Efficacy, Safety, Tolerability and Pharmacokinetics of KAE609 in Adult Patients With Acute, Uncomplicated Plasmodium Falciparum or Vivax Malaria Mono-infection

• ClinicalTrials.gov Identifier: NCT01524341
• Recruitment Status: Completed
• First Posted: February 1, 2012
• Last Update Posted: May 13, 2013
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: January 30, 2012
• First Posted Date: February 1, 2012
• Last Update Posted Date: May 13, 2013
• Study Start Date: January 2012
• Actual Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 30, 2012)

Parasite clearance time [ Time Frame: From baseline to the time point when the blood parasite count is zero(up to a maximum of 5 days) ]

Calculated based on parasite count in blood. In thin film, use actual WBCs/µl, of blood to calculate parasite density by using the following formula: parasites/µl= #parasites× actual WBC/#WBCs counted. In thick film, assume that there are 250 RBCs per HPF, RBC count from 8 HPF equal 2000 RBC, Use actual RBCs/µl blood to calculate parasite density by using the following formula: parasites/µl= # of parasites in 8HPF/2000)× actual RBC.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 20, 2012)

• Number of participants with adverse events [ Time Frame: vital signs: Days 1 through 6; ECG: Days1, 2, 3; Labs: Days 2, 3, 5, study completion ]
  Number of participants with adverse events determined by Vital sign(body temperature, blood pressure and pulse rate): pre dose, 4, 8, 12, 16, 20, 24 hours post dose on Day 1: then 6, 12, 18, 24 hours post dose on each day during domiciles period until at least two consecutive normal temperature readings are obtained, then it will measure daily until Day 6. ECG: 3-4 hours post dose on day1; pre dose, 3-4 hours post dose on Day 2; pre dose, 3-4 hours post dose on Day 3 and study completion. Lab evaluation: Day 2, Day3 and Day5, study completion.
• Area under the curve (AUC)0-24h on Day 1 and Day 3 [ Time Frame: Day 1 and Day 3 ]
  The parent drug in plasma samples will be analyzed. On Day 1: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose. *The 24h sampling of first post dose should be taken before the second dose. On Day 3: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 144, and 192 hours post dose
• The accumulation ratio (Racc) (=AUC0-24h, day3/AUC0-24h, day1) [ Time Frame: Day 1 and Day 3 ]
  The parent drug in plasma samples will be analyzed. On Day 1: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose. *The 24h sampling of first post dose should be taken before the second dose. On Day 3: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 144, and 192 hours post dose
• Maximum concentration (Cmax) on Day 1 and Day 3 [ Time Frame: Day 1 and Day 3 ]
  The parent drug in plasma samples will be analyzed. On Day 1: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose. *The 24h sampling of first post dose should be taken before the second dose. On Day 3: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 144, and 192 hours post dose
• Time to maximum concentration (Tmax) on Day 1 and Day 3 [ Time Frame: Day 1 and Day 3 ]
  The parent drug in plasma samples will be analyzed. On Day 1: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose. *The 24h sampling of first post dose should be taken before the second dose. On Day 3: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 144, and 192 hours post dose
• Half-life (T1/2) [ Time Frame: Day 3 ]
  The parent drug in plasma samples will be analyzed On Day 3: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 144, and 192 hours post dose
• Clearance (CL/F ) [ Time Frame: Day 3 ]
  The parent drug in plasma samples will be analyzed On Day 3: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 144, and 192 hours post dose
• The apparent volume of distribution during the terminal elimination phase following extravascular administration (Vz/F) [ Time Frame: Day 3 ]
  The parent drug in plasma samples will be analyzed. On Day 3: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 144, and 192 hours post dose

Original Secondary Outcome Measures (submitted: January 30, 2012)

