Onchocerciasis
Conditions
Brief summary
The primary purpose of this study is to determine a dose of moxidectin for children 4 to 11 years that is equivalent to an 8 mg dose administered for treatment of onchocerciasis in people 12 years and over. The secondary purpose is to evaluate the safety and pharmacokinetics of a single dose of moxidectin in children and adolescents aged 4 to 17 years.
Interventions
DRUGMoxidectin
2 mg tablets
Sponsors
Medicines Development for Global Health
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Prospective, age-stratified, adaptive, open-label, single-dose study with 3, age-defined cohorts. Cohort 1 (12 to 17 years, n = 9) and Cohort 2 (8 to 11 years, n = 9) will receive moxidectin 8 mg. Cohort 3 (4 to 7 years, n = 9) will receive moxidectin at a dose to be determined from safety and pharmacokinetic data analyses of Cohorts 1 and 2. If the starting dose for Cohorts 2 and 3 results in at least 3 subjects with moxidectin exposures above the target range, a revised dose will be determined in decrements of 2 mg and the Cohort(s) will be repeated with at least 9 new subjects. For Cohort 3, if the starting dose results in at least 3 subjects with moxidectin exposures below the target range, a revised dose will be determined in increments of 2 mg to a maximum dose of 8 mg.Therefore, it is expected that the study will enroll 27 subjects. However, if additional cohorts are required to meet pharmacokinetic outcomes, up to a maximum of 63 subjects may be enrolled.
Eligibility
Sex/Gender
ALL
Age
4 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Aged 4 to 17 years, inclusive: 1. Cohort I: 12 to 17 years; 2. Cohort II: 8 to 11 years; 3. Cohort III: 4 to 7 years; 2. Live in a region designated by the World Health Organization (WHO) as endemic for O. volvulus infection (World Health Organization, 2019). Specifically, participants will be recruited from the Kpassa sub-district of the Nkwanta North district.The specific communities will include Wii, Jagri-Do, and Azua where mass drug administration with ivermectin for onchocerciasis commenced in October 2017; 3. Willing and able to remain at the study clinic from Screening up to Day 7; 4. Provision of parental or guardian written informed consent and assent / lack of expression of 'deliberate objection' (as appropriate for age); 5. Females of childbearing potential must commit to using a reliable method of contraception as per local family planning guidelines from Baseline (pre-treatment on Day 0) until approximately 6 months after treatment with study drug.
Exclusion criteria
1. History of serious medical or psychiatric condition which, in the opinion of the investigator, would put the subject at increased risk by participating in the study or jeopardize study outcomes; 2. Known or suspected concurrent clinically significant renal, cardiac, pulmonary, vascular, metabolic (thyroid disorders, adrenal disease), immunological disorders or malignancy, congenital heart disease, chronic lung disease; 3. Has received an investigational product within 28 days or 5 half-lives of Baseline, whichever is longer; 4. Has received ivermectin or any other anti-helminthic treatments within 28 days of Baseline; 5. Has received a vaccination within 7 days of Baseline; 6. Known or suspected hypersensitivity to macrocyclic lactones or excipients used in the formulation of moxidectin; 7. Poor venous access; 8. Unable to swallow tablets (flat oval, 8.0 millimeters (mm) x 4.5 mm x 3.0 mm); 9. Weight: 1. Cohort I (12 to 17 years): \< 30 kg; 2. Cohort II (8 to 11 years): \< 18 kg; 3. Cohort III (4 to 7 years): \< 12 kg; 10. Clinically relevant laboratory abnormalities at Screening, including: 1. Hemoglobin \< 9.5 grams per deciliter (g/dL); 2. Neutrophil (granulocyte) count \< 1.5 x 109/L; 3. Platelet count \< 110 x 109/L; 4. Alanine aminotransferase (ALT) \> 1.5 times the upper limit of normal range (ULN); 5. Total bilirubin \> 1.5 times ULN; 11. Hepatitis B, Hepatitis C, or human immunodeficiency virus (HIV) positive; 12. Known or suspected malaria or other ongoing viral, bacterial, or plasmodium infection at Screening and/or Baseline; 13. Loa loa co-infection; 14. Unwilling, unlikely or unable to comply with all protocol specified assessments; 15. For females of child bearing potential, pregnant or breastfeeding, or planning to become pregnant; 16. Previous enrolment in this study; 17. Is a sibling of another child already enrolled in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Versus Time