DON in Pediatric Cerebral Malaria: A Phase I/IIa Dose-Escalation Safety Study
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 152
- 试验地点
- 2
- 主要终点
- Incidence of systemic AEs occurring within 14 days after the administration of DON
研究概览
简要总结
The goal of this clinical trial is to evaluate the safety of a single intravenous dose of DON in healthy adults, adults with uncomplicated malaria, and children 12 months-14 years old with clinically defined Cerebral Malaria. The main objectives are:
- Evaluate the safety of a single intravenous dose of DON in healthy adults and adults with uncomplicated malaria ( Part 1)
- Determine the safety of a single dose of DON in children 12 months-14 years old with World Health Organization (WHO) clinically defined CM (Part 2 :Cohort 1-4)
- Determine the pharmacokinetic (PK) profile of a single dose of DON in healthy adults, adults with uncomplicated malaria and children with CM (Part 1, and Cohorts 1-4 of Part 2)
- Determine if administration of a single intravenous dose of DON as an adjunctive therapy in children with CM is associated with improved intracerebral blood flow dynamics on transcranial doppler (TCD) (Part 2 :Cohort 1-4)
- Determine if administration of a single intravenous dose of DON as an adjunctive therapy in children with CM is associated with a reduction in brain volume score on magnetic resonance imaging (MRI) (Part 2 :Cohort 1-4)
- Determine if administration of a single intravenous dose of DON as an adjunctive therapy in children with cerebral malaria is associated with changes in electroencephalogram (EEG) pattern (Part 2 :Cohort 1-4)
- Exploratory: Explore the metabolic mechanisms of action of adjunctive DON in children with CM
Healthy adult participants will receive:
- anti-emetic ondansetron
- one dose of DON
Adults with uncomplicated malaria will receive:
- anti-emetic ondansetron
- one dose of DON
- artemisinin-combination therapies per Malawi Ministry of Health guidelines
Pediatric participants will receive:
- one dose of DON
- anti-emetic ondansetron and per Malawi Ministry of Health guidelines:
- enteral lumefantrine-artemether therapy, and
- artesunate therapy
详细描述
The initial study to be conducted under this IND is a 2-part dose escalation study. The first part (Adults) contains 2 groups that will be open-label, dose escalation, and will define the safety of 6-diazo-5-oxo-L-norleucine (DON) in African adults (>18 years old), who are healthy or who have uncomplicated malaria.
Each of the two adult groups will enroll 40 participants broken down into 4 dosage groups with safety evaluations before each dose increase. The first 10 participants enrolled will receive 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, the dose will be increased to 1.0 mg/kg IV DON, and then 5.0 mg/kg IV DON, and then the final group will receive 10.0 mg/kg IV DON. Each adult dosage group contains 10 healthy participants and 10 participants with uncomplicated malaria. The total number of adult participants enrolled is 80 (20 participants at 4 doses). All participants will receive only one dose of DON.
Adult participants will receive a premedication dose of the antiemetic ondansetron, 5 mg IV, administered 30 minutes prior to DON, and repeated 8 and 16 hours later. The duration of study participation for all adult participants is six months.
Part 2 (pediatric) of the study will be a randomized, placebo-controlled, dose-escalation study in children ages 12 months to 14 years with cerebral malaria to determine safety. Pediatric enrollments will span three malaria seasons, which will be carried out in Study Years 3-5, with a planned interim analysis after cohort 3.
