Clinical trial NCT03231943: GSK3640254 First Time in Human (FTIH) Study in Healthy Volunteers
Official title: A Double-Blind (Sponsor Unblinded), Randomized, Placebo-Controlled, Single and Repeated Dose Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of GSK3640254 in Healthy Participants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Infection, Human Immunodeficiency Virus
HIV Infections
Keywords: FTIH
Healthy
Tolerability
Dose-escalation
HIV-1
Safety
PK
GSK3640254
Maturation inhibitor
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2017-07-27
Enrollment: 78
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: This is a dose-escalation study and dose will be escalated based on the safety data of the initial dose.
Primary purpose: TREATMENT

Brief summary: Human immuno deficiency virus 1 (HIV-1) infections continues to be a serious health threat throughout the world and development of medicines with new mechanism of action have an important role to play. GSK3640254 is a maturation inhibitor (MI) and can be effective in HIV-1 treatment. This randomized, 2-part, single and repeat increasing dose study will collect information on safety, tolerability and drug levels in the body of in healthy subjects for GSK3640254. The information collected in this study will help in further clinical development of GSK3640254, including a Phase IIA Proof of Concept (PoC) study in HIV-infected subjects. Approximately 16 healthy subjects will be randomized to receive single oral dose of GSK3640254 and placebo in Part 1 and approximately 56 healthy subjects will be randomized to receive repeat oral dose of GSK3640254 or placebo in Part 2. All doses will be given immediately after a moderate fat meal. Maximum duration of study participation will be approximately 12 weeks.


Eligibility criteria: Inclusion Criteria:

* Subjects must be 18 to 55 years of age inclusive, at the time of signing the informed consent.
* Subjects who are overtly healthy as determined by medical evaluation including medical history and psychiatric history, physical examination, laboratory tests, and 24 hour Holter monitoring.
* Body weight \>=50.0 kilogram (kg) (110 pounds) for men and 45.0kg (99 pounds) for women and body mass index (BMI) within the range 18.5-32.0 kg per meter square (kg/m\^2) (inclusive).
* Male or female subjects. A male subject must agree to use contraception during the treatment period and for at least 14 weeks following the last dose, corresponding to the time needed to eliminate study treatment for potential genotoxic and teratogenic study treatments plus an additional 90 days (spermatogenesis cycle). In addition, male subjects must refrain from donating sperm during this period. A female subject is eligible to participate if she is not a woman of childbearing potential (WOCBP).
* Capable of giving signed informed consent.

Exclusion Criteria:

* Alanine transaminase (ALT) \>1.5 into upper limit of normal (ULN).
* Bilirubin \>1.5 into ULN (isolated bilirubin \>1.5 into ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities.
* Pre-existing clinically relevant, in the opinion of the primary investigator (PI), gastro-intestinal pathology or diagnosis - example irritable bowel syndrome, inflammatory bowel disease, and/or significant Baseline signs and symptoms.
* Medical history of cardiac arrhythmias or cardiac disease or a family or personal history of long QT syndrome.
* Any known or suspected pre-existing psychiatric condition.
* Any other clinical condition (including but not limited to active substance use) or prior therapy that, in the opinion of the Investigator, would make the subject unsuitable for the study; unable to comply with dosing requirements; or unable to comply with study visits; or a condition that could affect the absorption, distribution, metabolism or excretion of the drug.
* Unable to refrain from the use of prescription or non-prescription drugs (with the exception of paracetamol), including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication and for the duration of the study, unless in the opinion of the Investigator and ViiV Healthcare Sponsor and medical monitor, the medication will not interfere with the study medications, procedures, or compromise subject safety.
* Unwillingness to abstain from ingestion of any food or drink containing grapefruit and grapefruit juice, Seville oranges, blood oranges, or pomelos within 7 days prior to the first dose of study treatment(s) or until the end of the study.