Curve of Moxidectin. | Pre-dose (Screening) and post-dose at Hours 1, 2, 4, 8, 24 and 72 and Days 7, 14 and 28. | Moxidectin concentration in plasma collected at pre-specified intervals after dosing with oral moxidectin determined using a validated liquid chromatography-mass spectrometry(MS)/MS method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration Versus Time Curve (Zero to Infinity) of Moxidectin | Pre-dose (Screening) and post-dose at Hours 1, 2, 4, 8, 24 and 72, Days 7, 14 and 28 and Week 12. | Moxidectin concentration in plasma collected at pre-specified intervals after dosing with oral moxidectin determined using a validated liquid chromatography-mass spectrometry(MS)/MS method. |
| Maximum Observed Plasma Concentrations (Cmax) of Moxidectin | Pre-dose (Screening) and post-dose at Hours 1, 2, 4 and 8. | Moxidectin concentration in plasma collected at pre-specified intervals after dosing with oral moxidectin determined using a validated liquid chromatography-mass spectrometry(MS)/MS method. |
| Incidence and Severity of Adverse Events. | Day 0 to Week 24 inclusive. | Incidence and severity of adverse events, assessed by the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Paediatric Adverse Events, Version 2.1. |
Countries
Ghana
Participant flow
Recruitment details
The first participant was screened on 29 March 2021 and the last participant last study visit was completed on 28 September 2022. Participants were recruited from communities in the Kpassa sub-district of the Oti region in Ghana, which is endemic for onchocerciasis.
Participants by arm
| Arm | Count |
|---|---|
| 12 to 17 Years Moxidectin 8 mg Cohort 1: Nine (9) participants aged 12 to 17 years at Screening received a single oral dose of moxidectin 8 mg and were followed for 24 weeks for pharmacokinetic and safety outcomes. | 9 |
| 8 to 11 Years Moxidectin 6 mg Cohort 2: Nine (9) participants aged 8 to 11 years at Screening received a single oral dose of moxidectin 6 mg and were followed for 24 weeks for pharmacokinetic and safety outcomes. | 9 |
| 8 to 11 Years Moxidectin 8 mg Cohort 2: Nine (9) participants aged 8 to 11 years at Screening received a single oral dose of moxidectin 8 mg and were followed for 24 weeks for pharmacokinetic and safety outcomes. | 9 |
| 4 to 7 Years Moxidectin 4 mg Cohort 3: Nine (9) participants aged 4 to 7 years at Screening received a single oral dose of moxidectin 4 mg and were followed for 24 weeks for pharmacokinetic and safety outcomes. | 9 |
| Total | 36 |
Baseline characteristics
| Characteristic | 8 to 11 Years Moxidectin 6 mg | Total | 12 to 17 Years Moxidectin 8 mg | 4 to 7 Years Moxidectin 4 mg | 8 to 11 Years Moxidectin 8 mg |
|---|---|---|---|---|---|
| Age, Continuous | 9.1 years STANDARD_DEVIATION 1.05 | 9.5 years STANDARD_DEVIATION 3.19 | 13.7 years STANDARD_DEVIATION 1.66 | 5.4 years STANDARD_DEVIATION 1.33 | 9.7 years STANDARD_DEVIATION 0.87 |
| BMI | 15.19 kg/m2 STANDARD_DEVIATION 1.068 | 15.50 kg/m2 STANDARD_DEVIATION 1.683 | 17.39 kg/m2 STANDARD_DEVIATION 1.745 | 14.20 kg/m2 STANDARD_DEVIATION 0.919 | 15.23 kg/m2 STANDARD_DEVIATION 1.12 |
| Height | 130.09 cm STANDARD_DEVIATION 9.307 | 130.44 cm STANDARD_DEVIATION 17.381 | 149.74 cm STANDARD_DEVIATION 10.318 | 108.81 cm STANDARD_DEVIATION 7.922 | 133.11 cm STANDARD_DEVIATION 10.59 |
| Mean upper arm circumference at Screening | 18.42 cm STANDARD_DEVIATION 0.981 | 18.63 cm STANDARD_DEVIATION 2.644 | 21.78 cm STANDARD_DEVIATION 2.065 | 15.68 cm STANDARD_DEVIATION 1.347 | 18.66 cm STANDARD_DEVIATION 1.591 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 36 Participants | 9 Participants | 9 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Ghana | 9 participants | 36 participants | 9 participants | 9 participants | 9 participants |
| Sex: Female, Male Female | 6 Participants | 21 Participants | 4 Participants | 6 Participants | 5 Participants |
| Sex: Female, Male Male | 3 Participants | 15 Participants | 5 Participants | 3 Participants | 4 Participants |
| Weight | 25.89 kg STANDARD_DEVIATION 4.567 | 27.34 kg STANDARD_DEVIATION 9.766 | 39.42 kg STANDARD_DEVIATION 8.754 | 16.90 kg STANDARD_DEVIATION 2.662 | 27.13 kg STANDARD_DEVIATION 4.844 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 36 |
| other Total, other adverse events | 4 / 9 | 7 / 9 | 6 / 9 | 7 / 9 | 24 / 36 |
| serious Total, serious adverse events | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 36 |
Outcome results
Primary
Area Under the Plasma Concentration Versus Time Curve of Moxidectin.