In cohort 1 we will first enroll 6 sentinel pediatric participants who will receive intravenous artesunate therapy, enteral lumefantrine-artemether therapy, and either adjunctive DON 0.1 mg/kg or placebo randomized 2:1.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Part 1: None (Open Label) Part 2: Blinded (Participants/ Caregivers, Study Staff)
入排标准
- 年龄范围
- 12 Months 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •For Healthy Adults (Part 1):
- •18 years and older
- •Informed consent obtained and ICF signed
- •Temperature ≤ 37.5 °C
- •BMI 18.5-25 kg/m2
- •Creatinine ≤ 110 mmol/L (≤ 1.2 mg/dL; males) or ≤ 90 mmol/L (≤ 1.0 mg/dL; females)
- •Hemoglobin ≥ 7 g/dL or hematocrit/ packed-cell volume (PCV) ≥ 20%
- •Thick or thin blood smear negative for asexual forms of P. falciparum
- •Negative pregnancy test for persons of child-bearing potential
- •For Adults with Uncomplicated Malaria (Part 1):
- •18 years and older
- •Informed consent obtained and ICF signed
- •Temperature ≥ 38 °C or history of fever in the past 24 hours
- •Thick or thin blood smear positive for asexual forms of P. falciparum (parasite count and speciation documented)
- •Hemoglobin ≥ 7 g/dL or hematocrit/ PCV ≥ 20%
- •BMI 18.5-25 kg/m2
- •Creatinine ≤ 110 mmol/L (≤ 1.2 mg/dL; males) or ≤ 90 mmol/L (≤ 1.0 mg/dL; females)
- •Glasgow coma score of 15
- •Respiratory rate ≤ 20 breaths/ minute
- •Oxygen saturation ≥ 90% on room air
- •Negative pregnancy test for person of child-bearing potential
- •For Children with Cerebral Malaria (Part 2):
- •Age 12 months-14 years old
- •Informed consent obtained and ICF signed by parent or guardian
- •Temperature ≥ 38 °C or history of fever in the last 24 hours
- •Thick or thin blood smear positive for asexual forms of P. falciparum
- •Blantyre coma score ≤ 2
- •No other explanation for coma by history or physical exam
- •Hematocrit or PCV ≥ 18%
- •Negative pregnancy test for persons of child-bearing potential
- •Creatinine ≤ 1.5 mg/dL
- •Aspartate aminotransferase (AST) < 280 IU/L
- •Alanine aminotransferase (ALT) < 195 IU/L
排除标准
- •(All Participants):
- •Pregnancy or lactation (participants of child-bearing potential ages 9-59 years will undergo pregnancy testing prior to administration of the intervention)
- •Participants attempting to become pregnant
- •Currently taking highly active antiretroviral therapy (HAART)
- •Currently taking anti-tuberculosis medications
- •Allergy to ondansetron or ceftriaxone
- •Additional Exclusion Criteria for Children with Cerebral Malaria (Part 2):
- •Cloudy cerebrospinal fluid (indicative of a probable bacterial central nervous system infection)
- •Severe malnutrition (>3 standard deviations below the mean weight for height and/ or mid-upper arm circumference (MUAC) ≤11.5 cm
- •Allergy to ondansetron or ceftriaxone
- •Coma for > 72 hours
- •Have taken a CYP3A4 inhibitor within 7 days of enrollment
研究组 & 干预措施
Dose escalation in healthy Malawian adults - 10.0 mg/kg IV DON
The first 10 healthy adult participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, the dose will be increased to 1.0 mg/kg IV DON and then 5.0 mg/kg IV DON the final group will receive 10.0 mg/kg IV DON.
干预措施: 6-diazo-5-oxo-L-norleucine (DON) (Drug)
Dose escalation in healthy Malawian adults - 0.1 mg/kg IV DON
The first 10 healthy adult participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, the dose will be increased to 1.0 mg/kg IV DON and then 5.0 mg/kg IV DON the final group will receive 10.0 mg/kg IV DON.
干预措施: 6-diazo-5-oxo-L-norleucine (DON) (Drug)
Dose escalation in healthy Malawian adults - 5.0 mg/kg IV DON
The first 10 healthy adult participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, the dose will be increased to 1.0 mg/kg IV DON and then 5.0 mg/kg IV DON the final group will receive 10.0 mg/kg IV DON.
干预措施: 6-diazo-5-oxo-L-norleucine (DON) (Drug)
Dose escalation in healthy Malawian adults - 1.0 mg/kg IV DON
The first 10 healthy adult participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, the dose will be increased to 1.0 mg/kg IV DON and then 5.0 mg/kg IV DON the final group will receive 10.0 mg/kg IV DON.
干预措施: 6-diazo-5-oxo-L-norleucine (DON) (Drug)
Dose escalation in Malawian children with cerebral malaria - 0.1 mg/kg IV DON - Cohort 2
10 participants will receive 0.1 mg/kg IV DON, and 2 will receive placebo.
