Trial Outcomes & Findings for SJ733 Induced Blood Stage Malaria Challenge Study (NCT NCT02867059)
NCT ID: NCT02867059
Last Updated: 2020-05-05
Results Overview
The parasite reduction ratio (PRR) provides an estimate of the efficacy of an antimalarial treatment and is the ratio of the parasite density between admission and 48 h post antimalarial treatment. The primary efficacy variable is parasite reduction ratio (PRR) of parasites based on qPCR after administration of SJ733. The PRR was estimated using the slope of the optimal fit of the log-linear relationship of the parasitaemia decay. PRR was calculated for each subject using the retrospective 18S rRNA qPCR data. If the model fit was adequate for the subject (defined as overall model p-value \<0.001), the slope and corresponding standard error from the log-linear regression was used to calculate the overall cohort specific PRR.
Recruitment status
COMPLETED
Study phase
PHASE1
Target enrollment
17 participants
Primary outcome timeframe
Until End of Study (Day 28±3)
Results posted on
2020-05-05
Participant Flow
Participant milestones
| Measure |
First Dose
The dose used in the first cohort was determined on the basis of the safety and PK data generated in the FIM study (NCT02661373) currently ongoing in United States (US) and will be 150 mg.
(+)-SJ000557733: (+)-SJ000557733 (SJ733), in short SJ733, will be the second PfATP4 inhibitor to enter clinical development after KAE609 (Novartis) which is currently in Phase 2 stage. KAE609 (cipargamin; previously known as NITD609) is a spirotetrahydro-β-carbolines (spiroindolone). KAE609 inhibits QP15C20\_SJ733\_Challenge Protocol\_v2.0\_26July2016 Page 28 of 110 PfATP4, which results in a disruption of parasite sodium homeostasis. Compared to KAE609, SJ733 has the potential to be a very fast acting, antimalarial drug for human therapeutic application and may have a different safety profile in human participants. Finally, SJ733 blocks parasite transmission in vivo at potencies close to those where it is efficacious in blood stages, indicating its potential for transmission blockade in humans.
|
Second Dose
Depending on the pharmacodynamics data (effect of SJ733 on parasitaemia) obtained from this first cohort, the dose in Cohort 2 may be adjusted but will not exceed 600 mg.
(+)-SJ000557733: (+)-SJ000557733 (SJ733), in short SJ733, will be the second PfATP4 inhibitor to enter clinical development after KAE609 (Novartis) which is currently in Phase 2 stage. KAE609 (cipargamin; previously known as NITD609) is a spirotetrahydro-β-carbolines (spiroindolone). KAE609 inhibits QP15C20\_SJ733\_Challenge Protocol\_v2.0\_26July2016 Page 28 of 110 PfATP4, which results in a disruption of parasite sodium homeostasis. Compared to KAE609, SJ733 has the potential to be a very fast acting, antimalarial drug for human therapeutic application and may have a different safety profile in human participants. Finally, SJ733 blocks parasite transmission in vivo at potencies close to those where it is efficacious in blood stages, indicating its potential for transmission blockade in humans.
|
|---|---|---|
|
Overall Study
STARTED
|
7
|
10
|
|
Overall Study
COMPLETED
|
7
|
8
|
|
Overall Study
NOT COMPLETED
|
0
|
2
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
SJ733 Induced Blood Stage Malaria Challenge Study
Baseline characteristics by cohort
| Measure |
First Dose
n=7 Participants
The dose used in the first cohort was determined on the basis of the safety and PK data generated in the FIM study (NCT02661373) currently ongoing in United States (US) and will be 150 mg.
(+)-SJ000557733: (+)-SJ000557733 (SJ733), in short SJ733, will be the second PfATP4 inhibitor to enter clinical development after KAE609 (Novartis) which is currently in Phase 2 stage. KAE609 (cipargamin; previously known as NITD609) is a spirotetrahydro-β-carbolines (spiroindolone). KAE609 inhibits QP15C20\_SJ733\_Challenge Protocol\_v2.0\_26July2016 Page 28 of 110 PfATP4, which results in a disruption of parasite sodium homeostasis. Compared to KAE609, SJ733 has the potential to be a very fast acting, antimalarial drug for human therapeutic application and may have a different safety profile in human participants. Finally, SJ733 blocks parasite transmission in vivo at potencies close to those where it is efficacious in blood stages, indicating its potential for transmission blockade in humans.
|
Second Dose
n=10 Participants
Depending on the pharmacodynamics data (effect of SJ733 on parasitaemia) obtained from this first cohort, the dose in Cohort 2 may be adjusted but will not exceed 600 mg.
