Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Palbociclib · 21 trials · 20 indications
pathological complete response will be assessed according to Le Chevalier's classification between two arms
-Defined as the time from the date of treatment to the date of death, censored at the last follow-up otherwise.
An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product; the event did not need to have a causal relationship with the treatment. All AEs reported after initiation of study drug treatment were considered as TEAE. AE severity was graded according to Common Terminology Criteria for AEs (CTCAE) version 4.03. Grade 1 AEs are mild AEs; Grade 2 AEs are moderate AEs; Grade 3 AEs are severe AEs, Grade 4 AEs are life-threatening consequences and Grade 5 AEs are deaths related to AEs. Each AE was counted once for the participant in the most severe severity.
An AE was any untoward medical occurrence in a clinical investigation participant administered a product; the event did not need to have a causal relationship with the treatment. All AEs reported after initiation of study drug treatment were considered as TEAE. AE severity was graded according to CTCAE version 4.03. Grade 1 AEs are mild AEs; Grade 2 AEs are moderate AEs; Grade 3 AEs are severe AEs, Grade 4 AEs are life-threatening consequences and Grade 5 AEs are deaths related to AEs. Palbociclib-related TEAEs were determined by the investigator.
An SAE was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both SAEs and AEs. Palbociclib-related SAEs were determined by the investigator.
PFS is the time from the date of randomization to the date of the first documentation of objective progression of disease (PD)or death due to any cause in absence of documented PD. Participants lacking an evaluation of tumor response after randomization had their PFS time censored on the date of randomization with the duration of a day. Participants with documentation of PD or death after a long interval (2 or more incomplete or non-evaluable assessments) since the last tumor assessment were censored at the time of last objective assessment that did not show PD. The length of PFS was calculated as PFS time (months) =\[progression/death date(censor date) - randomization date + 1\]/30.4. Progression is defined using Response Evaluation Criteria in Solid Tumors(RECIST v1.1) a 20% increase in the sum of diameters of target lesions and the sum must also demonstrate an absolute increase of at least 5mm or unequivocal progression of existing non-target lesions or the appearance of new lesions.
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
EFS is defined as the time from randomization until first event (ie, progression, recurrence following response, second malignancy or death without progression or recurrence).
For Dose Escalation/Determination Part: DLT defined as any of the following events occurring during the first treatment cycle and considered at least possibly-related to study medication:Grade 4 neutropenia lasting greater than 7 days;Grade 4 thrombocytopenia lasting greater than 7 days or need for platelet transfusion for a platelet count of \< 20,000 per cubic millimeters twice within a 7-day period;greater than 14-day delay in the start of a subsequent course because of neutropenia or thrombocytopenia;Grade 3 or greater non-hematologic toxicities despite optimal treatment;any Grade 2 or greater non-hematologic toxicity requiring discontinuation or interruption of palbociclib for 7 or more consecutive days during the first cycle or any grade non-hematologic toxicity that delays the start of Cycle 2 by more than 14 days;clinically significant non-hematologic laboratory test abnormality Grade 3 or greater not resolving to Grade 1 or baseline within 7 days.
For Dose Expansion and Tumor-Specific Expansion Parts: Adverse events to be reported during treatment and for at least 28 days after last dose.
For Dose Expansion and Tumor-Specific Expansion Parts: patients with confirmed Complete Response or Partial Response per Response Evaluation Criteria in Solid Tumors (RECIST, v.1.1) or modified Response Assessment in Neuro-Oncology (RANO) for central nervous system malignancies, or International Neuroblastoma Response Criteria (INRC) for neuroblastoma, during study treatment, assessed approximately every 2 to 4 cycles (each cycle is approximately 21 days).
Log fold change in anti-proliferative activity of Letrozole versus Tamoxifen within cohorts of hormone receptor positive breast cancer for patients with invasive lobular and ductal carcinoma during the window phase. Higher absolute value indicates larger change in the anti-proliferative activity
Residual Cancer Burden index (RCB) between hormone receptor positive invasive breast cancer patients given endocrine therapy plus palbociclib (Arm C) and endocrine therapy alone (Arm D). RCB score is used to assess the response to neoadjuvant chemotherapy in breast cancer patients and is in a scale of 0 to infinity. Higher RCB score indicates more tumor burden remaining, thus worse outcome.
