Therapeutic Efficacy Study of AL and DP in Western Kenya
Condition: Malaria,Falciparum
MeSH terms: Malaria; Malaria, Falciparum
Study type: Interventional

Summary: 
      Artemether-lumefantrine (AL) was adopted as first-line antimalarial therapy in Kenya in 2006,
      and dihydroartemisinin-piperaquine (DP) as the second-line therapy in 2010. In order to
      monitor the efficacy and potential development of resistance of Plasmodium falciparum
      parasites to these two drugs, we will conduct an in-vivo study to monitor the efficacy of
      these antimalarial therapies.

      A standardized World Health Organization (WHO) in-vivo efficacy study will be conducted in
      western Kenya among children 6-59 months of age with symptomatic, uncomplicated malaria
      visiting the out-patient department of hospitals and/or clinics in western Kenya.

      In this study, 350 children will be randomly assigned to be treated with either AL or DP.
      Clinical, parasitologic, and hematologic parameters will be monitored over a 42-day follow-up
      period. Molecular analysis will be conducted to determine the frequency of markers of
      antimalarial resistance, and to differentiate recrudescence from reinfection. Results from
      this antimalarial drug efficacy study will be used to assist the Kenya national malaria
      control program (NMCP) in evaluating the national malaria treatment policy.
    

Detailed description: 
      Aim & Objectives

      Aim: To assess the therapeutic efficacy of AL and DP for symptomatic, uncomplicated P.
      falciparum infections among children based on parasitologic, clinical, and hematologic
      parameters.

      Objectives

      i. To measure the clinical and parasitological efficacy of AL and DP among patients aged 6-59
      months with symptomatic, uncomplicated P. falciparum malaria,

        1. Primary efficacy endpoint: PCR-corrected parasitemia by day 42, the adequate clinical
           and parsitological response (ACPR)

        2. Secondary efficacy endpoints:

             -  Determine the proportion of children with early treatment failure (ETF) and late
                treatment failure (LTF) by determining the presence of parasitemia on days 3, 7,
                14, 28, 35, and 42

             -  To determine the frequency of existing molecular markers for drug resistance and
                identify new molecular markers

             -  Evaluate drug concentration levels at day 7

             -  Evaluate duration of malaria HRP2/pLDH RDT positivity after appropriate treatment
                with AL and DP

      Design and Methodology Design: Randomized open-label clinical trial.

        1. Study site. The study will be conducted at hospitals and/or clinics in western Kenya.
           This region of Kenya has some of the highest prevalence of malaria in Kenya. The
           decision of the site/s for each study will be determined prior to the initiation of each
           study and by criteria including: 1) sufficient number of children <5 years of age
           presenting to the site with symptomatic, uncomplicated malaria in the prior year, 2) ≥20
           children presenting to the study site with symptomatic laboratory confirmed malaria per
           week, and 3) willingness of the staff to participate in the trial including the clinical
           and laboratory aspects.

        2. Study population. The population of interest consists of patients aged 6-59 months
           diagnosed with symptomatic, uncomplicated P. falciparum malaria consulting at the study
           site, and whose parents or guardians give permission for study inclusion.

        3. Intervention. Participants will be randomized to receive a standard weight-based regimen
           of: (1) artemether-lumefantrine (Coartem®, Novartis Pharmaceuticals Corporation,
           Missouri, USA) or (2) dihydroartemisinin-piperaquine (Duo-Cotecxin®, Holley-Cotec
           Pharmaceuticals, Beijing, China).

        4. Consenting and Screening. Parents/guardians of patients presenting to the outpatient
           clinics with a clinical diagnosis of uncomplicated malaria will be approached by a team
           member and asked if they would be interested in joining the research study. The team
           member will explain the purpose and the procedures of the study, will review the
           inclusion and exclusion criteria with the parent/caregiver, and if the patient is
           eligible, and the patient/caregiver agrees, will then administer the consent to the
           parent/guardian.