* Participation in another concurrent clinical study or prior clinical study (with the exception of imaging trials) prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
* Where participation in the study would result in donation of blood or blood products in excess of 500 milliliter (mL) within 56 days.
* Presence of hepatitis B surface antigen (HBsAg), or positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
* A positive pre-study drug/alcohol screen.
* A positive test for a diagnostic HIV-1 polymerase chain reaction (PCR).
* Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
* Exclusion criteria for screening ECG: Heart rate \<45 or \>100 beats per minute (bpm) for males and \<50 or \>100 bpm for females; PR interval \<120 or \>220 millisecond (msec); QRS duration \<70 or \>120 msec; the Fridericia's QT correction formula (QTcF) interval \>450 msec.
* Evidence of previous myocardial infarction (does not include ST segment changes associated with re-polarization).
* Any conduction abnormality (including but not specific to left or right complete bundle branch block, Atrioventricular block \[2nd degree or higher\], Wolff-Parkinson-White \[WPW\] syndrome).
* Sinus Pauses \>3 seconds.
* Any significant arrhythmia which, in the opinion of the Investigator or GlaxoSmithKline/ViiV medical monitor, will interfere with the safety for the individual subject.
* Non-sustained or sustained ventricular tachycardia (3 consecutive ventricular ectopic beats).
* History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of \>14 units. One unit is equivalent to 8 gram of alcohol: a half-pint approximately 240 mL of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
* Regular use of tobacco- or nicotine-containing products within 3 months prior to screening.
* History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or medical monitor, contraindicates their participation.

Primary outcomes:
measure: Part 1:Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs)
timeFrame: Up to Day 15
measure: Part 1: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils, Platelets.
timeFrame: Baseline (Day -2), 24 hours, 48 hours, 96 hours and Follow up (Day 15)
measure: Part 1: Change From Baseline in Hematology Parameters: Erythrocytes.
timeFrame: Baseline (Day -2), 24 hours, 48 hours, 96 hours and Follow up (Day 15)
measure: Part 1: Change From Baseline in Hematology Parameters: Erythrocytes Mean Corpuscular Volume (Erythrocyte MCV).
timeFrame: Baseline (Day -2), 24 hours, 48 hours, 96 hours and Follow up (Day 15)
measure: Part 1: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin (Erythrocyte MCH)
timeFrame: Baseline (Day -2), 24 hours, 48 hours, 96 hours and Follow up (Day 15)
measure: Part 1: Change From Baseline in Hematology Parameter: Hematocrit
timeFrame: Baseline (Day -2), 24 hours, 48 hours, 96 hours and Follow up (Day 15)
measure: Part 1: Change From Baseline in Hematology Parameter: Percentage of Reticulocytes
timeFrame: Baseline (Day -2), 24 hours, 48 hours, 96 hours and Follow up (Day 15)
measure: Part 1: Change From Baseline in Hematology Parameter: Hemoglobin (Hb)
timeFrame: Baseline (Day -2), 24 hours, 48 hours, 96 hours and Follow up (Day 15)
measure: Part 1: Change From Baseline in Clinical Chemistry Parameter: Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphate (ALP)
timeFrame: Baseline (Day -2), 24 hours, 48 hours, 96 hours and Follow up (Day 15)
measure: Part 1: Change From Baseline in Clinical Chemistry Parameters : Bicarbonate, Calcium, Chloride, Magnesium, Phosphate, Potassium, Sodium, Urea
timeFrame: Baseline (Day -2), 24 hours, 48 hours, 96 hours and Follow up (Day 15)
