Efficacy, Safety and Tolerability of KAF156 in Combination With Lumefantrine Solid Dispersion Formulation (LUM-SDF) in Pediatric Population With Uncomplicated Plasmodium Falciparum Malaria

NCT ID: NCT04546633

Last Updated: 2024-09-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 295 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-02-16
• Study Completion Date: 2024-08-28

Brief Summary

This study aims to determine the efficacy, safety and tolerability of the investigational drug KAF156 in combination with a solid dispersion formulation of lumefantrine (LUM-SDF) in pediatric patients (6 months to < 18 years of age) with uncomplicated P. falciparum malaria. There is an unmet medical need for anti-malarial treatment with a new mechanism of action to reduce the probability of developing resistance.

Detailed Description

This Phase 2 study aims to evaluate the efficacy, safety and tolerability of the investigational drug KAF156 and a Solid Dispersion Formulation of lumefantrine (LUM-SDF) when administered in combination in pediatric patients 6 months to < 18 years of age with uncomplicated Plasmodium falciparum malaria. In addition, pharmacokinetics (PK) of the drug combination will also be evaluated.

There will be three age-descending cohorts: Run-in Cohort, Cohort 1 and Cohort 2.

It is important to understand the impact of food on exposure. In adult healthy volunteers, LUM-SDF alone has shown a food effect whereas KAF156 does not have a food effect. This new study will first explore the effect of food on lumefantrine and KAF156 PK in malaria patients 12 to < 18 years old with malaria caused by P. falciparum before younger patients are assessed.

Then, efficacy, safety and tolerability of the combination of KAF156 and LUM-SDF will be evaluated in younger patients, first in Cohort 1 of patients 2 to < 12 years old and then in Cohort 2 of patients 6 months to < 2 years old.

Conditions

Uncomplicated Plasmodium Falciparum Malaria

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Run-in - KAF156 and LUM-SDF QD for 2 days in fasted condition

KAF156 and LUM-SDF QD (once daily) for 2 days in fasted condition

Group Type: EXPERIMENTAL

KAF156

Intervention Type: DRUG

Provided as 50 mg or 100 mg tablets, to be taken QD 2 or 3 Days in combination with LUM-SDF, dose is based on body weight

LUM-SDF

Intervention Type: DRUG

Provided as 60 mg, 120 mg or 240 mg powder in sachet, to be taken QD 2 or 3 Days in combination with KAF156, dose is based on body weight

Run-in - KAF156 and LUM-SDF QD for 2 days in fed condition

KAF156 and LUM-SDF QD (once daily) for 2 days in fed condition

Group Type: EXPERIMENTAL

KAF156

Intervention Type: DRUG

Provided as 50 mg or 100 mg tablets, to be taken QD 2 or 3 Days in combination with LUM-SDF, dose is based on body weight

LUM-SDF

Intervention Type: DRUG

Provided as 60 mg, 120 mg or 240 mg powder in sachet, to be taken QD 2 or 3 Days in combination with KAF156, dose is based on body weight

Cohort 1/2 - KAF156 and LUM-SDF QD (once daily) in either a 2-day or 3-day dose regimen

KAF156 and LUM-SDF QD (once daily) in either a 2-day or 3-day dose regimen. Food recommendation will be issued after the Run-in Cohort based on efficacy, safety, tolerability and PK data).

Group Type: EXPERIMENTAL

KAF156

Intervention Type: DRUG

Provided as 50 mg or 100 mg tablets, to be taken QD 2 or 3 Days in combination with LUM-SDF, dose is based on body weight

LUM-SDF

Intervention Type: DRUG

Provided as 60 mg, 120 mg or 240 mg powder in sachet, to be taken QD 2 or 3 Days in combination with KAF156, dose is based on body weight

Cohort 1/2 - Coartem® BID (twice a day) for 3 days

Coartem® BID (twice a day) for 3 days (will be administered with food and doses will be based on patient's body weight as per product label).