An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Dose limiting toxicity was defined as any of the following TEAEs occurring during the second cycle of treatment and possibly attributable to the combination of letrozole plus Palbociclib: 1. Grade 4 hematologic toxicity (including platelets \<25,000/μL, ANC \<500/μL). 2. Grade 3 neutropenia associated with a documented infection or fever ≥38.5°C. 3. Grade ≥3 non-hematologic toxicities, except those that have not been maximally treated (eg, nausea, vomiting, diarrhea, hypertension). 4. Delay by ≥1 week in receiving the next scheduled dose of either study treatment due to persisting treatment-related toxicities (platelet count \<50,000/μL; ANC \<1,000/μL; nonhematologic toxicities of Grade ≥3 severity). 5. Inability to deliver at least 80% of the planned Palbociclib or letrozole doses during Cycle 2 due to toxicity possibly attributable to the study treatment.
PFS was defined as the time from randomization (or the first dose of study treatment for non-randomized studies) to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. PFS calculated as (Weeks or Months) = (first event date minus randomization or the first dose date plus 1) divided by 7 (or 30.44 if in months). PFS is usually characterized by the median, 25% percentile,75% percentile and their 95% Confidence Intervals (CIs).
area under the plasma concentration versus time curve from time 0 to infinity
maximum plasma concentration
Adverse events (AEs) considered as dose limiting toxicities (DLTs) included: hematologic: Grade 4 neutropenia lasting \>4 days; Febrile neutropenia (defined as neutropenia Grade\>=3 \[absolute neutrophil count {ANC}\<1000 cells/cubic millimeter {mm\^3}\] and a body temperature \>=38.5 \[degrees centigrade\]℃) requiring antibiotic or antifungal treatment; any Grade 4 thrombocytopenia (\<25000/mm\^3 or 25.0\*10\^9/\[liter\]L). Non-hematologic: Grade \>=3 toxicities, except those that had not been maximally treated (eg, nausea, vomiting, diarrhea). Any AE that caused a palbociclib treatment interruption of greater than 7 consecutive days or caused any combination of interruption/reduction for \>=14 days. Any AE that caused omission or reduction of at least 2 of the 3 weekly doses of nab-P.
Cmax of palbociclib in the single-dose part (lead-in phase) was observed directly from data.
Tmax for palbociclib in the single-dose part (lead-in phase) was observed directly from data as time of first occurrence.
AUC10 for palbociclib in the single-dose part (lead-in phase) was obtained by linear/log trapezoidal method.
AUC24 is AUCtau, where the dosing interval (tau) is 24 hours. AUC24 in the single-dose part (lead-in phase) for palbociclib was obtained by linear/log trapezoidal method.
AUClast for palbociclib in the single-dose part (lead-in phase) was obtained by linear/log trapezoidal method.
AUCinf for palbociclib in the single-dose part (lead-in phase) was calculated as AUClast + (Clast/kel), where Clast was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis and kel was the rate constant for terminal phase obtained by linear regression of the log-linear concentration-time curve.
Kel for palbociclib in the single-dose part (lead-in phase) was obtained by linear regression of the log-linear concentration-time curve.
MRT for palbociclib in the single-dose part (lead-in phase) was calculated as AUMCinf/AUCinf, where AUMCinf was area under the first moment curve from time 0 to infinity.
t1/2 for palbociclib in the single-dose part (lead-in phase) was calculated as Loge(2)/kel.
CL/F for palbociclib in the single-dose part (lead-in phase) was calculated as Dose/AUCinf.
Vz/F for palbociclib in the single-dose part (lead-in phase) was calculated as Dose/(AUCinf \* kel).
Css,max of palbociclib in the multiple-dose part (Cycle 1) was observed directly from data.
Css,min of palbociclib in the multiple-dose part (Cycle 1) was observed directly from data.
AUCss,tau of palbociclib in the multiple-dose part (Cycle 1) was determined by linear/log trapezoidal method.
Css,av of palbociclib in the multiple-dose part (Cycle 1) was calculated as AUCss,tau/tau, where tau was 24 hours.
Tss,max of palbociclib in the multiple-dose part (Cycle 1) was observed directly from data as time of first occurrence within tau (=24 hours) at steady state.
Vz/F of palbociclib in the multiple-dose part (Cycle 1) was calculated as Dose/(AUCss,tau \* kel), where AUCss,tau was the AUC within a dosing interval of tau (=24 hours) at steady state and kel was the terminal phase rate constant following multiple-dose calculated by a linear regression of the log-linear concentration-time curve.
t1/2 of palbociclib in the multiple-dose part (Cycle 1) was calculated as ln (2)/kel, where kel was the terminal phase rate constant following multiple-dose calculated by a linear regression of the log-linear concentration-time curve.