measure: Part 1: Change From Baseline in Cholesterol, Glucose, High Density Lipoprotein (HDL) Cholesterol, Low Density Cholesterol (LDL) Cholesterol, Triglycerides
timeFrame: Baseline (Day -2) and Day 1 (96 hours) and Follow up (Day 15)
measure: Part 1: Change From Baseline in Chemistry Parameter: Glucose
timeFrame: Baseline (Day -2) and Day 1 (96 hours) and Follow up (Day 15)
measure: Part 1: Change From Baseline in Clinical Chemistry Parameter: Bilirubin, Creatinine, Direct Bilirubin
timeFrame: Baseline (Day -2), 24 hours, 48 hours, 96 hours and Follow up (Day 15)
measure: Part 1: Change From Baseline in Clinical Chemistry Parameter: Protein
timeFrame: Baseline (Day -2), 24 hours, 48 hours, 96 hours and Follow up (Day 15)
measure: Part 1: Number of Participants With Abnormal Urinalysis
timeFrame: Up to Day 15
measure: Part 1: Change From Baseline in Vital Signs: Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
timeFrame: Baseline (Day -1), 1,2,4.5,6,12,24,48,72,96 hours post dose and Follow up (Day 15)
measure: Part 1: Change From Baseline in Vital Signs: Pulse Rate
timeFrame: Baseline (Day -1), 1,2,4.5,6,12,24,48,72,96 hours post dose and Follow up (Day 15)
measure: Part 1: Change From Baseline in Vital Signs: Temperature
timeFrame: Baseline (Day -1), 1,2,4.5,6,12,24,48,72,96 hours post dose and Follow up (Day 15)
measure: Part 1: Change From Baseline in Vital Sign: Respiratory Rate
timeFrame: Baseline (Day -1), 1,2,4.5,6,12,24,48,72,96 hours post dose and Follow up (Day 15)
measure: Part 1: Number of Participants With Abnormal Electrocardiogram (ECG) Findings
timeFrame: Baseline (Day 1 predose), 1,2,4,6,12,24,48,72,96 hours post dose and Follow up (Day 15)
measure: Part 2: Number of Participants AEs and SAEs
timeFrame: Up to Day 28
measure: Part 2: Change From Baseline in Abnormal Hematology Findings: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils, Platelets.
timeFrame: Baseline (Day -2), Pre dose on Days 2,4,6,8,10,12,14 Day 14 : 48 and 96 hours post dose, Follow up (Day 28)
measure: Part 2: Change From Baseline in Hematology Parameter: Erythrocytes
timeFrame: Baseline (Day -2), Pre dose on Days 2,4,6,8,10,12,14 Day 14: 48 and 96 hours post dose, Follow up (Day 28)
measure: Part 2: Change From Baseline in Hematology Parameter: Erythrocytes MCV
timeFrame: Baseline (Day -2), pre dose on Days 2,4,6,8,10,12,14 Day 14: 48 and 96 hours post dose, Follow up (Day 28)
measure: Part 2: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin (Erythrocyte MCH)
timeFrame: Baseline (Day -2), pre dose on Days 2,4,6,8,10,12,14 Day 14: 48 and 96 hours post dose, Follow up (Day 28)
measure: Part 2: Change From Baseline in Hematology Parameter: Hematocrit
timeFrame: Baseline (Day -2), pre dose on Days 2,4,6,8,10,12,14 Day 14: 48 and 96 hours post dose, Follow up (Day 28)
measure: Part 2: Change From Baseline in Hematology Parameter: Percentage of Reticulocytes
timeFrame: Baseline (Day -2), pre dose on Days 2,4,6,8,10,12,14 Day 14: 48 and 96 hours post dose, Follow up (Day 28)
measure: Part 2: Change From Baseline in Hematology Parameter: Hb
timeFrame: Baseline (Day -2), pre dose on Days 2,4,6,8,10,12,14 Day 14: 48 and 96 hours post dose, Follow up (Day 28)
measure: Part 2: Change From Baseline in Chemistry Parameter: ALT, AST,ALP
timeFrame: Baseline (Day -2), pre dose on Days 2,4,6,8,10,12,14 Day14: 48 and 96 hours post dose, Follow up (Day 28)
measure: Part 1: Change From Baseline in Bicarbonate, Calcium, Chloride, Cholesterol, Magnesium, Phosphate, Potassium, Sodium, Urea
timeFrame: Baseline (Day -2), pre dose on Days 2,4,6,8,10,12,14 Day 14: 48 and 96 hours post dose, Follow up (Day 28)
