Navitoclax and Vistusertib in Treating Patients With Relapsed Small Cell Lung Cancer and Other Solid Tumors

Phase 1/2 Study of Navitoclax Plus Vistusertib in Patients With Relapsed Small Cell Lung Cancer (SCLC) and Other Solid Tumors

Status

Terminated

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03366103

Enrollment

Registered

2017-12-08

Start date

2018-03-20

Completion date

2022-09-21

Last updated

2023-10-17

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Metastatic Malignant Solid Neoplasm, Recurrent Lung Small Cell Carcinoma, Recurrent Malignant Solid Neoplasm, Refractory Malignant Solid Neoplasm, Stage III Lung Small Cell Carcinoma, by American Joint Committee on Cancer (AJCC) v7, Stage IIIA Lung Small Cell Carcinoma AJCC v7, Stage IIIB Lung Small Cell Carcinoma AJCC v7, Stage IV Lung Small Cell Carcinoma AJCC v7, Unresectable Solid Neoplasm

Brief summary

This phase I/II trial studies the best dose and side effects of navitoclax and how well it works when given together with vistusertib in treating patients with small cell lung cancer and solid tumors that have come back (relapsed). Drugs used in chemotherapy, such as navitoclax, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Vistusertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving navitoclax and vistusertib may work better than navitoclax alone in treating patients with small cell lung cancer and solid tumors.

Detailed description

PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of the combination of navitoclax and vistusertib in patients with advanced solid tumors. (Phase I) II. To determine the maximum tolerated dose (MTD), dose limiting toxicities (DLT), and recommended phase 2 doses (RP2D) of navitoclax and vistusertib. (Phase I) III. To determine the objective response rate (ORR), defined as complete plus partial response, of the combination of navitoclax and vistusertib in patients with recurrent small cell lung cancer (SCLC). (Phase II) SECONDARY OBJECTIVES: I. To evaluate the pharmacokinetics of navitoclax and vistusertib when administered together. (Phase I) II. To observe and record anti-tumor activity. (Phase I) III. To confirm the safety and tolerability of navitoclax and vistusertib at the RP2D. (Phase II) IV. To estimate progression free survival (PFS) and overall survival (OS) of the combination of navitoclax and vistusertib at the RP2D. (Phase II) V. To estimate disease control rate (DCR) of the combination of navitoclax and vistusertib at the RP2D. (Phase II) CORRELATIVE OBJECTIVES: I. To assess pharmacodynamic changes in levels of phosphorylated 4EBP1 (p4EBP1) the ratio of p4EBP1 to total (p4EBP1/4EBP1) in paired pre-treatment and on-treatment biopsies at the RP2D. (Phase II) II. To correlate changes in BAX and MCL-1 with response. (Phase II) III. To estimate the baseline inter-patient variability in p4EBP1, pS6, BAX, and MCL-1. (Phase II) IV. To explore exposure-response relationships between navitoclax and vistusertib exposure and the pharmacodynamic endpoints (safety, efficacy, and laboratory correlatives). (Phase II) OUTLINE: This is a phase I, dose-escalation study followed by a phase II study. Patients receive navitoclax orally (PO) once daily (QD) and vistusertib PO twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days and then every 8-12 weeks for up to 2 years.