CL/F of palbociclib in the multiple-dose part (Cycle 1) was calculated as Dose/AUCss,tau, where AUCss,tau was the AUC within a dosing interval of tau (=24 hours) at steady state.
PTF of palbociclib in the multiple-dose part (Cycle 1) was determined as (Css,max - Css,min)/Css,av. Css,max and Css,min were observed directly from data while Css,av was calculated as AUCss,tau/tau, where tau was 24 hours.
Rac of palbociclib was determined as AUCss,tau/AUCsd,tau, where AUCss,tau (tau=24 hours) was from multiple-dose part (Cycle 1) and AUCsd,tau was AUC24 from single-dose part (lead-in phase).
Rss of palbociclib was calculated as AUCss,tau/AUCinf, where AUCss,tau (tau=24 hours) was from multiple-dose part (Cycle 1) and AUCinf was from single-dose part (lead-in phase).
AUCinf is area under the plasma concentration time curve from time 0 extrapolated infinite time. It is calculated as AUClast + (Clast/kel), where AUClast is area under the concentration-time curve from time 0 to the time of the last quantifiable concentration, Clast is the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Cmax is maximum plasma concentration. It is observed directly from data.
AUC (0 - 8)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8). It is obtained from AUC (0 - t) plus AUC (t - 8).
AUC (0 - 8)DN= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8) divided by dose. It is obtained from AUC (0 - t) plus AUC (t - 8) all divided by the administered dose.
AUC (0 - 8)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8). It is obtained from AUC (0 - t) plus AUC (t - 8).
AUC (0 - 8)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8). It is obtained from AUC (0 - t) plus AUC (t - 8).
Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast)
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
Cumulative radioactivity recovered in urine is the percent of the administered radioactive dose that is observed in the cumulative urine samples.
Cumulative radioactivity recovered in fecal is the percent of the administered radioactive dose that is observed in the cumulative fecal samples.
| Arm | Type | Description |
|---|---|---|
| Fulvestrant 500mg + Palbociclib 125mg | ACTIVE_COMPARATOR | \+ Goserelin 3.6 mg if pre or peri menopausal patient - duration 4 months |
| Fulvestrant 500mg + Placebos | PLACEBO_COMPARATOR | \+ Goserelin 3.6 mg if pre or peri menopausal patient - duration 4 months |
| Arm 1: Palbociclib + Cetuximab | EXPERIMENTAL | * Palbociclib by mouth 125 mg/daily on Days 1-21 of each 28 day cycle * Cetuximab: Initial dose 400mg/m\^2 intravenous (IV); Subsequent doses 250 mg/m\^2 IV, weekly |
| Arm 2: Cetuximab | ACTIVE_COMPARATOR | -Cetuximab: Initial dose 400mg/m\^2 intravenous (IV); Subsequent doses 250 mg/m\^2 IV, weekly |
| Palbociclib + Letrozole | EXPERIMENTAL | palbociclib and letrozole combination |
| Arm A | EXPERIMENTAL | Given until objective progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurs first. |
| Arm B | ACTIVE_COMPARATOR | Given until objective progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurs first. |
| Arm 1 | OTHER | Cetuximab |
| Arm 2 | EXPERIMENTAL | Palbociclib plus Cetuximab |
| Arm 3 | OTHER | Palbociclib plus Fulvestrant |
| Arm 4 | OTHER | Palbociclib plus Letrozole |
| Phase 2 Arm A | EXPERIMENTAL | Palbociclib in combination with irinotecan and temozolomide. |
| Phase 1 | EXPERIMENTAL | Palbociclib in combination with temozolomide and irinotecan and/or with topotecan and cyclophosphamide. |
| Phase 2 Arm B | ACTIVE_COMPARATOR | Irinotecan and temozolomide alone. |
| Phase 1 Tumor specific cohort - Neuroblastoma | EXPERIMENTAL | Palbociclib in combination with topotecan and cyclophosphamide. |
| Arm A Tamoxifen followed by Endocrine Therapy | EXPERIMENTAL | Tamoxifen is given in the Window of Treatment phase for 2 weeks followed by Endocrine Therapy for 24 weeks. |
| Arm B Letrozole Followed By Endocrine Therapy | EXPERIMENTAL | Letrozole is given in the Window of Treatment phase for 2 weeks followed by Endocrine Therapy for 24 weeks. |