Group Type: ACTIVE_COMPARATOR

Coartem

Intervention Type: DRUG

Coartem® (dispersible tablets in blister pack) (for Cohorts 1 and 2), dose is based on body weight

Interventions

KAF156

Provided as 50 mg or 100 mg tablets, to be taken QD 2 or 3 Days in combination with LUM-SDF, dose is based on body weight

Intervention Type: DRUG

LUM-SDF

Provided as 60 mg, 120 mg or 240 mg powder in sachet, to be taken QD 2 or 3 Days in combination with KAF156, dose is based on body weight

Intervention Type: DRUG

Coartem

Coartem® (dispersible tablets in blister pack) (for Cohorts 1 and 2), dose is based on body weight

Intervention Type: DRUG

Other Intervention Names

Lumefantrine Solid Dispersion Formulation

Eligibility Criteria

Inclusion Criteria

1. In run-in cohort: Male and female patients 12 to < 18 years of age, with a body weight

• 35.0 kg In Cohort 1: Male and female patients 2 to < 12 years of age, with a body weight ≥ 10.0 kg In Cohort 2: Male and female patients 6 months to < 2 years of age, with a body weight
• 5.0 kg

2. Microscopic confirmation of P. falciparum by Giemsa-stained thick and thin films

3. P. falciparum parasitemia of ≥ 1,000 and ≤ 150,000 parasites/μL at the time of prescreening for the Run-in Cohort; and P. falciparum parasitemia of ≥ 1,500 and ≤ 150,000 parasites/μL at the time of pre-screening for Cohorts 1 and 2

4. Axillary temperature ≥ 37.5 ºC or oral/tympanic/rectal temperature ≥ 38.0 ºC; or history of fever during the previous 24 hours (at least documented verbally)

5. Written informed consent has been obtained from parent / legal guardian before any assessment is performed. If the parent/legal guardian is unable to read and write, then a witnessed consent according to local ethical standards is permitted. Patients who are capable of providing assent, must provide assent with parental/legal guardian consent or as per local ethical guidelines

6. The patient and his/her parent/legal guardian is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions and is likely to complete the study as planned

Exclusion Criteria

1. Mixed Plasmodium infections as per light microscopy results

2. Signs and symptoms of severe malaria according to WHO 2015 (see Section 16.4)

3. Significant, non-plasmodial co-infections including tuberculosis

4. Patients with concurrent febrile illnesses (e.g., typhoid fever, known or suspected COVID19)

5. Known relevant liver disease e.g. chronic hepatitis, cirrhosis, compensated or decompensated, history of hepatitis B or C, hepatitis B or A vaccination in last 3 months, known gallbladder or bile duct disease, acute or chronic pancreatitis

6. Major congenital defects

7. Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection or family history of congenital or hereditary immunodeficiency

8. Immunosuppressive therapy (steroids, immune modulators or immune suppressors) within 3 months prior to recruitment. (For corticosteroids, this will mean prednisone, or equivalent, ≥ 0.5 mg/kg/day. Inhaled and topical steroids are allowed)

9. Repeated vomiting (defined as more than 3 times in the 24 hours prior to inclusion in the study) or severe diarrhea (defined as more than 3 watery stools in the 24 hours prior to inclusion in the study)

10. Active duodenal ulcer, ulcerative colitis, Crohn's disease, chronic (i.e., > 2 weeks) use of non-steroidal anti-inflammatory drugs (NSAIDs)

11. Clinically relevant abnormalities of electrolyte balance which require correction, e.g., hypokalemia, hypocalcemia or hypomagnesemia

12. Anemia (hemoglobin level <7 g/dL)

13. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs (e.g., HIV patients on ART therapy or TB patients on treatment), or which may jeopardize the patient in case of participation in the study. The investigator should make this determination in consideration of the patient's medical history and/or clinical or laboratory evidence of any of the following:

• AST/ALT > 3 x the upper limit of normal range (ULN), regardless of the level of total bilirubin
• AST/ALT > 1.5 and ≤ 2 x ULN and total bilirubin is > ULN Total bilirubin > 2 x ULN regardless of the level of AST/ALT

14. Resting QT interval corrected by Fridericia's formula (QTcF) > 450 ms at screening

15. Creatinine > 2 x ULN in the absence of dehydration. In case of dehydration, creatinine should be < 2 x ULN after oral/parenteral rehydration

16. Any severe disease condition which might prohibit participation in this study

17. Known chronic underlying disease such as sickle cell disease, and severe cardiac, renal, or hepatic impairment

18. Known active or uncontrolled thyroid disease

19. Inability to swallow oral medication (in tablet and/or liquid form)

20. Patients with prior antimalarial therapy or antibiotics with antimalarial activity within minimum of their five (5) plasma half-lives (or within 4 weeks of screening if half-life is unknown)

21. Use of other investigational drugs within 30 days of dosing or until the expected pharmacodynamic effect has returned to baseline, whichever is longer

22. Patients taking medications prohibited by the protocol

23. Previous participation in any malaria vaccine study or received malaria vaccine in any other circumstance within 3 months of dosing

24. History or family history of long QT syndrome or sudden cardiac death, or any other clinical condition known to prolong the QTc interval, such as history of symptomatic cardiac arrhythmias, clinically relevant bradycardia or severe heart disease

25. Use of agents known to prolong the QT interval unless it can be permanently discontinued for the duration of study

26. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes

For the Run-in Cohort only:

27. Pregnant or nursing (lactating) patients

28. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using basic methods of contraception during dosing of investigational drug. Basic contraception methods include:

• Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking investigational drug. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
• Male sterilization (at least 6 m prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps).

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking investigational drug. Women are considered not of child bearing potential if they 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.

For Cohorts 1 and 2 only:

29. Patients of child bearing potential, defined as all girls post first menarche (except for Run-in Cohort)

• Minimum Eligible Age: 6 Months
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

European and Developing Countries Clinical Trials Partnership (EDCTP)

OTHER_GOV

Sponsor Role: collaborator

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Banfora, , Burkina Faso

Novartis Investigative Site

Bobo-Dioulasso, , Burkina Faso

Novartis Investigative Site

Ouagadougou, , Burkina Faso

Novartis Investigative Site

Sabou, , Burkina Faso

Novartis Investigative Site

Abidjan, , Côte d’Ivoire

Novartis Investigative Site

Commune de La Kenya Lubumbashi, Du Haut Katanga, Democratic Republic of the Congo

Novartis Investigative Site

Lambaréné, , Gabon

Novartis Investigative Site

Kati, , Mali

Novartis Investigative Site

Sotouba, , Mali

Countries

Burkina Faso; Côte d’Ivoire; Democratic Republic of the Congo; Gabon; Mali

References

Ogutu B, Yeka A, Kusemererwa S, Thompson R, Tinto H, Toure AO, Uthaisin C, Verma A, Kibuuka A, Lingani M, Lourenco C, Mombo-Ngoma G, Nduba V, N'Guessan TL, Nassa GJW, Nyantaro M, Tina LO, Singh PK, El Gaaloul M, Marrast AC, Chikoto H, Csermak K, Demin I, Mehta D, Pathan R, Risterucci C, Su G, Winnips C, Kaguthi G, Fofana B, Grobusch MP. Ganaplacide (KAF156) plus lumefantrine solid dispersion formulation combination for uncomplicated Plasmodium falciparum malaria: an open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial. Lancet Infect Dis. 2023 Sep;23(9):1051-1061. doi: 10.1016/S1473-3099(23)00209-8. Epub 2023 Jun 13.

Reference Type: DERIVED

PMID: 37327809 (View on PubMed)

Other Identifiers

2021-003583-27

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CKAF156A2203

Identifier Type: -

Identifier Source: org_study_id