A Study to Find the Minimum Inhibitory Concentration of KAE609 in Adult Male Patients With P. Falciparum Monoinfection

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01836458
• Collaborator: (none)
• Enrollment: 25
• Location: 1
• Arms: 4
• Duration (Months): 13.9
• Patients Per Site Per Month: 1.8

Study Details

Study Description

Brief Summary

This study aims to determine the Minimum Inhibitory Concentration of KAE609 in adult male patients with acute, uncomplicated malaria due to P.falciparum monoinfection after single dosing with KAE609

Condition or Disease	Intervention/Treatment	Phase
Malaria	Drug: KAE609	Phase 2

Detailed Description

There will be a total of approximately 45 patients recruited into this study and six doses of KAE609 and will be investigated.The dose groups will run in sequence. Patient will be given a single dose of KAE609 and be followed up for 42 days.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label Study to Find the Minimum Inhibitory Concentration(MIC) of KAE609 in Adult Male Patients With Acute, Uncomplicated Malaria Due to Plasmodium Falciparum Monoinfection
• Study Start Date: Jan 1, 2014
• Actual Primary Completion Date: Mar 1, 2015
• Actual Study Completion Date: Mar 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose 1: 30 mg Single dose of KAE609 30 mg	Drug: KAE609; Patients will receive KAE609 single dose at a different dose level in each cohort.
Experimental: Dose 2: 20 mg Single dose of KAE609 20 mg	Drug: KAE609; Patients will receive KAE609 single dose at a different dose level in each cohort.
Experimental: Dose 3: 10 mg Single dose of KAE609 10 mg	Drug: KAE609; Patients will receive KAE609 single dose at a different dose level in each cohort.
Experimental: Dose 4: 15 mg Single dose of KAE609 15 mg	Drug: KAE609; Patients will receive KAE609 single dose at a different dose level in each cohort.

Outcome Measures

Primary Outcome Measures

1. Minimum Inhibitory Concentration (MIC) of KAE609 [Up to Day 8 after a single dose of KAE609]

   To observe the exposure-response (PK/PD) relationship for a single dose of KAE609. The key parameter is MIC, defined as the concentration at which the relative rate of change in parasitemia is equal to zero. Approximation of MIC will assist in identifying the optimal dose of KAE609, which will be one component of a future combination antimalarial. MIC could not be determined due to small sample size no data was collected from any participants.

Secondary Outcome Measures

1. Median Time to Parasite Clearance [pre-dose, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 54, 60, 66, 72 hours post dose of KAE609]

   Parasite clearance time will be estimated using thick/thin blood films.

2. Median Time to Fever Clearance [Day 1 to Day 5]

   Fever is monitored on participants every 4 hours for the first 24 hours, then every 6 hours until negative reading obtained.

3. Percentage of Patients PCR-corrected Cure Rate by Day 28, Day 35 & Day 42 [Day 28, Day 35 & Day 42]

   PCR-corrected cure rate after a single dose of KAE609 by Day 28, Day 35 & Day 42. PCR-corrected cure rate accounts for failures due to reappearance of parasites that were present in the blood before treatment (i.e. recrudescent infection) but not for failures due to a post-treatment inoculation (i.e. new infection).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Monoinfection with P. falciparum confirmed by microscopy

• Asexual P. falciparum parasitemia count of 5,000 to 50,000/µL

• Axillary temperature ≥37.5 ºC or oral/tympanic/rectal temperature ≥38 ºC; or similar documented temperature during the previous 24 hours

• Body weight between 40 to 90 kg

Key Exclusion Criteria:

• Signs and symptoms of severe malaria according to World Health Organization (WHO) 2010 criteria

• Mixed Plasmodium infection, i.e. infection with more than one species of malaria parasites

• Use of other investigational drugs within 30 days or within 5 half-lives of enrollment, whichever is longer

• History of antimalarial use within 2 months of screening

• Use of any antibiotics with antimalarial activity or other prohibited medication within 14 days of screening

• Long QT syndrome or QTc using Fridericia's formula >430 msec

• History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases

• Hemoglobin level <10 g/dL

• Liver disease or injury as indicated by elevated liver tests such as SGPT (ALT) or SGOT (AST) >2 times the upper limit of normal

• Renal dysfunction as indicated by serum creatinine >2 times the upper limit of normal in the absence of dehydration; in case of dehydration, serum creatinine should be <2 times the upper limit of normal after oral or parental rehydration