| Tamoxifen Followed By Endocrine Therapy and Palbociclib | EXPERIMENTAL | Tamoxifen is given in the Window of Treatment phase for 2 weeks followed by Endocrine Therapy in combination with Palbociclib for 24 weeks. |
| Letrozole Followed By Endocrine Therapy and Palbociclib | EXPERIMENTAL | Letrozole is given in the Window of Treatment phase for 2 weeks followed by Endocrine Therapy in combination with Palbociclib for 24 weeks. |
| Palbociclib plus Cetuximab | EXPERIMENTAL | Palbociclib, 125 mg, orally once daily (QD) with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle; in combination with Cetuximab, 400 mg/m2 initial dose as a 120-minute IV infusion followed by 250 mg/m2 weekly infused over 60 minutes. |
| Placebo plus Cetuximab | ACTIVE_COMPARATOR | Placebo orally QD with food on Day 1 to Day 21 followed by 7 days off treatment in a 28-day cycle; in combination with Cetuximab, 400 mg/m2 initial dose as a 120-minute IV infusion followed by 250 mg/m2 weekly infused over 60 minutes. |
| palbociclib tablet with/without PPI | EXPERIMENTAL | palbociclib tablet formulation alone in period 1 + palbociclib tablet formulation plus rabeprazole in period 2 |
| Palbociclib + Nab-Paclitaxel | EXPERIMENTAL | Palbociclib oral dosing on Days 1 to 21 of each 28-day cycle. Nab-paclitaxel IV dosing on Days -2, 6, and 13 of Cycle 1, and on Days 1, 8, and 15 of subsequent cycles. |
| Cohort 1 | EXPERIMENTAL | Combination therapy of palbociclib and letrozole |
| Healthy Volunteers | EXPERIMENTAL | Cohort of Healthy Volunteers |
| Mild Hepatic Impairment | EXPERIMENTAL | Cohort of mild hepatic impairment subjects meeting the criteria for Child-Pugh Class A |
| Moderate Hepatic Impairment | EXPERIMENTAL | Cohort of moderate hepatic impairment subjects meeting the criteria for Child-Pugh Class B |
| Severe Hepatic Impairment | EXPERIMENTAL | Cohort of severe hepatic impairment subjects meeting the criteria for Child-Pugh Class C |
| Normal Renal Function | EXPERIMENTAL | - |
| Mild Renal Impairment | EXPERIMENTAL | - |
| Moderate Renal Impairment | EXPERIMENTAL | - |
| Severe Renal Impairment | EXPERIMENTAL | - |
| Treatment A (Reference) | OTHER | - |
| Treatment B (Test) | OTHER | - |
| Treatment C (Test) | OTHER | - |
| Healthy Subjects of Japanese Descent | EXPERIMENTAL | Enrolled Japanese subjects will receive four palbociclib single doses of differing dose amounts in fixed sequence over four treatment periods. |
| Healthy Non-Asian Subjects | EXPERIMENTAL | Enrolled healthy non-Asian subjects will receive a single 125mg oral dose of palbociclib in a single treatment period. |
| Single-Arm Fixed-Sequence | EXPERIMENTAL | Subjects will receive two different interventions in fixed-sequence two-period study. In the first period the subjects will receive a single-dose of palbociclib. In the second period, subjects will receive 12 days of rifampin and a single dose of palbociclib on day 8. In both periods, subjects will undergo pharmacokinetic sampling at prespecified time points up to 120 hours post palbociclib dose. |
| Palbociclib given to Healthy Volunteers | EXPERIMENTAL | - |
| Sequence 1 | EXPERIMENTAL | Subjects randomized to Sequence 1 will receive Treatment A followed by Treatment B. Treatment A is a single 2 mg oral dose of midazolam alone. Treatment B is made up of 8 daily 125 mg oral doses of PD-0332991 and a single 2 mg oral midazolam dose on day 7 immediately after the day 7 PD-0332991 dose. |
| Sequence 2 | EXPERIMENTAL | Subjects randomized to Sequence 2 will receive Treatment B followed by Treatment A with a washout of no less than 14 days in between.Treatment B is made up of 8 daily 125 mg oral doses of PD-0332991 and a single 2 mg oral midazolam dose on day 7 immediately after the day 7 PD-0332991 dose. There will be a minimum washout of 14 days prior to beginning Treatment A. Treatment A is a single 2 mg oral dose of midazolam alone. |
| Radio-labeled Dose Arm | EXPERIMENTAL | - |
| Reference | ACTIVE_COMPARATOR | This is the reference formulation |
| NF1 | EXPERIMENTAL | This is a test formulation |
