry, urine analysis and ophthalmological analysis All time-points after treatment start
Secondary Outcome Pharmacokinetic Part 1 ABBV 4083 and albendazole sulfoxide AUCtau, Cmax, Cmin, CL and t½ Day 0, Day 1, Day 3, Day 6 and Day 13
Secondary Outcome Pharmacokinetic Part 2. ABBV 4083 and albendazole sulfoxide AUCtau, Cmax, Cmin, CL and t½ Day 0, Day 1, Day 6 and Day 13
Secondary Outcome Pharmacokinetic outcome Relationship between presence or absence of Wolbachia in female adult worms in each subject with respect to ABBV-4083 and albendazole sulfoxide PK parameters Month 6
Secondary Outcome Pharmacokinetic Relationship between status of adult female worms with respect to ABBV-4083 and albendazole sulfoxide PK parameters Month 24
Secondary Outcome Pharmacokinetic outcome Relationship between presence or absence of skin microfilariae with respect to ABBV-4083 and albendazole sulfoxide PK parameters Month 24
Secondary Outcome Pharmacokinetic outcome Relationship between reduction in skin microfilarial density over time in relation to ABBV-4083 and albendazole sulfoxide concentrations All time-points
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Masi Manimba General and Referral Hospital Avenue Foreami No 1 Masi Manimba Kwilu Congo
Kimpese General and Referral Hospital Village Mankayi Kimpese Kongo Cen Congo
FUNDING SOURCES
Name of source Street address City Postal code Country
Drugs for Neglected Diseases Initiative 15, chemin Camille-VIDART Geneva 1202 Switzerland
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Drugs for Neglected 15, chemin Camille-VIDART Geneva 1202 Switzerland Charities/Societies/Foundation
COLLABORATORS
Name Street address City Postal code Country
National Control Programme of neglected tropical diseases with preventive chemotheraphy 36, avenue de la justice, Commune de la Gombe Kinshasa BP 3088 Congo
National control programme of neglected tropical diseases with preventive chemotherapy 1 North Waukegan Road North Chicago 60064 United States of America
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Felix Masa fakwaso@extern.dndi.org +24381663309 Avenue Foreami No.1
City Postal code Country Position/Affiliation
Masi manimba Kwilu Congo Principal Investigator
Role Name Email Phone Street address
Principal Investigator Aimee Nzeza fnzeza@extern.dndi.org +243899948476 General and Referral Hospital Kimpese
City Postal code Country Position/Affiliation
Kimpese Kongo Cen Congo Principal Investigator
Role Name Email Phone Street address
Public Enquiries Virginie Pillet vpillet@dndi.org +41225551958 chemin Camille-VIDART
City Postal code Country Position/Affiliation
Geneva 1202 Switzerland Clinical Project Manager
Role Name Email Phone Street address
Scientific Enquiries Sabine Specht sspecht@dndi.org +41229076614 chemin Camille-VIDART
City Postal code Country Position/Affiliation
Geneva 1202 Switzerland Head of Filarial Clinical Programme
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Summary results will be shared once clinical study report will be available Study Protocol Within 12 months of finalisation of clinical study report Open access
URL Results Available Results Summary Result Posting Date First Journal Publication Date
Summary of results will be shared once clinical study report is available No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information