• Known to be immunocompromised (including HIV infection) or are receiving immunosuppressive therapy at the time or enrollment; HIV testing is not required

• Known history of hepatitis B or C; testing is not required

• Febrile condition due to diseases other than malaria (e.g. acute lower respiratory tract infection), known underlying chronic or severe disease (e.g. cardiac, hepatic, renal, gastrointestinal, neurologic, or psychiatric disease), or any condition precluding enrollment into this study according to the investigator

• Severe vomiting defined as >3 times during the previous 24 hours or inability to tolerate oral medication; severe diarrhea defined as ≥3 watery stools during the previous 24 hours

• Severe malnutrition defined by a body mass index (BMI) <18.5 kg/m2 or unintentional loss of weight ≥10% with evidence of suboptimal intake resulting in loss of subcutaneous fat and/or severe muscle wasting

• Active tuberculosis or history of taking anti-tuberculosis medications within 24 months prior to screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Ho Chi Minh		Vietnam

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01836458
• Other Study ID Numbers: CKAE609A2201
• First Posted: Apr 19, 2013
• Last Update Posted: Oct 31, 2016
• Last Verified: Sep 1, 2016

• Keywords provided by Novartis Pharmaceuticals: Malaria, KAE609
• Additional relevant MeSH terms: Malaria

Study Results

Participant Flow

Arm/Group Title	Dose 1: 30 mg	Dose 2: 20 mg	Dose 3: 10 mg	Dose 4: 15 mg
Arm/Group Description	Single dose of KAE609 30 mg	Single dose of KAE609 20 mg	Single dose of KAE609 10 mg	Single dose of KAE609 15 mg
Period Title: Overall Study
STARTED	7	4	7	7
COMPLETED	4	2	2	1
NOT COMPLETED	3	2	5	6

Baseline Characteristics

Arm/Group Title	Dose 1: 30 mg	Dose 2: 20 mg	Dose 3: 10 mg	Dose 4: 15 mg	Total
Arm/Group Description	Single dose of KAE609 30 mg	Single dose of KAE609 20 mg	Single dose of KAE609 10 mg	Single dose of KAE609 15 mg	Total of all reporting groups
Overall Participants	7	4	7	7	25
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.7 (11.84)	32.8 (7.93)	30.6 (8.24)	34.7 (8.79)	32.7 (9.04)
Sex/Gender, Customized (participants) [Number]
MALE	7 100%	4 100%	7 100%	7 100%	25 100%

Outcome Measures

1. Primary Outcome

Title	Minimum Inhibitory Concentration (MIC) of KAE609
Description	To observe the exposure-response (PK/PD) relationship for a single dose of KAE609. The key parameter is MIC, defined as the concentration at which the relative rate of change in parasitemia is equal to zero. Approximation of MIC will assist in identifying the optimal dose of KAE609, which will be one component of a future combination antimalarial. MIC could not be determined due to small sample size no data was collected from any participants.
Time Frame	Up to Day 8 after a single dose of KAE609

Outcome Measure Data

Analysis Population Description

The primary Outcome Measure (OM) could not be determined due to small sample size no data was collected from any participants.

Arm/Group Title	Dose 1: 30 mg	Dose 2: 20 mg	Dose 3: 10 mg	Dose 4: 15 mg
Arm/Group Description	Single dose of KAE609 30 mg	Single dose of KAE609 20 mg	Single dose of KAE609 10 mg	Single dose of KAE609 15 mg
Measure Participants	0	0	0	0

2. Secondary Outcome

Title	Median Time to Parasite Clearance
Description	Parasite clearance time will be estimated using thick/thin blood films.
Time Frame	pre-dose, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48, 54, 60, 66, 72 hours post dose of KAE609

Outcome Measure Data

Analysis Population Description

Pharmacodynamic Analysis Set includes all enrolled patients

Arm/Group Title	Dose 1: 30 mg	Dose 2: 20 mg	Dose 3: 10 mg	Dose 4: 15 mg
Arm/Group Description	Single dose of KAE609 30 mg	Single dose of KAE609 20 mg	Single dose of KAE609 10 mg	Single dose of KAE609 15 mg
Measure Participants	7	4	7	7
Median (95% Confidence Interval) [hours]	24.00	63.00	54.00	60.00