Interventions

BIOLOGICALNavitoclax

Given PO

DRUGVistusertib

Given PO

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* PHASE 1 SPECIFIC ELIGIBILITY CRITERIA * Patients must have histologically or cytologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective * PHASE 2 SPECIFIC ELIGIBILITY CRITERIA * Patients must have histologically or cytologically confirmed small cell lung cancer whose disease has relapsed or progressed after \>= 1 prior therapy, one of which must have been a platinum doublet; pathology confirmation must be done at Sidney Kimmel Comprehensive Cancer Center (SKCCC) or at the local participating site * Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as \>= 20 mm (\>= 2 cm) by chest x-ray or as \>= 10 mm (\>= 1 cm) with computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam * Subjects must be willing to undergo 2 sets of core needle biopsies (pre-treatment and on-treatment), if there are lesions amenable to biopsy; an optional core biopsy will be requested at progression * GENERAL ELIGIBILITY CRITERIA * Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 70%) * Life expectancy of greater than 12 weeks * Leukocytes \>= 3,000/mcL * Absolute neutrophil count \>= 1,500/mcL * Hemoglobin \>= 9.0 g/dL * Platelets \>= 100,000/mcL * Activated partial thromboplastin time (aPTT), prothrombin time (PT) =\< 1.2 x upper limit of normal (ULN) * Total bilirubin =\< 1.5 x ULN (patients with Gilbert's syndrome may have serum bilirubin \> 1.5 ULN) * Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional ULN if no demonstrable liver metastases or =\< 5 x ULN in the presence of liver metastases * Creatinine =\< 1.5 x ULN and concurrent creatinine clearance (CrCl) \>= 50 mL/min/1.73 m\^2 for patients with creatinine (Cr) \> 1.5 x ULN * Proteinuria \< 1+ on dipstick testing (if 2+ seen on first test, retest \>= 24 hours later) * Patients with a history of central nervous system (CNS) metastases must have documentation of stable or improved status based on brain imaging for at least 2 weeks after completion of definitive treatment and within 2 weeks prior to first dose of study drug, off or on a stable dose of corticosteroids * Patients must have completed chemotherapy, biological or radiotherapy \>= 3 weeks prior to entering the study * Patients must have recovered to =\< grade 1 adverse events or to =\< grade 2 alopecia and sensory neuropathy due to prior treatment * Patients must be able to understand and the willingness to sign a written informed consent document * Patients must be able to swallow pills * The effects of navitoclax and vistusertib on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and up to 90 days following completion of therapy; for women this should include one highly effective method of contraception and one barrier method as defined below * Highly effective methods include: * Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); * Vasectomized partner; * Medroxyprogesterone acetate depot injection; * Placement of a copper-banded intrauterine device (IUD) or intrauterine system (IUS); * Bilateral tubal ligation; * Barrier methods include: * Condom; * Occlusive cap (e.g. diaphragm or cervical/vault caps) with spermicide * Please note: use of other oral, injected or implanted hormonal methods of contraception cannot be considered highly effective as it is currently unknown whether vistusertib may reduce their effectiveness; periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception * Additionally, male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must agree to use condoms for the duration of the study and for 90 days following completion of therapy * Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment, women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post-menopausal (amenorrheic for at least 12 months) * Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 90 days after completion of navitoclax and/or vistusertib administration

Exclusion criteria

* PHASE 2 SPECIFIC

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Dose Limiting Toxicities (Phase I)	Up to 30 days after last treatment, an average of 3 months	Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0. The number of participants with dose limiting toxicities at each dose level will be reported with exact binomial 95% confidence intervals. All patients who receive at least 1 dose of both study drugs, regardless of their eligibility for the study, will be evaluable for toxicity.
Overall Response Rate (ORR) (Phase II)	Up to 1.5 years	Defined as Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. partial response or complete response, of the combination in patients with recurrent small cell lung cancer. The ORR will be reported with its corresponding 95% confidence interval.

Secondary

Measure	Time frame	Description
Number of Participants Experiencing Adverse Events by Grade (Phase II)	Up to 1.5 years	Graded by NCI CTCAE v 4.0. The number of participants with toxicities by grade in the phase 2 study will be reported with exact binomial 95% confidence intervals.
Occurrence of a Bi-directional Pharmacokinetic (PK) Interaction	Through Day 15	Concentrations of each study agent present in the blood at the specified time point are reported for each study agent.
Progression Free Survival (PFS) (Phase II)	Up to 1.5 years	Based on RECIST 1.1. Standard life table methods will be used to analyze PFS. We will report the one-year and median PFS with 95% confidence intervals.
Overall Survival (OS) at Year 1 (Phase II)	At Year 1	Standard life table methods will be used to analyze OS. We will report the one-year and median OS with 95% confidence intervals.
Disease Control Rate (Phase II)	Up to 1.5 years	Based on RECIST 1.1. The proportion of patients achieving disease control will be reported with exact 95% binomial confidence intervals.

