| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Severe Plasmodium falciparum Malaria |
|
| E.1.1.1 | Medical condition in easily understood language |
| Severe Malaria caused by the Plasmodium falciparum parasite |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Parasitic Diseases [C03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 26.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10069722 |
| E.1.2 | Term | Complicated malaria |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To assess the efficacy of IV cipargamin |
|
| E.2.2 | Secondary objectives of the trial |
• To assess clinical outcome
• To assess the presence/absence of individual signs of severe malaria
• To assess the risk of hemolysis
• To assess the risk of long term neurological sequelae
• To evaluate parasite clearance dynamics
• To assess other efficacy endpoints
• To evaluate the safety and tolerability of IV cipargamin
• To assess the plasma pharmacokinetics of IV cipargamin
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Cohort 1: Participants aged ≥ 12 years with moderately severe malaria as defined in Barnes et al (2004) (prostration and/or repeated vomiting) without presence of other signs of severe malaria (Section 16.4) and with high P. falciparum parasitemia (60,000-250,000 parasites per µl).
Subsequent Cohorts 2 to 5: Participants diagnosed with severe malaria as defined in Section 16.4 (modified version of severe malaria criteria in WHO 2014) and P. falciparum parasite count of ≥ 5000 per µl
Cohort 2: Participants aged ≥ 12 years Cohort 3: Participants aged 6 - <12 years
Cohort 4: Participants aged 2 - < 6 years
Cohort 5: Participants aged ≥6 months - <2 years
2. Written informed consent form must be obtained prior to any study related procedure. If the participant is unable to read and write or otherwise incapable of signing an informed consent, then a witnessed consent according to local ethical standards is permitted (formally documented and witnessed, ideally via an independent trusted witness). Participants aged < 18 years, who are capable of providing assent, must provide assent with parental/legal guardian consent or as per local ethical guidelines. The participant or parent/legal guardian (in case of pediatric participants) is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions for their child and is likely to complete the study as planned
|
|
| E.4 | Principal exclusion criteria |
Participants meeting any of the following criteria are not eligible for inclusion in this study.
1. Exclusion criteria applying to all Cohorts 1 to 5:
1. Mixed Plasmodium infections
2. Treatment with quinine or artemisinin derivative or any other antimalarial drug or any antibiotic with known antimalarial activity within 12 hours of screening
3. Known underlying illness, surgical or medical condition, which is not related to ongoing event of severe malaria and which might jeopardize the participant's health in case of participation in the study or which might alter the distribution, metabolism or excretion of study treatment, e.g. :
• neurological or neurodegenerative disorders,
• cardiac, renal, or hepatic disease, diabetes,
• epilepsy, cerebral palsy,
• known or suspected to be HIV-1 positive and/or receiving antiretroviral treatment
• malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases
• known or suspected cases of active infections or concurrent febrile illness such as TB, Typhoid, COVID-19 etc.
4. Known history of ECG abnormalities indicating significant risk of safety for participants such as:
a. Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker
b. History of familial long QT syndrome or known family history of Torsades de Pointes
c. QTcF > 450 ms in males and QTcF > 460 ms in females aged ≥ 12 years old and QTcF > 450 ms in females aged < 12 years.
5. Signs/symptoms of severe malnutrition in general accordance with WHO guidelines:
• Under 18 years: <-3 Z-scores of WHO growth standard for weight-for- height/length (in children < 5 years) or BMI for age (5-18 years), or very low mid- upper arm circumference (MUAC <115 mm in children < 12 years, <160mm 12- 18 years), or bilateral pitting edema
• Over 18 years: BMI < 16 kg/m2 or MUAC < 160mm or bilateral pitting edema
6. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of enrollment, or within 30 days, whichever is longer; or longer if required by local regulations
7. Participants taking prohibited medication defined as per Section 6.2.3
8. Pregnant or nursing (lactating) women
9. Female of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective contraception methods (listed below) during dosing and until one week after last IV dose or until start of next menstruation after last dose of oral standard of care (Coartem), whichever is later. Required highly effective contraception methods include:
a. Total abstinence (when this is in line with the preferred and usual lifestyle of the participant). Periodic abstinence (i.e., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception
b. Male partner sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that participant
c. Female sterilization (have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment
d. Use of oral (e.g. estrogen, synthetic progestins), injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormonal vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment. Coartem can reduce the effectiveness of hormonal
contraceptives, female participants using oral, transdermal patch, or other systemic hormonal contraceptives are required to use an additional non-hormonal method of birth control, e.g., barrier contraceptives during dosing of oral Coartem and until the start of next menstruation after completion of oral treatment.
e. Females are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of child- bearing potential.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Proportion of participants with ≥ 90% P.
falciparum parasite reduction at 12 hours |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Proportion of participants with clinical success over time. Clinical success at 48 hours is considered as the key secondary endpoint
• Proportion of participants with individual signs of severe malaria over time
• Proportion of participants developing hemolysis (early and delayed) after treatment
• Proportion of participants with neurological sequelae at Day 29
• Proportions of participants with ≥ 90% parasite reduction at 24 and 48 hours, PCE slope half-life, Time to P. falciparum parasite clearance (PCT), P. falciparum parasite reduction ratios (PRR) at 12, 24 and 48 hours, Proportion of participants with recrudescence and reinfection by Day 29
• Time (days and hours) to switch to oral therapy Day of discharge from hospital, Time (hours) to recover from prostration
• Standard safety/tolerability assessments (incidence of serious adverse events (SAEs), mortality, in-hospital mortality, adverse events (AEs), and routine safety and laboratory assessments)
• PK parameters of cipargamin: Cmax, T1/2, AUC, CL and Vz
Alpha-1-acid glycoprotein level over time and correlation of AAG concentration with cipargamin PK parameters
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Burkina Faso |
| Congo, The Democratic Republic of the |
| Gabon |
| Mozambique |
| Nigeria |
| Rwanda |
| Tanzania, United Republic of |
| Uganda |
| Côte d’Ivoire |
| India |
| Kenya |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
Print