(+)-SJ000557733: (+)-SJ000557733 (SJ733), in short SJ733, will be the second PfATP4 inhibitor to enter clinical development after KAE609 (Novartis) which is currently in Phase 2 stage. KAE609 (cipargamin; previously known as NITD609) is a spirotetrahydro-β-carbolines (spiroindolone). KAE609 inhibits QP15C20\_SJ733\_Challenge Protocol\_v2.0\_26July2016 Page 28 of 110 PfATP4, which results in a disruption of parasite sodium homeostasis. Compared to KAE609, SJ733 has the potential to be a very fast acting, antimalarial drug for human therapeutic application and may have a different safety profile in human participants. Finally, SJ733 blocks parasite transmission in vivo at potencies close to those where it is efficacious in blood stages, indicating its potential for transmission blockade in humans.
|
Total
n=17 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
25.14 years
STANDARD_DEVIATION 4.807 • n=5 Participants
|
25.08 years
STANDARD_DEVIATION 3.261 • n=7 Participants
|
25.11 years
STANDARD_DEVIATION 3.827 • n=5 Participants
|
|
Sex: Female, Male
Female
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
7 Participants
n=5 Participants
|
10 Participants
n=7 Participants
|
17 Participants
n=5 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Asian
|
1 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Black or African American
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
6 Participants
n=5 Participants
|
9 Participants
n=7 Participants
|
15 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
|
Body Mass Index (BMI)
|
25.14 kg/m^2
STANDARD_DEVIATION 4.807 • n=5 Participants
|
25.08 kg/m^2
STANDARD_DEVIATION 3.261 • n=7 Participants
|
25.11 kg/m^2
STANDARD_DEVIATION 3.827 • n=5 Participants
|
PRIMARY outcome
Timeframe: Until End of Study (Day 28±3)Population: Two subjects in Cohort 2a were excluded from PRR analyses because they were not dosed with SJ733. Of the remaining 8 subjects in cohorts 2a/2b, one subject did not have a significant optimal regression fit and was excluded from the cohort-specific analysis. As such, 7 subjects contributed to calculations of a cohort-specific PRR for cohorts 2a/2b.
The parasite reduction ratio (PRR) provides an estimate of the efficacy of an antimalarial treatment and is the ratio of the parasite density between admission and 48 h post antimalarial treatment. The primary efficacy variable is parasite reduction ratio (PRR) of parasites based on qPCR after administration of SJ733. The PRR was estimated using the slope of the optimal fit of the log-linear relationship of the parasitaemia decay. PRR was calculated for each subject using the retrospective 18S rRNA qPCR data. If the model fit was adequate for the subject (defined as overall model p-value \<0.001), the slope and corresponding standard error from the log-linear regression was used to calculate the overall cohort specific PRR.
Outcome measures
| Measure |
First Dose 150mg
n=7 Participants
The dose used in the first cohort was determined on the basis of the safety and PK data generated in the FIM study (NCT02661373) currently ongoing in United States (US) and will be 150 mg.
(+)-SJ000557733: (+)-SJ000557733 (SJ733), in short SJ733, will be the second PfATP4 inhibitor to enter clinical development after KAE609 (Novartis) which is currently in Phase 2 stage. KAE609 (cipargamin; previously known as NITD609) is a spirotetrahydro-β-carbolines (spiroindolone). KAE609 inhibits QP15C20\_SJ733\_Challenge Protocol\_v2.0\_26July2016 Page 28 of 110 PfATP4, which results in a disruption of parasite sodium homeostasis. Compared to KAE609, SJ733 has the potential to be a very fast acting, antimalarial drug for human therapeutic application and may have a different safety profile in human participants. Finally, SJ733 blocks parasite transmission in vivo at potencies close to those where it is efficacious in blood stages, indicating its potential for transmission blockade in humans.
|
Second Dose 600mg
n=7 Participants
Depending on the pharmacodynamics data (effect of SJ733 on parasitaemia) obtained from this first cohort, the dose in Cohort 2 may be adjusted but will not exceed 600 mg.