Moxidectin concentration in plasma collected at pre-specified intervals after dosing with oral moxidectin determined using a validated liquid chromatography-mass spectrometry(MS)/MS method.
Time frame: Pre-dose (Screening) and post-dose at Hours 1, 2, 4, 8, 24 and 72 and Days 7, 14 and 28.
Population: The Pharmacokinetic Analysis Set included all participants who received moxidectin and provided a minimum number of plasma samples for the determination of Pharmacokinetic (PK) parameters, defined as one (1) sample taken at each of hours 4, 24 and 72, plus one (1) sample taken at either Day 14 or Day 28. Subjects were analyzed according to the dose received.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 12 to 17 Years MOX 8 mg | Area Under the Plasma Concentration Versus Time Curve of Moxidectin. | 2680 (hr*ng/mL)/mg | Geometric Coefficient of Variation 24.7 |
| 8 to 11 Years MOX 6 mg | Area Under the Plasma Concentration Versus Time Curve of Moxidectin. | 2230 (hr*ng/mL)/mg | Geometric Coefficient of Variation 52.3 |
| 8 to 11 Years MOX 8 mg | Area Under the Plasma Concentration Versus Time Curve of Moxidectin. | 3310 (hr*ng/mL)/mg | Geometric Coefficient of Variation 23 |
| 4 to 7 Years MOX 4 mg | Area Under the Plasma Concentration Versus Time Curve of Moxidectin. | 1880 (hr*ng/mL)/mg | Geometric Coefficient of Variation 26.5 |
Secondary
Area Under the Concentration Versus Time Curve (Zero to Infinity) of Moxidectin
Moxidectin concentration in plasma collected at pre-specified intervals after dosing with oral moxidectin determined using a validated liquid chromatography-mass spectrometry(MS)/MS method.
Time frame: Pre-dose (Screening) and post-dose at Hours 1, 2, 4, 8, 24 and 72, Days 7, 14 and 28 and Week 12.
Population: The Pharmacokinetic Analysis Set included all participants who received moxidectin and provided a minimum number of plasma samples for the determination of PK parameters, defined as one (1) sample taken at each of hours 4, 24 and 72, plus one (1) sample taken at either Day 14 or Day 28. Subjects were analyzed according to the dose received.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 12 to 17 Years MOX 8 mg | Area Under the Concentration Versus Time Curve (Zero to Infinity) of Moxidectin | 3140 (hr*ng/mL)/mg | Geometric Coefficient of Variation 24.8 |
| 8 to 11 Years MOX 6 mg | Area Under the Concentration Versus Time Curve (Zero to Infinity) of Moxidectin | 2490 (hr*ng/mL)/mg | Geometric Coefficient of Variation 59.2 |
| 8 to 11 Years MOX 8 mg | Area Under the Concentration Versus Time Curve (Zero to Infinity) of Moxidectin | 3780 (hr*ng/mL)/mg | Geometric Coefficient of Variation 29.2 |
| 4 to 7 Years MOX 4 mg | Area Under the Concentration Versus Time Curve (Zero to Infinity) of Moxidectin | 2000 (hr*ng/mL)/mg | Geometric Coefficient of Variation 29.3 |
Secondary
Incidence and Severity of Adverse Events.
Incidence and severity of adverse events, assessed by the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Paediatric Adverse Events, Version 2.1.
Time frame: Day 0 to Week 24 inclusive.