Other

Measure	Time frame	Description
Change in Ratio p4EBP1/4EBP1	Baseline up to 1.5 years	Descriptive statistics and box plots with jittered data points will be used to visualize all raw data. Will be assessed with paired t-tests.
Change in BAX and MCl-1 Expression	Baseline up to 1.5 years	Descriptive statistics and box plots with jittered data points will be used to visualize all raw data. Will be assessed with paired t-tests.
Pharmacodynamic Parameters	Up to 1.5 years	Exploratory correlative studies with pharmacodynamic (biological endpoints, toxicity and efficacy) will be analyzed using nonparametric statistics.
Change in Ratio pS6/S6	Baseline up to 1.5 years	Descriptive statistics and box plots with jittered data points will be used to visualize all raw data. Will be assessed with paired t-tests.
Change in p4EBP1 Expression	Baseline up to 1.5 years	Descriptive statistics and box plots with jittered data points will be used to visualize all raw data. Will be assessed with paired t-tests.

Countries

United States

Participant flow

Recruitment details

Phase 1: 03/20/2018 - 11/11/2019 Phase 2: 7/29/2020 - 5/19/2021

Participants by arm

Arm	Count
Phase 1 - Dose Level 1 Patients receive navitoclax 150 mg orally (PO) once a day (QD) and vistusertib 35 mg PO twice a day (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.	9
Phase 1 - Dose Level 2 Patients receive navitoclax 250 mg PO QD and vistusertib 35 mg PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.	5
Phase 2 Patients receive navitoclax 250 mg PO QD and vistusertib 35 mg PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.	1
Total	15

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Adverse Event	0	1	0
Overall Study	Disease Progression	3	1	0

Baseline characteristics

Characteristic	Total	Phase 1 - Dose Level 1	Phase 2	Phase 1 - Dose Level 2
Age, Continuous	60 years	49 years	77 years	67 years
Body Surface Area (BSA)	1.9 m^2	1.90 m^2	2.03 m^2	1.76 m^2
Eastern Cooperative Oncology Group (ECOG) Performance Status Able to carry on normal activity, minor symptoms	1 Participants	0 Participants	0 Participants	1 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status Asymptomatic	3 Participants	2 Participants	0 Participants	1 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status Symptomatic, fully ambulatory	11 Participants	7 Participants	1 Participants	3 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	14 Participants	8 Participants	1 Participants	5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants	1 Participants	0 Participants	0 Participants
Height	167.6 cm	167.6 cm	172.7 cm	165.0 cm
Primary site of disease Appendix	1 Participants	1 Participants	0 Participants	0 Participants
Primary site of disease Breast	2 Participants	2 Participants	0 Participants	0 Participants
Primary site of disease Cervix	1 Participants	1 Participants	0 Participants	0 Participants
Primary site of disease Colon	2 Participants	2 Participants	0 Participants	0 Participants
Primary site of disease Lung	8 Participants	2 Participants	1 Participants	5 Participants
Primary site of disease Pleura	1 Participants	1 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	0 Participants	0 Participants	1 Participants
Race (NIH/OMB) Black or African American	1 Participants	1 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants	1 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	12 Participants	7 Participants	1 Participants	4 Participants
Region of Enrollment United States	15 participants	9 participants	1 participants	5 participants
Sex: Female, Male Female	9 Participants	6 Participants	0 Participants	3 Participants
Sex: Female, Male Male	6 Participants	3 Participants	1 Participants	2 Participants
Weight	75 kg	75 kg	86.2 kg	68.5 kg

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	6 / 9	3 / 5	1 / 1
other Total, other adverse events	9 / 9	5 / 5	1 / 1
serious Total, serious adverse events	2 / 9	2 / 5	0 / 1

Outcome results

Primary

Number of Participants With Dose Limiting Toxicities (Phase I)

Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0. The number of participants with dose limiting toxicities at each dose level will be reported with exact binomial 95% confidence intervals. All patients who receive at least 1 dose of both study drugs, regardless of their eligibility for the study, will be evaluable for toxicity.

Time frame: Up to 30 days after last treatment, an average of 3 months

Population: Phase 1 participants were included in this analysis. Please see AE section for additional details.