measure: Part 2: Change From Baseline in Cholesterol, HDL Cholesterol, LDL Cholesterol, Triglycerides
timeFrame: Baseline (Day -2), Day 8 (pre dose), Day 14 (48 hours) post dose and Follow up (Day 28)
measure: Part 2: Change From Baseline in Chemistry Parameter: Glucose
timeFrame: Baseline (Day -2), Day 8 (predose), Day 14 (48 hours) post dose and Follow up (Day 28)
measure: Part 2: Change From Baseline in Chemistry Parameter: Bilirubin, Creatinine, Direct Bilirubin
timeFrame: Baseline (Day -2), pre dose on Days 2,4,6,8,10,12,14 Day 14: 48 and 96 hours post dose, Follow up (Day 28)
measure: Part 2: Change From Baseline in Chemistry Parameter: Protein
timeFrame: Baseline (Day -2), pre dose on Days 2,4,6,8,10,12,14 Day 14: 48 and 96 hours post dose, Follow up (Day 28)
measure: Part 2: Number of Participants With Abnormal Urinalysis
timeFrame: Up to Day 28
measure: Part 2: Change From Baseline in Vital Signs: SBP and DBP
timeFrame: Baseline (Day -1), pre dose on Days 1,2,4,6,8,10,12,and 14 (pre dose and 72 hours) and Follow up (Day 28)
measure: Part 2: Change From Baseline in Vital Sign: Pulse Rate
timeFrame: Baseline (Day -1), pre dose on Days 1,2,4,6,8,10,12, and 14 (pre dose and 72 hours) and Follow up (Day 28)
measure: Part 2: Change From Baseline in Vital Sign: Temperature
timeFrame: Baseline (Day -1), pre dose on Days 1,2,4,6,8,10,12, and 14 (pre dose and 72 hours) and Follow up (Day 28)
measure: Part 2: Change From Baseline in Vital Sign: Respiratory Rate
timeFrame: Baseline (Day -1), pre dose on Days 1,2,4,6,8,10,12 and 14 (pre dose and 72 hours) and Follow up (Day 28)
measure: Part 2: Number of Participants With Abnormal ECG Findings
timeFrame: Day 1 (0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4.5, 5, 5.5, 6, 8, 12, 24 hours); Pre-dose on Days 3, 4, 6, 8, 10, 12; Day 14: Pre-dose, 1, 2, 4.5, 5, 6, 12, 24, 48, 72 and 96 hours post-dose and follow up (Day 28)
Secondary outcomes:
measure: Part 1: Area Under the Plasma Concentration Time Curve (AUC) From Zero to 24 Hour (AUC[0-24]) of GSK3640254
timeFrame: Pre-dose and 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12,24 hours post-dose
measure: Part 1: AUC From Zero to Time of Last Sample Taken (AUC[0-Tlast]) of GSK3640254
timeFrame: Pre-dose and 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12, 24, 48, 72 and 96 hours post-dose
measure: Part 1: AUC From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC[0-inf]) of GSK3640254
timeFrame: Pre-dose and 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12, 24, 48, 72 and 96 hours post-dose
measure: Part 1: Apparent Terminal Phase Half-life (T1/2) of GSK3640254
timeFrame: Pre-dose and 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12, 24, 48, 72 and 96 hours post-dose
measure: Part 1: Apparent Oral Clearance (CL/F) of GSK3640254
timeFrame: Pre-dose and 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12, 24, 48, 72 and 96 hours post-dose
measure: Part 1: Maximum Observed Concentration (Cmax), Concentration of GSK3640254 at 24 Hours (C24) and Last Quantifiable Concentration (Clast) of GSK3640254
timeFrame: Pre-dose and 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12, 24, 48, 72 and 96 hours post-dose
measure: Part 1: Time of Occurrence of Cmax (Tmax), Lag Time (Tlag), and Time to Reach Clast (Tlast) of GSK3640254
timeFrame: Pre-dose and 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12, 24, 48, 72 and 96 hours post-dose
measure: Part 2: AUC(0-24) of GSK3640254: Day 1
timeFrame: Pre-dose and 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12 and 24 hours post-dose on Day 1
measure: Part 2: Cmax, C24 of GSK3640254 on Day 1
