Study to Assess Adverse Events, Change in Disease Activity and How Oral ABBV-4083 Capsules When Given Alone or In Combination With Albendazole Capsules Moves in The Body of Adult Participants With Onchocerca Volvulus Infection

The study was terminated at the conclusion of Part 1, and Part 2 of the study was not conducted.

• ABBV-4083 (Drug), also known as Tylamac: Oral Capsule
• Placebo for ABBV-4083 (Drug): Oral Capsule
• Albendazole (Drug), also known as Zentel: Oral encapsulated tablets
• Placebo for Albendazole (Drug): Oral Capsule

Primary outcomes

• Part 1: Percentage of Live Female Adult Worms Without Wolbachia at Month 6 as Assessed By Immunohistology of Nodules [At Month 6]: The Wolbachia endobacteria status of each live female adult worm was determined by immunohistology of nodules collected after nodulectomy at the Month 6 visit.

Secondary outcomes

• Part 1: Percentage of Live Female Adult Worms With Only Degenerated Embryos in the Uterus Per Participant at Month 6 [At Month 6]: The percentage of live female adult worms with only degenerated embryos in the uterus per participant was determined after nodulectomy at the Month 6 visit.
• Part 1: Percentage of Live Female Adult Worms Out of All Female Adult Worms Per Participant at Month 6 [At Month 6]: The percentage of live female adult worms out of all female adult worms per participant was determined after nodulectomy at the Month 6 visit.
• Part 1: Percentage of Participants Without Microfilariae in Nodular Tissue at Month 6 [At Month 6]: The absence of microfilariae in nodular tissue per participant was determined after nodulectomy at the Month 6 visit.
• Part 1: Percentage of Participants Without Skin Microfilariae at Month 3 [At Month 3]: The presence or absence of microfilariae in skin was determined at the Month 3 visit.
• Part 1: Percentage of Participants Without Skin Microfilariae at Month 6 [At Month 6]: The presence or absence of microfilariae in skin was determined at the Month 6 visit.
• Part 1: Mean Within-Participant Change From Baseline in Skin Microfilarial Density at Month 3 [Baseline, Month 3]: Skin microfilarial density is defined as the mean number of microfilariae/mg of skin per participant.
• Part 1: Mean Within-Participant Change From Baseline in Skin Microfilarial Density at Month 6 [Baseline, Month 6]: Skin microfilarial density is defined as the mean number of microfilariae/mg of skin per participant.
• Part 1: Percentage of Nodules That Contain at Least 1 Live Female Adult Worm Without Wolbachia Assessed by PCR at Month 6 [At Month 6]: The Wolbachia endobacteria status of each live female adult worm was determined by PCR of nodules collected after nodulectomy at the Month 6 visit.

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

* Diagnosis of Onchocerca volvulus infection at time of Screening:

  * Presence of at least one excisable subcutaneous nodule/ onchocercoma detected on palpation;
  * O. volvulus infection diagnosed by skin snip method: documented mfpositivity on skin assessment on at least 2 out of 4 skin snips.
* Body weight > 40 kg at Screening.
* For women of child-bearing potential, acceptance of the requirement to use a highly effective form of birth control from Day 0 until at least 1 month after the final intake of study drug (Part 1: day 43; Part 2: 1 month after the administration of ivermectin or matching placebo at the Month 6 visit). Choice of birth control method must be clearly documented.

Exclusion Criteria:

* Participation in any studies other than purely observational studies within 3 months prior to Screening, or during the trial, or within 5 times the half-life of the drug tested in the previous clinical trial or is currently in the follow-up period for any clinical trial.
* Any vaccination within 4 weeks prior to investigational medicinal product (IMP) administration.
* Acute infection and/or febrile illness requiring therapy within 14 days prior to IMP administration.
* Administration of medication or herbal preparations as follows:

  * Administration of any medication (with the exception of diclofenac, paracetamol, ibuprofen and aspirin) or herbal preparation within 14 days prior to IMP administration;
  * Use of strong CYP3A inhibitors or inducers including but not limited to ritonavir, ketoconazole, rifampicin, phenytoin, phenobarbital, carbamazepine, cimetidine within 14 days or 10 half-lives, whichever is longer, prior to IMP administration;
  * Use of other drugs known to interact with albendazole i.e. praziquantel, theophylline or dexamethasone, within 14 days or 10 half-lives, whichever is longer, prior to IMP administration;
  * Antifilarial therapies, or medication that may have an antifilarial effect.
* Requirement for and inability to avoid ivermectin during the first 6 months after IMP administration. Requirement for albendazole during the first 28 days after IMP administration or more than one dose per year thereafter given in MDA.
* Presence of any of the following at Screening, that could interfere with the objectives of the trial or the safety of the participant, in the opinion of the Investigator:

  * Clinically significant abnormal physical and/or neurological examination or laboratory findings;
  * Any clinically significant medical condition. Including, but not limited to significant acute or chronic liver or kidney condition or cardiovascular disease, active infection, current or previous epilepsy, known human immunodeficiency virus infection, disclosed by review of medical history or concomitant medication.
* Ophthalmological history or conditions that could interfere with the objectives of the trial or compromise the safety of the subject in the opinion of the Investigator, assessed at Screening.
* History of drug or alcohol abuse within 6 months prior to IMP administration.
* Use of alcohol within 48 hours and/or use of drugs of abuse within 15 days before IMP administration.
* Clinically significant history of cardiac abnormality, and/or relevant pathological abnormalities in the ECG in the screening period.
* Abnormal laboratory test results at Screening.
* History of severe drug allergy, non-allergic drug reactions, severe adverse reaction to any drug, or multiple drug allergies.
* 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.
* Blood donation within 8 weeks prior to Screening or blood transfusion received within 1 year prior to Screening.
* Coincidental infection with high Loa loa load at Screening.
* Current hyperreactive onchodermatitis or severe manifestation due to onchocerciasis.
* Any other past or current condition that the Investigator feels would exclude the participant from the study or place the subject at undue risk.
* For women of child-bearing potential: pregnant, based on date of last menstrual period, and pregnancy test prior to first intake of IMP, or breastfeeding.
* Unwilling or unable to comply with the requirements of the study protocol for the entire duration of the study, in the opinion of the Investigator.
* Unable to participate in the study as per local law, if applicable.