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
Phase 1 - Dose Level 1	Number of Participants With Dose Limiting Toxicities (Phase I)	DLT	0 Participants
Phase 1 - Dose Level 1	Number of Participants With Dose Limiting Toxicities (Phase I)	No DLT	6 Participants
Phase 1 - Dose Level 2	Number of Participants With Dose Limiting Toxicities (Phase I)	DLT	2 Participants
Phase 1 - Dose Level 2	Number of Participants With Dose Limiting Toxicities (Phase I)	No DLT	1 Participants

Primary

Overall Response Rate (ORR) (Phase II)

Defined as Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. partial response or complete response, of the combination in patients with recurrent small cell lung cancer. The ORR will be reported with its corresponding 95% confidence interval.

Time frame: Up to 1.5 years

Population: Only one participant was enrolled.

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
Phase 1 - Dose Level 1	Overall Response Rate (ORR) (Phase II)	Partial Response (PR) or Complete Response (CR)	0 Participants
Phase 1 - Dose Level 1	Overall Response Rate (ORR) (Phase II)	Stable Disease (SD)	0 Participants
Phase 1 - Dose Level 1	Overall Response Rate (ORR) (Phase II)	Progression (PD)	1 Participants

Secondary

Disease Control Rate (Phase II)

Based on RECIST 1.1. The proportion of patients achieving disease control will be reported with exact 95% binomial confidence intervals.

Time frame: Up to 1.5 years

Population: Only one participant was enrolled.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Phase 1 - Dose Level 1	Disease Control Rate (Phase II)	0 Participants

Secondary

Number of Participants Experiencing Adverse Events by Grade (Phase II)

Graded by NCI CTCAE v 4.0. The number of participants with toxicities by grade in the phase 2 study will be reported with exact binomial 95% confidence intervals.

Time frame: Up to 1.5 years

Population: Only one participant was enrolled.

Arm	Measure	Group	Value (NUMBER)
Phase 1 - Dose Level 1	Number of Participants Experiencing Adverse Events by Grade (Phase II)	Grade 1 Adverse Events	1 participants
Phase 1 - Dose Level 1	Number of Participants Experiencing Adverse Events by Grade (Phase II)	Grade 2 Adverse Events	1 participants
Phase 1 - Dose Level 1	Number of Participants Experiencing Adverse Events by Grade (Phase II)	Grade 3 Adverse Events	0 participants
Phase 1 - Dose Level 1	Number of Participants Experiencing Adverse Events by Grade (Phase II)	Grade 4 Adverse Events	0 participants
Phase 1 - Dose Level 1	Number of Participants Experiencing Adverse Events by Grade (Phase II)	Grade 5 Adverse Events	0 participants

Secondary

Occurrence of a Bi-directional Pharmacokinetic (PK) Interaction

Concentrations of each study agent present in the blood at the specified time point are reported for each study agent.

Time frame: Through Day 15

Population: Participants in both phases were included. Some data was not collected at each timepoint.