timeFrame: Pre-dose and 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12 hours post-dose on Day 1
measure: Part 2: Tmax, Tlag of GSK3640254 on Day 1
timeFrame: Pre-dose and 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,6,8,12 hours post-dose on Day 1
measure: Part 2: Tmax GSK3640254 on Day 14
timeFrame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours after Day 14 dose
measure: Part 2: Cmax of GSK3640254 on Day 14
timeFrame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours after Day 14 dose
measure: Part 2: AUC From Pre-dose to the End of the Dosing Interval at Steady State (AUC[0-tau]): Day 14
timeFrame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24 hours after Day 14 dose
measure: Part 2: Plasma Trough Concentration (Ctau) of GSK3640254: Day 14
timeFrame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours after Day 14 dose
measure: Part 2: T1/2 of GSK3640254: Day 14
timeFrame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours after Day 14 dose
measure: Part 2: CL/F of GSK3640254: Day 14
timeFrame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours after Day 14 dose
measure: Part 1: Dose Proportionality (AUC[0-inf]) Following Single Dose of GSK3640254 on Day 1
timeFrame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours post dose
measure: Part 1: Dose Proportionality (AUC0-24) Following Single Dose of GSK3640254 on Day 1
timeFrame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24 hours post dose
measure: Part 1: Dose Proportionality for Cmax Following Single Dose of GSK3640254 on Day 1
timeFrame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours post dose
measure: Part 2: Dose Proportionality (AUC0-tau) Following Repeated Dose of GSK3640254 on Day 14
timeFrame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours after Day 14 dose
measure: Part 2: Dose Proportionality (Ctrough) Following Repeated Dose of GSK3640254 on Day 14
timeFrame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours after Day 14 dose
measure: Part 2: Dose Proportionality (Cmax) Following Repeated Dose of GSK3640254 on Day 14
timeFrame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours after Day 14 dose
measure: Part 2: Accumulation Ratio of AUC(0-tau) (R [AUC{0-TAU}]) From Day 1 to Day 14
timeFrame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours after Day 14 dose
measure: Part 2: Accumulation Ratio of Cmax (R [CMAX]) From Day 1 to Day 14
timeFrame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours after Day 14 dose
measure: Part 2: Accumulation Ratio of C(Tau) (R[CTAU]) From Day 2 to Day 15
timeFrame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours after Day 15 dose
measure: Part 2: Pre-dose Concentration of GSK3640254 on Day 2 to Day 14
timeFrame: Pre-dose on Days 2,3,4,6,8,10,12 and 14
measure: Part 2: Dose Proportionality (Cmax) Following Repeated Dose of GSK3640254 at Day 1
timeFrame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours post dose
measure: Part 2: Dose Proportionality (AUC0-24) Following Repeated Dose of GSK3640254 at Day 1
timeFrame: Pre-dose and 0.5,1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 24, 48, 72 and 96 hours post dose
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: ViiV Healthcare
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Joshi SR, Fernando D, Igwe S, McKenzie L, Krishnatry AS, Halliday F, Zhan J, Greene TJ, Xu J, Ferron-Brady G, Lataillade M, Min S. Phase I evaluation of the safety, tolerability, and pharmacokinetics of GSK3640254, a next-generation HIV-1 maturation inhibitor. Pharmacol Res Perspect. 2020 Dec;8(6):e00671. doi: 10.1002/prp2.671.