Population: The Safety Analysis Set included all participants who received any exposure to moxidectin. Subjects were analyzed according to the dose received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 12 to 17 Years MOX 8 mg | Incidence and Severity of Adverse Events. | Grade 2 Moderate | 1 Participants |
| 12 to 17 Years MOX 8 mg | Incidence and Severity of Adverse Events. | Grade 3 Severe | 0 Participants |
| 12 to 17 Years MOX 8 mg | Incidence and Severity of Adverse Events. | Grade 4 Life-threatening | 0 Participants |
| 12 to 17 Years MOX 8 mg | Incidence and Severity of Adverse Events. | TEAEs by Severity Grade 1 Mild | 3 Participants |
| 12 to 17 Years MOX 8 mg | Incidence and Severity of Adverse Events. | All Treatment-emergent Adverse Events (TEAEs) | 4 Participants |
| 8 to 11 Years MOX 6 mg | Incidence and Severity of Adverse Events. | TEAEs by Severity Grade 1 Mild | 6 Participants |
| 8 to 11 Years MOX 6 mg | Incidence and Severity of Adverse Events. | Grade 2 Moderate | 1 Participants |
| 8 to 11 Years MOX 6 mg | Incidence and Severity of Adverse Events. | All Treatment-emergent Adverse Events (TEAEs) | 7 Participants |
| 8 to 11 Years MOX 6 mg | Incidence and Severity of Adverse Events. | Grade 3 Severe | 0 Participants |
| 8 to 11 Years MOX 6 mg | Incidence and Severity of Adverse Events. | Grade 4 Life-threatening | 0 Participants |
| 8 to 11 Years MOX 8 mg | Incidence and Severity of Adverse Events. | Grade 3 Severe | 0 Participants |
| 8 to 11 Years MOX 8 mg | Incidence and Severity of Adverse Events. | All Treatment-emergent Adverse Events (TEAEs) | 6 Participants |
| 8 to 11 Years MOX 8 mg | Incidence and Severity of Adverse Events. | TEAEs by Severity Grade 1 Mild | 6 Participants |
| 8 to 11 Years MOX 8 mg | Incidence and Severity of Adverse Events. | Grade 2 Moderate | 1 Participants |
| 8 to 11 Years MOX 8 mg | Incidence and Severity of Adverse Events. | Grade 4 Life-threatening | 0 Participants |
| 4 to 7 Years MOX 4 mg | Incidence and Severity of Adverse Events. | TEAEs by Severity Grade 1 Mild | 6 Participants |
| 4 to 7 Years MOX 4 mg | Incidence and Severity of Adverse Events. | All Treatment-emergent Adverse Events (TEAEs) | 7 Participants |
| 4 to 7 Years MOX 4 mg | Incidence and Severity of Adverse Events. | Grade 3 Severe | 1 Participants |
| 4 to 7 Years MOX 4 mg | Incidence and Severity of Adverse Events. | Grade 4 Life-threatening | 0 Participants |
| 4 to 7 Years MOX 4 mg | Incidence and Severity of Adverse Events. | Grade 2 Moderate | 2 Participants |
Secondary
Maximum Observed Plasma Concentrations (Cmax) of Moxidectin
Moxidectin concentration in plasma collected at pre-specified intervals after dosing with oral moxidectin determined using a validated liquid chromatography-mass spectrometry(MS)/MS method.
Time frame: Pre-dose (Screening) and post-dose at Hours 1, 2, 4 and 8.
Population: The Pharmacokinetic Analysis Set included all participants who received moxidectin and provided a minimum number of plasma samples for the determination of PK parameters, defined as one (1) sample taken at each of hours 4, 24 and 72, plus one (1) sample taken at either Day 14 or Day 28. Subjects were analyzed according to the dose received.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 12 to 17 Years MOX 8 mg | Maximum Observed Plasma Concentrations (Cmax) of Moxidectin | 83.1 ng/mL | Geometric Coefficient of Variation 19.1 |
| 8 to 11 Years MOX 6 mg | Maximum Observed Plasma Concentrations (Cmax) of Moxidectin | 82.1 ng/mL | Geometric Coefficient of Variation 41.2 |
| 8 to 11 Years MOX 8 mg | Maximum Observed Plasma Concentrations (Cmax) of Moxidectin | 115 ng/mL | Geometric Coefficient of Variation 25.6 |
| 4 to 7 Years MOX 4 mg | Maximum Observed Plasma Concentrations (Cmax) of Moxidectin | 86.4 ng/mL | Geometric Coefficient of Variation 28.3 |