3. Secondary Outcome

Title	Median Time to Fever Clearance
Description	Fever is monitored on participants every 4 hours for the first 24 hours, then every 6 hours until negative reading obtained.
Time Frame	Day 1 to Day 5

Outcome Measure Data

Analysis Population Description

Pharmacodynamic Analysis Set includes all enrolled patients

Arm/Group Title	Dose 1: 30 mg	Dose 2: 20 mg	Dose 3: 10 mg	Dose 4: 15 mg
Arm/Group Description	Single dose of KAE609 30 mg	Single dose of KAE609 20 mg	Single dose of KAE609 10 mg	Single dose of KAE609 15 mg
Measure Participants	7	4	7	7
Median (90% Confidence Interval) [hours]	9.83	12.38	15.75	11.83

4. Secondary Outcome

Title	Percentage of Patients PCR-corrected Cure Rate by Day 28, Day 35 & Day 42
Description	PCR-corrected cure rate after a single dose of KAE609 by Day 28, Day 35 & Day 42. PCR-corrected cure rate accounts for failures due to reappearance of parasites that were present in the blood before treatment (i.e. recrudescent infection) but not for failures due to a post-treatment inoculation (i.e. new infection).
Time Frame	Day 28, Day 35 & Day 42

Outcome Measure Data

Analysis Population Description

Pharmacodynamic Analysis Set includes all enrolled patients.

Arm/Group Title	Dose 1: 30 mg	Dose 2: 20 mg	Dose 3: 10 mg	Dose 4: 15 mg
Arm/Group Description	Single dose of KAE609 30 mg	Single dose of KAE609 20 mg	Single dose of KAE609 10 mg	Single dose of KAE609 15 mg
Measure Participants	7	4	7	7
Day 28	57.1	50.0	28.6	14.3
Day 35	57.1	50.0	28.6	14.3
Day 42	57.1	50.0	28.6	14.3

Adverse Events

Arm/Group Title	Dose 1: 30mg		Dose 2: 20mg		Dose 3: 10mg		Dose 4: 15mg
Arm/Group Description	Single dose of KAE609 30 mg		Single dose of KAE609 20 mg		Single dose of KAE609 10 mg		Single dose of KAE609 15 mg
All Cause Mortality
	Dose 1: 30mg		Dose 2: 20mg		Dose 3: 10mg		Dose 4: 15mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Dose 1: 30mg		Dose 2: 20mg		Dose 3: 10mg		Dose 4: 15mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/4 (0%)		0/7 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Dose 1: 30mg		Dose 2: 20mg		Dose 3: 10mg		Dose 4: 15mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/7 (57.1%)		3/4 (75%)		7/7 (100%)		5/7 (71.4%)
Blood and lymphatic system disorders
Anaemia	0/7 (0%)		0/4 (0%)		1/7 (14.3%)		0/7 (0%)
Gastrointestinal disorders
Abdominal pain upper	0/7 (0%)		0/4 (0%)		1/7 (14.3%)		0/7 (0%)
Abnormal faeces	0/7 (0%)		1/4 (25%)		0/7 (0%)		0/7 (0%)
Diarrhoea	0/7 (0%)		0/4 (0%)		0/7 (0%)		1/7 (14.3%)
Nausea	1/7 (14.3%)		0/4 (0%)		1/7 (14.3%)		0/7 (0%)
Hepatobiliary disorders
Hyperbilirubinaemia	0/7 (0%)		1/4 (25%)		3/7 (42.9%)		1/7 (14.3%)
Investigations
Alanine aminotransferase increased	1/7 (14.3%)		0/4 (0%)		0/7 (0%)		0/7 (0%)
Blood alkaline phosphatase increased	1/7 (14.3%)		2/4 (50%)		3/7 (42.9%)		4/7 (57.1%)
Musculoskeletal and connective tissue disorders
Myalgia	1/7 (14.3%)		0/4 (0%)		0/7 (0%)		0/7 (0%)
Nervous system disorders
Headache	1/7 (14.3%)		1/4 (25%)		0/7 (0%)		0/7 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/7 (0%)		1/4 (25%)		0/7 (0%)		0/7 (0%)
Skin and subcutaneous tissue disorders
Rash vesicular	0/7 (0%)		0/4 (0%)		0/7 (0%)		1/7 (14.3%)
Vascular disorders
Hypertensive crisis	1/7 (14.3%)		0/4 (0%)		0/7 (0%)		0/7 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.