Participant flow

Outcome results

• Part 1: Percentage of Live Female Adult Worms Without Wolbachia at Month 6 as Assessed By Immunohistology of Nodules (Primary), Number, Percentage of worms without Wolbachia: Part 1: ABBV-4083 400 mg + Albendazole Pbo for 7 Days, Then ABBV-4083 Pbo for 7 Days 6.0 (2.6 to 13.2); Part 1: ABBV-4083 400 mg + Albendazole Pbo for 7 Days, Then ABBV-4083 400 mg for 7 Days 2.3 (0.6 to 8.0); Part 1: ABBV-4083 400 mg + Albendazole 400 mg for 7 Days, Then ABBV-4083 Pbo for 7 Days 0.0 (0.0 to 4.5); Part 1: ABBV-4083/Albendazole 400 mg 3 d; ABBV-4083 400 mg/Albendazole Pbo 4 d; ABBV-4083 Pbo 7 d 0.0 (0.0 to 4.1); Part 1: ABBV-4083 Pbo + Albendazole 400 mg for 7 Days, Then ABBV-4083 Pbo for 7 Days 2.6 (0.7 to 9.0)
• Part 1: Percentage of Live Female Adult Worms With Only Degenerated Embryos in the Uterus Per Participant at Month 6 (Secondary), Mean, Percentage of worms per participant: Part 1: ABBV-4083 400 mg + Albendazole Pbo for 7 Days, Then ABBV-4083 Pbo for 7 Days 0.48 +/- 2.086; Part 1: ABBV-4083 400 mg + Albendazole Pbo for 7 Days, Then ABBV-4083 400 mg for 7 Days 7.67 +/- 18.420; Part 1: ABBV-4083 400 mg + Albendazole 400 mg for 7 Days, Then ABBV-4083 Pbo for 7 Days 9.82 +/- 19.578; Part 1: ABBV-4083/Albendazole 400 mg 3 d; ABBV-4083 400 mg/Albendazole Pbo 4 d; ABBV-4083 Pbo 7 d 7.59 +/- 23.813; Part 1: ABBV-4083 Pbo + Albendazole 400 mg for 7 Days, Then ABBV-4083 Pbo for 7 Days 10.16 +/- 18.064 (p =0.036)
• Part 1: Percentage of Live Female Adult Worms Out of All Female Adult Worms Per Participant at Month 6 (Secondary), Mean, Percentage of worms per participant: Part 1: ABBV-4083 400 mg + Albendazole Pbo for 7 Days, Then ABBV-4083 Pbo for 7 Days 84.27 +/- 19.904; Part 1: ABBV-4083 400 mg + Albendazole Pbo for 7 Days, Then ABBV-4083 400 mg for 7 Days 77.74 +/- 32.445; Part 1: ABBV-4083 400 mg + Albendazole 400 mg for 7 Days, Then ABBV-4083 Pbo for 7 Days 78.03 +/- 29.811; Part 1: ABBV-4083/Albendazole 400 mg 3 d; ABBV-4083 400 mg/Albendazole Pbo 4 d; ABBV-4083 Pbo 7 d 79.37 +/- 27.013; Part 1: ABBV-4083 Pbo + Albendazole 400 mg for 7 Days, Then ABBV-4083 Pbo for 7 Days 79.52 +/- 30.496 (p =0.869)
• Part 1: Percentage of Participants Without Microfilariae in Nodular Tissue at Month 6 (Secondary), Number, Percentage of participants: Part 1: ABBV-4083 400 mg + Albendazole Pbo for 7 Days, Then ABBV-4083 Pbo for 7 Days 22.7; Part 1: ABBV-4083 400 mg + Albendazole Pbo for 7 Days, Then ABBV-4083 400 mg for 7 Days 26.9; Part 1: ABBV-4083 400 mg + Albendazole 400 mg for 7 Days, Then ABBV-4083 Pbo for 7 Days 41.7; Part 1: ABBV-4083/Albendazole 400 mg 3 d; ABBV-4083 400 mg/Albendazole Pbo 4 d; ABBV-4083 Pbo 7 d 31.8; Part 1: ABBV-4083 Pbo + Albendazole 400 mg for 7 Days, Then ABBV-4083 Pbo for 7 Days 30.4 (p =0.559)
• Part 1: Percentage of Participants Without Skin Microfilariae at Month 3 (Secondary), Number, Percentage of participants: Part 1: ABBV-4083 400 mg + Albendazole Pbo for 7 Days, Then ABBV-4083 Pbo for 7 Days 3.2; Part 1: ABBV-4083 400 mg + Albendazole Pbo for 7 Days, Then ABBV-4083 400 mg for 7 Days 3.2; Part 1: ABBV-4083 400 mg + Albendazole 400 mg for 7 Days, Then ABBV-4083 Pbo for 7 Days 3.6; Part 1: ABBV-4083/Albendazole 400 mg 3 d; ABBV-4083 400 mg/Albendazole Pbo 4 d; ABBV-4083 Pbo 7 d 3.6; Part 1: ABBV-4083 Pbo + Albendazole 400 mg for 7 Days, Then ABBV-4083 Pbo for 7 Days 3.3 (p =0.981)