• Safety and tolerability [ Time Frame: vital signs: Days 1 through 6; ECG: Days1, 2, 3; Labs: Days 2, 3, 5, study completion ]
  Determined by vital signs, ECG evaluations, laboratory evaluations and adverse events. Vital sign(body temperature, blood pressure and pulse rate): pre dose, 4, 8, 12, 16, 20, 24 hours post dose on Day 1: then 6, 12, 18, 24 hours post dose on each day during domiciles period until at least two consecutive normal temperature readings are obtained, then it will measure daily until Day 6. ECG: 3-4 hours post dose on day1; pre dose, 3-4 hours post dose on Day 2; pre dose, 3-4 hours post dose on Day 3 and study completion. Lab evaluation: Day 2, Day3 and Day5, study completion.
• Area under the curve (AUC)0-24h on Day 1 and Day 3 [ Time Frame: Day 1 and Day 3 ]
  The parent drug in plasma samples will be analyzed. On Day 1: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose. *The 24h sampling of first post dose should be taken before the second dose. On Day 3: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 144, and 192 hours post dose
• The accumulation ratio (Racc) (=AUC0-24h, day3/AUC0-24h, day1) [ Time Frame: Day 1 and Day 3 ]
  The parent drug in plasma samples will be analyzed. On Day 1: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose. *The 24h sampling of first post dose should be taken before the second dose. On Day 3: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 144, and 192 hours post dose
• Maximum concentration (Cmax) on Day 1 and Day 3 [ Time Frame: Day 1 and Day 3 ]
  The parent drug in plasma samples will be analyzed. On Day 1: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose. *The 24h sampling of first post dose should be taken before the second dose. On Day 3: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 144, and 192 hours post dose
• Time to maximum concentration (Tmax) on Day 1 and Day 3 [ Time Frame: Day 1 and Day 3 ]
  The parent drug in plasma samples will be analyzed. On Day 1: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post dose. *The 24h sampling of first post dose should be taken before the second dose. On Day 3: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 144, and 192 hours post dose
• Half-life (T1/2) [ Time Frame: Day 3 ]
  The parent drug in plasma samples will be analyzed On Day 3: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 144, and 192 hours post dose
• Clearance (CL/F ) [ Time Frame: Day 3 ]
  The parent drug in plasma samples will be analyzed On Day 3: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 144, and 192 hours post dose
• The apparent volume of distribution during the terminal elimination phase following extravascular administrationi(Vz/F) [ Time Frame: Day 3 ]
  The parent drug in plasma samples will be analyzed. On Day 3: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 144, and 192 hours post dose

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy, Safety, Tolerability and Pharmacokinetics of KAE609 in Adult Patients With Acute, Uncomplicated Plasmodium Falciparum or Vivax Malaria Mono-infection
• Official Title: A Proof-of-concept, Open Label, 3-day Repeated Dose Study to Assess Efficacy, Safety, Tolerability and Pharmacokinetics of KAE609 in Adult Patients With Acute, Uncomplicated Plasmodium Falciparum or Vivax Malaria Mono-infection
• Brief Summary: This study will assess efficacy, safety , tolerability and PK in uncomplicated adult malaria patients with P. vivax or P. falciparum infection after 3 day dosing with KAE609 at 30 mg/day
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Malaria

Intervention

Drug: KAE609

KAE609 was supplied as capsules for oral use.

Study Arms

• Experimental: Cohort 1
  10 subjects with Plasmodium vivax malaria will receive 30 mg KAE609 once a day for three days
  Intervention: Drug: KAE609
• Experimental: Cohort 2
  10 subjects with Plasmodium falciparum malaria will receive 30 mg KAE609 once a day for three days
  Intervention: Drug: KAE609

• Publications *: White NJ, Pukrittayakamee S, Phyo AP, Rueangweerayut R, Nosten F, Jittamala P, Jeeyapant A, Jain JP, Lefèvre G, Li R, Magnusson B, Diagana TT, Leong FJ. Spiroindolone KAE609 for falciparum and vivax malaria. N Engl J Med. 2014 Jul 31;371(5):403-10. doi: 10.1056/NEJMoa1315860.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 9, 2013): 27
• Original Estimated Enrollment (submitted: January 30, 2012): 20
• Actual Study Completion Date: June 2012
• Actual Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Male and female patients aged 20 to 60 years
• Presence of mono-infection of P. falciparum or P. vivax
• Weight between 40 kg to 90 kg

Exclusion Criteria:

• Patients with signs and symptoms of severe/complicated malaria
• Mixed Plasmodium infection
• Presence of other serious or chronic clinical condition requiring hospitalization.
• Severe malnutrition
• Significant chronic medical conditions which in the opinion of the investigator preclude enrollment into the study

Other protocol-defined inclusion/exclusion criteria may apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 20 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Thailand

Administrative Information

• NCT Number: NCT01524341
• Other Study ID Numbers: CKAE609X2201
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Study Sponsor: Novartis Pharmaceuticals
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: May 2013