| NF2 | EXPERIMENTAL | This is a test formulation |
| SOL | EXPERIMENTAL | This is a test formulation |
| Name | Type | Description |
|---|---|---|
| Fulvestrant 500mg | DRUG | All patients in all arms will receive Fulvestrant 500mg |
| Palbociclib 125mg | DRUG | Dose reduction to 100 mg and 75 mg |
| Goserelin 3.6 MG | DRUG | Only for pre or peri menopausal patient |
| Placebos | DRUG | Placebo |
| Palbociclib | DRUG | Administered on an outpatient basis |
| Cetuximab | DRUG | Given intravenously over approximately 60 minutes |
| Letrozole | DRUG | Letrozole will be administered orally at 2.5 mg once daily as continuous daily dosing schedule according to product labeling and in compliance with its local prescribing information. |
| Fulvestrant | DRUG | Fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1, and then on Day 1 of each subsequent 28 day cycle. |
| Placebo | DRUG | Placebo orally continuously dosed for 3 weeks followed by 1 week off; repeated at each subsequent cycle. |
| Temozolomide | DRUG | Phase 1 and Phase 2: Administered at 100 mg/m2 (oral or intravenous), on days 1-5 of a 21-day cycle |
| Irinotecan | DRUG | Phase 1 and Phase 2: Administered at 50 mg/m2 (intravenous), on days 1-5 of a 21-day cycle |
| Topotecan | DRUG | Phase 1 only : Administered at 0.75 mg/m2 (intravenous), on days 1-5 of a 21-day cycle |
| Cyclophosphamide | DRUG | Phase 1 only: Administered at 250 mg/m2 (intravenous), on days 1-5 of a 21-day cycle |
| Tamoxifen | DRUG | - |
| Endocrine Therapy | DRUG | - |
| PD 0332991 | DRUG | 125 mg/d capsules orally for 3 out of 4 weeks in repeated cycles |
| Rabeprazole | DRUG | rabeprazole as PPI |
| Nab-Paclitaxel | DRUG | Nab-paclitaxel IV dosing on Days -2, 6, and 13 of Cycle 1, and on Days 1, 8, and 15 of subsequent cycles. |
| Palbociclib 75 mg Capsule | DRUG | Single oral 75 mg dose of palbociclib followed by serial PK sampling up to 192 hours post-dose (up to 120 hours post-dose for the healthy volunteer cohort). |
| Palbociclib Formulation Reference | DRUG | 125 mg single dose of palbociclib formulation with 16 micrometer API particle size and dissolution level 1, which is representative of the intended commercial hard gelatin capsule. |
| Palbociclib Formulation Test | DRUG | 125 mg single dose of palbociclib formulation with 41 micrometer API particle size and dissolution level 1 |
| Palbociclib 75mg | DRUG | In Period 1, Japanese subjects will receive a single oral 75mg dose of palbociclib with food. Serial PK assessments will be collected over the next 120 hours. |
| Palbociclib 100mg | DRUG | In Period 3, Japanese subjects will receive a single oral 100mg dose of palbociclib with food. Serial PK assessments will be collected over the next 120 hours. |
| Rifampin | DRUG | In period 2, subjects will receive 12 daily oral doses of 600mg of rifampin and a single 125mg oral dose of palbociclib on day 8. Subjects will undergo palbociclib pharmacokinetic sampling at prespecified time points up to 120 hours post palbociclib dose. |
| palbociclib capsule: phase 1 and 2 studies | DRUG | 125 mg dose of palbociclib. Formulation used in phase 1 and 2 studies |
| Palbociclib capsule: phase 3 studies | DRUG | 125 mg dose of palbociclib. Formulation used in phase 3 studies |
| Palbociclib capsule: ICH | DRUG | 125 mg dose of palbociclib. Intended final market formulation |
| Midazolam | DRUG | Treatment A includes a single 2 mg oral dose of midazolam alone. Treatment B includes a single 2 mg oral midazolam dose on day 7 immediately after the day 7 PD-0332991 dose. |
| PD-0332991 | DRUG | Treatment B includes 8 daily 125 mg oral doses of PD-0332991. |
| [14C]-PD-0332991 | RADIATION | A single 125 mg oral dose of PD-0332991 containing approximately 100 microcurie of \[14C\]-PD-0332991. |
Inclusion Criteria: 1. Written informed consent prior to beginning specific protocol procedures including expected cooperation of the patients for the treatment and follow-up must be obtained and documented according to the local regulatory requirements. 2. Age \>18. 3. Postmenopausal women or pre-...