干预措施: 6-diazo-5-oxo-L-norleucine (DON) (Drug)
Dose escalation in Malawian children with cerebral malaria - placebo
Cohort 1 will dose 2 participants to receive placebo Cohort 2 will dose 2 participants to receive placebo Cohort 3 will dose 4 participants to receive placebo Cohort 4 will dose 12 participants to receive placebo
干预措施: Placebo (Drug)
Dose escalation in Malawian adults with uncomplicated malaria - 5.0 mg/kg IV DON
The first 10 adults with uncomplicated malaria participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, the dose will be increased to 1.0 mg/kg IV DON and then 5.0 mg/kg IV DON, and then the final group will receive 10.0 mg/kg IV DON.
干预措施: 6-diazo-5-oxo-L-norleucine (DON) (Drug)
Dose escalation in Malawian children with cerebral malaria - 1.0 mg/kg IV DON - Cohort 3
14 participants will receive 1.0 mg/kg IV DON, and 4 will receive placebo.
干预措施: 6-diazo-5-oxo-L-norleucine (DON) (Drug)
Dose escalation in Malawian children with cerebral malaria - 0.1 mg/kg IV DON - Cohort 1
After adult doses are shown to be safe. Of the first 6 children with cerebral malaria enrolled, 4 will receive 0.1 mg/kg IV DON, and 2 will receive placebo.
干预措施: 6-diazo-5-oxo-L-norleucine (DON) (Drug)
Dose escalation in Malawian adults with uncomplicated malaria - 0.1 mg/kg IV DON
The first 10 adults with uncomplicated malaria participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, the dose will be increased to 1.0 mg/kg IV DON and then 5.0 mg/kg IV DON, and then the final group will receive 10.0 mg/kg IV DON.
干预措施: 6-diazo-5-oxo-L-norleucine (DON) (Drug)
Dose escalation in Malawian adults with uncomplicated malaria - 10.0 mg/kg IV DON
The first 10 adults with uncomplicated malaria participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, the dose will be increased to 1.0 mg/kg IV DON and then 5.0 mg/kg IV DON, and then the final group will receive 10.0 mg/kg IV DON.
干预措施: 6-diazo-5-oxo-L-norleucine (DON) (Drug)
Dose escalation in Malawian children with cerebral malaria - 0.1 or 1.0 mg/kg IV DON - Cohort 4
36 participants will receive 0.1 mg/kg IV DON (n=12) or 1.0 mg/kg IV DON (n=12), and 12 will receive placebo.
干预措施: 6-diazo-5-oxo-L-norleucine (DON) (Drug)
Dose escalation in Malawian adults with uncomplicated malaria - 1.0 mg/kg IV DON
The first 10 adults with uncomplicated malaria participants enrolled will receive a single 0.1 mg/kg intravenous (IV) DON. If this dose is proven safe, in each subsequent group of 10, the dose will be increased to 1.0 mg/kg IV DON and then 5.0 mg/kg IV DON, and then the final group will receive 10.0 mg/kg IV DON.
干预措施: 6-diazo-5-oxo-L-norleucine (DON) (Drug)
结局指标
主要结局
Incidence of systemic AEs occurring within 14 days after the administration of DON
时间窗: 14 days
Number of AEs
Incidence of local AEs occurring within 14 days after the administration of DON
时间窗: 14 days
Number of AEs
Incidence of systemic SAEs occurring within 14 days after the administration of DON
时间窗: 14 days
Number of SAEs - pediatric arms only
Assessment of Blantyre Coma Score
时间窗: 14 days
Time to Blantyre Coma Score of 5
次要结局
- PK measurement of DON in sera of recipients measured by half life(Measured through 18 hours post infusion)
- PK measurement of DON in sera of recipients measured by volume of distribution(Measured through 18 hours post infusion)
- PK measurement of DON in sera of recipients measure by maximum concentration (Cmax)(Measured through 18 hours post infusion)
- PK measurement of DON in sera of recipients measure by time of maximal concentration (Tmax)(Measured through 18 hours post infusion)
- PK measurement of DON in sera of recipients measure by area under the concentrations vs. time curve (AUC)(Measured through 18 hours post infusion)
- PK measurement of DON in sera of recipients measure by clearance(Measured through 18 hours post infusion)
- PK measurement of DON in sera of recipients measure by elimination rate(Measured through 18 hours post infusion)
- PK measurement of DON in sera of recipients measure by terminal T1/2(Measured through 18 hours post infusion)
研究者
Douglas Postels
Professor of Pediatric Neurology
Children's National Research Institute