• Part 1: Percentage of Participants Without Skin Microfilariae at Month 6 (Secondary), Number, Percentage of participants: Part 1: ABBV-4083 400 mg + Albendazole Pbo for 7 Days, Then ABBV-4083 Pbo for 7 Days 0; Part 1: ABBV-4083 400 mg + Albendazole Pbo for 7 Days, Then ABBV-4083 400 mg for 7 Days 0; Part 1: ABBV-4083 400 mg + Albendazole 400 mg for 7 Days, Then ABBV-4083 Pbo for 7 Days 0; Part 1: ABBV-4083/Albendazole 400 mg 3 d; ABBV-4083 400 mg/Albendazole Pbo 4 d; ABBV-4083 Pbo 7 d 0; Part 1: ABBV-4083 Pbo + Albendazole 400 mg for 7 Days, Then ABBV-4083 Pbo for 7 Days 7.1 (p =0.157)
• Part 1: Mean Within-Participant Change From Baseline in Skin Microfilarial Density at Month 3 (Secondary), Mean, Mean number of microfilariae/mg of skin: Part 1: ABBV-4083 400 mg + Albendazole Pbo for 7 Days, Then ABBV-4083 Pbo for 7 Days -0.44 +/- 5.576; Part 1: ABBV-4083 400 mg + Albendazole Pbo for 7 Days, Then ABBV-4083 400 mg for 7 Days -7.99 +/- 16.180; Part 1: ABBV-4083 400 mg + Albendazole 400 mg for 7 Days, Then ABBV-4083 Pbo for 7 Days 2.43 +/- 13.148; Part 1: ABBV-4083/Albendazole 400 mg 3 d; ABBV-4083 400 mg/Albendazole Pbo 4 d; ABBV-4083 Pbo 7 d 1.36 +/- 12.189; Part 1: ABBV-4083 Pbo + Albendazole 400 mg for 7 Days, Then ABBV-4083 Pbo for 7 Days -1.03 +/- 10.787 (p =0.619)
• Part 1: Mean Within-Participant Change From Baseline in Skin Microfilarial Density at Month 6 (Secondary), Mean, Mean number of microfilariae/mg of skin: Part 1: ABBV-4083 400 mg + Albendazole Pbo for 7 Days, Then ABBV-4083 Pbo for 7 Days -0.19 +/- 6.330; Part 1: ABBV-4083 400 mg + Albendazole Pbo for 7 Days, Then ABBV-4083 400 mg for 7 Days 5.55 +/- 24.293; Part 1: ABBV-4083 400 mg + Albendazole 400 mg for 7 Days, Then ABBV-4083 Pbo for 7 Days -1.19 +/- 32.856; Part 1: ABBV-4083/Albendazole 400 mg 3 d; ABBV-4083 400 mg/Albendazole Pbo 4 d; ABBV-4083 Pbo 7 d -2.72 +/- 19.769; Part 1: ABBV-4083 Pbo + Albendazole 400 mg for 7 Days, Then ABBV-4083 Pbo for 7 Days -1.67 +/- 14.223 (p =0.386)
• Part 1: Percentage of Nodules That Contain at Least 1 Live Female Adult Worm Without Wolbachia Assessed by PCR at Month 6 (Secondary), Number, Percentage of nodules: Part 1: ABBV-4083 400 mg + Albendazole Pbo for 7 Days, Then ABBV-4083 Pbo for 7 Days 0; Part 1: ABBV-4083 400 mg + Albendazole Pbo for 7 Days, Then ABBV-4083 400 mg for 7 Days 0; Part 1: ABBV-4083 400 mg + Albendazole 400 mg for 7 Days, Then ABBV-4083 Pbo for 7 Days 0; Part 1: ABBV-4083/Albendazole 400 mg 3 d; ABBV-4083 400 mg/Albendazole Pbo 4 d; ABBV-4083 Pbo 7 d 0; Part 1: ABBV-4083 Pbo + Albendazole 400 mg for 7 Days, Then ABBV-4083 Pbo for 7 Days 0

Adverse events

Time frame: All-cause mortality and adverse events were collected from the time informed consent was signed through the end of the study. Median time on follow-up was 201 days for Arms A, B, C, and all participants randomized to receive ABBV-4083; 210 days for Arm D; and 213 days for Arm E.

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2021-11-09)
• Statistical Analysis Plan (PDF, 2023-03-24)

• ABBVIE INC., Study director, AbbVie