           Study enrolment procedures:

           - The patient will be assigned a unique study identification number; this will be used
           to identify all forms and blood samples from that patient

             -  Children will be evaluated by clinical staff for signs of febrile illness other
                than malaria, and signs of severe disease/ danger signs

             -  Demographic and clinical data will be entered into a standardized form, including
                age, gender, axillary temperature, height, and body weight

             -  A fingerprick will be performed to prepare a thick and a thin blood smear for
                microscopy, malaria RDT, hemoglobin determination by HemoCue®, and a filter paper
                blood for later PCR testing; the total blood volume collected will be <500
                microliters.

             -  Blood smear: The first thick smear will be stained with 10% Giemsa and quickly
                assessed for the presence of malaria parasitemia and an estimate of the parasite
                density.

        5. Randomization & Blinding. Children will be block randomized to one of the study arms.
           The allocation will be blinded only to the microscopists reading the blood films.

      Clinical Procedures.

        1. After confirmation of enrolment:

             1. In order to easily identify patients in the community, digital photograph of both
                the child and parent/ guardian will be taken to verify the child's identity on
                repeat visits

             2. After randomization (day 0), each child will receive the (first) daily dose of
                study medication under direct observation and will be monitored for vomiting for 30
                minutes. If a child vomits within 30 minutes of receiving their initial dose, the
                child will be retreated with the same dose of medication and observed for an
                additional 30 minutes. If vomiting continues, the child will be withdrawn from the
                study, and given rescue medication.

             3. If the child is taking AL, the parent will be given the evening dose to administer
                at home. Study personnel will attempt to confirm adherence by:

        1. Calling the parent/guardian twice to remind to dose the child

        2. Request the parent/guardian to return with the blister pack so that a study member can
           visualize the number of doses remaining

        3. Give the parent/guardian a reserve dose in the event that the child vomits the dose;
           request that the parent/guardian return the extra dose on day 7 to prevent
           administration of the extra dose.

      b. Follow-up

        1. Each child will return on days 1 and 2 for subsequent doses. Clinical reassessments will
           be made on days 1-3, 7, and then weekly until day 42 inclusive.

        2. Patients will be advised to return on any day or night during the follow-up period if
           symptoms return and not to wait for scheduled visit days. We will call the
           parent/guardian of the child the day prior to a visit to remind them to come to the
           clinic. Patients who do not present to the study site for follow-up visits will be
           followed at home within 24 hours.

        3. Parents will be reimbursed for transport per KEMRI/CDC guidelines for each visit to
           cover their travel expenses, and a long-lasting insecticide-treated bed net will be
           offered to the parent of each enrolled child at the time of enrollment.

           c. Blood samples.

           Blood films for parasite count will be obtained and examined on days 0, 2, 3, 7, 14, 21,
           28, 35, and 42, on day 1 in case of sign/symptoms of severe malaria, and on any other
           day if the patient spontaneously returns with fever or worsening symptoms. Hemoglobin
           status will be measured on days 0, 7, 14, 28 and 42. A filter paper blood spot or blood
           collected in a microtainer tube (<1 ml blood) will be collected on day 7 to assess drug
           levels, and additionally on days 0, and after day 7 to assess parasite genotypes in the
           setting of late clinical failures; additional filter paper samples will be collected
           after day 3 in case of treatment failure and used to test for parasite species and
           polymorphism to distinguish between reinfection and recrudescence and for molecular
           markers of drug resistance as described below.

           Rescue Treatment.

           Patients with recrudescent infection or reinfection during the follow-up period will be
           treated with quinine. Patients with severe malaria will be referred to the hospital for
           in-patient treatment according to Kenya national guidelines (currently parenteral
           quinine or artesunate).

           Concomitant Treatment.

           Using standard clinic procedures, clinic personnel will administer supportive treatment
           to patients as necessary:

           • Antipyretics will be given for temperatures > 37.5C as per national policy.

           • Ferrous sulfate/ folate will be given to all children with hemoglobin <10 mg/dl as per
           national Integrated Management of Childhood Illness (IMCI) Guidelines

           • Anti-helminthics will be given to all children as per national IMCI Guidelines

           Study Endpoints

           Valid study end-points include treatment failure, completion of the follow-up period
           without treatment failure, loss to follow-up, withdrawal from study (voluntary or
           involuntary, and protocol violation). Loss to follow-up occurs when, despite all
           reasonable effort, an enrolled patient who does not attend the scheduled visits cannot
           be found within 3 days of their scheduled visit.