(+)-SJ000557733: (+)-SJ000557733 (SJ733), in short SJ733, will be the second PfATP4 inhibitor to enter clinical development after KAE609 (Novartis) which is currently in Phase 2 stage. KAE609 (cipargamin; previously known as NITD609) is a spirotetrahydro-β-carbolines (spiroindolone). KAE609 inhibits QP15C20\_SJ733\_Challenge Protocol\_v2.0\_26July2016 Page 28 of 110 PfATP4, which results in a disruption of parasite sodium homeostasis. Compared to KAE609, SJ733 has the potential to be a very fast acting, antimalarial drug for human therapeutic application and may have a different safety profile in human participants. Finally, SJ733 blocks parasite transmission in vivo at potencies close to those where it is efficacious in blood stages, indicating its potential for transmission blockade in humans.
|
|---|---|---|
|
Activity of SJ733 Administered Orally on Clearance of P. Falciparum Blood Stage Parasites From the Blood in Healthy Subjects (Men and WNCBP)
|
172 Parasite Reduction Rate (PRR)
Interval 103.0 to 286.0
|
11551 Parasite Reduction Rate (PRR)
Interval 5348.0 to 24944.0
|
PRIMARY outcome
Timeframe: for up to 25th day post SJ733 treatment or longer as determind by the principal investigatorThe safety and tolerability of SJ733 in healthy subjects (men and WNCBP) following infection with blood stage P. falciparum during the IBSM challenge study will be evaluated by observation of occurrence of adverse events.
Outcome measures
| Measure |
First Dose 150mg
n=7 Participants
The dose used in the first cohort was determined on the basis of the safety and PK data generated in the FIM study (NCT02661373) currently ongoing in United States (US) and will be 150 mg.
(+)-SJ000557733: (+)-SJ000557733 (SJ733), in short SJ733, will be the second PfATP4 inhibitor to enter clinical development after KAE609 (Novartis) which is currently in Phase 2 stage. KAE609 (cipargamin; previously known as NITD609) is a spirotetrahydro-β-carbolines (spiroindolone). KAE609 inhibits QP15C20\_SJ733\_Challenge Protocol\_v2.0\_26July2016 Page 28 of 110 PfATP4, which results in a disruption of parasite sodium homeostasis. Compared to KAE609, SJ733 has the potential to be a very fast acting, antimalarial drug for human therapeutic application and may have a different safety profile in human participants. Finally, SJ733 blocks parasite transmission in vivo at potencies close to those where it is efficacious in blood stages, indicating its potential for transmission blockade in humans.
|
Second Dose 600mg
n=8 Participants
Depending on the pharmacodynamics data (effect of SJ733 on parasitaemia) obtained from this first cohort, the dose in Cohort 2 may be adjusted but will not exceed 600 mg.
(+)-SJ000557733: (+)-SJ000557733 (SJ733), in short SJ733, will be the second PfATP4 inhibitor to enter clinical development after KAE609 (Novartis) which is currently in Phase 2 stage. KAE609 (cipargamin; previously known as NITD609) is a spirotetrahydro-β-carbolines (spiroindolone). KAE609 inhibits QP15C20\_SJ733\_Challenge Protocol\_v2.0\_26July2016 Page 28 of 110 PfATP4, which results in a disruption of parasite sodium homeostasis. Compared to KAE609, SJ733 has the potential to be a very fast acting, antimalarial drug for human therapeutic application and may have a different safety profile in human participants. Finally, SJ733 blocks parasite transmission in vivo at potencies close to those where it is efficacious in blood stages, indicating its potential for transmission blockade in humans.
|
|---|---|---|
|
Number of Participants With Adverse Events
|
7 Participants
|
8 Participants
|
Adverse Events
First Dose
Serious events: 0 serious events
Other events: 7 other events
Deaths: 0 deaths
Second Dose
Serious events: 0 serious events
Other events: 8 other events
Deaths: 0 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
First Dose
n=7 participants at risk
The dose used in the first cohort was determined on the basis of the safety and PK data generated in the FIM study (NCT02661373) currently ongoing in United States (US) and will be 150 mg.
(+)-SJ000557733: (+)-SJ000557733 (SJ733), in short SJ733, will be the second PfATP4 inhibitor to enter clinical development after KAE609 (Novartis) which is currently in Phase 2 stage. KAE609 (cipargamin; previously known as NITD609) is a spirotetrahydro-β-carbolines (spiroindolone). KAE609 inhibits QP15C20\_SJ733\_Challenge Protocol\_v2.0\_26July2016 Page 28 of 110 PfATP4, which results in a disruption of parasite sodium homeostasis. Compared to KAE609, SJ733 has the potential to be a very fast acting, antimalarial drug for human therapeutic application and may have a different safety profile in human participants. Finally, SJ733 blocks parasite transmission in vivo at potencies close to those where it is efficacious in blood stages, indicating its potential for transmission blockade in humans.
|
Second Dose
n=8 participants at risk
Depending on the pharmacodynamics data (effect of SJ733 on parasitaemia) obtained from this first cohort, the dose in Cohort 2 may be adjusted but will not exceed 600 mg.