Arm	Measure	Group	Value (MEAN)	Dispersion
Phase 1 - Dose Level 1	Occurrence of a Bi-directional Pharmacokinetic (PK) Interaction	Vistusertib Cycle 1 Day 15 Concentration 2 hours after dose (C2h)	1061 ng/ml	Standard Deviation 675
Phase 1 - Dose Level 1	Occurrence of a Bi-directional Pharmacokinetic (PK) Interaction	Vistusertib Cycle 1 Day 1 Concentration 2 hours after dose (C2h)	372 ng/ml	Standard Deviation 266
Phase 1 - Dose Level 1	Occurrence of a Bi-directional Pharmacokinetic (PK) Interaction	Navitoclax Cycle 1 Day 15 maximum concentration (Cmax)	2393 ng/ml	Standard Deviation 913
Phase 1 - Dose Level 1	Occurrence of a Bi-directional Pharmacokinetic (PK) Interaction	Navitoclax Cycle 1 Day 1 Concentration 6 hours after dose (C6h)	1808 ng/ml	Standard Deviation 980
Phase 1 - Dose Level 1	Occurrence of a Bi-directional Pharmacokinetic (PK) Interaction	Vistusertib average of individual steady-state trough concentration (avg Cmin,ss)	211 ng/ml	Standard Deviation 207
Phase 1 - Dose Level 1	Occurrence of a Bi-directional Pharmacokinetic (PK) Interaction	Navitoclax average of individual steady-state trough concentration (avg Cmin,ss)	1145 ng/ml	Standard Deviation 289
Phase 1 - Dose Level 1	Occurrence of a Bi-directional Pharmacokinetic (PK) Interaction	Navitoclax Cycle 1 Day 15 Concentration 6 hours after dose (C6h)	2260 ng/ml	Standard Deviation 993
Phase 1 - Dose Level 2	Occurrence of a Bi-directional Pharmacokinetic (PK) Interaction	Vistusertib Cycle 1 Day 15 Concentration 2 hours after dose (C2h)	1032 ng/ml	Standard Deviation 832
Phase 1 - Dose Level 2	Occurrence of a Bi-directional Pharmacokinetic (PK) Interaction	Navitoclax average of individual steady-state trough concentration (avg Cmin,ss)	1966 ng/ml	Standard Deviation 999
Phase 1 - Dose Level 2	Occurrence of a Bi-directional Pharmacokinetic (PK) Interaction	Navitoclax Cycle 1 Day 1 Concentration 6 hours after dose (C6h)	3254 ng/ml	Standard Deviation 1233
Phase 1 - Dose Level 2	Occurrence of a Bi-directional Pharmacokinetic (PK) Interaction	Navitoclax Cycle 1 Day 15 Concentration 6 hours after dose (C6h)	2830 ng/ml	Standard Deviation 1190
Phase 1 - Dose Level 2	Occurrence of a Bi-directional Pharmacokinetic (PK) Interaction	Navitoclax Cycle 1 Day 15 maximum concentration (Cmax)	3060 ng/ml	Standard Deviation 1070
Phase 1 - Dose Level 2	Occurrence of a Bi-directional Pharmacokinetic (PK) Interaction	Vistusertib average of individual steady-state trough concentration (avg Cmin,ss)	559 ng/ml	Standard Deviation 550
Phase 1 - Dose Level 2	Occurrence of a Bi-directional Pharmacokinetic (PK) Interaction	Vistusertib Cycle 1 Day 1 Concentration 2 hours after dose (C2h)	419 ng/ml	Standard Deviation 108
Navitoclax 250 mg Reduced to 150 mg + Vistusertib 35 mg	Occurrence of a Bi-directional Pharmacokinetic (PK) Interaction	Vistusertib average of individual steady-state trough concentration (avg Cmin,ss)	238.5 ng/ml	—
Navitoclax 250 mg Reduced to 150 mg + Vistusertib 35 mg	Occurrence of a Bi-directional Pharmacokinetic (PK) Interaction	Navitoclax Cycle 1 Day 15 Concentration 6 hours after dose (C6h)	3450 ng/ml	—
Navitoclax 250 mg Reduced to 150 mg + Vistusertib 35 mg	Occurrence of a Bi-directional Pharmacokinetic (PK) Interaction	Vistusertib Cycle 1 Day 15 Concentration 2 hours after dose (C2h)	273 ng/ml	—
Navitoclax 250 mg Reduced to 150 mg + Vistusertib 35 mg	Occurrence of a Bi-directional Pharmacokinetic (PK) Interaction	Navitoclax Cycle 1 Day 15 maximum concentration (Cmax)	3910 ng/ml	—
Navitoclax 250 mg Reduced to 150 mg + Vistusertib 35 mg	Occurrence of a Bi-directional Pharmacokinetic (PK) Interaction	Navitoclax average of individual steady-state trough concentration (avg Cmin,ss)	2283 ng/ml	—

Secondary

Overall Survival (OS) at Year 1 (Phase II)

Standard life table methods will be used to analyze OS. We will report the one-year and median OS with 95% confidence intervals.

Time frame: At Year 1

Population: Only one participant was enrolled.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Phase 1 - Dose Level 1	Overall Survival (OS) at Year 1 (Phase II)	0 Participants

Secondary

Progression Free Survival (PFS) (Phase II)

Based on RECIST 1.1. Standard life table methods will be used to analyze PFS. We will report the one-year and median PFS with 95% confidence intervals.

Time frame: Up to 1.5 years

Population: Only one participant was enrolled.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Phase 1 - Dose Level 1	Progression Free Survival (PFS) (Phase II)	0 Participants

Other Pre-specified

Change in BAX and MCl-1 Expression

Descriptive statistics and box plots with jittered data points will be used to visualize all raw data. Will be assessed with paired t-tests.

Time frame: Baseline up to 1.5 years