           Handling of Unexpected or Adverse Events.

           a. Identifying, managing and reporting adverse events. Existing data suggest that the
           drug combinations proposed in this study are safe. The combination of
           artemether-lumefantrine has been shown to be safe and highly efficacious. The
           combination of DHA-piperaquine has been shown to be safe, with mild adverse events,
           primarily gastrointestinal, headache, and mild QTc prolongation. Most severe allergic
           reactions would be expected to manifest within an hour of taking the dose. We will
           counsel parents to return immediately if their child develops a raised rash (i.e.,
           urticaria) or difficulty breathing suggestive of a severe allergic reaction.

           b. Emergency Care. Mild adverse reactions will be noted in the case report form; no
           further action will be taken by study staff, except in the case of vomiting. For
           vomiting, the study medication will be re-administered according to the protocol. In the
           event of significant vomiting, initially ORS (oral rehydration solution) will be
           administered. If ORS is not tolerated, the patient will be referred to the hospital for
           management. In the case of any severe adverse reaction (e.g., difficulty breathing,
           convulsions, change in mental status), subjects will also be referred to hospital for
           management. Patients with signs of severe malaria, persistent vomiting or severe side
           effects will be referred to the hospital to receive parenteral therapy with quinine and
           relevant supportive treatments.

           c. Reporting adverse events. Any adverse event which is severe, unexpected, and possibly
           related to the research, as well as any unanticipated problems involving risks to
           subjects or others and any occurrences of serious or continuing non-compliance will be
           reported to the KEMRI and CDC IRB, according to their respective policies on incident
           reporting. Fatal outcomes will be reported within 2 days. A home visit will be conducted
           following the death of a child to assess the duration of illness, signs and symptoms of
           illness.

           Laboratory procedures: Polymerase Chain Reaction (PCR)

           In order to differentiate a recrudescence (same parasite strain) from reinfection
           (different parasite strain), a genotypic analysis based on merozoite surface protein-1
           (msp1), merozoite surface protein 2 (msp2) and glutamate-rich protein (glurp) will be
           performed by PCR. Nested mutation-specific PCR, pyrosequencing or sequencing will be
           performed to analyze drug resistant mutations. We will investigate artemisinin
           resistance by evaluating mutations in the P. falciparum K-13 propeller gene, and
           potentially other genes including Pfcrt ,Pfmdr1.10 We plan to assess for the presence of
           these mutations in the western Kenyan parasite populations and characterize any
           potential new molecular markers as new information appears in the literature.

           Data analysis

           Data will be analyzed using two methods: survival analysis where children are included
           in the analysis until the last day before drop-out and a per-protocol analysis excluding
           all reinfections.

           The final analysis will include:

           - A description of the patients screened, and the distribution of the reasons for study
           exclusion.

             -  A description of the patients included in the study.

             -  The PCR corrected and uncorrected proportion of ETF, LCF, LPF, and ACPR in each
                treatment arm at day 28 and day 42 with 95% confidence intervals using survival
                analysis.

             -  Frequency of side effects, severe malaria, anemia, and hospitalizations by
                treatment arm

             -  The frequency of molecular markers for drug resistance

           Ethical Considerations

           The research will be conducted in compliance with the protocol, good clinical practice
           (GCP) guidelines, and all applicable regulatory requirements. Approvals will be obtained
           from KEMRI ERC and CDC IRB.
    

Intervention name(s): Artemether-lumefantrine (AL); Dihydroartemisinin-piperaquine (DP)
Intervention type(s): Drug; Drug
Intervention description(s): AL is the current first-line antimalarial in Kenya, per Kenya Ministry of Health.; DP is the current second-line antimalarial in Kenya, per Kenya Ministry of Health.
Other intervention name(s): Coartem; Duocotexin
Intervention MeSH terms: Lumefantrine; Artemether; Piperaquine; Artemether, Lumefantrine Drug Combination; Artenimol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Malaria; Kenya; Therapeutiic Efficacy; Artemether-lumefantrine; Dihydroartemisinin-piperaquine