(+)-SJ000557733: (+)-SJ000557733 (SJ733), in short SJ733, will be the second PfATP4 inhibitor to enter clinical development after KAE609 (Novartis) which is currently in Phase 2 stage. KAE609 (cipargamin; previously known as NITD609) is a spirotetrahydro-β-carbolines (spiroindolone). KAE609 inhibits QP15C20\_SJ733\_Challenge Protocol\_v2.0\_26July2016 Page 28 of 110 PfATP4, which results in a disruption of parasite sodium homeostasis. Compared to KAE609, SJ733 has the potential to be a very fast acting, antimalarial drug for human therapeutic application and may have a different safety profile in human participants. Finally, SJ733 blocks parasite transmission in vivo at potencies close to those where it is efficacious in blood stages, indicating its potential for transmission blockade in humans.
|
|---|---|---|
|
Blood and lymphatic system disorders
Lymphopenia
|
42.9%
3/7 • Number of events 3
|
0.00%
0/8
|
|
Cardiac disorders
Tachycardia
|
57.1%
4/7 • Number of events 4
|
25.0%
2/8 • Number of events 2
|
|
Eye disorders
Eye Irritation
|
0.00%
0/7
|
12.5%
1/8 • Number of events 1
|
|
Gastrointestinal disorders
Abdominal Discomfort
|
0.00%
0/7
|
25.0%
2/8 • Number of events 2
|
|
Gastrointestinal disorders
Haematochezia
|
14.3%
1/7 • Number of events 1
|
0.00%
0/8
|
|
Gastrointestinal disorders
Nausea
|
28.6%
2/7 • Number of events 2
|
37.5%
3/8 • Number of events 3
|
|
Gastrointestinal disorders
Vomiting
|
0.00%
0/7
|
12.5%
1/8 • Number of events 1
|
|
General disorders
Chills
|
85.7%
6/7 • Number of events 6
|
62.5%
5/8 • Number of events 6
|
|
General disorders
Fatigue
|
0.00%
0/7
|
12.5%
1/8 • Number of events 1
|
|
General disorders
Malaise
|
57.1%
4/7 • Number of events 4
|
37.5%
3/8 • Number of events 3
|
|
General disorders
Puncture site erythema
|
0.00%
0/7
|
12.5%
1/8 • Number of events 1
|
|
General disorders
Pyrexia
|
71.4%
5/7 • Number of events 18
|
62.5%
5/8 • Number of events 9
|
|
Infections and infestations
Upper respiratory tract infection
|
0.00%
0/7
|
37.5%
3/8 • Number of events 3
|
|
Investigations
Alanine aminotransferase increased
|
42.9%
3/7 • Number of events 5
|
12.5%
1/8 • Number of events 1
|
|
Investigations
Aspartate aminotransferase increased
|
14.3%
1/7 • Number of events 2
|
0.00%
0/8
|
|
Investigations
Lymphocyte count decreased
|
14.3%
1/7 • Number of events 1
|
25.0%
2/8 • Number of events 2
|
|
Investigations
Neutrophil count decreased
|
14.3%
1/7 • Number of events 1
|
12.5%
1/8 • Number of events 1
|
|
Investigations
Urine output increased
|
0.00%
0/7
|
12.5%
1/8 • Number of events 1
|
|
Investigations
White blood cell count decreased
|
14.3%
1/7 • Number of events 1
|
12.5%
1/8 • Number of events 1
|
|
Metabolism and nutrition disorders
Decreased appetite
|
14.3%
1/7 • Number of events 1
|
12.5%
1/8 • Number of events 1
|
|
Musculoskeletal and connective tissue disorders
Arthralgia
|
14.3%
1/7 • Number of events 2
|
25.0%
2/8 • Number of events 3
|
|
Musculoskeletal and connective tissue disorders
Back pain
|
14.3%
1/7 • Number of events 1
|
0.00%
0/8
|
|
Musculoskeletal and connective tissue disorders
Myalgia
|
71.4%
5/7 • Number of events 5
|
75.0%
6/8 • Number of events 7
|
|
Nervous system disorders
Headache
|
85.7%
6/7 • Number of events 11
|
75.0%
6/8 • Number of events 15
|
|
Nervous system disorders
Lethargy
|
28.6%
2/7 • Number of events 2
|
37.5%
3/8 • Number of events 3
|
|
Nervous system disorders
Paraesthesia
|
14.3%
1/7 • Number of events 1
|
0.00%
0/8
|
|
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
|
14.3%
1/7 • Number of events 1
|
0.00%
0/8
|
|
Skin and subcutaneous tissue disorders
Hyperhidrosis
|
42.9%
3/7 • Number of events 3
|
25.0%
2/8 • Number of events 2
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place
Restriction type: GT60