A Phase 2A Study of a Novel Antimalarial Pyrrolidinamide in Adult Patients With Uncomplicated P. Falciparum Malaria

Official title

A Phase 2A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of a Novel Antimalarial Pyrrolidinamide at Different Doses and Dose Durations, in Adult Patients With Uncomplicated P. Falciparum Malaria

Overview

The study will evaluate the safety and efficacy of a new antimalarial drug GSK3772701 (a pyrrolidinamide), using different doses and treatment durations, in adult participants with uncomplicated Plasmodium (P.) falciparum malaria.

Interventions

• Drug GSK3772701 600 mg
  A 600 mg dose of GSK3772701 administered orally, as 4 capsules of 150 mg.
• Drug GSK3772701 900 mg
  A 900 mg dose of GSK3772701 administered orally, as 6 capsules of 150 mg.
• Drug GSK3772701 150 mg
  A daily 150 mg dose of GSK3772701 administered orally on Day 1 and Day 2, as 1 capsule.
• Drug GSK3772701 400 mg
  A daily 400 mg dose of GSK3772701 administered orally on Day 1 and Day 2, as 2 capsules of 150 mg and 1 capsule of 100 mg.
• Drug GSK3772701 50 mg
  A daily 50 mg dose of GSK3772701 administered orally on Day 1, Day 2 and Day 3, as 1 capsule.

Primary outcome measures

• Number of participants with serious adverse events (SAEs) overall, treatment related, and by severity [Time frame: From the date of informed consent signing (up to 24 hours prior to Day 1) up to Day 40 (end of the follow-up period)]
• Number of participants with non-serious AEs overall, treatment related, and by severity [Time frame: From Day 1 up to Day 40]

Secondary outcome measures (8)

• Area under the concentration (AUC) - time curve (AUC[0-t]) of GSK3772701 [Time frame: From Day 1 to Day 7]
• AUC(0-t) extrapolated to infinity (AUC[0-inf]) of GSK3772701 [Time frame: From Day 1 to Day 7]
• Maximum observed concentration (Cmax) of GSK3772701 [Time frame: From Day 1 to Day 7]
• Time to maximum observed drug concentration (Tmax) of GSK3772701 [Time frame: From Day 1 to Day 7]
• Apparent terminal half-life (t1/2) of GSK3772701 [Time frame: From Day 1 to Day 7]
• Trough concentration (Ctau) of GSK3772701 following multiple dose administration [Time frame: From Day 2 to Day 7]
• Observed accumulation ratio (R) of GSK3772701 for AUC [AUC(Ro)] following multiple dose administration [Time frame: From Day 2 or Day 3 to Day 7, compared to Day 1]
• Observed accumulation ratio of GSK3772701 based on Cmax (RCmax) following multiple doses [Time frame: From Day 2 or Day 3 to Day 7, compared to Day 1]

Eligibility criteria

Inclusion criteria

• Male and female patients aged 18 to 65 years.
• Presence of malaria due to mono-infection with P. falciparum confirmed by:

• Fever, as defined by axillary temperature >=37.5°C or oral/tympanic temperature >=38°C and,
• Microscopically confirmed P. falciparum malaria parasite mono-infection,
• A parasite count between 2,000 to 60,000 asexual parasite count/µL of blood for P. falciparum.
• Have a BMI between >=18 and <=30 kg/m2.
• Able to swallow oral medication.
• Signed informed consent, acknowledging understanding and willingness to comply with the requirements of the study. If the patient is unable to write, thumb print consent, signed by an impartial witness is permitted according to local ethical considerations.
• Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:

• Is a woman of non-childbearing potential (WONCBP) or
• Is a woman of childbearing potential (WOCBP) and using an acceptable contraceptive method, from Study Day 1, and during the study intervention period (40 +/-3 days).

Exclusion criteria

• Patients with signs and symptoms of severe/complicated malaria according to the WHO 2024 Criteria.
• Mixed Plasmodium infection, i.e., infection with more than one malaria (plasmodium) species (by microscopy; participant to be withdrawn from study treatment if PCR subsequently indicates presence of mixed infection).
• Abnormal values: QTcF >450 msec or QTcF >480 msec for patients with bundle branch block.
• Any clinically significant ECG abnormalities at Screening unrelated to malaria (including but not limited to, second degree AV block (Mobitz Type 2), complete heart block, ST changes, atrial fibrillation, atrial flutter, supraventricular tachycardia, ventricular tachycardia, prolonged QT interval.
• History of malignancy (or current malignancy) of any organ system (other than localized carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
• Creatinine >=2 x ULN.
• Significant illness within two weeks prior to screening.
• Positive HIV antibody test at screening, or history of HIV infection based on past positive test result, clinical record or current treatment.
• Severe vomiting, defined as more than 3 times in the 24 hours before screening or inability to tolerate oral treatment.
• Severe diarrhoea defined as more than 3 watery stools per day in the 24 hours before screening.
• Known history or evidence (based on clinical examination or investigation) of uncontrolled active cardiovascular disease (including hypertension), respiratory disease (including active tuberculosis even if treatment is ongoing), liver cirrhosis or liver disease (based on prior investigation, clinical signs and/or interpretation of liver enzymes), other active hepatic, renal, gastrointestinal, immunological, neurological, endocrine, infectious, or psychiatric disease.
• Anaemia (Hb <=8.0g/dl) or known clinically important chronic underlying haematological disease such as sickle cell disease at screening.
• Significant chronic medical conditions which in the opinion of the investigator preclude enrolment into the study.
• Have received any antimalarial treatment in the preceding 6 weeks (see Section 6.10), as determined by history or medical record.
• Prior enrolment in this study and receipt of treatment with GSK3772701.
• Use of other investigational drugs at the time of enrolment, or within 6 weeks, or 5 half-lives prior to enrolment into this study, whichever is longer; or longer if required by local regulations, and for any other limitation of participation in an investigational trial based on local regulations.
• History of hypersensitivity to the study drug or drug formulation and capsule (Hypromellose (hydroxypropyl methylcellulose)) constituents.
• History of drug or alcohol abuse within 3 months prior to dosing, or clinical evidence of such abuse.
• Participants who in the opinion of the Investigator are unsuitable for participation in the study or cannot be enrolled due to logistical reasons.
• ALT >2.0 x ULN.
• Total bilirubin >1.5 x ULN; Participants with Gilbert's syndrome can be included with total bilirubin >1.5xULN as long as direct bilirubin is <=1.5xULN.
• Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to first dose of study intervention.
• Positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study intervention.

Note: Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained.

• Positive hepatitis C RNA test result at screening or within 3 months prior to first dose of study intervention.

Note: Test is optional and participants with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07545681 · 223257

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